Antitumor compounds and their applications

Abstract

The present invention relates to an antitumor compound and its application, specifically to a ligand conjugate or its tautomer, mesomeric, ceraminic form, enantiomer, diastereomer, or mixture form thereof, or a pharmaceutically acceptable salt thereof, and also to a method for preparing said ligand conjugate and its application.

Description

Detailed Description of the Invention

[0001] [Technical field] The present application relates to the biomedical field, specifically to anti-tumor compounds and their applications.

[0002] [Background technology] Antibody drug conjugates (ADCs) are a method of binding monoclonal antibodies or antibody fragments to biologically active cytotoxins via stable chemical linker compounds, making full use of the specificity of antibodies to surface antigen binding on normal and tumor cells and the high efficiency of cytotoxic substances to exert antitumor effects. Although the application of camptothecin derivative exatecan in antibody drug conjugates (ADCs) has been reported in the literature, there is a need in the art to further develop ADC drugs with better therapeutic effects and higher safety.

[0003] [Summary of the Invention] [Means for solving the problem] In one aspect, the present application provides a ligand conjugate or a tautomer, mesomeric, ceramiric, enantiomeric, diastereomeric, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said ligand conjugate comprises the structure shown in formula (I):

[0004] [ka]

[0005] In one embodiment, the structure represented by formula (I) includes the structure represented by (Ia).

[0006] [ka]

[0007] In one embodiment, the structure represented by formula (I) includes the structure represented by (Ib).

[0008] [ka]

[0009] wherein R1 and R2 are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C8 haloalkyl group, and an optionally substituted C1-C8 deuterated alkyl group; or R1 and R2, taken together with the carbon atom to which they are attached, form a structure selected from the group consisting of optionally substituted alicyclic groups, optionally substituted aliphatic heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups; L is an optionally substituted linker; Ab is a ligand and a is a number greater than 0, where a is a decimal or an integer.

[0010] In the structure shown in formula (I), L is the linker -L1-L2-L3-L4-L5-. In the structure of formula (I), L1 is optionally substituted

[0011] [ka] and said L1 is directly linked to said Ab.

[0012] In the structure shown in formula (I), the L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 -C(O)-, optionally substituted -(CH2CH2O) n -C(O)- and optionally substituted -(CH2) p is a group selected from the group consisting of -C(O)-, X1 is selected from the group consisting of -O-, optionally substituted -C(O)-NH-, optionally substituted aryl groups, optionally substituted heteroaryl groups, optionally substituted heteroalicyclic groups, and optionally substituted alicyclic groups; Here, m1, m2 and n are each independently selected from integers of at least 0, and p is selected from integers of 2-8.

[0013] In the structure shown in formula (I), the L2 is an optionally substituted -(CH2CH2O) n -C(O)-. In the structure shown in formula (I), where n is 2.

[0014] In the structure shown in formula (I), the L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 -C(O)-. In the structure shown in formula (I), X1 is selected from the group consisting of -O- and optionally substituted -C(O)-NH-.

[0015] In the structure shown in formula (I), m1 is 2. In the structure shown in formula (I), m2 is 2. In the structure shown in formula (I), X1 is a group selected from the group consisting of optionally substituted aryl groups and optionally substituted heteroaryl groups.

[0016] In the structure shown in formula (I), X1 is an optionally substituted phenyl group. In the structure shown in formula (I), X1 is an optionally substituted pyridyl group.

[0017] In the structure shown in formula (I), m1 is 0. In the structure shown in formula (I), m2 is 1. In the structure shown in formula (I), X1 is an optionally substituted

[0018] [ka] It is.

[0019] In the structure shown in formula (I), X1 is an optionally substituted cyclohexyl group. In the structure shown in formula (I), m1 is 1.

[0020] In the structure shown in formula (I), m2 is 0. In the structure shown in formula (I), the L2 is an optionally substituted -(CH2) p -C(O)-.

[0021] In the structure shown in formula (I), where p is 5. In the structure shown in formula (I), the L2 is optionally substituted

[0022] [ka] , optionally replaced

[0023] [ka] , optionally replaced

[0024] [ka] , optionally replaced

[0025] [ka] , optionally replaced

[0026] [ka] , optionally replaced

[0027] [ka] , optionally replaced

[0028] [ka] , optionally replaced

[0029] [ka] and optionally replaced

[0030] [ka] The structure is selected from the following:

[0031] In the structure shown in formula (I), L3 is a peptide residue. In the structure shown in formula (I), L3 is a peptide residue composed of an amino acid selected from the group consisting of phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid and glycine.

[0032] In the structure shown in formula (I), L3 is a peptide residue composed of an amino acid selected from the group consisting of glycine, phenylalanine, valine and citrulline.

[0033] In the structure shown in formula (I), L3 is a peptide residue selected from the group consisting of -glycine-phenylalanine-glycine-(-Gly-Phe-Gly-), -glycine-glycine-phenylalanine-glycine-(-Gly-Gly-Phe-Gly-) and -valine-citrulline-(-Val-Cit-).

[0034] In the structure shown in formula (I), L3 is

[0035] [ka] The structure is selected from the following:

[0036] In the structure shown in formula (I), L4 is an optionally substituted -L 4a -NR4-CH2-L 4b - and L 4a does not exist or is 4a is optionally replaced

[0037] [ka] and

[0038] L 4b does not exist or is 4b is optionally replaced

[0039] [ka] and

[0040] R4 and R5 are each independently selected from the group consisting of hydrogen and optionally substituted alkyl groups. In the structure of formula (I), L4 is optionally substituted

[0041] [ka] It is.

[0042] In the structure of formula (I), L4 is optionally substituted

[0043] [ka] It is.

[0044] In the structure of formula (I), L4 is optionally substituted

[0045] [ka] It is.

[0046] In the structure of formula (I), L4 is optionally substituted

[0047] [ka] It is.

[0048] In the structure shown in formula (I), R4 is selected from the group consisting of hydrogen and an optionally substituted methyl group. In the structure shown in formula (I), R5 is selected from the group consisting of hydrogen and an optionally substituted methyl group.

[0049] In the structure of formula (I), L4 is optionally substituted

[0050] [ka] , optionally replaced

[0051] [ka] , optionally replaced

[0052] [ka] , optionally replaced

[0053] [ka] and optionally replaced

[0054] [ka] The structure is selected from the following:

[0055] In the structure of formula (I), L5 is optionally substituted

[0056] [ka] and L5 is

[0057] [ka] is directly linked to the structure of the formula

[0058] R6 and R7 are each independently selected from the group consisting of hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group, and an optionally substituted cycloalkylalkyl group, or R6 and R7 together with the atom to which they are attached form an optionally substituted cycloalkyl group; Here, v is selected from a number that is at least 0.

[0059] In the structure of formula (I), L5 is optionally substituted

[0060] [ka] and L5 is

[0061] [ka] is directly linked to the structure of the formula

[0062] R6 and R7 are each independently selected from the group consisting of hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group, and an optionally substituted cycloalkylalkyl group, or R6 and R7 together with the atom to which they are attached form an optionally substituted cycloalkyl group; Here, v is selected from a number that is at least 0.

[0063] In the structure of formula (I), L5 is optionally substituted

[0064] [ka] and L5 is

[0065] [ka] is directly linked to the structure of the formula

[0066] R6 and R7 are each independently selected from the group consisting of hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group, and an optionally substituted cycloalkylalkyl group, or R6 and R7 together with the atom to which they are attached form an optionally substituted cycloalkyl group; Here, v is selected from a number that is at least 0.

[0067] In the structure shown in formula (I), R6 is hydrogen. In the structure shown in formula (I), R6 is an optionally substituted methyl group.

[0068] In the structure shown in formula (I), R6 is a methyl group substituted with fluorine. In the structure shown in formula (I), R6 is a trifluoromethyl group.

[0069] In the structure shown in formula (I), R6 is an optionally substituted cycloalkyl group. In the structure shown in formula (I), R6 is an optionally substituted cyclopropyl group.

[0070] In the structure shown in formula (I), R7 is hydrogen. In the structure shown in formula (I), R6 and R7 together with the atom to which they are attached form an optionally substituted cyclopropyl group.

[0071] In the structure shown in formula (I), R6 and R7 together with the atom to which they are attached form an optionally substituted cyclobutyl group. In the structure shown in formula (I), where v is 0.

[0072] In the structure shown in formula (I), where v is 1. In the structure of formula (I), L5 is optionally substituted

[0073] [ka] , optionally replaced

[0074] [ka] , optionally replaced

[0075] [ka] , optionally replaced

[0076] [ka] , optionally replaced

[0077] [ka] , optionally replaced

[0078] [ka] , optionally replaced

[0079] [ka] and optionally replaced

[0080] [ka] The structure is selected from the following:

[0081] In the ligand conjugate of the present application, wherein said Ab is an antibody or an antigen-binding fragment thereof. In the ligand conjugate of the present application, wherein said antibody is selected from the group consisting of a murine antibody, a chimeric antibody, a humanized antibody and a fully human antibody.

[0082] The ligand conjugate of the present application, wherein said antibody is a monoclonal antibody. In the ligand conjugate of the present application, wherein said antigen-binding fragment is selected from the group consisting of Fab, Fab', Fv fragment, F(ab')2, F(ab)2, scFv, di-scFv, VHH and dAb.

[0083] In the ligand conjugate of the present application, wherein said Ab comprises a HER2 antibody and / or a TROP2 antibody. In the ligand conjugate of the present application, wherein the Ab comprises HCDR1, HCDR2 and HCDR3 of a heavy chain variable region, the amino acid sequence of the HCDR1 is SEQ ID NO: ID NO:1, the amino acid sequence of said HCDR2 is as shown in SEQ ID NO:2, and the amino acid sequence of said HCDR3 is as shown in SEQ ID NO:3.

[0084] In the ligand conjugate of the present application, wherein the Ab comprises LCDR1, LCDR2 and LCDR3 of a light chain variable region, the amino acid sequence of LCDR1 is SEQ ID NO: The amino acid sequence of LCDR2 is as shown in SEQ ID NO:4. ID NO:5, and the amino acid sequence of said LCDR3 is as set forth in SEQ ID NO:6.

[0085] In the ligand conjugate of the present application, wherein said Ab comprises a heavy chain variable region, the amino acid sequence of said heavy chain variable region is as shown in SEQ ID NO:7.

[0086] In the ligand conjugate of the present application, wherein said Ab comprises a light chain variable region, the amino acid sequence of said light chain variable region is as set forth in SEQ ID NO:8.

[0087] In the ligand conjugate of the present application, wherein said Ab comprises a heavy chain, the amino acid sequence of said heavy chain is as shown in SEQ ID NO:9.

[0088] In the ligand conjugate of the present application, wherein said Ab comprises a light chain, the amino acid sequence of said light chain is as shown in SEQ ID NO:10.

[0089] In the ligand conjugate of the present application, wherein the Ab comprises HCDR1, HCDR2 and HCDR3 of a heavy chain variable region, the amino acid sequence of the HCDR1 is SEQ ID NO: The amino acid sequence of HCDR2 is as shown in SEQ ID NO:11. The amino acid sequence of the HCDR3 is as shown in SEQ ID NO:12. As shown in ID NO:13.

[0090] In the ligand conjugate of the present application, wherein the Ab comprises LCDR1, LCDR2 and LCDR3 of a light chain variable region, the amino acid sequence of LCDR1 is SEQ ID NO: The amino acid sequence of LCDR2 is as shown in SEQ ID NO:14. The amino acid sequence of the LCDR3 is as shown in SEQ ID NO:15. As shown in ID NO:16.

[0091] In the ligand conjugate of the present application, wherein said Ab comprises a heavy chain variable region, the amino acid sequence of said heavy chain variable region is as shown in SEQ ID NO:17.

[0092] In the ligand conjugate of the present application, wherein said Ab comprises a light chain variable region, the amino acid sequence of said light chain variable region is as set forth in SEQ ID NO:18.

[0093] In the ligand conjugate of the present application, wherein said Ab comprises a heavy chain, the amino acid sequence of said heavy chain is as shown in SEQ ID NO:19.

[0094] In the ligand conjugate of the present application, wherein said Ab comprises a light chain, the amino acid sequence of said light chain is as set forth in SEQ ID NO:20.

[0095] In another aspect, the present application further provides a ligand conjugate or a tautomer, mesomeric, ceramiric, enantiomeric, diastereomeric, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said ligand conjugate is

[0096] [ka] Selected from the structure of TIFF2024523422000042.tif229169TIFF2024523422000043.tif150169,

[0097] Here, Ab is a ligand, a is a number greater than 0, and a is a decimal or an integer. In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said ligand conjugate comprises the structure shown in formula (II):

[0098] [ka]

[0099] Where: R1 and R2 are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C8 haloalkyl group, and an optionally substituted C1-C8 deuterated alkyl group; or R1 and R2, taken together with the carbon atom to which they are attached, form a structure selected from the group consisting of optionally substituted alicyclic groups, optionally substituted aliphatic heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups; Lx is a linking group, and the Lx is 1x -L2-L3-L4-L5-, 1x is directly or indirectly linked to the ligand.

[0100] In one embodiment, the structure represented by formula (II) includes a structure represented by formula (II-a).

[0101] [ka]

[0102] In one embodiment, the structure represented by formula (II) includes a structure represented by formula (II-b).

[0103] [ka]

[0104] In the structure represented by formula (II), 1x is linked directly or indirectly to a sulfhydryl group of the ligand. In the structure represented by formula (II), 1x is optionally replaced

[0105] [ka] It is.

[0106] In the structure shown in formula (II), the L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 -C(O)-, optionally substituted -(CH2CH2O) n -C(O)- and optionally substituted -(CH2) p -C(O)-, X1 is selected from the group consisting of -O-, optionally substituted -C(O)-NH-, optionally substituted aryl groups, optionally substituted heteroaryl groups, optionally substituted heteroalicyclic groups, and optionally substituted alicyclic groups; Here, m1, m2 and n are each independently selected from integers of at least 0, and p is selected from integers of 2-8.

[0107] In the structure shown in formula (II), the L2 is an optionally substituted -(CH2CH2O)n Includes -C(O)-. In the structure shown in formula (II), n is 2.

[0108] In the structure shown in formula (II), the L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 -C(O)-. In the structure shown in formula (II), X1 is selected from the group consisting of -O- and optionally substituted -C(O)-NH-.

[0109] In the structure shown in formula (II), m1 is 2. In the structure shown in formula (II), m2 is 2. In the structure shown in formula (II), X1 is a group selected from the group consisting of optionally substituted aryl groups and optionally substituted heteroaryl groups.

[0110] In the structure shown in formula (II), X1 is an optionally substituted phenyl group. In the structure shown in formula (II), X1 is an optionally substituted pyridyl group.

[0111] In the structure shown in formula (II), m1 is 0. In the structure shown in formula (II), m2 is 1. In the structure shown in formula (II), X1 is an optionally substituted

[0112] [ka] It is.

[0113] In the structure shown in formula (II), X1 is an optionally substituted cyclohexyl group. In the structure shown in formula (II), m1 is 1.

[0114] In the structure shown in formula (II), m2 is 0. In the structure shown in formula (II), the L2 is an optionally substituted -(CH2) p -C(O)-.

[0115] In the structure shown in formula (II), where p is 5. In the structure shown in formula (II), the L2 is optionally substituted

[0116] [ka] , optionally replaced

[0117] [ka] , optionally replaced

[0118] [ka] , optionally replaced

[0119] [ka] , optionally replaced

[0120] [ka] , optionally replaced

[0121] [ka] , optionally replaced

[0122] [ka] , optionally replaced

[0123] [ka] and optionally replaced

[0124] [ka] The structure is selected from the following:

[0125] In the structure shown in formula (II), L3 is a peptide residue. In the structure shown in formula (II), L3 is a peptide residue composed of an amino acid selected from the group consisting of phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid and glycine.

[0126] In the structure shown in formula (II), L3 is a peptide residue composed of an amino acid selected from the group consisting of glycine, phenylalanine, valine and citrulline.

[0127] In the structure shown in formula (II), L3 is a peptide residue selected from the group consisting of -glycine-phenylalanine-glycine-(-Gly-Phe-Gly-), -glycine-glycine-phenylalanine-glycine-(-Gly-Gly-Phe-Gly-) and -valine-citrulline-(-Val-Cit-).

[0128] In the structure represented by formula (II), L3 is

[0129] [ka] The structure includes a structure selected from the group consisting of:

[0130] In the structure shown in formula (II), L4 is an optionally substituted -L 4a -NR4-CH2-L 4b - and L 4a does not exist or is 4a is optionally replaced

[0131] [ka] and

[0132] L 4b does not exist or is 4b is optionally replaced

[0133] [ka] and

[0134] R4 and R5 are each independently selected from the group consisting of hydrogen and optionally substituted alkyl groups. In the structure shown in formula (II), L4 is optionally substituted

[0135] [ka] It is.

[0136] In the structure shown in formula (II), L4 is optionally substituted

[0137] [ka] It is.

[0138] In the structure shown in formula (II), L4 is optionally substituted

[0139] [ka] It is.

[0140] In the structure shown in formula (II), L4 is optionally substituted

[0141] [ka] It is.

[0142] In the structure shown in formula (II), R4 is selected from the group consisting of hydrogen and an optionally substituted methyl group. In the structure shown in formula (II), R5 is selected from the group consisting of hydrogen and an optionally substituted methyl group.

[0143] In the structure shown in formula (II), L4 is optionally substituted

[0144] [ka] , optionally replaced

[0145] [ka] , optionally replaced

[0146] [ka] , optionally replaced

[0147] [ka] and optionally replaced

[0148] [ka] The structure is selected from the following:

[0149] In the structure shown in formula (II), L5 is optionally substituted

[0150] [ka] and L5 is

[0151] [ka] is directly linked to the structure of the formula

[0152] R6 and R7 are each independently selected from the group consisting of hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group, and an optionally substituted cycloalkylalkyl group, or R6 and R7 together with the atom to which they are attached form an optionally substituted cycloalkyl group; Here, v is selected from a number that is at least 0.

[0153] In the structure shown in formula (II), L5 is optionally substituted

[0154] [ka] and L5 is

[0155] [ka] is directly linked to the structure of the formula

[0156] R6 and R7 are each independently selected from the group consisting of hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group, and an optionally substituted cycloalkylalkyl group, or R6 and R7 together with the atom to which they are attached form an optionally substituted cycloalkyl group; Here, v is selected from a number that is at least 0.

[0157] In the structure shown in formula (II), L5 is optionally substituted

[0158] [ka] and L5 is

[0159] [ka] is directly linked to the structure of the formula

[0160] R6 and R7 are each independently selected from the group consisting of hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group, and an optionally substituted cycloalkylalkyl group, or R6 and R7 together with the atom to which they are attached form an optionally substituted cycloalkyl group; Here, v is selected from a number that is at least 0.

[0161] In the structure shown in formula (II), R6 is hydrogen. In the structure shown in formula (II), R6 is an optionally substituted methyl group.

[0162] In the structure shown in formula (II), R6 is a methyl group substituted with fluorine. In the structure shown in formula (II), R6 is a trifluoromethyl group.

[0163] In the structure shown in formula (II), R6 is an optionally substituted cycloalkyl group. In the structure shown in formula (II), R6 is an optionally substituted cyclopropyl group.

[0164] In the structure shown in formula (II), R7 is hydrogen. In the structure shown in formula (II), R6 and R7 together with the atom to which they are attached form an optionally substituted cyclopropyl group.

[0165] In the structure shown in formula (II), R6 and R7 together with the atom to which they are attached form an optionally substituted cyclobutyl group. In the structure shown in formula (II), where v is 0.

[0166] In the structure shown in formula (II), where v is 1. In the structure shown in formula (II), L5 is optionally substituted

[0167] [ka] , optionally replaced

[0168] [ka] , optionally replaced

[0169] [ka] , optionally replaced

[0170] [ka] , optionally replaced

[0171] [ka] , optionally replaced

[0172] [ka] , optionally replaced

[0173] [ka] and optionally replaced

[0174] [ka] The structure is selected from the following:

[0175] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said ligand conjugate is

[0176] [ka] Selected from the structures TIFF2024523422000085.tif238169TIFF2024523422000086.tif90169.

[0177] In another aspect, the present application further provides a linker as shown in formula (L-1) for linking a Drug unit and a Ligand to obtain a Ligand-Drug conjugate: Formula (L-1): -L1-L2-L3-L4-L5- where L1 is optionally substituted

[0178] [ka] and

[0179] The L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 -C(O)- and optionally substituted -(CHCHO) n-C(O)- group of radicals, X1 is selected from the group consisting of -O-, optionally substituted -C(O)-NH-, optionally substituted aryl groups, optionally substituted heteroaryl groups, optionally substituted heteroalicyclic groups, and optionally substituted alicyclic groups; wherein m1, m2, and n are each independently selected from an integer of at least 0; In the structure shown in formula (L-1), n ​​is 2.

[0180] In the structure represented by formula (L-1), X1 is selected from the group consisting of -O- and optionally substituted -C(O)-NH-. In the structure represented by formula (L-1), m1 is 2.

[0181] In the structure represented by formula (L-1), m2 is 2. In the structure represented by formula (L-1), X1 is a group selected from the group consisting of optionally substituted aryl groups and optionally substituted heteroaryl groups.

[0182] In the structure shown in formula (L-1), X1 is an optionally substituted phenyl group. In the structure represented by formula (L-1), X1 is an optionally substituted pyridyl group.

[0183] In the structure represented by formula (L-1), m1 is 0. In the structure represented by formula (L-1), m2 is 1. In the structure represented by formula (L-1), X1 is an optionally substituted

[0184] [ka] It is.

[0185] In the structure represented by formula (L-1), X1 is an optionally substituted cyclohexyl group. In the structure represented by formula (L-1), m1 is 1.

[0186] In the structure represented by formula (L-1), m2 is 0. In the structure represented by formula (L-1), L2 is an optionally substituted

[0187] [ka] , optionally replaced

[0188] [ka] , optionally replaced

[0189] [ka] , optionally replaced

[0190] [ka] , optionally replaced

[0191] [ka] , optionally replaced

[0192] [ka] , optionally replaced

[0193] [ka] and optionally replaced

[0194] [ka] The structure is selected from the following:

[0195] In the structure shown in formula (L-1), L3 is a peptide residue selected from the group consisting of -glycine-phenylalanine-glycine-(-Gly-Phe-Gly-), -glycine-glycine-phenylalanine-glycine-(-Gly-Gly-Phe-Gly-) and -valine-citrulline-(-Val-Cit-).

[0196] In the structure represented by formula (L-1), L3 is

[0197] [ka] The structure is selected from the group consisting of:

[0198] In the structure represented by formula (L-1), L4 is an optionally substituted -L 4a -NR4-CH2-L 4b - and L 4a does not exist or is 4a is optionally replaced

[0199] [ka] and

[0200] L 4b does not exist or is 4b is optionally replaced

[0201] [ka] and

[0202] R4 and R5 are each independently selected from the group consisting of hydrogen and optionally substituted alkyl groups. In the structure represented by formula (L-1), L4 is an optionally substituted

[0203] [ka] It is.

[0204] In the structure represented by formula (L-1), L4 is an optionally substituted

[0205] [ka] , optionally replaced

[0206] [ka] , optionally replaced

[0207] [ka] , optionally replaced

[0208] [ka] and optionally replaced

[0209] [ka] The structure is selected from the following:

[0210] In the structure represented by formula (L-1), L5 is an optionally substituted

[0211] [ka] and L5 is

[0212] [ka] is directly linked to the structure of the formula

[0213] R6 and R7 are each independently selected from the group consisting of hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group, and an optionally substituted cycloalkylalkyl group, or R6 and R7 together with the atom to which they are attached form an optionally substituted cycloalkyl group; Here, v is selected from a number that is at least 0.

[0214] In the structure represented by formula (L-1), the L5 is optionally substituted

[0215] [ka] and L5 is

[0216] [ka] is directly linked to the structure of the formula

[0217] R6 and R7 are each independently selected from the group consisting of hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group, and an optionally substituted cycloalkylalkyl group, or R6 and R7 together with the atom to which they are attached form an optionally substituted cycloalkyl group; Here, v is selected from a number that is at least 0.

[0218] In the structure represented by formula (L-1), L5 is an optionally substituted

[0219] [ka] and L5 is

[0220] [ka] is directly linked to the structure of the formula

[0221] R6 and R7 are each independently selected from the group consisting of hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group, and an optionally substituted cycloalkylalkyl group, or R6 and R7 together with the atom to which they are attached form an optionally substituted cycloalkyl group; Here, v is selected from a number that is at least 0.

[0222] In the structure represented by formula (L-1), R6 is hydrogen. In the structure represented by formula (L-1), R6 is an optionally substituted methyl group.

[0223] In the structure represented by formula (L-1), R6 is a methyl group substituted with fluorine. In the structure represented by formula (L-1), R6 is a trifluoromethyl group.

[0224] In the structure represented by formula (L-1), R6 is an optionally substituted cycloalkyl group. In the structure represented by formula (L-1), R7 is hydrogen.

[0225] In the structure shown in formula (L-1), R6 and R7 together with the atom to which they are attached form an optionally substituted cyclopropyl group. In the structure shown in formula (L-1), R6 and R7 together with the atom to which they are attached form an optionally substituted cyclobutyl group.

[0226] In the structure represented by formula (L-1), v is 0. In the structure represented by formula (L-1), v is 1. In the structure represented by formula (L-1), L5 is an optionally substituted

[0227] [ka] , optionally replaced

[0228] [ka] , optionally replaced

[0229] [ka] , optionally replaced

[0230] [ka] , optionally replaced

[0231] [ka] , optionally replaced

[0232] [ka] , optionally replaced

[0233] [ka] and optionally replaced

[0234] [ka] The structure is selected from the following:

[0235] In another aspect, the present application further provides a linker or a tautomer, mesomeric, ceramiric, enantiomeric, diastereomeric, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said linker is

[0236] [ka] TIFF2024523422000121.tif100170.

[0237] In another embodiment, the present application further provides a linker as shown in formula (L-2) for linking a Drug unit and a Ligand to obtain a Ligand-Drug conjugate: Formula (L-2): -L1-L2-L3-L4-L5- L1 is optionally substituted

[0238] [ka] and

[0239] L2 is optionally replaced

[0240] [ka] , optionally replaced

[0241] [ka] , optionally replaced

[0242] [ka] , optionally replaced

[0243] [ka] , optionally replaced

[0244] [ka] , optionally replaced

[0245] [ka] , optionally replaced

[0246] [ka] , optionally replaced

[0247] [ka] and optionally replaced

[0248] [ka] A structure selected from the group consisting of:

[0249] L3 is

[0250] [ka] The structure is selected from the group consisting of:

[0251] L4 is an optionally substituted -L 4a -NR4-CH2-L 4b - and L 4a does not exist or is 4a is optionally replaced

[0252] [ka] and

[0253] L 4b does not exist or is 4b is optionally replaced

[0254] [ka] And L 4a and L 4b does not exist at the same time,

[0255] R4 and R5 are each independently selected from the group consisting of hydrogen and optionally substituted alkyl groups; The L5 is optionally substituted

[0256] [ka] , optionally replaced

[0257] [ka] , optionally replaced

[0258] [ka] , optionally replaced

[0259] [ka] , optionally replaced

[0260] [ka] , optionally replaced

[0261] [ka] , optionally replaced

[0262] [ka] and optionally replaced

[0263] [ka] The structure is selected from the group consisting of:

[0264] In the structure represented by formula (L-2), L4 is an optionally substituted

[0265] [ka] It is.

[0266] In the structure represented by formula (L-2), L4 is an optionally substituted

[0267] [ka] It is.

[0268] In the structure represented by formula (L-2), L4 is an optionally substituted

[0269] [ka] It is.

[0270] In the structure represented by formula (L-2), L4 is an optionally substituted

[0271] [ka] , optionally replaced

[0272] [ka] , optionally replaced

[0273] [ka] and optionally replaced

[0274] [ka] The structure is selected from the following:

[0275] In another aspect, the present application further provides a linker or a tautomer, mesomeric, ceramiric, enantiomeric, diastereomeric, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said linker is

[0276] [ka] The structure includes a structure selected from the group consisting of:

[0277] In another aspect, the present application relates to a ligand conjugate of the present application, or a tautomer, mesomeric, ceramimeric, enantiomeric, diastereomeric, or mixture thereof, or a pharma- ceutically acceptable salt, prodrug or solvate thereof, and / or a compound of the present application, and optionally a pharma- ceutical composition comprising a pharma- ceutically acceptable carrier is further provided.

[0278] In another aspect, the present application further provides the use of the ligand conjugate of the present application, or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt, prodrug or solvate thereof, the compound of the present application, and / or the pharmaceutical composition of the present application, in the preparation of a medicament for treating and / or preventing a tumor.

[0279] In one embodiment, the tumor is selected from tumors associated with expression of targets of HER2 and TROP2. In one embodiment, the tumors associated with expression of the target include tumors with high expression of the target and / or tumors that are positive for the target.

[0280] In one embodiment, the tumor comprises a solid tumor and / or a hematological tumor. In one embodiment, the tumor is selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, bladder cancer, colorectal cancer, endometrial cancer, renal cancer, lung cancer, pancreatic cancer, prostate cancer and thyroid cancer.

[0281] In one embodiment, the tumor is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, endometrial cancer, urothelial cancer, lung cancer, prostate cancer, colorectal cancer, gastric cancer, esophageal cancer, bladder cancer, renal cancer, pancreatic cancer, thyroid cancer and head and neck cancer.

[0282] [Effects of the invention] Those skilled in the art will readily appreciate other aspects and advantages of the present application from the following detailed description. In the following detailed description, only exemplary embodiments of the present application are shown and described. As those skilled in the art will appreciate, the contents of this application allow those skilled in the art to make changes to the specific embodiments disclosed without departing from the spirit and scope of the present invention referred to in this application. Correspondingly, the descriptions in the specification of the present application are illustrative only and not limiting. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0283] Hereinafter, the embodiments of the present invention will be described with reference to specific examples. However, those skilled in the art will easily understand other advantages and effects of the present invention from the contents disclosed in this specification. In this application, the term "ligand" generally refers to a polymeric compound that can recognize and bind to an antigen or receptor associated with a target cell. The role of the ligand is to present a drug to a target cell population that binds to the ligand, and 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 this application, the ligand can be represented as Ab, and the ligand antigen forms a connection bond with the connection unit through a heteroatom on the ligand, and can be an antibody or an antigen-binding fragment thereof, and the antibody can be selected from a chimeric antibody, a humanized antibody, a fully human antibody, or a mouse antibody, and the antibody can be a monoclonal antibody. For example, the antibody can be an antibody or an antigen-binding fragment thereof that targets a target selected from the group consisting of HER2 and TROP2.

[0284] In this application, the term "Trop2" or "TROP2" generally refers to a single-pass transmembrane type I plasma membrane protein. In this application, the term "Trop2" further includes homologs, variants and isoforms of Trop2, including splice isoforms. The term "Trop" further includes Trop2 homologues, proteins having one or more sequences in variants and isoforms, as well as fragments of said sequences, so long as they are variant proteins (inclusive isoforms). Trop2 can be human Trop2. For example, Uniprot accession number P09758 provides a description of Trop2 and the sequence.

[0285] In this application, the term "HER2" generally refers to human epidermal growth factor receptor 2 (HER2). For example, the term "HER2" refers to any native HER2 from any human source. The term includes "full-length" and unprocessed HER2, as well as any form of HER2 (e.g., mature protein) that results from processing within a cell. The term also includes naturally occurring variants and isoforms of HER2, such as splice variants or allelic variants. For example, Uniprot Accession No. P04626 provides a description of HER2 and sequences.

[0286] In this application, the term "trastuzumab" generally refers to an antibody that targets HER2. For example, trastuzumab is described in US20060275305A1. In this application, trastuzumab can refer to an antibody or antigen-binding fragment that includes the heavy chain variable region CDR1-3 and the light chain variable region CDR1-3 of trastuzumab. In this application, trastuzumab can refer to an antibody or antigen-binding fragment that includes the heavy chain variable region and the light chain variable region of trastuzumab.

[0287] In the present application, the term "peptide residue" generally refers to a residue formed by combining one or more amino acid residues. For example, one or more amino acids in a polypeptide residue may be optionally substituted. For example, a polypeptide residue in the present application may include glycine-glycine-phenylalanine-glycine (Gly-Gly-Phe-Gly).

[0288] In this application, the term "drug unit" generally refers to a chemical moiety that directly or indirectly binds an antibody or antigen-binding fragment to form an immunoconjugate. For example, a "drug unit" includes, but is not limited to, a compound having antitumor activity as described herein. For example, a drug unit includes a topoisomerase inhibitor.

[0289] In this application, the term "antitumor active compound" generally refers to a compound that has the ability to reduce the proliferation rate, survival rate or metastatic activity of tumor cells. For example, antitumor activity can be demonstrated by a decrease in the growth rate of abnormal cells or a stabilization or reduction in tumor size that occurs during treatment, or by an increase in survival time due to treatment compared to a control without treatment. Antitumor activity can be evaluated using recognized in vitro or in vivo tumor models, such as xenograft models.

[0290] In this application, the term "topoisomerase inhibitor" generally refers to compounds or derivatives thereof, including topoisomerase I inhibitors and topoisomerase II inhibitors. Examples of topoisomerase I inhibitors include, but are not limited to, camptothecin and its analogs. For example, topoisomerase refers to an enzyme that breaks the phosphodiester bond of one or two strands of DNA, then unwinds and seals it, thereby correcting the number of DNA strands.

[0291] In this application, the term "camptothecin analog" generally refers to a compound that is structurally similar to or derived from camptothecin. For example, the structure of camptothecin is set forth in CAS Registry Number 7689-03-4. For example, a camptothecin analog is exatecan (CAS Registry Number 171335-80). -1).

[0292] In this application, the term "tumor" generally refers to any new pathological tissue growth. In this application, angiogenesis is part of the characteristics of a tumor. A tumor can be benign or malignant. The term "tumor" is generally used to refer to benign or malignant tumors, while the term "cancer" is generally used to refer to malignant tumors that can be metastatic or non-metastatic. For research, these tumor tissues can be isolated from readily available sources by methods well known to those skilled in the art.

[0293] In this application, the term "alkyl group" generally refers to a residue derived by removing a hydrogen atom from an alkane. The alkyl group may be substituted or unsubstituted, substituted or unsubstituted. The term "alkyl group" generally refers to a saturated linear or branched chain aliphatic hydrocarbon group having a residue derived by removing a hydrogen atom from the same carbon atom or two different carbon atoms of a parent alkane, which may be a linear or branched chain group containing 1 to 20 carbon atoms, e.g., a chain alkyl group containing 1 to 12 carbon atoms, e.g., 1 to 6 carbon atoms. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, and the like. An alkyl group can be substituted or unsubstituted, substituted or unsubstituted, for example, when substituted, the substituents can be substituted at any available point of attachment and the substituents can be independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heptane, phenyl ... and may be substituted by one or more substituents selected from a cycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, and an oxo group, and may be, for example, hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SON2NH2, -OC(O)H, -N(H)SO2H, or C(O)H. 1-6 It may be an aliphatic group.

[0294] In this application, the term "alkylene group" refers to a saturated, straight or branched chain aliphatic hydrocarbon group having two residues derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, which may be a straight or branched chain group containing typically 1 to 20 carbon atoms, for example, the term "methylene group" may refer to a residue derived by two hydrogen atoms from a group of one carbon atom. The methylene group may be substituted or unsubstituted, substituted or unsubstituted, for example, alkylene groups containing 1 to 12 carbon atoms, for example, 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH-), 1,1-ethylene (-CH(CH)-), 1,2-ethylene (-CHCH)-, 1,1-propylene (-CH(CHCH)-), 1,2-propylene (-CHCH(CH)-), 1,3-propylene (-CHCHCHCH-), 1,4-butylene (-CHCHCHCHCH-), 1,5-butylene (-CHCHCHCHCHCH-), and the like. Alkylene groups can be substituted or unsubstituted, substituted or unsubstituted, for example, when substituted, the substituents can be substituted at any available point of attachment, said substituents being optionally substituted with one or more substituents independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups, for example, hydrogen, protium, fluorine, arsenic ... hydrogen, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or C 1-6 It may be an aliphatic group. The methylene or alkylene group may be substituted or unsubstituted.

[0295] In this application, the term "alkenyl group" generally refers to a straight or branched chain hydrocarbon group containing one or more double bonds. Specific examples of alkenyl groups include allyl groups, homoallyl groups, vinyl groups, crotyl groups, butenyl groups, pentenyl groups, and hexenyl groups. 2-6 Specific examples of long chain alkenyl groups include butadienyl, pentadienyl, hexadienyl and hexatrienyl groups, and branched forms thereof. One of the unsaturated bonds (double bonds) may be at any one of the carbon chains. Alkenyl groups may be substituted or unsubstituted.

[0296] In this application, the term "alkenylene group" generally refers to a residue derived by removing two hydrogen atoms from a carbon atom of an alkene. For example, it can be an arylene group, a vinylene group, a butenylene group, a pentenylene group, a hexenylene group, etc. The alkenylene group can be substituted or unsubstituted.

[0297] In this application, the term "alkynyl group" generally refers to unsaturated straight or branched chain alkynyl groups such as ethynyl, 1-propynyl, propargyl, butynyl, etc. Alkynyl groups can be substituted or unsubstituted.

[0298] In this application, the term "alkynylene group" generally refers to a residue derived by removing two hydrogen atoms from a carbon atom of an alkyne, and can be, for example, an ethynylene group, a propynylene group, a propargylene group, a butynylene group, etc. An alkynylene group can be substituted or unsubstituted.

[0299] In this application, the term "aryl group" generally refers to a residue derived by removing one hydrogen atom from an aromatic ring. The term "aromatic ring" refers to a 6-14 membered all carbon monocyclic or fused polycyclic ring (i.e., rings that share adjacent pairs of carbon atoms) having a conjugated π electron system, which may be 6-10 membered, for example, benzene and naphthalene. The aromatic ring may be fused to a heteroaryl group, a heterocyclic group, or a cycloalkyl ring, where the ring that is attached to the parent structure is an aryl ring. The aryl group may be substituted or unsubstituted, and if substituted, the substituents may be one or more of the following groups, which are independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups. The aryl group may be substituted or unsubstituted.

[0300] In this application, the term "arylene group" generally refers to a residue derived by removing two hydrogen atoms from a carbon atom of an aromatic ring. For example, it can be a phenylene group and a naphthylene group. An arylene group can be substituted or unsubstituted.

[0301] In this application, the term "heteroaryl group" generally refers to a residue derived by removing one hydrogen atom from a carbon atom of a heteroaromatic ring. The term "heteroaromatic ring" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. A heteroaryl group is , 5-10 membered, 5 or 6 membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted, and if substituted, the substituents can be one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio. The heteroaryl group can be substituted or unsubstituted.

[0302] In this application, the term "heteroarylene group" generally refers to a residue derived by removing two hydrogen atoms from a carbon atom of a heteroaromatic ring. For example, it may be a furylidine group, a thienylene group, a pyridylene group, a pyrrolene group, a pyrimidinylene group, a pyrazinylene group, an imidazolylene group, a tetrazolylene group, etc. The heteroarylene group may be substituted or unsubstituted.

[0303] In this application, the term "alicyclic group" generally refers to a residue derived by removing hydrogen atoms from the same carbon atom or from multiple different carbon atoms of an alicyclic ring. The term "cycloalkane" generally refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, where the carbocyclic ring contains 3 to 20 carbon atoms, can contain 3 to 12 carbon atoms, can contain 3 to 10 carbon atoms, can contain 3 to 8 carbon atoms. Non-limiting examples of alicyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., and polycyclic carbocyclic rings can include spiro, fused, and bridged carbocyclic rings. An alicyclic group may be substituted or unsubstituted. In this application, the term "carbocyclic group" generally refers to a residue derived by removing one hydrogen atom from a carbon atom bearing a carbocyclic ring. The term "carbocycle" generally refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, where the carbocycle contains 3 to 20 carbon atoms, can contain 3 to 12 carbon atoms, can contain 3 to 10 carbon atoms, can contain 3 to 8 carbon atoms. Non-limiting examples of monocyclic carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, cyclooctane, etc., and polycyclic carbocycles can include spiro, fused, and bridged carbocycles. Carbocyclic groups can be substituted or unsubstituted. In some cases, alicyclic and carbocycle can be used interchangeably.

[0304] In this application, the term "partially unsaturated" generally refers to a ring structure containing at least one double or triple bond between ring molecules. The term "partially unsaturated" includes ring structures having multiple unsaturations, but is not intended to include aromatic or heteroaromatic rings as defined in this application. The term "unsaturated" refers to a moiety having one or more degrees of unsaturation.

[0305] In this application, the term "aliphatic cyclylene group" generally refers to a residue derived by removing two hydrogen atoms from a carbon atom of an alicyclic ring, such as a cyclopropanylene group, a cyclobutanylene group, a cyclopentanylene group, a cyclopentenylene group, a cyclohexylene group, a cyclohexenylene group, a cyclohexadienylene group, a cycloheptanylene group, The aliphatic cyclylene group may be a cycloheptatrienylene group, a cyclooctanylene group, etc., and the polycyclic carbocycle may include spiro rings, fused rings, and bridged rings and carbocycles. The aliphatic cyclylene group may be substituted or unsubstituted.

[0306] In this application, the term "aliphatic heterocyclic group" generally refers to a stable non-aromatic 3- to 7-membered monocyclic carbocyclic ring structure, a fused 7- to 10-membered bicyclic heterocyclic ring structure, or a bridged 6- to 10-membered bicyclic heterocyclic ring structure, which ring structures may be saturated or partially saturated and, in addition to the carbon atoms, further contain one or more heteroatoms, where the heteroatoms are selected from the group consisting of oxygen, sulfur, and nitrogen. For example, it may contain 1 to 4 heteroatoms as defined above. When used to refer to an atom on an aliphatic heterocyclic ring structure, the term "nitrogen" may include the nitrogen at which a substitution reaction has occurred. For example, an aliphatic heterocyclic group can include a "heterocycloalkyl group", which can refer to a stable non-aromatic 3- to 7-membered monocyclic alkane structure, a fused 7- to 10-membered bicyclic heterocyclic structure, or a bridged 6- to 10-membered bicyclic heterocyclic structure, and in addition to the carbon atoms, these ring structures can further include one or more heteroatoms, where the heteroatoms are selected from the group consisting of oxygen, sulfur, and nitrogen. For example, one to four heteroatoms as defined above. The heterocycloalkyl group can be substituted or unsubstituted. The aliphatic heterocyclic group can be substituted or unsubstituted.

[0307] In this application, the term "aliphatic heterocyclylene group" generally refers to a residue derived by removing two hydrogen atoms from a carbon atom of an aliphatic heterocycle. The aliphatic heterocyclylene group may be substituted or unsubstituted.

[0308] In this application, the term "optionally" or "optionally" generally refers to the subsequently described event or circumstance that may, but need not, occur, and the description includes cases where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" refers to the alkyl group that may, but need not, be present, and the description can include cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0309] In this application, the term "substituted" generally refers to one or more hydrogen atoms in a group, e.g., up to 5, e.g., 1 to 3 hydrogen atoms, being independently replaced by a corresponding number of substituents. Substituents are present only at 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 group or a hydroxy group having a free hydrogen may be unstable if it is attached to a carbon atom having an unsaturated (e.g., ethylene) bond. For example, optionally substituted substituents are optionally selected from hydrogen, protium, deuterium, tritium, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups, e.g., hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SON2NH2, -OC(O)H, -N(H)SO2H, or C(O)H. 1-6 It may be an aliphatic group.

[0310] In this application, as will be appreciated by those skilled in the art, terms such as "alkyl group", "alkenyl group", "cycloalkyl group", and the like may in a particular instance be preceded by a label indicating the number of atoms present in the group, e.g., C1-C4 alkyl group, C3-C7 cycloalkoxy group, C The subscript number following the "C" indicates the number of carbon atoms in the group. For example, a C3 alkyl group refers to an alkyl group having three carbon atoms (e.g., n-propyl, isopropyl), and C 1-10 In the formula: wherein the group members can have any number of carbon atoms in the range of 1 to 10.

[0311] One or more hydrogen atoms in the group are replaced by a corresponding number of substituents, for example up to 5, for example 1 to 3 hydrogen atoms, independently of each other. Substituents are present only at possible chemical positions, and a person skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino group or a hydroxy group with free hydrogen may be unstable if it is bonded to a carbon atom with an unsaturated (e.g., olefinic) bond.

[0312] In this application, the term "compound" generally refers to a substance having two or more different elements. For example, the compound of this application may be an organic compound, for example, the compound of this application may be a compound having a molecular weight of 500 or less, a compound having a molecular weight of 1000 or less, a compound having a molecular weight of 1000 or more, a compound having a molecular weight of 1000 or more, a compound having a molecular weight of 10000 or more, or a compound having a molecular weight of 10000 or more. In this application, the compound may also refer to a compound bound via a chemical bond, for example, a compound in which one or more molecules having a molecular weight of 1000 or less are bound to a biopolymer via a chemical bond, and the biopolymer may be a high polysaccharide, a protein, a nucleic acid, a polypeptide, etc. For example, the compound of this application may include a compound in which a protein is bound to one or more molecules having a molecular weight of 1000 or less, a compound in which a protein is bound to one or more molecules having a molecular weight of 10000 or less, or a compound in which a protein is bound to one or more molecules having a molecular weight of 10000 or less.

[0313] In this application, the term "comprising" generally means the inclusion of the explicitly specified features but not the exclusion of other elements. The terms "more than" and "less than" generally refer to the inclusive case of the number itself.

[0314] In this application, the term "about" generally refers to a variation within 0.5% to 10% above and below the specified value, for example, a variation within 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 the specified value.

[0315] In this application, the compounds of this application include the tautomers, mesomers, ceramimes, enantiomers, and / or diastereomers of the compound. In this application, the term "diastereomer" generally refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers may have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. In this application, the terms "tautomers" or "tautomeric forms" are used interchangeably and generally refer to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as proton prototropic tautomers) include interconversions via proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via rearrangement of some of the bond electrons. In this application, the term "mesomer" refers to an atom that contains asymmetry within a molecule, but has symmetric elements such that the total optical rotation within the molecule is zero. The term "ceramic" or "ceramic mixture" refers to a material that consists of equimolar amounts of two enantiomeric substances.

[0316] In this application, certain atoms of the compounds of this application may exist in one or more isotopic forms. For example, hydrogen can be 1 H), deuterium ( 2 H) and tritium ( 3 H), and carbon can exist in three different isotopes ( 12 C. 13 C and 14 C). Examples of isotopes that may be incorporated in the compounds of the present application are: 15 N, 18 O. 17 O. 18 F, 32 P, 33 P, 129I, 131 I, 123 I, 124 I, 125 I, or similar isotopes. Thus, the compounds of the present application may be enriched in one or more of these isotopes compared to the natural abundance of these isotopes. As known to those of skill in the art, such isotopically enriched compounds can be used in a variety of applications. For example, deuterium (e.g. 2 Substitution of heavier isotopes of hydrogen (H) may provide certain therapeutic advantages due to their increased metabolic stability. For example, deuterium ( 2 The natural abundance of deuterium (H) is about 0.015%. Thus, in nature, there is one deuterium atom for every approximately 6500 hydrogen atoms. Thus, deuterium-containing compounds of the present application have a deuterium abundance of greater than 0.015% at one or more positions (as the case may be). Unless otherwise indicated, structures described in the present application may also include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, all compounds that are consistent with the remainder and 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.

[0317] In the present application, the term "pharmaceutical composition" generally refers to a mixture of one or more compounds described in the present application or their physiologically / pharmaceutical acceptable salts or prodrug drugs with other chemical components, as well as other components such as physiologically / pharmaceutical acceptable carriers and excipients. The pharmaceutical composition can facilitate administration to the living body and favor the absorption of the active ingredient to exert biological activity. The preparation of conventional pharmaceutical compositions can refer to conventional techniques commonly used in the art.

[0318] In this application, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" generally refers to a salt of a compound or ligand-drug conjugate of the application, or a salt of a compound described in this application, which is safe and effective when used in a mammal and can have appropriate biological activity, and the antibody-antibody drug conjugate compound of the application can form a salt with an acid, and 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, or p-toluenesulfonate.

[0319] In this application, the term "conjugate" generally refers to compounds of the application that are connected to each other through one or more connecting structures, such as compounds prepared through one or more chemical reactions, or through one or more connecting structures, such as a bridge, spacer, or connecting moiety.

[0320] In this application, the term "pharmaceutically acceptable carrier" generally refers to a carrier for administering a therapeutic agent, such as an antibody or polypeptide, genes and other therapeutic agents. The term refers to any drug carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition and that can be administered without undue toxicity. For example, a pharmaceutically acceptable carrier can be distinguished from a nucleic acid vector used in genetic engineering to contain a target gene. Suitable carriers can be large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polyamino acids, amino acid copolymers, lipid aggregates and inactivated virus granules. These carriers are well known to those skilled in the art. Pharmaceutically acceptable carriers in therapeutic compositions include water, saline, glycerol, and the like. The carrier may also contain liquids, such as alcohol and ethanol. These carriers can also contain auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like.

[0321] In this application, "antibody" can generally include monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological properties. Antibodies can be murine, human, humanized, chimeric, or derived from other species. Antibodies are proteins generated by the immune system that recognize and bind specific antigens. Target antigens generally have a plethora of binding sites (also called epitopes) that are identified by the CDRs of various antibodies. Each antibody that specifically binds to a different epitope has a different structure. Thus, an antigen can have one or more corresponding antibodies. Antibodies include full-length immunoglobulin molecules or immunologically active portions of full-length immunoglobulin molecules, i.e., molecules that contain an antigen or a portion thereof that specifically binds to a target of interest, such targets including, but not limited to, cancer cells or cells that produce autoimmune antibodies associated with autoimmune diseases. The immunoglobulins described in this application can have any type (e.g., IgG, IgE, IgM, IgD and IgA), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule. The immunoglobulins can be derived from any species. However, in one embodiment, the immunoglobulins are derived from human, mouse or rabbit. An "antibody fragment" can include a portion of a full-length antibody, generally its antigen-binding region or variable region. Examples of antibody fragments include Fab, Fab', F(ab')2 and Fv fragments, bibodies, linear antibodies, minibodies, fragments prepared by Fab expression libraries, anti-idiotypic (anti-Id) antibodies; CDRs (complementarity determining regions), any epitope-binding fragments of the above that immunospecifically bind to cancer cell antigens, viral antigens or microbial antigens, single-chain antibody molecules, and multispecific antibodies consisting of antibody fragments. The antibodies constituting the antibody drug conjugates in this application can maintain their original wild-state antigen-binding ability. Thus, an antibody in the present application can, for example, specifically bind to an antigen.The antigens referred to include, for example, tumor-associated antigens (TAA), cell surface receptor proteins and other cell surface molecules, cell survival regulators, cell proliferation regulators, molecules associated with tissue growth and differentiation (e.g., with known or predicted functionality), lymphokines, cytokines, molecules involved in regulating cell circulation, molecules involved in angiogenesis, and molecules associated with angiogenesis (e.g., antigens to which known antibodies bind may be one or a subset of the above categories, while other subsets include molecules / antigens with other special properties (compared to the target antigen)). Antibodies applied in antibody drug conjugates include, but are not limited to, antibodies against cell surface receptors and tumor-associated antigens. Such tumor-associated antigens are well known in the art and can be prepared using antibody preparation methods and information well known in the art. These targets can be specifically expressed on the surface of one or more cancer cells, but are poorly or not expressed at all on the surface of one or more non-cancerous cells. Usually, such tumor-associated polypeptides can be more overexpressed on the surface of cancer cells compared to the surface of non-cancerous cells.

[0322] In this application, the term "chimeric antibody" refers to an antibody in which the variable region of a mouse-derived antibody is fused to the constant region of a human antibody, which can reduce the immune response reaction usually induced by a mouse-derived antibody. To establish a chimeric antibody, a hybridoma secreting a specific mouse-derived monoclonal antibody can be established, and then the variable region gene is cloned from the mouse hybridoma cell, and if necessary, the constant region gene of a human antibody is cloned, and the mouse variable region gene is linked to the human constant region gene to form a chimeric gene, which is then inserted into an expression carrier, allowing the chimeric antibody molecule to be expressed in a eukaryotic or prokaryotic system.

[0323] In this application, the term "humanized antibody", also known as CDR-grafted antibody, generally refers to an antibody produced by grafting mouse CDR sequences onto a human antibody variable region framework, i.e., a different type of human germline antibody framework sequence. It can overcome the xenogeneic reactions induced by chimeric antibodies that retain a large amount of mouse protein components. Such framework sequences can be obtained from public DNA databases or published references that contain germline antibody gene sequences. For example, germline DNA sequences of human heavy and light chain variable region genes are available in the "VBase" human germline sequence database.

[0324] In this application, the term "fully human antibody", "fully human antibody" or "fully human-derived antibody", also referred to as "fully human monoclonal antibody", refers to the variable and constant regions of the antibody, which can be humanized to eliminate immunogenic and toxic side effects. The development of monoclonal antibodies has gone through four stages, namely, mouse-derived monoclonal antibodies, chimeric monoclonal antibodies, humanized monoclonal antibodies and fully human monoclonal antibodies, respectively. The antibody or ligand described in this application can be a fully human monoclonal antibody. The techniques related to the preparation of fully human antibodies include human hybridoma technology, EBV-transformed B lymphocyte technology, phage display technology, transgenic mouse antibody preparation technology and single B cell antibody preparation technology, etc.

[0325] In this application, the term "CDR" generally refers to one of the six hypervariable regions in the variable domain of an antibody that are primarily responsible for antigen binding. One of the most commonly used definitions of the six CDRs is provided by Kabat EA et al., Chothia et al., and MacCallum et al. As used in this application, the Kabat definition of CDRs can be applied to CDR1, CDR2 and CDR3 of the light chain variable domain (CDRL1, CDRL2, CDRL3 or L1, L2, L3) and CDR1, CDR2 and CDR3 of the heavy chain variable domain (CDRH1, CDRH2, CDRH3 or H1, H2, H3).

[0326] In the present application, the term "a group capable of coupling to a sulfhydryl group" generally refers to the fact that compound A has a sulfhydryl group, compound B has a group capable of coupling to a sulfhydryl group, and compound B reacts with the sulfhydryl group of compound A via the group capable of coupling to a sulfhydryl group, thereby realizing binding between compound A and compound B.

[0327] In this application, the term "linker" generally refers to a chemical structure fragment or bond that is connected at one end to one group and at the other end to another group, and can also be connected to another linker and then to a drug and / or a ligand. The directly or indirectly connected ligand can refer to the group being directly linked to the ligand via a covalent bond, or can refer to the group being connected to the ligand via a linker. For example, the linker can be a structure shown in the linker described in this application. For example, a chemical structure fragment or bond including an acid-labile linker structure (e.g., hydrazone), a protease-sensitive (e.g., peptidase-sensitive) linker structure, a photolabile linker structure, a dimethyl linker structure, or a disulfide-containing linker structure can be used as a linker.

[0328] In this application, the term "linking group" generally refers to a group capable of binding to another group. For example, a compound having a linking group can realize the binding between the compound and another group by a coupling reaction between the linking group and the other group. For example, a maleimide group can be used as a linking group.

[0329] In the present application, the term disease "associated with expression" of a target generally refers to the occurrence and / or progression of the disease being associated with the expression level of the target. For example, the expression level of the target is increased, i.e., highly expressed, in cells from a diseased area, such as a particular tissue or organ of a patient, compared to the expression level of normal cells from the tissue or organ. Alternatively, the expression level of the target is decreased, i.e., low expressed, in cells from a diseased area, such as a particular tissue or organ of a patient, compared to the expression level of normal cells from the tissue or organ. Alternatively, the cells from a diseased area, such as a particular tissue or organ of a patient, express the target, i.e., are positive. Alternatively, the cells from a diseased area, such as a particular tissue or organ of a patient, do not express the target, i.e., are negative. For example, the expression characteristics of the target can be determined by standard measurements known in the art.

[0330] In this application, the term "effective amount" generally refers to an amount of a therapeutic agent that treats, alleviates or prevents a target disease or condition, or that exhibits a detectable therapeutic or preventive effect. The exact effective amount for a particular subject depends on the subject's physical shape and health, the nature and extent of the disease, and the therapeutic agent and / or combination of therapeutic agents selected to be administered. Thus, it is meaningless to pre-specify the exact effective amount. However, for a particular given situation, the effective amount can be determined using routine experimentation, and can be determined by the clinician.

[0331] Unless otherwise indicated, all compounds appearing in this application are intended to include all possible optical isomers, including single chiral compounds or mixtures of various different chiral compounds (i.e., chiral isomers). In all compounds in this application, each chiral carbon atom can optionally be in the R or S configuration, or a mixture of the R and S configurations.

[0332] In this application, the term "compound of the application" generally refers to a compound of the application. The term further includes various crystal forms, pharma- ceutically acceptable salts, hydrates or solvates of the compound of the application.

[0333] When trade names are used herein, the trade names are intended to include formulations of the trade name product, its corresponding generic versions, and the active pharmaceutical ingredients of the trade name product.

[0334] Detailed Description of the Invention In one aspect, the present application provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said compound can comprise the structure shown in formula (I):

[0335] [ka]

[0336] for example,

[0337] [ka] It may be

[0338] wherein R1 and R2 can each independently be selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C8 haloalkyl group, and an optionally substituted C1-C8 deuterated alkyl group; or R1 and R2, taken together with the carbon atom to which they are attached, can form a structure selected from the group consisting of an optionally substituted alicyclic group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group; L can be an optionally substituted linker; Ab can be a ligand and a can be a number that is at least zero.

[0339] For example, in the structure shown in formula (I), the L can include a linker L1, which can be directly or indirectly linked to a ligand. For example, the L1 can be an optionally substituted

[0340] [ka] For example, L1 in the structure shown in formula (I) can exist in an open ring form as shown in the following formula:

[0341] [ka]

[0342] For example, in the structure shown in formula (I), the L may further include a linker L2. For example, the L2 may be directly or indirectly linked to the L1. For example, the L2 may be an optionally substituted -(CH2) m1 -X1-(CH2) m2 -C(O)-, optionally substituted -(CH2CH2O) n -C(O)- and optionally substituted -(CH2) pX1 may include a group selected from the group consisting of -C(O)-, an optionally substituted -C(O)-NH-, an optionally substituted aryl group, an optionally substituted heteroaryl group, any heteroalicyclic group, and an optionally substituted alicyclic group, wherein m1, m2, and n may each independently be selected from a number that is at least 0.

[0343] For example, in the structure shown in formula (I), L2 is optionally substituted -(CH2CH2O) n For example, where n is 2, it may include -C(O)-.

[0344] For example, in the structure shown in formula (I), L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 For example, X1 can be selected from the group consisting of -O- and optionally substituted -C(O)-NH-. For example, m1 can be 2. For example, m2 can be 2.

[0345] For example, in the structure shown in formula (I), X1 can include a group selected from the group consisting of an optionally substituted aryl group and an optionally substituted heteroaryl group. For example, X1 can include an optionally substituted phenyl group. For example, X1 can include an optionally substituted pyridyl group. For example, m1 can be 0. For example, m2 can be 1.

[0346] For example, in the structure shown in formula (I), X1 can include an optionally substituted heteroalicyclic group containing two oxygen atoms.

[0347] [ka] For example, X1 can include an optionally substituted cyclohexyl group. For example, m1 can be 1. For example, m2 can be 0.

[0348] For example, in the structure shown in formula (I), L2 is an optionally substituted -(CH2) p For example, p can be 5.

[0349] For example, in the structure shown in formula (I), L2 is optionally substituted

[0350] [ka] , optionally replaced

[0351] [ka] , optionally replaced

[0352] [ka] , optionally replaced

[0353] [ka] , optionally replaced

[0354] [ka] , optionally replaced

[0355] [ka] , optionally replaced

[0356] [ka] and optionally replaced

[0357] [ka] The structure may include a structure selected from the group consisting of:

[0358] For example, in the structure shown in formula (I), the L may further include a linker L3. For example, the L3 may be directly or indirectly linked to the L2. For example, the L3 may include a peptide residue.

[0359] For example, the L3 can comprise a peptide residue consisting of an amino acid selected from the group consisting of phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid and glycine. For example, the L3 can comprise a peptide residue consisting of an amino acid selected from the group consisting of glycine, phenylalanine, valine and citrulline. For example, the L3 can comprise a peptide residue selected from the group consisting of -glycine-phenylalanine-glycine-(-Gly-Phe-Gly-), -glycine-glycine-phenylalanine-glycine-(-Gly-Gly-Phe-Gly-) and -valine-citrulline-(-Val-Cit-).

[0360] For example, in the structure shown in formula (I), L3 is

[0361] [ka] The structure may include a structure selected from the group consisting of:

[0362] For example, in the structure shown in formula (I), the L may further include a linker L4. For example, the L4 may be directly or indirectly linked to the L3.

[0363] For example, in the structure shown in formula (I), L4 is an optionally substituted -L 4a -NR4-CH2-L 4b - may contain L 4a does not exist or is 4a is optionally replaced

[0364] [ka] L 4b does not exist or is 4b is optionally replaced

[0365] [ka] wherein R4 and R5 can each independently be selected from the group consisting of hydrogen and an optionally substituted alkyl group.

[0366] For example, in the structure shown in formula (I), L4 is optionally substituted

[0367] [ka] For example, the L4 may include an optionally substituted

[0368] [ka] For example, the L4 may include an optionally substituted

[0369] [ka] For example, the L4 may include an optionally substituted

[0370] [ka] For example, R4 may be selected from the group consisting of hydrogen and an optionally substituted methyl group. For example, R5 may be selected from the group consisting of hydrogen and an optionally substituted methyl group.

[0371] For example, in the structure shown in formula (I), L4 is optionally substituted

[0372] [ka] , optionally replaced

[0373] [ka] , optionally replaced

[0374] [ka] , optionally replaced

[0375] [ka] and optionally replaced

[0376] [ka] The structure may include a structure selected from the group consisting of:

[0377] For example, in the structure shown in formula (I), the L may further include a linker L5. For example, the L5 may be directly or indirectly linked to the L4.

[0378] For example, in the structure shown in formula (I), L5 is optionally substituted

[0379] [ka] wherein R and R can each independently be selected from the group consisting of hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group, and an optionally substituted cycloalkylalkyl group, or R and R together with the atom to which they are attached can form an optionally substituted cycloalkyl group, where v is at least 0.

[0380] For example, in the structure shown in formula (I), R6 can be hydrogen. For example, R6 can be an optionally substituted methyl group. For example, R6 can be an optionally substituted halomethyl group. For example, R6 can be a methyl group substituted by fluorine. For example, R6 can be a trifluoromethyl group. For example, R6 can be an optionally substituted cycloalkyl group. For example, R6 can be an optionally substituted cyclopropyl group. For example, in the structure shown in formula (I), R7 can be hydrogen.

[0381] For example, in the structure shown in formula (I), R6 and R7 together with the atom to which they are attached can form an optionally substituted cyclopropyl group. For example, R6 and R7 together with the atom to which they are attached can form an optionally substituted cyclobutyl group. For example, v can be 0. For example, v can be 1.

[0382] For example, in the structure shown in formula (I), L5 is optionally substituted

[0383] [ka] , optionally replaced

[0384] [ka] , optionally replaced

[0385] [ka] , optionally replaced

[0386] [ka] , optionally replaced

[0387] [ka] , optionally replaced

[0388] [ka] , optionally replaced

[0389] [ka] and optionally replaced

[0390] [ka] The structure may include a structure selected from the group consisting of:

[0391] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said compound can comprise the structure shown in formula (I):

[0392] [ka]

[0393] for example,

[0394] [ka]

[0395] It may be wherein R1 and R2 can each independently be selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C8 haloalkyl group, and an optionally substituted C1-C8 deuterated alkyl group; or R1 and R2, taken together with the carbon atom to which they are attached, can form a structure selected from the group consisting of an optionally substituted alicyclic group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group; L can be an optionally substituted linker, said L can include -L1-L2-L3-L4-L5-; Ab can be a ligand and a can be a number that is at least zero.

[0396] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said compound can comprise the structure shown in formula (I):

[0397] [ka]

[0398] for example,

[0399] [ka] It may be

[0400] wherein R1 and R2 can each independently be selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C8 haloalkyl group, and an optionally substituted C1-C8 deuterated alkyl group; or R1 and R2, taken together with the carbon atom to which they are attached, can form a structure selected from the group consisting of an optionally substituted alicyclic group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group; L can be an optionally substituted linker, said L can include -L1-L2-L3-L4-L5-; Ab can be a ligand and a can be a number that is at least 0; wherein L1 can comprise a linker linked to a sulfhydryl group; The L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 -C(O)-, optionally substituted -(CH2CH2O) n -C(O)- and optionally substituted -(CH2) p X1 may include a group selected from the group consisting of -C(O)-, an optionally substituted -C(O)-NH-, an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted heteroalicyclic group containing two oxygen atoms and four carbon atoms, and an optionally substituted cyclohexyl group. wherein m1, m2, and n are each independently selected from a number that is at least 0; said L3 can comprise a peptide residue; The L4 is optionally substituted

[0401] [ka] , optionally replaced

[0402] [ka] , optionally replaced

[0403] [ka] or optionally replaced

[0404] [ka] For example, R4 may be selected from the group consisting of hydrogen and an optionally substituted C1-C6 alkyl group. For example, R5 may be selected from the group consisting of hydrogen and an optionally substituted C1-C6 alkyl group;

[0405] The L5 is optionally substituted

[0406] [ka] wherein R and R can each independently be selected from the group consisting of hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group, and an optionally substituted cycloalkylalkyl group, or R and R taken together with the atom to which they are attached can include can be selected from a number that is at least 0. For example, a cycloalkylalkyl group in this application can refer to an alkyl group substituted with a cycloalkyl group, where the cycloalkylalkyl group can be optionally substituted with another group.

[0407] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said compound can comprise the structure shown in formula (I):

[0408] [ka]

[0409] for example,

[0410] [ka]

[0411] It may be wherein R1 and R2 can each independently be selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C8 haloalkyl group, and an optionally substituted C1-C8 deuterated alkyl group; Or, R1 and R2, together with the carbon atom to which they are attached, may be an optionally substituted alicyclic group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl ... a structure selected from the group consisting of an aryl group and an optionally substituted heteroaryl group, L can be an optionally substituted linker, said L can include -L1-L2-L3-L4-L5-; Ab can be a ligand and a can be a number that is at least 0; wherein L1 is optionally substituted

[0412] [ka] may include

[0413] The L2 is optionally substituted

[0414] [ka] , optionally replaced

[0415] [ka] , optionally replaced

[0416] [ka] , optionally replaced

[0417] [ka] , optionally replaced

[0418] [ka] , optionally replaced

[0419] [ka] , optionally replaced

[0420] [ka] and optionally replaced

[0421] [ka] and

[0422] The L3 is

[0423] [ka] and

[0424] The L4 is optionally substituted

[0425] [ka] , optionally replaced

[0426] [ka] , optionally replaced

[0427] [ka] , optionally replaced

[0428] [ka] and optionally replaced

[0429] [ka] and

[0430] The L5 is optionally substituted

[0431] [ka] , optionally replaced

[0432] [ka] , optionally replaced

[0433] [ka] , optionally replaced

[0434] [ka] , optionally replaced

[0435] [ka] , optionally replaced

[0436] [ka] , optionally replaced

[0437] [ka] and optionally replaced

[0438] [ka] The structure may include a structure selected from the group consisting of:

[0439] For example, an Ab in the present application can include an antibody or an antigen-binding fragment thereof. For example, the antibody may be selected from the group consisting of a mouse antibody, a chimeric antibody, a humanized antibody, and a fully human antibody. For example, the antibody may comprise a monoclonal antibody. For example, the antibody may comprise a bispecific antibody. For example, the antigen-binding fragment may be selected from the group consisting of a Fab, a Fab', an Fv fragment, F(ab')2, F(ab)2, scFv, di-scFv, VHH, and a dAb.

[0440] For example, wherein the Ab can be selected from the group consisting of a HER2 antibody and a TROP2 antibody. The ligands described in the present application may comprise at least one CDR in the antibody heavy chain variable region VH, said CDRs may be defined according to Kabat.

[0441] In the present application, the ligand may comprise an HCDR1, which may comprise an amino acid sequence as set forth in any one of SEQ ID NOs: 1 and 11. The CDRs may be defined according to Kabat.

[0442] In the present application, the ligand may comprise an HCDR2, which may comprise an amino acid sequence as set forth in any one of SEQ ID NOs: 2 and 12. The CDRs may be defined according to Kabat.

[0443] In the present application, the ligand may comprise an HCDR3, which may comprise an amino acid sequence as set forth in any one of SEQ ID NOs: 3 and 13. The CDRs may be defined according to Kabat.

[0444] In the present application, the isolated ligand may comprise HCDR1-3, wherein the HCDR1 comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1 and 11, the HCDR2 may comprise an amino acid sequence as set forth in any one of SEQ ID NOs: 2 and 12, and the HCDR3 may comprise an amino acid sequence as set forth in any one of SEQ ID NOs: 3 and 13. The CDRs may be defined according to Kabat.

[0445] For example, the ligands described herein may comprise HCDR1-3, where HCDR1 may comprise the amino acid sequence shown in SEQ ID NO:1, HCDR2 may comprise the amino acid sequence shown in SEQ ID NO:2, and HCDR3 may comprise the amino acid sequence shown in SEQ ID NO:3. For example, the ligands described herein may have HER2 binding ability. The CDRs may be defined according to Kabat.

[0446] For example, the ligands described herein may comprise HCDR1-3, where HCDR1 may comprise the amino acid sequence shown in SEQ ID NO:11, HCDR2 may comprise the amino acid sequence shown in SEQ ID NO:12, and HCDR3 may comprise the amino acid sequence shown in SEQ ID NO:13. For example, the ligands described herein may have TROP2 binding ability. The CDRs may be defined according to Kabat.

[0447] In the present application, the ligand may comprise at least one CDR in the antibody light chain variable region VL. The CDRs described in the present application may be defined according to Kabat or according to Chothia, and the CDR sequences defined by various methods are all within the scope of protection of the present application.

[0448] In the present application, the ligand may comprise an LCDR1, which may comprise an amino acid sequence as set forth in any one of SEQ ID NOs: 4 and 14. The CDRs may be defined according to Kabat.

[0449] In the present application, the ligand may comprise an LCDR2, which may comprise the amino acid sequence shown in any one of SEQ ID NOs: 5 and 15. The CDRs may be defined according to Kabat.

[0450] In the present application, the ligand may comprise an LCDR3, and the LCDR3 may comprise an amino acid sequence as set forth in any one of SEQ ID NOs: 6 and 16. The CDRs may be defined according to Kabat.

[0451] In the present application, the isolated ligand can comprise LCDR1-3, wherein the LCDR1 comprises the amino acid sequence shown in any one of SEQ ID NOs: 4 and 14, and the LCDR2 comprises the amino acid sequence shown in any one of SEQ ID NOs: 5 and 15. 1, and said LCDR3 comprises the amino acid sequence shown in any one of SEQ ID NOs: 6 and 16. The CDRs may be defined according to Kabat.

[0452] For example, the ligands described herein may comprise LCDR1-3, where the LCDR1 may comprise the amino acid sequence shown in SEQ ID NO:4, the LCDR2 may comprise the amino acid sequence shown in SEQ ID NO:5, and the LCDR3 may comprise the amino acid sequence shown in SEQ ID NO:6. For example, the ligands described herein may have HER2 binding ability. The CDRs may be defined according to Kabat.

[0453] For example, the ligands described herein may comprise LCDR1-3, where the LCDR1 may comprise the amino acid sequence shown in SEQ ID NO:14, the LCDR2 may comprise the amino acid sequence shown in SEQ ID NO:15, and the LCDR3 may comprise the amino acid sequence shown in SEQ ID NO:16. For example, the ligands described herein may have TROP2 binding ability. The CDRs may be defined according to Kabat.

[0454] In the present application, the ligand may comprise LCDR1-3 and HCDR1-3, wherein the HCDR1 comprises an amino acid sequence as set forth in any one of SEQ ID NOs:1 and 11, the HCDR2 comprises an amino acid sequence as set forth in any one of SEQ ID NOs:2 and 12, the HCDR3 comprises an amino acid sequence as set forth in any one of SEQ ID NOs:3 and 13, the LCDR1 comprises an amino acid sequence as set forth in any one of SEQ ID NOs:4 and 14, the LCDR2 comprises an amino acid sequence as set forth in any one of SEQ ID NOs:5 and 15, and the LCDR3 comprises an amino acid sequence as set forth in any one of SEQ ID NOs:6 and 16. The CDRs may be defined according to Kabat.

[0455] For example, a ligand described in the present application may comprise LCDR1-3 and HCDR1-3, wherein said HCDR1 comprises the amino acid sequence set forth in SEQ ID NO:1, said HCDR2 comprises the amino acid sequence set forth in SEQ ID NO:2, said HCDR3 comprises the amino acid sequence set forth in SEQ ID NO:3, said LCDR1 comprises the amino acid sequence set forth in SEQ ID NO:4, said LCDR2 comprises the amino acid sequence set forth in SEQ ID NO:5, and said LCDR3 comprises the amino acid sequence set forth in SEQ ID NO:6. The CDRs may be defined according to Kabat.

[0456] For example, the ligand described in the present application may comprise LCDR1-3 and HCDR1-3, wherein said HCDR1 comprises the amino acid sequence set forth in SEQ ID NO:11, said HCDR2 comprises the amino acid sequence set forth in SEQ ID NO:12, said HCDR3 comprises the amino acid sequence set forth in SEQ ID NO:13, said LCDR1 comprises the amino acid sequence set forth in SEQ ID NO:14, said LCDR2 comprises the amino acid sequence set forth in SEQ ID NO:15, and said LCDR3 comprises the amino acid sequence set forth in SEQ ID NO:16. The CDRs may be defined according to Kabat.

[0457] In the present application, the ligand may comprise a heavy chain variable region VH, wherein the VH may comprise an amino acid sequence as set forth in any one of SEQ ID NOs:7 and 17.

[0458] In the present application, the ligand may comprise a light chain variable region VL, wherein the VL may comprise an amino acid sequence as set forth in any one of SEQ ID NOs:8 and 18.

[0459] In the present application, the ligand may comprise a light chain variable region VL and a heavy chain variable region VH, wherein the VH may comprise an amino acid sequence as set forth in any one of SEQ ID NOs:7 and 17, and the VL may comprise an amino acid sequence as set forth in any one of SEQ ID NOs:8 and 18.

[0460] For example, the ligands described herein can comprise a light chain variable region, VL, and a heavy chain variable region, VH, wherein the VH can comprise the amino acid sequence shown in SEQ ID NO:7, and the VL can comprise the amino acid sequence shown in SEQ ID NO:8. For example, the ligands described herein can have HER2 binding ability.

[0461] For example, the ligands described herein may comprise a light chain variable region, VL, and a heavy chain variable region, VH, wherein the VH may comprise the amino acid sequence shown in SEQ ID NO: 17, and the VL may comprise the amino acid sequence shown in SEQ ID NO: 18. For example, the ligands described herein may have TROP2 binding ability.

[0462] In the present application, the ligand may comprise HCDR1-3 in a heavy chain variable region VH, and the VH may comprise an amino acid sequence as shown in any one of SEQ ID NOs:7 and 17.

[0463] In the present application, the ligand may comprise LCDR1-3 in a light chain variable region VL, wherein the VL may comprise an amino acid sequence as shown in any one of SEQ ID NOs:8 and 18.

[0464] In the present application, the ligand may comprise LCDR1-3 in the light chain variable region VL and HCDR1-3 in the heavy chain variable region VH, wherein the VH may comprise an amino acid sequence as shown in any one of SEQ ID NOs:7 and 17, and the VL may comprise an amino acid sequence as shown in any one of SEQ ID NOs:8 and 18.

[0465] For example, a ligand described in the present application may comprise LCDR1-3 in a light chain variable region VL and HCDR1-3 in a heavy chain variable region VH, wherein said VH has the sequence of SEQ ID NO: The VL may comprise the amino acid sequence set forth in SEQ ID NO:7, and the VL may comprise the amino acid sequence set forth in SEQ ID NO:8. For example, the ligand described in the present application may have HER2 binding ability.

[0466] For example, a ligand described in the present application may comprise LCDR1-3 in a light chain variable region VL and HCDR1-3 in a heavy chain variable region VH, wherein said VH has the sequence of SEQ ID NO: The VL may comprise the amino acid sequence set forth in SEQ ID NO: 17, and the VL may comprise the amino acid sequence set forth in SEQ ID NO: 18. For example, the ligand described in the present application may have TROP2 binding ability.

[0467] In the present application, the ligand may comprise a heavy chain, the heavy chain being represented by SEQ ID NO: It may comprise the amino acid sequence shown in any one of SEQ ID NOs:9 and 19.

[0468] In the present application, the ligand may comprise a light chain, the light chain being represented by SEQ ID NO: It may comprise the amino acid sequence shown in any one of SEQ ID NOs:10 and 20.

[0469] In the present application, the ligand may comprise an antibody light chain and an antibody heavy chain, wherein the heavy chain may comprise an amino acid sequence as set forth in any one of SEQ ID NOs:9 and 19, and the light chain may comprise an amino acid sequence as set forth in any one of SEQ ID NOs:10 and 20.

[0470] In the present application, the ligand can include an antibody light chain and an antibody heavy chain, wherein the heavy chain can include the amino acid sequence shown in SEQ ID NO:9 and the light chain can include the amino acid sequence shown in SEQ ID NO:10.

[0471] In the present application, the ligand can include an antibody light chain and an antibody heavy chain, wherein the heavy chain can include the amino acid sequence shown in SEQ ID NO:19 and the light chain can include the amino acid sequence shown in SEQ ID NO:20.

[0472] The antibodies of the present application can be prepared using techniques well known in the art, such as hybridoma techniques, recombinant DNA techniques, phage display techniques, synthetic techniques or a combination of such techniques, or other techniques known in the art. Variants can refer to amino acid sequence mutants of antibodies, as well as covalent derivatives of native polypeptides, so long as the biological activity comparable to that of the native polypeptide is retained. The difference between the amino acid sequence mutant and the native amino acid sequence is generally that one or more amino acids in the native amino acid sequence are substituted, or one or more amino acids in the polypeptide sequence are deleted and / or inserted. Deletion mutants include fragments of the native polypeptide and N-terminal and / or C-terminal truncation mutants. Usually, the amino acid sequence mutant has at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% or more homology compared to the native sequence.

[0473] For example, here, the a can be used as the average value of the molar ratio of drug molecules to antibody molecules in an antibody-drug conjugate obtained by coupling a single antibody molecule to a drug molecule, and a can be an integer or decimal of 1 to 8, for example, a can be about 1 to about 2, about 1 to about 3, about 1 to about 4, about 1 to about 5, about 1 to about 6, about 1 to about 7, or about 1 to about 8, and m can be about 2 to about 8, about 3 to about 8, about 4 to about 8, about 5 to about 8, about 6 to about 8, about 7 to about 8, or about 1, about 2, about 3, about 4, about 5, about 6, about 7, or about 8. For example, here, the a can be measured by a method selected from the group consisting of hydrophobic chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis, and liquid phase mass spectrometry.

[0474] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said compound is

[0475] [ka] TIFF2024523422000220.tif244170TIFF2024523422000221.tif206169TIFF2024523422000222.tif227169TIFF2024523422000223.tif223169,

[0476] Here, Ab is a ligand, a is a number greater than 0, and a is a decimal or an integer. In one aspect, the present application provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said compound comprises the structure shown in formula (II): Can be done,

[0477] [ka]

[0478] for example,

[0479] [ka] It may be

[0480] wherein R1 and R2 can each independently be selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C8 haloalkyl group, and an optionally substituted C1-C8 deuterated alkyl group; or R1 and R2, taken together with the carbon atom to which they are attached, can form a structure selected from the group consisting of an optionally substituted alicyclic group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group; Lx can be a linking group.

[0481] For example, in the structure shown in formula (II), Lx is a linking group L 1x and wherein L 1x can be linked directly or indirectly to the ligand. 1x can be linked directly or indirectly to the sulfhydryl group of the Ligand. 1x is optionally replaced

[0482] [ka] For example, L in the structure shown in formula (II) can be 1x can exist in the ring-open form shown in the formula:

[0483] [ka]

[0484] For example, in the structure shown in formula (II), the Lx may further include a linker L2. For example, the L2 may include the L 1x For example, the L2 can be linked directly or indirectly to an optionally substituted -(CH2) m1 -X1-(CH2) m2 -C(O)-, optionally substituted -(CH2CH2O) n -C(O)- and optionally substituted -(CH2) p X1 may include a group selected from the group consisting of -C(O)-, an optionally substituted -C(O)-NH-, an optionally substituted aryl group, an optionally substituted heteroaryl group, any heteroalicyclic group, and an optionally substituted alicyclic group, wherein m1, m2, and n may each independently be selected from a number that is at least 0.

[0485] For example, in the structure shown in formula (II), L2 is an optionally substituted -(CH2CH2O) n For example, where n is 2, it may include -C(O)-.

[0486] For example, in the structure shown in formula (II), L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 For example, X1 can be selected from the group consisting of -O- and optionally substituted -C(O)-NH-. For example, m1 can be 2. For example, m2 can be 2.

[0487] For example, in the structure shown in formula (II), X1 can include a group selected from the group consisting of an optionally substituted aryl group and an optionally substituted heteroaryl group. For example, X1 can include an optionally substituted phenyl group. For example, X1 can include an optionally substituted pyridyl group. For example, m1 can be 0. For example, m2 can be 1.

[0488] For example, in the structure shown in formula (II), X1 can include an optionally substituted heteroalicyclic group containing two oxygen atoms.

[0489] [ka] For example, X1 can include an optionally substituted cyclohexyl group. For example, m1 can be 1. For example, m2 can be 0.

[0490] For example, in the structure shown in formula (II), L2 is an optionally substituted -(CH2) p For example, p can be 5.

[0491] For example, in the structure shown in formula (II), L2 is optionally substituted

[0492] [ka] , optionally replaced

[0493] [ka] , optionally replaced

[0494] [ka] , optionally replaced

[0495] [ka] , optionally replaced

[0496] [ka] , optionally replaced

[0497] [ka] , optionally replaced

[0498] [ka] and optionally replaced

[0499] [ka] The structure may include a structure selected from the group consisting of:

[0500] For example, in the structure shown in formula (II), the Lx may further include a linker L3. For example, the L3 may be directly or indirectly linked to the L2. For example, the L3 may include a peptide residue.

[0501] For example, the L3 can comprise a peptide residue consisting of an amino acid selected from the group consisting of phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid and glycine. For example, the L3 can comprise a peptide residue consisting of an amino acid selected from the group consisting of glycine, phenylalanine, valine and citrulline. For example, the L3 can comprise a peptide residue selected from the group consisting of -glycine-phenylalanine-glycine-(-Gly-Phe-Gly-), -glycine-glycine-phenylalanine-glycine-(-Gly-Gly-Phe-Gly-) and -valine-citrulline-(-Val-Cit-).

[0502] For example, in the structure shown in formula (II), L3 is

[0503] [ka] The structure may include a structure selected from the group consisting of:

[0504] For example, in the structure shown in formula (II), the Lx may further include a linker L4. For example, the L4 may be directly or indirectly linked to the L3.

[0505] For example, in the structure shown in formula (II), L4 is an optionally substituted -L 4a -NR4-CH2-L 4b - may contain L 4a does not exist or is 4ais optionally replaced

[0506] [ka] L 4b does not exist or is 4b is optionally replaced

[0507] [ka] wherein R4 and R5 can each independently be selected from the group consisting of hydrogen and an optionally substituted alkyl group.

[0508] For example, in the structure shown in formula (II), L4 is optionally substituted

[0509] [ka] For example, the L4 may include an optionally substituted

[0510] [ka] For example, the L4 may include an optionally substituted

[0511] [ka] For example, the L4 may include an optionally substituted

[0512] [ka] For example, R4 may be selected from the group consisting of hydrogen and an optionally substituted methyl group. For example, R5 may be selected from the group consisting of hydrogen and an optionally substituted methyl group.

[0513] For example, in the structure shown in formula (II), L4 is optionally substituted

[0514] [ka] , optionally replaced

[0515] [ka] , optionally replaced

[0516] [ka] , optionally replaced

[0517] [ka] and optionally replaced

[0518] [ka] The structure may include a structure selected from the group consisting of:

[0519] For example, in the structure shown in formula (II), the Lx may further include a linker L5. For example, the L5 may be directly or indirectly linked to the L4.

[0520] For example, in the structure shown in formula (II), L5 is optionally substituted

[0521] [ka] R6 and R7 can each independently be selected from hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group, or R6 and R7 together with the atom to which they are attached can form an optionally substituted cycloalkyl group, where v is at least 0.

[0522] For example, in the structure shown in formula (II), R6 can be hydrogen. For example, R6 can be an optionally substituted methyl group. For example, R6 can be an optionally substituted halomethyl group. For example, R6 can be a methyl group substituted by fluorine. For example, R6 can be a trifluoromethyl group. For example, R6 can be an optionally substituted cycloalkyl group. For example, R6 can be an optionally substituted cyclopropyl group. For example, in the structure shown in formula (I), R7 can be hydrogen.

[0523] For example, in the structure shown in formula (II), R6 and R7 together with the atom to which they are attached can form an optionally substituted cyclopropyl group. For example, R6 and R7 together with the atom to which they are attached can form an optionally substituted cyclobutyl group. For example, v can be 0. For example, v can be 1.

[0524] For example, in the structure shown in formula (II), L5 is optionally substituted

[0525] [ka] , optionally replaced

[0526] [ka] , optionally replaced

[0527] [ka] , optionally replaced

[0528] [ka] , optionally replaced

[0529] [ka] , optionally replaced

[0530] [ka] , optionally replaced

[0531] [ka] and optionally replaced

[0532] [ka] The structure may include a structure selected from the group consisting of:

[0533] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said compound can comprise the structure shown in formula (II):

[0534] [ka]

[0535] for example,

[0536] [ka] It may be

[0537] Here, R1 and R2 each independently represent a hydrogen atom, a deuterium atom, a halogen atom, or any optionally substituted C1-C8 alkyl groups, optionally substituted C1-C8 haloalkyl groups, and optionally substituted C1-C8 deuterated alkyl groups; or R1 and R2, taken together with the carbon atom to which they are attached, can form a structure selected from the group consisting of an optionally substituted alicyclic group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group; Lx can be an optionally substituted linking group, said Lx being 1x -L2-L3-L4-L5- may be included.

[0538] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said compound can comprise the structure shown in formula (II):

[0539] [ka]

[0540] for example,

[0541] [ka] It may be

[0542] wherein R1 and R2 can each independently be selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C8 haloalkyl group, and an optionally substituted C1-C8 deuterated alkyl group; or R1 and R2, taken together with the carbon atom to which they are attached, can form a structure selected from the group consisting of an optionally substituted alicyclic group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group; Lx can be an optionally substituted linker, said Lx being 1x -L2-L3-L4-L5- Here, the L 1x can include a linking group capable of linking to a sulfhydryl group; The L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 -C(O)-, optionally substituted -(CH2CH2O) n -C(O)- and optionally substituted -(CH2) p -C(O)-, X1 can be selected from the group consisting of -O-, an optionally substituted -C(O)-NH-, an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted heteroalicyclic group containing two oxygen atoms and four carbon atoms, and an optionally substituted cyclohexyl group, wherein m1, m2, and n can each independently be selected from a number that is at least 0; said L3 can comprise a peptide residue; The L4 is optionally substituted

[0543] [ka] , optionally replaced

[0544] [ka] , optionally replaced

[0545] [ka] or optionally replaced

[0546] [ka] For example, R4 may be selected from the group consisting of hydrogen and an optionally substituted C1-C6 alkyl group. For example, R5 may be selected from the group consisting of hydrogen and an optionally substituted C1-C6 alkyl group;

[0547] The L5 is optionally substituted

[0548] [ka] wherein R6 and R7 can each independently be selected from the group consisting of hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group, and an optionally substituted cycloalkylalkyl group, or R6 and R7 together with the atom to which they are attached can form an optionally substituted cycloalkyl group, where v can be selected from a number that is at least 0. For example, a cycloalkylalkyl group in this application can refer to an alkyl group substituted by a cycloalkyl group, where the cycloalkylalkyl group can be optionally substituted by another group.

[0549] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said compound can comprise the structure shown in formula (II):

[0550] [ka]

[0551] for example,

[0552] [ka] It may be

[0553] wherein R1 and R2 can each independently be selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C8 haloalkyl group, and an optionally substituted C1-C8 deuterated alkyl group; or R1 and R2, taken together with the carbon atom to which they are attached, can form a structure selected from the group consisting of an optionally substituted alicyclic group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group; Lx can be an optionally substituted linking group, said Lx being 1x -L2-L3-L4-L5- Here, the L 1x is optionally replaced

[0554] [ka] may include

[0555] The L2 is optionally substituted

[0556] [ka] , optionally replaced

[0557] [ka] , optionally replaced

[0558] [ka] , optionally replaced

[0559] [ka] , optionally replaced

[0560] [ka] , optionally replaced

[0561] [ka] , optionally replaced

[0562] [ka] and optionally replaced

[0563] [ka] and

[0564] The L3 is

[0565] [ka] and

[0566] The L4 is optionally substituted

[0567] [ka] , optionally replaced

[0568] [ka] , optionally replaced

[0569] [ka] , optionally replaced

[0570] [ka] and optionally replaced

[0571] [ka] and

[0572] The L5 is optionally substituted

[0573] [ka] , optionally replaced

[0574] [ka] , optionally replaced

[0575] [ka] , optionally replaced

[0576] [ka] , optionally replaced

[0577] [ka] , optionally replaced

[0578] [ka] , optionally replaced

[0579] [ka] and optionally replaced

[0580] [ka] The structure may include a structure selected from the group consisting of:

[0581] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said compound is

[0582] [ka] The structure may include a structure selected from the group consisting of: TIFF2024523422000293.tif224170TIFF2024523422000294.tif242170TIFF2024523422000295.tif214169TIFF2024523422000296.tif186169.

[0583] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said compound can comprise the structure shown in formula (III):

[0584] [ka]

[0585] for example,

[0586] [ka]

[0587] It may be Where: R1 and R2 may each independently be selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C8 haloalkyl group, and an optionally substituted C1-C8 deuterated alkyl group; or R1 and R2, taken together with the carbon atom to which they are attached, can form a structure selected from the group consisting of an optionally substituted alicyclic group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group; L can be an optionally substituted linker.

[0588] For example, in the structure shown in formula (III), the L can include a linker L1, which can be directly or indirectly linked to a ligand.

[0589] For example, in the structure shown in formula (III), L1 is optionally substituted

[0590] [ka] For example, L1 in the structure shown in formula (III) can exist in an open ring form as shown in the following formula:

[0591] [ka]

[0592] For example, in the structure shown in formula (III), L may further include a linker L2. For example, in the structure shown in formula (III), the L2 can be linked directly or indirectly to the L1.

[0593] For example, in the structure shown in formula (III), L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 -C(O)-, optionally substituted -(CH2CH2O) n -C(O)- and optionally substituted -(CH2) p may include a group selected from the group consisting of: -C(O)-; X1 can be selected from the group consisting of -O-, optionally substituted -C(O)-NH-, optionally substituted aryl groups, optionally substituted heteroaryl groups, any heteroalicyclic group, and optionally substituted alicyclic groups; Here, m1, m2, and n can each independently be selected from a number that is at least 0.

[0594] For example, in the structure shown in formula (III), L2 is an optionally substituted -(CH2CH2O) n It may contain -C(O)-. For example, in the structure shown in formula (III), where n is 2.

[0595] For example, in the structure shown in formula (III), L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 It may contain -C(O)-. For example, in the structure shown in formula (III), X1 can be selected from the group consisting of -O- and optionally substituted -C(O)-NH-.

[0596] For example, in the structure shown in formula (III), where m1 can be 2. For example, in the structure shown in formula (III), where m2 can be 2.

[0597] For example, in the structure shown in formula (III), X1 can include a group selected from the group consisting of optionally substituted aryl groups and optionally substituted heteroaryl groups.

[0598] For example, in the structure shown in formula (III), X1 can include an optionally substituted phenyl group. For example, in the structure shown in formula (III), X1 can include an optionally substituted pyridyl group.

[0599] For example, in the structure shown in formula (III), where m1 can be 0. For example, in the structure shown in formula (III), where m2 can be 1.

[0600] For example, in the structure shown in formula (III), X1 can include an optionally substituted heteroalicyclic group containing two oxygen atoms. For example, in the structure shown in formula (III), X1 is optionally substituted

[0601] [ka] may include.

[0602] For example, in the structure shown in formula (III), X1 can include an optionally substituted cyclohexyl group. For example, in the structure shown in formula (III), where m1 can be 1.

[0603] For example, in the structure shown in formula (III), where m2 can be 0. For example, in the structure shown in formula (III), L2 is an optionally substituted -(CH2) p It may contain -C(O)-.

[0604] For example, in the structure shown in formula (III), where p can be 5. For example, in the structure shown in formula (III), L2 is optionally substituted

[0605] [ka] , optionally replaced

[0606] [ka] , optionally replaced

[0607] [ka] , optionally replaced

[0608] [ka] , optionally replaced

[0609] [ka] , optionally replaced

[0610] [ka] , optionally replaced

[0611] [ka] and optionally replaced

[0612] [ka] The structure may include a structure selected from the group consisting of:

[0613] For example, in the structure shown in formula (III), L may further include a linker L3. For example, in the structure shown in formula (III), the L3 can be linked directly or indirectly to the L2.

[0614] For example, in the structure shown in formula (III), L3 can include a peptide residue. For example, in the structure shown in formula (III), L3 may contain a peptide residue consisting of an amino acid selected from the group consisting of phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid and glycine.

[0615] For example, in the structure shown in formula (III), L3 can include a peptide residue consisting of an amino acid selected from the group consisting of glycine, phenylalanine, valine, and citrulline.

[0616] For example, in the structure shown in formula (III), L3 may comprise a peptide residue selected from the group consisting of -glycine-phenylalanine-glycine-(-Gly-Phe-Gly-), -glycine-glycine-phenylalanine-glycine-(-Gly-Gly-Phe-Gly-) and -valine-citrulline-(-Val-Cit-).

[0617] For example, in the structure shown in formula (III), L3 is

[0618] [ka] The structure may include a structure selected from the group consisting of:

[0619] For example, in the structure shown in formula (III), L may further include a linker L4. For example, in the structure shown in formula (III), the L4 can be directly or indirectly linked to the L3.

[0620] For example, in the structure shown in formula (III), L4 is an optionally substituted -L4a -NR4-CH2-L 4b - may contain L 4a does not exist or is 4a is optionally replaced

[0621] [ka] may include

[0622] L 4b does not exist or is 4b is optionally replaced

[0623] [ka] may include

[0624] R4 and R5 can each independently be selected from the group consisting of hydrogen and optionally substituted alkyl groups. For example, in the structure shown in formula (III), L4 is optionally substituted

[0625] [ka] may include.

[0626] For example, in the structure shown in formula (III), L4 is optionally substituted

[0627] [ka] may include.

[0628] For example, in the structure shown in formula (III), L4 is optionally substituted

[0629] [ka] may include.

[0630] For example, in the structure shown in formula (III), L4 is optionally substituted

[0631] [ka] may include.

[0632] For example, in the structure shown in formula (III), R4 can be selected from the group consisting of hydrogen and an optionally substituted methyl group. For example, in the structure shown in formula (III), R5 can be selected from the group consisting of hydrogen and an optionally substituted methyl group.

[0633] For example, in the structure shown in formula (III), L4 is optionally substituted

[0634] [ka] , optionally replaced

[0635] [ka] , optionally replaced

[0636] [ka] , optionally replaced

[0637] [ka] and optionally replaced

[0638] [ka] The structure may include a structure selected from the group consisting of:

[0639] For example, in the structure shown in formula (III), L may further include a linker L5. For example, in the structure shown in formula (III), the L5 can be linked directly or indirectly to the L4.

[0640] For example, in the structure shown in formula (III), L5 is optionally substituted

[0641] [ka] may include

[0642] R6 and R7 can each independently be selected from the group consisting of hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group, and an optionally substituted cycloalkylalkyl group, or R6 and R7 together with the atom to which they are attached can form an optionally substituted cycloalkyl group; Here, v can be selected from a number that is at least 0.

[0643] For example, in the structure shown in formula (III), R6 can be hydrogen. For example, in the structure shown in formula (III), R6 can be an optionally substituted methyl group.

[0644] For example, in the structure shown in formula (III), R6 can be an optionally substituted halomethyl group. For example, in the structure shown in formula (III), R6 may be a methyl group substituted with fluorine.

[0645] For example, in the structure shown in formula (III), R6 can be a trifluoromethyl group. For example, in the structure shown in formula (III), R6 can be an optionally substituted cycloalkyl group.

[0646] For example, in the structure shown in formula (III), R6 can be an optionally substituted cyclopropyl group. For example, in the structure shown in formula (III), R7 can be hydrogen.

[0647] For example, in the structure shown in formula (III), R6 and R7, together with the atom to which they are attached, can form an optionally substituted cyclopropyl group.

[0648] For example, in the structure shown in formula (III), R6 and R7, together with the atom to which they are attached, can form an optionally substituted cyclobutyl group.

[0649] For example, in the structure shown in formula (III), where v can be 0. For example, in the structure shown in formula (III), where v can be 1.

[0650] For example, in the structure shown in formula (III), L5 is optionally substituted

[0651] [ka] , optionally replaced

[0652] [ka] , optionally replaced

[0653] [ka] , optionally replaced

[0654] [ka] , optionally replaced

[0655] [ka] , optionally replaced

[0656] [ka] , optionally replaced

[0657] [ka] and optionally replaced

[0658] [ka] The structure may include a structure selected from the group consisting of:

[0659] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said compound is

[0660] [ka] The structure may include a structure selected from the group consisting of: TIFF2024523422000332.tif242170 TIFF2024523422000333.tif204170 TIFF2024523422000334.tif233170 TIFF2024523422000335.tif121170.

[0661] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein the compound can comprise the structure shown in formula (L-1): Formula (L-1): -L1-L2-L3-L4-L5- Where: L1, L2, L3, L4 and L5 can each independently be a linker; wherein L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 -C(O)- and optionally substituted -(CHCHO) n may include a group selected from the group consisting of: -C(O)-; X1 can be selected from the group consisting of -O-, optionally substituted -C(O)-NH-, optionally substituted aryl groups, optionally substituted heteroaryl groups, optionally substituted heteroalicyclic groups, and optionally substituted alicyclic groups; Here, m1, m2, and n can each independently be selected from a number that is at least 0.

[0662] For example, in the structure shown in formula (L-1), L2 is an optionally substituted -(CH2CH2O) n For example, where n is 2, it may include -C(O)-.

[0663] For example, in the structure shown in formula (L-1), L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 For example, X1 can be selected from the group consisting of -O- and optionally substituted -C(O)-NH-. For example, m1 can be 2. For example, m2 can be 2.

[0664] For example, in the structure shown in formula (L-1), X1 can include a group selected from the group consisting of an optionally substituted aryl group and an optionally substituted heteroaryl group. For example, X1 can include an optionally substituted phenyl group. For example, X1 can include an optionally substituted pyridyl group. For example, m1 can be 0. For example, m2 can be 1.

[0665] For example, in the structure shown in formula (L-1), X1 can include an optionally substituted heteroalicyclic group containing two oxygen atoms.

[0666] [ka] For example, X1 can include an optionally substituted cyclohexyl group. For example, m1 can be 1. For example, m2 can be 0.

[0667] For example, in the structure represented by formula (L-1), L2 is optionally substituted

[0668] [ka] , optionally replaced

[0669] [ka] , optionally replaced

[0670] [ka] , optionally replaced

[0671] [ka] , optionally replaced

[0672] [ka] , optionally replaced

[0673] [ka] and optionally replaced

[0674] [ka] The structure may include a structure selected from the group consisting of:

[0675] For example, in the structure represented by formula (L-1), L1 is optionally substituted

[0676] [ka] For example, L1 in the structure shown in formula (L-1) can exist in an open ring form as shown in the following formula:

[0677] [ka]

[0678] For example, in the structure shown in formula (L-1), the L3 can include a peptide residue. For example, the L3 can include a peptide residue consisting of an amino acid selected from the group consisting of phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid, and glycine. For example, the L3 can include a peptide residue consisting of an amino acid selected from the group consisting of glycine, phenylalanine, valine, and citrulline. For example, the L3 can include a peptide residue selected from the group consisting of -glycine-phenylalanine-glycine-(-Gly-Phe-Gly-), -glycine-glycine-phenylalanine-glycine-(-Gly-Gly-Phe-Gly-), and -valine-citrulline-(-Val-Cit-).

[0679] For example, in the structure represented by formula (L-1), L3 is

[0680] [ka] The structure may include a structure selected from the group consisting of:

[0681] For example, in the structure shown in formula (L-1), L4 is an optionally substituted -L 4a -NR4-CH2-L 4b - may contain L 4a does not exist or L 4a is optionally replaced

[0682] [ka] L 4b does not exist or is 4b is optionally replaced

[0683] [ka] wherein R4 and R5 can each independently be selected from the group consisting of hydrogen and an optionally substituted alkyl group.

[0684] For example, in the structure represented by formula (L-1), L4 is optionally substituted

[0685] [ka] , optionally replaced

[0686] [ka] , optionally replaced

[0687] [ka] or optionally replaced

[0688] [ka] For example, R4 may be selected from the group consisting of hydrogen and an optionally substituted methyl group. For example, R5 may be selected from the group consisting of hydrogen and an optionally substituted methyl group.

[0689] For example, in the structure represented by formula (L-1), L4 is optionally substituted

[0690] [ka] , optionally replaced

[0691] [ka] , optionally replaced

[0692] [ka] , optionally replaced

[0693] [ka] and optionally replaced

[0694] [ka] The structure may include a structure selected from the group consisting of:

[0695] For example, in the structure represented by formula (L-1), L5 is optionally substituted

[0696] [ka] and L5 may include

[0697] [ka] ,for example,

[0698] [ka] wherein R1 and R2 can each independently be selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C8 haloalkyl group, and an optionally substituted C1-C8 deuterated alkyl group; or

[0699] or R1 and R2, taken together with the carbon atom to which they are attached, can form a structure selected from the group consisting of an optionally substituted alicyclic group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group; R6 and R7 can each independently be selected from the group consisting of hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group, and an optionally substituted cycloalkylalkyl group, or R6 and R7, together with the atom to which they are attached, can form an optionally substituted cycloalkyl group, where v is selected from a number that is at least 0.

[0700] For example, in the structure shown in formula (L-1), R6 can be hydrogen. For example, R6 can be an optionally substituted methyl group. For example, R6 can be an optionally substituted halomethyl group. For example, R6 can be a methyl group substituted by fluorine. For example, R6 can be a trifluoromethyl group. For example, R6 can be an optionally substituted cycloalkyl group. For example, R6 can be an optionally substituted cyclopropyl group. For example, R7 can be hydrogen. For example, R6 and R7 can be taken together with the atom to which they are attached to form an optionally substituted cyclopropyl group. For example, R6 and R7 can be taken together with the atom to which they are attached to form an optionally substituted cyclobutyl group. For example, v can be 0. For example, v can be 1.

[0701] For example, in the structure represented by formula (L-1), L5 is optionally substituted

[0702] [ka] , optionally replaced

[0703] [ka] , optionally replaced

[0704] [ka] , optionally replaced

[0705] [ka] , optionally replaced

[0706] [ka] , optionally replaced

[0707] [ka] , optionally replaced

[0708] [ka] and optionally replaced

[0709] [ka] The structure may include a structure selected from the group consisting of:

[0710] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein the compound can comprise the structure shown in formula (L-1): Formula (L-1): -L1-L2-L3-L4-L5- Where: wherein L1 can comprise a linker linked to a sulfhydryl group; The L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 -C(O)- and optionally substituted -(CHCHO) n -C(O)-, X1 can be selected from the group consisting of -O-, an optionally substituted -C(O)-NH-, an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted heteroalicyclic group containing two oxygen atoms and four carbon atoms, and an optionally substituted cyclohexyl group, wherein m1, m2, and n can each independently be selected from a number that is at least 0; said L3 can comprise a peptide residue; The L4 is optionally substituted

[0711] [ka] , optionally replaced

[0712] [ka] , optionally replaced

[0713] [ka] or optionally replaced

[0714] [ka] For example, R4 may be selected from the group consisting of hydrogen and an optionally substituted C1-C6 alkyl group. For example, R5 may be selected from the group consisting of hydrogen and an optionally substituted C1-C6 alkyl group;

[0715] The L5 is optionally substituted

[0716] [ka] and L5 may include

[0717] [ka] ,for example,

[0718] [ka] wherein R1 and R2 can each independently be selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C8 haloalkyl group, and an optionally substituted C1-C8 deuterated alkyl group; or

[0719] Or, R1 and R2, together with the carbon atom to which they are attached, may be an optionally substituted alicyclic group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl ... a structure selected from the group consisting of an aryl group and an optionally substituted heteroaryl group, R6 and R7 can each independently be selected from the group consisting of hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group, and an optionally substituted cycloalkylalkyl group, or R6 and R7 together with the atom to which they are attached can form an optionally substituted cycloalkyl group, where v can be selected from a number that is at least 0. For example, a cycloalkylalkyl group in this application can refer to an alkyl group substituted by a cycloalkyl group, where the cycloalkylalkyl group can be optionally substituted by another group.

[0720] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein the compound can comprise the structure shown in formula (L-1): Formula (L-1): -L1-L2-L3-L4-L5- wherein L1 is optionally substituted

[0721] [ka] may include

[0722] The L2 is optionally substituted

[0723] [ka] , optionally replaced

[0724] [ka] , optionally replaced

[0725] [ka] , optionally replaced

[0726] [ka] , optionally replaced

[0727] [ka] , optionally replaced

[0728] [ka] and optionally replaced

[0729] [ka] and

[0730] The L3 is

[0731] [ka] and

[0732] The L4 is optionally substituted

[0733] [ka] , optionally replaced

[0734] [ka] , optionally replaced

[0735] [ka] , optionally replaced

[0736] [ka] and optionally replaced

[0737] [ka] and

[0738] The L5 is optionally substituted

[0739] [ka] , optionally replaced

[0740] [ka] , optionally replaced

[0741] [ka] , optionally replaced

[0742] [ka] , optionally replaced

[0743] [ka] , optionally replaced

[0744] [ka] , optionally replaced

[0745] [ka] and optionally replaced

[0746] [ka] wherein L5 comprises a structure selected from the group consisting of:

[0747] [ka] ,for example,

[0748] [ka] wherein R1 and R2 can each independently be selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C8 haloalkyl group, and an optionally substituted C1-C8 deuterated alkyl group; or

[0749] Alternatively, R1 and R2, together with the carbon atoms to which they are attached, can form a structure selected from the group consisting of an optionally substituted alicyclic group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group.

[0750] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said compound is

[0751] [ka] TIFF2024523422000401.tif130165.

[0752] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein the compound can comprise a structure as shown in formula (L-2): Formula (L-2): -L1-L2-L3-L4-L5- wherein L1, L2, L3, L4, and L5 can each independently be a linker; L4 is an optionally substituted -L 4a -NR4-CH2-L 4b - may contain L 4a does not exist or is 4ais optionally replaced

[0753] [ka] may include

[0754] L 4b does not exist or is 4b is optionally replaced

[0755] [ka] L 4a and L 4b may not exist at the same time,

[0756] R4 and R5 can each independently be selected from the group consisting of hydrogen and optionally substituted alkyl groups. For example, in the structure represented by formula (L-2), L4 is optionally substituted

[0757] [ka] , optionally replaced

[0758] [ka] , or optionally replaced

[0759] [ka] For example, R4 may be selected from the group consisting of hydrogen and an optionally substituted methyl group. For example, R5 may be selected from the group consisting of hydrogen and an optionally substituted methyl group.

[0760] For example, in the structure represented by formula (L-2), L4 is optionally substituted

[0761] [ka] , optionally replaced

[0762] [ka] , optionally replaced

[0763] [ka] and optionally replaced

[0764] [ka] The structure may include a structure selected from the group consisting of:

[0765] For example, in the structure represented by formula (L-2), L1 is optionally substituted

[0766] [ka] For example, L1 in the structure shown in formula (L-2) can exist in an open ring form as shown in the following formula:

[0767] [ka]

[0768] For example, in the structure shown in formula (L-2), L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 -C(O)-, optionally substituted -(CH2CH2O) n -C(O)- and optionally substituted -(CH2) pX1 may include a group selected from the group consisting of -C(O)-, an optionally substituted -C(O)-NH-, an optionally substituted aryl group, an optionally substituted heteroaryl group, any heteroalicyclic group, and an optionally substituted alicyclic group, wherein m1, m2, and n may each independently be selected from a number that is at least 0.

[0769] For example, in the structure shown in formula (L-2), L2 is an optionally substituted -(CH2CH2O) n For example, n can be 2.

[0770] For example, in the structure shown in formula (L-2), L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 For example, X1 can include -C(O)-. For example, X1 can be selected from the group consisting of -O- and optionally substituted -C(O)-NH-. For example, m1 can be 2. For example, m2 can be 2. For example, X1 can include a group selected from the group consisting of an optionally substituted aryl group and an optionally substituted heteroaryl group. For example, X1 can include an optionally substituted phenyl group. For example, X1 can include an optionally substituted pyridyl group. For example, m1 can be 0. For example, m2 can be 1. For example, X1 can include a heteroalicyclic group containing two optionally substituted oxygen atoms. For example, X1 can include an optionally substituted

[0771] [ka] For example, X1 can include an optionally substituted cyclohexyl group. For example, m1 can be 1. For example, m2 can be 0. For example, L2 can include an optionally substituted -(CH2) p For example, p can be 5.

[0772] For example, in the structure shown in formula (L-2), L2 is optionally substituted

[0773] [ka] , optionally replaced

[0774] [ka] , optionally replaced

[0775] [ka] , optionally replaced

[0776] [ka] , optionally replaced

[0777] [ka] , optionally replaced

[0778] [ka] , optionally replaced

[0779] [ka] and optionally replaced

[0780] [ka] The structure may include a structure selected from the group consisting of:

[0781] For example, in the structure shown in formula (L-2), the L3 can include a peptide residue. For example, the L3 can include a peptide residue consisting of an amino acid selected from the group consisting of phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid, and glycine. For example, the L3 can include a peptide residue consisting of an amino acid selected from the group consisting of glycine, phenylalanine, valine, and citrulline. For example, the L3 can include a peptide residue selected from the group consisting of -glycine-phenylalanine-glycine-(-Gly-Phe-Gly-), -glycine-glycine-phenylalanine-glycine-(-Gly-Gly-Phe-Gly-), and -valine-citrulline-(-Val-Cit-).

[0782] For example, in the structure represented by formula (L-2), L3 is

[0783] [ka] The structure may include a structure selected from the group consisting of:

[0784] For example, in the structure represented by formula (L-2), L5 is optionally substituted

[0785] [ka] and L5 may include

[0786] [ka] ,for example,

[0787] [ka] wherein R1 and R2 can each independently be selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C8 haloalkyl group, and an optionally substituted C1-C8 deuterated alkyl group; or

[0788] Alternatively, R1 and R2 can be taken together with the carbon atom to which they are attached to form a structure selected from the group consisting of an optionally substituted alicyclic group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group, and R6 and R7 can each independently be selected from the group consisting of hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group and an optionally substituted cycloalkylalkyl group, or R6 and R7 can be taken together with the atom to which they are attached to form an optionally substituted cycloalkyl group, where v is selected from a number that is at least 0.

[0789] For example, in the structure shown in formula (L-2), R6 can be hydrogen. For example, R6 can be an optionally substituted methyl group. For example, R6 can be an optionally substituted halomethyl group. For example, R6 can be a methyl group substituted by fluorine. For example, R6 can be a trifluoromethyl group. For example, R6 can be an optionally substituted cycloalkyl group. For example, R6 can be an optionally substituted cyclopropyl group. For example, R7 can be hydrogen. For example, R6 and R7 together with the atom to which they are attached can form an optionally substituted cyclopropyl group. For example, R6 and R7 together with the atom to which they are attached can form an optionally substituted cyclobutyl group. For example, v can be 0. For example, v can be 1.

[0790] For example, in the structure represented by formula (L-2), L5 is optionally substituted

[0791] [ka] , optionally replaced

[0792] [ka] , optionally replaced

[0793] [ka] , optionally replaced

[0794] [ka] , optionally replaced

[0795] [ka] , optionally replaced

[0796] [ka] , optionally replaced

[0797] [ka] and optionally replaced

[0798] [ka] The structure may include a structure selected from the group consisting of:

[0799] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein the compound can comprise a structure as shown in formula (L-2): Formula (L-2): -L1-L2-L3-L4-L5- wherein L1 can comprise a linker linked to a sulfhydryl group; The L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 -C(O)-, optionally substituted -(CH2CH2O) n -C(O)- and optionally substituted -(CH2) p -C(O)-, X1 can be selected from the group consisting of -O-, an optionally substituted -C(O)-NH-, an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted heteroalicyclic group containing two oxygen atoms and four carbon atoms, and an optionally substituted cyclohexyl group, wherein m1, m2, and n can each independently be selected from a number that is at least 0; said L3 can comprise a peptide residue; The L4 is optionally substituted

[0800] [ka] , optionally replaced

[0801] [ka] or optionally replaced

[0802] [ka] For example, R4 may be selected from the group consisting of hydrogen and an optionally substituted C1-C6 alkyl group. For example, R5 may be selected from the group consisting of hydrogen and an optionally substituted C1-C6 alkyl group;

[0803] The L5 is optionally substituted

[0804] [ka] and L5 may include

[0805] [ka] ,for example,

[0806] [ka] wherein R1 and R2 can each independently be selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C8 haloalkyl group, and an optionally substituted C1-C8 deuterated alkyl group; or

[0807] Alternatively, R1 and R2 together with the carbon atoms to which they are attached can form a structure selected from the group consisting of an optionally substituted alicyclic group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group, and R6 and R7 are each independently selected from the group consisting of hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group, and an optionally substituted cycloalkylalkyl group. or R6 and R7 together with the atom to which they are attached can form an optionally substituted cycloalkyl group, where v can be selected from a number that is at least 0. For example, a cycloalkylalkyl group in this application can refer to an alkyl group substituted with a cycloalkyl group, where the cycloalkylalkyl group can be optionally substituted with another group.

[0808] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein the compound can comprise a structure as shown in formula (L-2): Formula (L-2): -L1-L2-L3-L4-L5- wherein L1 is optionally substituted

[0809] [ka] may include

[0810] The L2 is optionally substituted

[0811] [ka] , optionally replaced

[0812] [ka] , optionally replaced

[0813] [ka] , optionally replaced

[0814] [ka] , optionally replaced

[0815] [ka] , optionally replaced

[0816] [ka] , optionally replaced

[0817] [ka] and optionally replaced

[0818] [ka] and

[0819] The L3 is

[0820] [ka] and

[0821] The L4 is optionally substituted

[0822] [ka] , optionally replaced

[0823] [ka] , optionally replaced

[0824] [ka] and optionally replaced

[0825] [ka] and

[0826] The L5 is optionally substituted

[0827] [ka] , optionally replaced

[0828] [ka] , optionally replaced

[0829] [ka] , optionally replaced

[0830] [ka] , optionally replaced

[0831] [ka] , optionally replaced

[0832] [ka] , optionally replaced

[0833] [ka] and optionally replaced

[0834] [ka] wherein L5 comprises a structure selected from the group consisting of:

[0835] [ka] ,for example,

[0836] [ka] wherein R1 and R2 can each independently be selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C8 haloalkyl group, and an optionally substituted C1-C8 deuterated alkyl group; or

[0837] Alternatively, R1 and R2, together with the carbon atoms to which they are attached, can form a structure selected from the group consisting of an optionally substituted alicyclic group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group.

[0838] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said compound is

[0839] [ka] The structure may include a structure selected from the group consisting of:

[0840] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein the compound can include a structure as shown in formula (Lx-1): Formula (Lx-1):L1x -L2-L3-L4-L5- Where: L 1x can include a linking group; L2, L3, L4 and L5 can each independently be a linker; wherein L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 -C(O)- and optionally substituted -(CHCHO) n may include a group selected from the group consisting of: -C(O)-; X1 can be selected from the group consisting of -O-, optionally substituted -C(O)-NH-, optionally substituted aryl groups, optionally substituted heteroaryl groups, optionally substituted heteroalicyclic groups, and optionally substituted alicyclic groups; Here, m1, m2, and n can each independently be selected from a number that is at least 0.

[0841] For example, in the structure represented by formula (Lx-1), L2 is an optionally substituted -(CH2CH2O) n It may contain -C(O)-. For example, in the structure shown in formula (Lx-1), n ​​can be 2.

[0842] For example, in the structure represented by formula (Lx-1), L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 It may contain -C(O)-.

[0843] For example, in the structure shown in formula (Lx-1), X1 can be selected from the group consisting of -O- and optionally substituted -C(O)-NH-.

[0844] For example, in the structure shown in formula (Lx-1), m1 can be 2. For example, in the structure shown in formula (Lx-1), m2 can be 2.

[0845] For example, in the structure shown in formula (Lx-1), X1 can include a group selected from the group consisting of an optionally substituted aryl group and an optionally substituted heteroaryl group.

[0846] For example, in the structure shown in formula (Lx-1), X1 can include an optionally substituted phenyl group. For example, in the structure shown in formula (Lx-1), X1 can include an optionally substituted pyridyl group.

[0847] For example, in the structure shown in formula (Lx-1), m1 can be 0. For example, in the structure shown in formula (Lx-1), m2 can be 1.

[0848] For example, in the structure shown in formula (Lx-1), X1 can include an optionally substituted heteroalicyclic group containing two oxygen atoms. For example, in the structure shown in formula (Lx-1), X1 is an optionally substituted

[0849] [ka] may include.

[0850] For example, in the structure shown in formula (Lx-1), X1 can include an optionally substituted cyclohexyl group. For example, in the structure shown in formula (Lx-1), m1 can be 1.

[0851] For example, in the structure shown in formula (Lx-1), m2 can be 0. For example, in the structure represented by formula (Lx-1), L2 is optionally substituted

[0852] [ka] , optionally replaced

[0853] [ka] , optionally replaced

[0854] [ka] , optionally replaced

[0855] [ka] , optionally replaced

[0856] [ka] , optionally replaced

[0857] [ka] and optionally replaced

[0858] [ka] The structure may include a structure selected from the group consisting of:

[0859] For example, in the structure represented by formula (Lx-1), 1x is optionally replaced

[0860] [ka] For example, L in the structure shown in formula (Lx-1) can be 1x can exist in the ring-open form shown in the formula:

[0861] [ka]

[0862] For example, in the structure shown in formula (Lx-1), L3 can contain a peptide residue. For example, in the structure shown in formula (Lx-1), L3 is selected from the group consisting of phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid, and glycine. The peptide may comprise a peptide residue consisting of amino acids selected from the group consisting of 1 to 3 amino acids.

[0863] For example, in the structure shown in formula (Lx-1), L3 can contain a peptide residue consisting of an amino acid selected from the group consisting of glycine, phenylalanine, valine, and citrulline.

[0864] For example, in the structure shown in formula (Lx-1), L3 may contain a peptide residue selected from the group consisting of -glycine-phenylalanine-glycine-(-Gly-Phe-Gly-), -glycine-glycine-phenylalanine-glycine-(-Gly-Gly-Phe-Gly-) and -valine-citrulline-(-Val-Cit-).

[0865] For example, in the structure represented by formula (Lx-1), L3 is

[0866] [ka] The structure may include a structure selected from the group consisting of:

[0867] For example, in the structure represented by formula (Lx-1), L4 is an optionally substituted -L 4a -NR4-CH2-L 4b - may contain L 4adoes not exist or is 4a is optionally replaced

[0868] [ka] may include

[0869] L 4b does not exist or is 4b is optionally replaced

[0870] [ka] may include

[0871] R4 and R5 can each independently be selected from the group consisting of hydrogen and optionally substituted alkyl groups. For example, in the structure represented by formula (Lx-1), L4 is optionally substituted

[0872] [ka] may include.

[0873] For example, in the structure represented by formula (Lx-1), L4 is optionally substituted

[0874] [ka] may include.

[0875] For example, in the structure represented by formula (Lx-1), L4 is optionally substituted

[0876] [ka] may include.

[0877] For example, in the structure represented by formula (Lx-1), L4 is optionally substituted

[0878] [ka] may include.

[0879] For example, in the structure shown in formula (Lx-1), R4 can be selected from the group consisting of hydrogen and an optionally substituted methyl group. For example, in the structure shown in formula (Lx-1), R5 can be selected from the group consisting of hydrogen and an optionally substituted methyl group.

[0880] For example, in the structure represented by formula (Lx-1), L4 is optionally substituted

[0881] [ka] , optionally replaced

[0882] [ka] , optionally replaced

[0883] [ka] , optionally replaced

[0884] [ka] and optionally replaced

[0885] [ka] The structure may include a structure selected from the group consisting of:

[0886] For example, in the structure represented by formula (Lx-1), L5 is optionally substituted

[0887] [ka] and L5 may include

[0888] [ka] ,for example,

[0889] [ka] wherein R1 and R2 can each independently be selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C8 haloalkyl group, and an optionally substituted C1-C8 deuterated alkyl group; or

[0890] or R1 and R2, taken together with the carbon atom to which they are attached, can form a structure selected from the group consisting of an optionally substituted alicyclic group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group; R6 and R7 can each independently be selected from the group consisting of hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group, and an optionally substituted cycloalkylalkyl group, or R6 and R7 together with the atom to which they are attached can form an optionally substituted cycloalkyl group; Here, v can be selected from a number that is at least 0.

[0891] For example, in the structure shown in formula (Lx-1), R6 can be hydrogen. For example, in the structure represented by formula (Lx-1), R6 is optionally substituted It may be a methyl group.

[0892] For example, in the structure shown in formula (Lx-1), R6 can be an optionally substituted halomethyl group. For example, in the structure represented by formula (Lx-1), R6 may be a methyl group substituted with fluorine.

[0893] For example, in the structure shown in formula (Lx-1), R6 can be a trifluoromethyl group. For example, in the structure shown in formula (Lx-1), R6 can be an optionally substituted cycloalkyl group.

[0894] For example, in the structure shown in formula (Lx-1), R6 can be an optionally substituted cyclopropyl group. For example, in the structure shown in formula (Lx-1), R7 can be hydrogen.

[0895] For example, in the structure shown in formula (Lx-1), R6 and R7, together with the atom to which they are attached, can form an optionally substituted cyclopropyl group.

[0896] For example, in the structure shown in formula (Lx-1), R6 and R7, together with the atom to which they are attached, can form an optionally substituted cyclobutyl group.

[0897] For example, in the structure shown in formula (Lx-1), v can be 0. For example, in the structure shown in formula (Lx-1), where v can be 1.

[0898] For example, in the structure represented by formula (Lx-1), L5 is optionally substituted

[0899] [ka] , optionally replaced

[0900] [ka] , optionally replaced

[0901] [ka] , optionally replaced

[0902] [ka] , optionally replaced

[0903] [ka] , optionally replaced

[0904] [ka] , optionally replaced

[0905] [ka] and optionally replaced

[0906] [ka] The structure may include a structure selected from the group consisting of:

[0907] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said compound is

[0908] [ka] The structure may include a structure selected from the group consisting of: TIFF2024523422000499.tif107148.

[0909] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein the compound can include a structure as shown in formula (Lx-2): Formula (Lx-2):L 1x -L2-L3-L4-L5- Here, L 1x can include a linking group; L2, L3, L4 and L5 can each independently be a linker; L4 is an optionally substituted -L 4a -NR4-CH2-L 4b - may contain L 4a does not exist or is 4a is optionally replaced

[0910] [ka] may include

[0911] L 4b does not exist or is 4b is optionally replaced

[0912] [ka] L 4a and L 4b may not exist at the same time,

[0913] R4 and R5 can each independently be selected from the group consisting of hydrogen and optionally substituted alkyl groups. For example, in the structure represented by formula (Lx-2), L4 is optionally substituted

[0914] [ka] Includes.

[0915] For example, in the structure represented by formula (Lx-2), L4 is optionally substituted

[0916] [ka] Includes.

[0917] For example, in the structure represented by formula (Lx-2), L4 is optionally substituted

[0918] [ka] may include.

[0919] For example, in the structure shown in formula (Lx-2), R4 can be selected from the group consisting of hydrogen and an optionally substituted methyl group. For example, in the structure shown in formula (Lx-2), R5 can be selected from the group consisting of hydrogen and an optionally substituted methyl group.

[0920] For example, in the structure represented by formula (Lx-2), L4 is optionally substituted

[0921] [ka] , optionally replaced

[0922] [ka] , optionally replaced

[0923] [ka] and optionally replaced

[0924] [ka] The structure may include a structure selected from the group consisting of:

[0925] For example, in the structure represented by formula (Lx-2), 1x is optionally replaced

[0926] [ka] For example, L in the structure shown in formula (Lx-2) can be 1x can exist in the ring-open form shown in the formula:

[0927] [ka]

[0928] For example, in the structure shown in formula (Lx-2), L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 -C(O)-, optionally substituted -(CH2CH2O) n -C(O)- and optionally substituted -(CH2) p may include a group selected from the group consisting of: -C(O)-; X1 is selected from the group consisting of -O-, optionally substituted -C(O)-NH-, optionally substituted aryl groups, optionally substituted heteroaryl groups, any heteroalicyclic group, and optionally substituted alicyclic groups; Here, m1, m2, and n can each independently be selected from a number that is at least 0.

[0929] For example, in the structure shown in formula (Lx-2), L2 is an optionally substituted -(CH2CH2O) n It may contain -C(O)-. For example, in the structure shown in formula (Lx-2), n can be 2.

[0930] For example, in the structure shown in formula (Lx-2), L2 is an optionally substituted -(CH2) m1 -X1-(CH2) m2 It may contain -C(O)-.

[0931] For example, in the structure shown in formula (Lx-2), X1 can be selected from the group consisting of -O- and optionally substituted -C(O)-NH-.

[0932] For example, in the structure shown in formula (Lx-2), m1 can be 2. For example, in the structure shown in formula (Lx-2), m2 can be 2.

[0933] For example, in the structure shown in formula (Lx-2), X1 can include a group selected from the group consisting of an optionally substituted aryl group and an optionally substituted heteroaryl group.

[0934] For example, in the structure shown in formula (Lx-2), X1 can include an optionally substituted phenyl group. For example, in the structure shown in formula (Lx-2), X1 can include an optionally substituted pyridyl group.

[0935] For example, in the structure shown in formula (Lx-2), m1 can be 0. For example, in the structure shown in formula (Lx-2), m2 can be 1.

[0936] For example, in the structure shown in formula (Lx-2), X1 can include an optionally substituted heteroalicyclic group containing two oxygen atoms. For example, in the structure shown in formula (Lx-2), X1 is an optionally substituted

[0937] [ka] may include.

[0938] For example, in the structure shown in formula (Lx-2), X1 can include an optionally substituted cyclohexyl group. For example, in the structure shown in formula (Lx-2), m1 can be 1.

[0939] For example, in the structure shown in formula (Lx-2), m2 can be 0. For example, in the structure shown in formula (Lx-2), L2 is an optionally substituted -(CH2) p It may contain -C(O)-.

[0940] For example, in the structure shown in formula (Lx-2), p can be 5. For example, in the structure represented by formula (Lx-2), L2 is optionally substituted

[0941] [ka] , optionally replaced

[0942] [ka] , optionally replaced

[0943] [ka] , optionally replaced

[0944] [ka] , optionally replaced

[0945] [ka] , optionally replaced

[0946] [ka] , optionally replaced

[0947] [ka] and optionally replaced

[0948] [ka] The structure may include a structure selected from the group consisting of:

[0949] For example, in the structure shown in formula (Lx-2), L3 can contain a peptide residue. For example, in the structure shown in formula (Lx-2), L3 may contain a peptide residue consisting of an amino acid selected from the group consisting of phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid and glycine.

[0950] For example, in the structure shown in formula (Lx-2), L3 can contain a peptide residue consisting of an amino acid selected from the group consisting of glycine, phenylalanine, valine, and citrulline.

[0951] For example, in the structure shown in formula (Lx-2), L3 may contain a peptide residue selected from the group consisting of -glycine-phenylalanine-glycine-(-Gly-Phe-Gly-), -glycine-glycine-phenylalanine-glycine-(-Gly-Gly-Phe-Gly-) and -valine-citrulline-(-Val-Cit-).

[0952] For example, in the structure represented by formula (Lx-2), L3 is

[0953] [ka] The structure may include a structure selected from the group consisting of:

[0954] For example, in the structure represented by formula (Lx-2), L5 is optionally substituted

[0955] [ka] and L5 may include

[0956] [ka] ,for example,

[0957] [ka] wherein R1 and R2 can each independently be selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C8 haloalkyl group, and an optionally substituted C1-C8 deuterated alkyl group; or

[0958] or R1 and R2, taken together with the carbon atom to which they are attached, can form a structure selected from the group consisting of an optionally substituted alicyclic group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group; R6 and R7 can each independently be selected from the group consisting of hydrogen, deuterium, an optionally substituted alkyl group, an optionally substituted haloalkyl group, an optionally substituted cycloalkyl group, and an optionally substituted cycloalkylalkyl group, or R6 and R7 together with the atom to which they are attached can form an optionally substituted cycloalkyl group; Here, v can be selected from a number that is at least 0.

[0959] For example, in the structure shown in formula (Lx-2), R6 can be hydrogen. For example, in the structure shown in formula (Lx-2), R6 may be an optionally substituted methyl group.

[0960] For example, in the structure shown in formula (Lx-2), R6 can be an optionally substituted halomethyl group. For example, in the structure represented by formula (Lx-2), R6 may be a methyl group substituted with fluorine.

[0961] For example, in the structure shown in formula (Lx-2), R6 can be a trifluoromethyl group. For example, in the structure shown in formula (Lx-2), R6 can be an optionally substituted cycloalkyl group.

[0962] For example, in the structure shown in formula (Lx-2), R6 can be an optionally substituted cyclopropyl group. For example, in the structure shown in formula (Lx-2), R7 can be hydrogen.

[0963] For example, in the structure shown in formula (Lx-2), R6 and R7, together with the atom to which they are attached, can form an optionally substituted cyclopropyl group.

[0964] For example, in the structure shown in formula (Lx-2), R6 and R7, together with the atom to which they are attached, can form an optionally substituted cyclobutyl group.

[0965] For example, in the structure shown in formula (Lx-2), v can be 0. For example, in the structure shown in formula (Lx-2), where v can be 1.

[0966] For example, in the structure represented by formula (Lx-2), L5 is optionally substituted

[0967] [ka] , optionally replaced

[0968] [ka] , optionally replaced

[0969] [ka] , optionally replaced

[0970] [ka] , optionally replaced

[0971] [ka] , optionally replaced

[0972] [ka] , optionally replaced

[0973] [ka] and optionally replaced

[0974] [ka] The structure may include a structure selected from the group consisting of:

[0975] In another aspect, the present application further provides a compound or a tautomer, mesomeric, ceramiric, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, wherein said compound is

[0976] [ka] The structure includes a structure selected from the group consisting of:

[0977] Pharmaceutical Compositions In addition to the active compound, the pharmaceutical compositions described in this application may contain one or more adjuvants, which may be selected from the group of ingredients such as fillers (diluents), binders, wetting agents, disintegrants and excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0978] The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as, for example, tablets, sugar-coated tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups. The oral administration composition may be prepared by any method known in the art for preparing pharmaceutical compositions, and the composition may include a binder, a filler, a lubricant, a disintegrant, or a pharma- ceutically acceptable wetting agent, and the composition may include one or more ingredients selected from the group consisting of sweeteners, flavorings, colorings, and preservatives. Aqueous suspensions can contain the active substance and an aqueous suspension excipient that is appropriately prepared for mixing. Aqueous suspensions can also contain one or more preservatives, such as one or more coloring agents, one or more flavoring agents, and one or more sweetening agents. Oily suspensions can be prepared by suspending the active substance in vegetable oil. Oily suspensions can contain a thickening agent. The above-mentioned sweetening agents and flavoring agents can also be added.

[0979] The pharmaceutical compositions may also be provided in the form of dispersible powders and granules for preparing an aqueous suspension by adding water and one or more of dispersing agents, wetting agents, suspending agents or preservatives. Other excipients such as sweeteners, flavorings and colorings may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid. The pharmaceutical compositions of the present application may also be in the form of oil-in-water emulsions.

[0980] The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Acceptable solvents or solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lentil. The oil solution can then be added to a mixture of water and glycerol and processed to form a microemulsion. The injectable solution or microemulsion can be injected into the patient's bloodstream by localized bolus injection. Alternatively, the solution and microemulsion can be administered in a manner that maintains a constant circulating concentration of the compound of the present application. In order to maintain such a constant concentration, a continuous intravenous drug delivery device can be used. For example, the device can be an intravenous pump.

[0981] The pharmaceutical compositions may be in the form of a sterile injection aqueous or oleaginous suspension for intramuscular and subcutaneous administration. Suitable dispersing or wetting agents and suspending agents, as described hereinabove, may be used in accordance with the known art. The suspension can be prepared using. The sterile injectable preparation can also be a sterile injectable solution or suspension prepared in a non-toxic diluent or solvent that is parenterally acceptable. Alternatively, sterile fixed oils can be conveniently used as a solvent or suspending medium.

[0982] The compounds of the present application can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid in the rectum and dissolves in the rectum to release the drug. Such materials include cocoa butter, glycerol gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.

[0983] As is well known to those skilled in the art, the dosage of a drug depends on various factors, including but not limited to the activity of the specific compound used, the age of the patient, the weight of the patient, the health condition of the patient, the behavior of the patient, the diet, the administration time, the administration method, the excretion rate, the combination of drugs, etc., and further, the optimal treatment method, such as the treatment mode, the compound described in the present application or its tautomers, mesomers, ceramides, enantiomers, diastereomers, or mixture forms thereof, or its pharmaceutically acceptable salts, and / or the daily dose of the compound or its tautomers, mesomers, ceramides, enantiomers, diastereomers, or mixture forms thereof, or its pharmaceutically acceptable salts, or the type of pharmaceutically acceptable salts, can be verified according to conventional treatment plans.

[0984] Preventive and / or therapeutic methods The present application provides the application of the compounds of the present application or their tautomers, mesomers, ceramides, enantiomers, diastereomers, or mixture forms thereof, or pharma- ceutically acceptable salts thereof and / or pharmaceutical compositions of the present application in the preparation of a drug, and the drug of the present application can be used to treat and / or prevent a tumor. For example, the tumors described in the present application can be selected from tumors associated with the expression of the targets of HER2 and TROP2. For example, the tumors associated with the expression of the targets described in the present application can include tumors with high expression of the targets and / or tumors positive for the targets. For example, the tumors described in the present application can include solid tumors and / or hematological tumors. For example, the tumors described in the present application can be selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, bladder cancer, colorectal cancer, endometrial cancer, kidney cancer, lung cancer, pancreatic cancer, prostate cancer, and thyroid cancer. For example, the tumor described in the present application can be selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, endometrial cancer, urothelial cancer, lung cancer, prostate cancer, colorectal cancer, gastric cancer, esophageal cancer, bladder cancer, kidney cancer, pancreatic cancer, thyroid cancer and head and neck cancer.

[0985] The present application provides a compound of the present application or a tautomer, mesomeric, ceraminic, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt thereof, and / or a pharmaceutical composition of the present application, which can be used to treat and / or prevent tumors. For example, the tumor described in the present application can be selected from tumors associated with expression of the targets of HER2 and TROP2. For example, the tumor associated with expression of the targets described in the present application can include tumors with high expression of the targets and / or tumors positive for the targets. For example, the tumor described in the present application can include solid tumors and / or hematological tumors. For example, the tumor described in the present application can be selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, bladder cancer, colorectal cancer, endometrial cancer, kidney cancer, lung cancer, pancreatic cancer, prostate cancer, and thyroid cancer. For example, the tumor described in the present application can be selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, endometrial cancer, urothelial cancer, lung cancer, prostate cancer, colorectal cancer, gastric cancer, esophageal cancer, bladder cancer, kidney cancer, pancreatic cancer, thyroid cancer and head and neck cancer.

[0986] The present application provides a method for treating and / or preventing a tumor, comprising administering to a subject in need thereof a compound of the present application or a tautomer, mesomeric, ceraminic, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt thereof, and / or a pharmaceutical composition of the present application. For example, the tumor described in the present application can be selected from tumors associated with expression of the targets of HER2 and TROP2. For example, the tumor associated with expression of the targets described in the present application can include tumors with high expression of the targets and / or tumors positive for the targets. For example, the tumor described in the present application can include solid tumors and / or hematological tumors. For example, the tumor described in the present application can be selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, bladder cancer, colorectal cancer, endometrial cancer, kidney cancer, lung cancer, pancreatic cancer, prostate cancer, and thyroid cancer. For example, the tumor described in the present application can be selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, endometrial cancer, urothelial cancer, lung cancer, prostate cancer, colorectal cancer, gastric cancer, esophageal cancer, bladder cancer, kidney cancer, pancreatic cancer, thyroid cancer and head and neck cancer.

[0987] Without intending to be limited by any theory, the following examples are only intended to illustrate the compounds, preparation methods, and uses of the present application, and are not intended to limit the scope of the present invention.

[0988] Working Example Example 1 Example 1.1

[0989] [ka] TIFF2024523422000534.tif240149

[0990] Phase 1 Compound 1a (50.00 g, 135.90 mmol) and 2-hydroxyacetate benzyl (45.00 g, 271.70 mmol) are added in a 1L three-necked bottle in sequence, and after replacing with nitrogen gas, anhydrous tetrahydrofuran (500 mL) is added. The reaction system is placed in an ice bath, anhydrous p-toluenesulfonic acid (2.30 g, 13.40 mmol) is added, and the reaction is continued for 2 hours while stirring under the ice bath. Water (1 L) and ethyl acetate (1 L) are added to the reaction solution, and the organic phase is washed with aqueous sodium bicarbonate solution, water, and aqueous sodium chloride solution in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue is purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to obtain compound 1b (27.00 g), yield: 42%.

[0991] MS-ESI calculated value [M+Na] + 497, Actual value: 497. Second Phase Compound 1b (17.00 g, 35.86 mmol) was dissolved in N,N-dimethylacetamide (170 mL), 1,8-diazobisspiro[5.4.0]undec-7-ene (2.78 g, 18.29 mmol) was added, and the mixture was reacted at room temperature for 1 hour under nitrogen gas protection. Pyridinium p-toluenesulfonate (4.59 g, 18.29 mmol), 1-hydroxybenzotriazole (4.59 g, 34.00 mmol), 1c (16.66 g, 33.18 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.37 g, 33.18 mmol) were then added to the reaction solution, and the mixture was allowed to react for 2.5 hours while stirring at room temperature after the addition was completed. 2-Methyltetrahydrofuran (175 mL) and saturated aqueous sodium chloride solution (260 mL) were added to the reaction solution, and the organic phase was extracted and separated. The aqueous phase was subsequently extracted with 2-methyltetrahydrofuran (100 mL x 2). The above organic phases were combined, and the organic phase was washed once with 10% citric acid (90 mL), three times with saturated sodium bicarbonate (175 mL x 3), and once with saturated physiological saline (100 mL). The mixture was washed twice, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to about 50 mL, added with isopropanol (120 mL), concentrated again to about 50 mL, added with isopropanol (300 mL), heated to 60°C and stirred for 1 hour, then cooled to 0-5°C and stirred for 2 hours, filtered off the solid, and rinsed with isopropanol at 5°C to obtain compound 1d (19.00 g), yield: 78%.

[0992] Third Stage Compound 1d (11.50 g, 15.65 mmol) is dissolved in a mixed solvent of tetrahydrofuran (230 mL) and water (115 mL), and 1,8-diazabicyclo5.4.0]undec-7-ene (10.70 g, 70.39 mmol) is added, and the mixture is reacted for 4 hours at room temperature under a nitrogen gas atmosphere while stirring. The reaction system is extracted five times with methyl t-butyl ether (100 mL x 5), and the aqueous phase is concentrated to obtain a yellow oily substance. Isoopropanol (70 mL) is added to dissolve the substance, and the solution is dropped into methyl t-butyl ether (700 mL), and a white solid is precipitated. The white solid is filtered, and the solid is dissolved in ethanol and then concentrated under reduced pressure to obtain white foam solid compound 1e (9.50 g), with a yield of 93%.

[0993] Phase 4 Compound 1e (1.00 g, 1.53 mmol) is dissolved in a mixed solution of acetonitrile (10 mL) and water (20 mL), 1f (0.54 g, 1.75 mmol) is added, and the mixture is reacted for 5 hours at room temperature under a nitrogen gas atmosphere while stirring. Water (20 mL) is added to the reaction system, the pH is adjusted to 3-4 with 0.5N aqueous hydrochloric acid, and the mixture is extracted four times with a mixed solvent of isopropanol / dichloromethane (V:V=4:1, 50 mL). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow oily substance, which is dissolved in a mixed solvent of dichloromethane / methanol (v:v=4:1, 5 mL). The solution is dropped into methyl t-butyl ether (100 mL), and a white solid is precipitated. The white solid is filtered to obtain compound 1g (850 mg), with a yield of 90%.

[0994] MS-ESI calculated value [M+Na]+ 639, Actual value: 639. Stage 5 Compound 1h (12.20 g, 46.39 mmol) was weighed into a three-necked bottle (500 mL), and after replacing with nitrogen gas, the reaction bottle was placed in an ice bath, anhydrous N,N-dimethylformamide (120 mL) was added, and imidazole (15.77 g, 232.00 mmol) and triethylsilyl chloride (27.97 g, 185.56 mmol) were added to the reaction system in sequence, and after stirring for 10 minutes, 4-dimethylaminopyridine (5.66 g, 46.39 mmol) was added, and the reaction was continued for 3 hours with stirring at 0 ° C. The reaction system was diluted with methyl t-butyl ether (1.20 L), and then water (1.2 L) was added to separate the liquids, and the aqueous phase was extracted with methyl t-butyl ether (1.2 L), and the organic phase was combined. The organic phase is washed once again with water (1.20 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which is purified by silica gel column chromatography (ethyl acetate:petroleum ether=0-100%) to give crude product 1i (16.00 g).

[0995] Stage 6 The crude product 1i (16.00 g, 32.59 mmol) and Lawesson's reagent (13.18 g, 32.59 mmol) were weighed in a three-necked bottle (1 L) in sequence, anhydrous toluene (600 mL) was added, and after replacing with nitrogen gas, the reaction system was heated to 125°C and refluxed for 5 hours. The reaction solution was concentrated to obtain a residue, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0 to 100%) to obtain the crude product 1j (16.00 g).

[0996] Stage 7 Dissolve the crude product 1j (16g crude product) in anhydrous tetrahydrofuran (640mL), add triethylamine trihydrofuran (11.93g, 74.00mmol) dropwise under ice bath, and after completion of dropwise addition, slowly warm to room temperature and react with stirring. After reacting at room temperature overnight, dilute the reaction system with ethyl acetate (1L), separate, wash the organic phase with saturated saline (500mL×2), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue, which is purified by silica gel column chromatography (ethyl acetate: petroleum ether=0~100%) to obtain compound 1k (6.38g), three-step yield: 49%.

[0997] Stage 8 Compound 1l (3.00 g, 12.00 mmol), 1k (4.33 g, 15.52 mmol), pyridinium p-toluenesulfonate (3.90 g, 15.50 mmol) and o-methylphenol (15 mL) were added to a 500 mL three-necked bottle, anhydrous toluene (300 mL) was added, and the reaction system was heated to 120 ° C after nitrogen gas replacement and reacted in an oil bath for 32 hours. The reaction system was cooled to room temperature, and solid insolubles were filtered off. The crude product was slurried with methyl t-butyl ether (60 mL) for 1 hour, filtered and dried to obtain compound 1m (3.0 g), yield: 51%.

[0998] Stage 9 Compound 1m (2.30 g, 4.67 mmol) was weighed into a 500 mL bottle, 6N aqueous hydrochloric acid (230 mL) was added, and the reaction system was heated to 110 ° C. and refluxed for 12 hours. The reaction system was filtered while hot to remove insolubles, and the filtrate was concentrated under reduced pressure to obtain crude product 1n (a diastereomeric group), which was purified by preparative HPLC to obtain compounds 1n-P1 (412 mg, TLC-less polar isomer) and 1n-P2 (495 mg, TLC-more polar isomer), yield: 34%.

[0999] Stage 10 Compound 1n-P1 (50 mg, 0.09 mmol), 1g (76 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31 mg, 0.16 mmol) and N,N-dimethylformamide (2 mL) are added to a 10 mL one-mouth bottle in sequence, then 2,4,6-trimethylpyridine (60 mg, 0.49 mmol) is added dropwise to the mixture, and after the addition is completed, the mixture is reacted for 3 hours while stirring at room temperature. The reaction liquid is added dropwise to methyl t-butyl ether (60 mL), a solid is precipitated, the solid is filtered, the solid is dissolved in a mixed solvent of dichloromethane / methanol (V:V=6:1, 30 mL), and concentrated to obtain a crude product, which is separated and purified by liquid phase preparation to obtain compound II-12-a (33 mg), yield: 35%.

[1000] MS-ESI calculated value [M+H] + 1050, Actual value: 1050. 1 H NMR(400MHz,DMSO-d6)δ 8.65(t,J=6.4Hz,1H),8.60(d,J=8.8Hz,1H),8.28(t,J=5.6Hz,1H),8.10(d,J=8.0Hz,1H),8.06(t,J=6.0Hz,1H),7.99(t,J=5.6Hz,1H) ,7.79(d,J=10.8Hz,1H),7.78(s,1H),7.28-7.14(m,5H),6.97(s,1H),5.90(d,J=16.4Hz,1H),5.70-5,60(m,1H),5.51(s,1H),5.46(d,J =2.8Hz,1H),5.30(d,J=19.6Hz,1H),4.67(d,J=6.4Hz,1H),4.51-4.41(m,1H),4.18-4.04(m,2H),3.77-3.73(m,1H),3.73-3.68(m,2H), 3.68-3.62(m,2H),3.62-3.58(m,1H),3.58-3.54(m,1H),3.38-3.31(m,2H),3.30-3.20(m,1H),3.20-3.08(m,1H),3.01(dd,J=14.0,4.8 Hz,1H),2.80-2.71(m,1H),2.37(s,3H),2.26-2.15(m,2H),2.08(t,J=7.6Hz,2H) ,1.94-1.82(m,2H),1.54-1.37(m,4H),1.25-1.10(m,2H),0.85(t,J=7.6Hz,3H).

[1001] Example 1.2

[1002] [ka]

[1003] Phase 1 Dissolve compound 2a (1.00 g, 7.52 mmol) in N,N-dimethylformamide (10 mL), add maleic anhydride (0.74 g, 7.52 mmol), react for 16 h at room temperature with stirring under nitrogen gas atmosphere, and record as solution A for later use.

[1004] In a 50 mL three-necked bottle, add N-hydroxysuccinimide (3.46 g, 30.08 mmol) and N,N-dimethylformamide (10 mL), cool to 0°C, add trifluoroacetic anhydride (6.31 g, 30.08 mmol) dropwise, and after completion of the dropwise addition, stir for 0.5 hours. Add 2,4,6-trimethylpyridine (5.46 g, 45.10 mmol), and after completion of the dropwise addition, continue to stir for 0.5 hours. Add this reaction solution dropwise to the above solution A, and after completion of the dropwise addition, react at room temperature for 16 hours while stirring. The reaction system was adjusted to pH 2-3 by adding 1N aqueous hydrochloric acid, extracted with dichloromethane (50 mL), the organic phase was washed with water three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was subjected to silica gel column chromatography (ethyl acetate:petroleum ether=0-100%) to obtain compound 2b (1.20 g), yield: 51%.

[1005] Second Phase Compound 2b (0.40 g, 1.29 mmol) was dissolved in a mixed solvent of acetonitrile (8 mL) and water (16 mL), and compound 1e (0.54 g, 0.80 mmol) was added. The mixture was reacted for 16 hours at room temperature under a nitrogen gas atmosphere while stirring. The reaction solution was concentrated under reduced pressure and then directly purified by preparative HPLC to obtain compound 2c (0.30 g), with a yield of 61%.

[1006] Third Stage Compound 1n (50 mg, 0.09 mmol), 2c (76 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31 mg, 0.16 mmol) and N,N-dimethylformamide (2 mL) are added in sequence to a 10 mL single-mouth bottle, and then 2,4,6-trimethylpyridine (60 mg, 0.49 mmol) is added dropwise to the mixture. After the addition is completed, the mixture is reacted for 3 hours while stirring at room temperature. The reaction solution is added dropwise to methyl t-butyl ether (60 mL), and a solid is precipitated. The solid is filtered out, and the solid is dissolved in a mixed solvent of dichloromethane / methanol (V:V=6:1, 30 mL) and concentrated to obtain a crude product. The crude product is purified by liquid-phase preparative HPLC to obtain compound II-1-a (16 mg), with a yield of 17%.

[1007] MS-ESI calculated value [M+H] + 1052, Actual value: 1052. 1 H NMR(400MHz,DMSO-d6)δ 8.65(t,J=6.8Hz,1H),8.61(d,J=9.2Hz,1H),8.28(t,J=4.4Hz,1H),8.14-8.06(m,2H),8.06(t,J=5.6Hz ,1H),7.82(d,J=11.2Hz,1H),7.79(s,1H),7.28-7.13(m,5H),6.99(s,2H),5.92(d,J=16.8Hz,1H),5.70- 5,60(m,1H),5.53(d,J=8.0Hz,1H),5.48(d,J=4.8Hz,1H),5.37(d,J=19.6Hz,1H),4.68(d,J=6.4Hz,1H),4 .51-4.41(m,1H),4.17-4.04(m,2H),3.72-3.68(m,2H),3.68-3.63(m,2H),3.62-3.58(m,1H),3.58-3.54(m ,3H),3.54-3.39(m,3H),3.48-3.43(m,2H),3.19-3.08(m,1H),3.06-2.97(m,1H),2.80-2.70(m,1H),2.70 -2.65(m,1H),2.39(s,3H),2.35-2.28(m,3H),2.27-2.18(m,2H),1.94-1.82(m,2H),0.85(t,J=7.2Hz,3H).

[1008] Example 1.3

[1009] [ka]

[1010] Phase 1 Compound 3a (10.00 g, 95.11 mmol) was dissolved in N,N-dimethylformamide (100 mL), maleic anhydride (9.32 g, 95.11 mmol) was added, and the mixture was reacted for 16 hours at room temperature under nitrogen gas protection with stirring. Water (250 mL) was added to the reaction solution, and the aqueous phase was extracted with dichloromethane / isopropanol (v:v=4:1, 200 mL x 3), and the organic phases were combined and concentrated under reduced pressure to obtain crude product 3b (12.00 g).

[1011] Second Phase The crude product 3b (4.00 g, 31.70 mmol) was dissolved in N,N-dimethylformamide (60 mL), bis(p-nitrobenzene) carbonate (16.40 g, 53.95 mmol) was added, and the mixture was heated to 30 ° C., followed by addition of N,N-diisopropylethylamine (4.18 g, 32.40 mmol), and the mixture was allowed to react for 2 hours while continuing to stir. The reaction solution was cooled to room temperature, water (600 mL) was added, and the aqueous phase was extracted with dichloromethane (300 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 ~ 100%) to obtain compound 3c (2.40 g), with a two-step yield of 13%.

[1012] Third Stage Compound 3c (400 mg, 1.14 mmol) was dissolved in a mixture of acetonitrile (8 mL) and water (16 mL), and compound 1e (760 mg, 1.13 mmol) was added and reacted for 16 hours at room temperature under nitrogen gas protection with stirring. The reaction solution was directly purified by preparative HPLC to obtain compound 3d (109 mg), yield: 15%.

[1013] Phase 4 Compound 1n-P1 (69 mg, 0.12 mmol), 3d (110 mg, 0.17 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44 mg, 0.23 mmol) and N,N-dimethylformamide (2.5 mL) are added in sequence to a single-mouth bottle (10 mL), and then 2,4,6-trimethylpyridine (84 mg, 0.69 mmol) is added dropwise to the mixture. The mixture is allowed to react for 3 hours while stirring at room temperature. The reaction solution is added dropwise to methyl t-butyl ether (75 mL), and a solid is precipitated. The solid is filtered off, and the solid is dissolved in a mixed solvent of dichloromethane / methanol (V:V=6:1, 30 mL), and concentrated under reduced pressure to obtain a residue. The residue is purified by preparative HPLC to obtain compound II-3-a (45 mg), yield: 35%.

[1014] MS-ESI calculated value [M+H] +1068.4, measured value: 1068.9. 1 H NMR(400MHz,DMSO-d6)δ 8.68(t,J=6.8Hz,1H),8.62(d,J=9.2Hz,1H),8.31(t,J=5.6Hz,1H),8.12(d,J=8.0Hz, 1H),7.99(t,J=5.6Hz,1H),7.78(s,1H),7.77(d,J=10.8Hz,1H),7.38(t,J=6.0Hz,1H), 7.27-7.13(m,5H),6.99(s,2H),5.90(d,J=16.4Hz,1H),5.70-5,61(m,1H),5.51(s,1H),5.46(d,J =4.4Hz,1H),5.29(d,J=19.6Hz,1H),4.67(d,J=6.4Hz,1H),4.51-4.41(m,1H),4.17-4.04(m,2H),4 .02-3.94(m,2H),3.79-3.67(m,3H),3.35-3.20(m,1H),3.20-3.07(m,1H),3.00(dd,J=14.0,4.4Hz ,1H),2.78-2.65(m,1H),2.37(s,3H),2.25-2.15(m,2H),1.92-1.82(m,2H),0.85(t,J=7.2Hz,3H).

[1015] Example 1.4

[1016]

change

[1017] Stage 1 Compound 4a (2.00 g, 7.52 mmol) and β-alanine (0.67 g, 7.52 mmol) are dissolved in acetonitrile (20 mL), the mixture is cooled to 0°C, N,N-diisopropylethylamine (1.94 g, 15.03 mmol) is added, and after the addition is completed, the mixture is returned to room temperature and reacted for 16 hours with continued stirring. Water (100 mL) is added to the reaction solution, and the mixture is extracted with dichloromethane / isopropanol (v:v=4:1, 250 mL x 10), and the organic phases are combined and concentrated to obtain a residue. The residue is purified by silica gel column chromatography (methanol:dichloromethane=0-100%) to obtain compound 4b (2.00 g).

[1018] Second Phase Compound 4b (1.80 g, 7.50 mmol) was dissolved in N,N-diisopropylethylamine (8 mL), dicyclohexylcarbodiimide (1.85 g, 9.00 mmol) was added, and the mixture was stirred for 30 minutes after the addition was complete. N-hydroxysuccinimide (0.95 g, 8.25 mmol) was then added, and the mixture was allowed to react at room temperature for 16 hours while stirring. The reaction solution was filtered and directly purified by preparative HPLC to give compound 4c (530 mg), with a yield of 21%.

[1019] Third Stage Compound 4c (0.50 g, 1.48 mmol) was dissolved in a mixed solvent of acetonitrile (8 mL) and water (16 mL), and 1e (0.98 g, 1.50 mmol) was added and reacted for 16 hours at room temperature under nitrogen gas protection with stirring. The reaction solution was separated and purified by liquid phase preparation to obtain compound 4d (42 mg), with a yield of 4%.

[1020] Phase 4 Compound 1n-P1 (26 mg, 0.046 mmol), 4d (42 mg, 0.065 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16 mg, 0.083 mmol) and N,N-dimethylformamide (1 mL) were added in sequence to a single-mouth bottle (10 mL), and then 2,4,6-trimethylpyridine (32 mg, 0.26 mmol) was added dropwise to the mixture. The reaction was allowed to proceed at room temperature for 3 hours. The reaction solution was added dropwise to methyl t-butyl ether (30 mL) to precipitate a solid, which was then filtered off and dissolved in a mixed solvent of dichloromethane / methanol (V:V=6:1, 30 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound II-2-a (13 mg), yield: 26%.

[1021] MS-ESI calculated value [M+H] + 1079.4, Actual value: 1079.9. 1 H NMR(400MHz,DMSO-d6)δ 8.68(t,J=6.8Hz,1H),8.63(d,J=8.8Hz,1H),8.31(t,J=6.0Hz,1H),8.18(t,J=7.2Hz,1H),8.10(d,J=7.2Hz,1H),8.03(t,J=5.6Hz,1H),7.98(t ,J=5.6Hz,1H),7.82(d,J=10.8Hz,1H),7.79(s,1H),7.28-7.13(m,5H), 6.98(s,2H),6.70(s,1H),5.90(d,J=16.8Hz,1H),5.70-5,60(m,1H),5.5 6-5.45(m,2H),5.36(d,J=19.6Hz,1H),4.68(d,J=6.8Hz,1H),4.53-4.4 2(m,1H),4.18-4.04(m,2H),3.78-3.64(m,5H),3.62-3.52(m,4H),3.22- 3.14(m,1H),3.06-2.97(m,1H),2.80-2.70(m,1H),2.68-2.65(m,1H),2 .39(s,3H),2.34-2.16(m,6H),1.92-1.82(m,2H),0.85(t,J=7.2Hz,3H).

[1022] Example 1.5

[1023] [ka]

[1024] Phase 1 Under nitrogen gas protection at 0°C, 1n (24.00mg, 0.053mmol) and 1g (32.78mg, 0.053mmol) are dissolved in N,N-dimethylformamide (1.5mL), N,N-diisopropylethylamine (17.10mg, 0.0133mmol) in N,N-dimethylformamide (0.4mL) solution is dropped, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (24.20mg, 0.064mmol) in N,N-dimethylformamide (0.6mL) solution is dropped again, and after the dropwise addition is completed, the mixture is kept at 0°C and reacted for 1 hour. The reaction solution is separated and purified to obtain compounds II-12-a (16mg) and II-12-b (19mg), with a total yield of 64%.

[1025] II-12-b: MS-ESI calculated value [M+H] + 1050.4, actual value: 1050.3. 1H NMR(400MHz,DMSO-d6)δ 8.71-8.61(m,2H),8.31(t,J=4.8Hz,1H),8.12(d,J=7.2Hz,1H),8.07(t,J=6.0Hz,1H),8.00(t,J =5.2Hz,1H),7.82(dd,J=10.8,2.0Hz,1H),7.80(s,1H),7.28-7.13(m,6H),6.99(s,2H),6.70(br s,1H),5.92(d,J=16.8Hz,1H),5.70-5,61(m,1H),5.52(d,J=17.2Hz,2H),5.37(d,J=19.6Hz,1H) ,4.68(d,J=6.8Hz,2H),4.51-4.41(m,1H),4.18-4.04(m,2H),3.77-3.50(m,7H),3.32-3.20(m,1H ),3.20-3.08(m,1H),3.07-2.96(m,1H),2.82-2.71(m,1H),2.39(s,3H),2.26-2.15(m,2H),2.09 (t,J=7.6Hz,2H),1.96-1.82(m,2H),1.52-1.39(m,4H),1.25-1.10(m,2H),0.85(t,J=7.6Hz,3H).

[1026] Example 1.6

[1027]

change

[1028] Stage 1 In a single-mouth bottle (25 mL), 1n (20 mg, 0.04 mmol) and a 1.2 mg / mL solution of glycolic acid in N,N-dimethylformamide (2.00 mL, 0.032 mmol) were added in sequence, the reaction system was cooled to 0°C, N,N-diisopropylethylamine (11 mg, 0.08 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16 mg, 0.04 mmol) were added in sequence, and the reaction system was allowed to react for 0.5 hours, after which a 1.2 mg / mL solution of glycolic acid in N,N-dimethylformamide (0.20 mL, 0.003 mmol) was added. l) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1mg) were added, and the reaction was continued for 1 hour. The reaction system was then diluted with ethyl acetate (80mL), and the organic phase was successively washed with 0.5N dilute hydrochloric acid (5mL x 1), saturated sodium bicarbonate solution (10mL x 2) and saturated saline (10mL x 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative thin layer chromatography (methanol:dichloromethane) to obtain compound X (2mg) and Y (5mg), with a total yield of 34%.

[1029] X:MS-ESI calculated value [M+H] + 510, actual value 510. 1 H NMR (400MHz, DMSO-d6) δ 8.54(d,J=8.8Hz,1H),7.82(d,J=10.8Hz,1H),7.80(s,1H),5.92(d,J=16.8H z,1H),5.69-5.60(m,1H),5.53(d,J=20.4Hz,1H),5.52(d,J=16.4Hz,1H),5. 35(d,J=20.0Hz,1H),4.15-3.98(m,2H),3.30-3.22(m,1H),3.19-3.09(m,1H ),2.40(s,3H),2.26-2.14(m,2H),1.96-1.84(m,2H),0.86(t,J=7.2Hz,3H).

[1030] Y:MS-ESI calculated value [M+H] +510, actual value 510. 1 H NMR (400MHz, DMSO-d6) δ 8.54(d,J=9.2Hz,1H),7.81(d,J=11.2Hz,1H),7.80(s,1H),6.69(s,1H),5.9 2(d,J=16.8Hz,1H),5.69-5.62(m,1H),5.62-5.56(m,1H),5.55-5.47(m,2H), 5.33(d,J=20.0Hz,1H),4.16-3.98(m,2H),3.30-3.20(m,1H),3.16-3.07(m,1 H),2.39(s,3H),2.26-2.15(m,2H),1.95-1.85(m,2H),0.86(t,J=7.2Hz,3H).

[1031] Example 2 Methods for preparing antibody-drug conjugates The antibody is dialyzed with 50 mM PB (pH 7.4 ± 0.1) buffer to obtain an antibody intermediate. Take 20 mg of the antibody intermediate, add 0.2 mL of 10 mM diethylenetriaminepentaacetic acid (DTPA) mother solution so that the final concentration of DTPA is 1 mM, add 10 mM tris(2-carboxyethyl)phosphine hydrochloride (TCEP) mother solution, the molar ratio of the reducing agent TCEP to the antibody is (2.4-2.6):1.0, and add 2 mL of 50 mM PB (pH 7.4 ± 0.1) buffer to the reaction system. After mixing well, place in a thermostatic mixer, the coupling reaction temperature is 25 ± 2 °C, the rotation speed is 400 rpm, and the coupling reaction is carried out for 120 to 150 minutes. After the coupling was completed, an appropriate amount of 5 mM linker-drug mother solution was added to each reaction system in turn in an ice-water bath, and the molar ratio of linker-drug to antibody was (8.0~10.0):1.0. After thorough mixing, the mixture was incubated in a constant temperature mixer. The mixture is placed in a mixer at a coupling reaction temperature of 25±2°C and a rotation speed of 400 rpm for 60-90 minutes. After coupling is complete, the ADC sample is dialyzed into a dialysis solution (20 mM His / His-HCl, pH 6.0±0.1) using an ultrafiltration centrifuge tube to obtain an ADC stock solution, which is then aliquoted and stored at -80°C.

[1032] [Table 1]

[1033] An exemplary TROP2 antibody sequence can comprise LCDR1-3 in the light chain variable region VL and HCDR1-3 in the heavy chain variable region VH, where the VH can comprise the amino acid sequence set forth in SEQ ID NO:17 and the VL can comprise the amino acid sequence set forth in SEQ ID NO:18.

[1034] Example 3 Detection of in vitro proliferation inhibition of human tumor cells Take human breast cancer cells SK-BR-3 or gastric cancer cells NCI-N87 in logarithmic growth phase, resuspend in complete medium, and adjust to appropriate concentration, then add 100μL / well to a 96-well cell culture plate. Place the cell culture plate in a 37℃, 5% CO2 incubator and culture overnight. Now, add the cell suspension to one 96-well plate and use CTG detection (CellTiter Glo assay kit, Promega, G7558) before adding the sample, and use it as the G0 value.

[1035] The linker-payload of the present application can be obtained by referring to the method of Example 1 of the present application, and the antibody-drug conjugate (ADC) of the present application can be obtained by referring to the method of Example 2 of the present application. For example, the linker-payload compound II-1 can be obtained by referring to the method of Example 1 of the present application, and ADCI-1 can be obtained by coupling with any antibody (e.g., HER2 antibody) by referring to the method of Example 2 of the present application. The control group sample can be prepared by coupling with any antibody (e.g., HER2 antibody) by referring to Example 2 of the present application.

[1036] The obtained ADC working solution was serially diluted using HP D300 and added to the cell culture plate in duplicate wells, with the final ADC concentration starting from 1 μM, and serially diluted 4-fold to create a total of nine concentrations. The cell culture plate was placed in a 37°C, 5% CO2 incubator and cultured for 120 hours, after which the cell plate was removed and equilibrated to room temperature, and the luminescence readings were detected using a CellTiter Glo assay kit (Promega, G7558) and a multi-function microplate reader (PerkinElmer, EnVision), and the efficacy inhibition rate curve was plotted using XLFit, and the IC 50 and G.I. 50 Calculate the value.

[1037] [Table 2]

[1038] [Table 3]

[1039] As shown in Tables 1 and 2, the activity test results show that the ADCs prepared from the compounds of the present application all exhibit certain antitumor activity, which is superior to the control ADC1. The structure of the control ADC1 is as follows:

[1040] [ka]

[1041] Detection of in vitro proliferation inhibition of human tumor cells Human tumor cells in logarithmic growth phase were harvested, digested, resuspended in fresh complete medium, and incubated at 4°C for 1 h at 4°C for 2 h at 4°C. The cells are then adjusted to a concentration of 1 μM and added to a 96-well cell culture plate at 150 μL / well. The cell culture plate is then placed in a 37°C, 5% CO2 incubator for overnight incubation. The next day, various concentrations of ADC samples to be tested (1 μM final concentration at 4-fold serial dilutions) or buffer controls are added to the corresponding wells of the cell culture plate, followed by incubation in a carbon dioxide incubator for 120 hours. After that, the test plate is equilibrated to room temperature and incubated with CellTiter Glo. Assay kit (Promega, G7558), luminescence readings are detected using a multi-function microplate reader (Enspire2300, PerkinElmer). Calculate the cell inhibition rate according to the following formula: Inhibition rate (%) = (1-(RLU) ADC -RLU 空白 ) / (RLU 緩衝液 -RLU 空白 )) x 100%. Valid using XLFit Draw the inhibition rate curve and calculate IC 50 The values ​​are calculated (see Table 3). The experimental results show that the inhibitory activities of the TROP2 antibody ADCI-Ia against multiple tumor cell lines with different target expression levels are all superior to the control ADC2 (see Table 3).

[1042] [Table 4]

[1043] As shown in Table 3, the activity test results show that the ADC prepared from the compound of the present application exhibits excellent antitumor activity, which is superior to the control ADC2. The structure of the control ADC2 is as follows:

[1044] [ka]

[1045] Example 4 In vivo antitumor effect measurement Gastric cancer cells NCI-N87 with high target expression in the logarithmic growth phase were taken, counted, adjusted to the corresponding concentration, resuspended in a 1:1 mixture of serum-free medium and Matrigel (Corning356234) on ice, and subcutaneously inoculated in 200 μL portions into the right back of BALB / c nude mice. After the tumors had grown to a measurable size, calipers were used to measure the long and short diameters of each tumor, and the tumor volume was calculated according to the following formula, V = (a × b 2 ) / 2, where a represents the long axis of the tumor and b represents the short axis of the tumor.

[1046] Mean tumor volume is 100-200mm 3 Once the tumors reach a tumor size of 100 mm, the animals are randomly divided into groups according to tumor volume. Tumor-bearing nude mice are injected intravenously with vehicle control (saline) or different doses of ADC (3 mg / kg or 10 mg / kg) once in total. The length and short diameter of the tumor are measured twice a week, and the weight of the animals is recorded. The tumor volume of each group is counted, and the tumor growth inhibition rate (TGI) is calculated according to the following formula: TGI=100%×[1-(TVt T -TV0 T ) / (TVt C -TV0 C )], where TVt T represents the tumor volume of the administration group on the measurement day, and TV0 T represents the tumor volume of the treatment group at the time of grouping, and TVt C represents the tumor volume of the vehicle control group on the day of measurement, and TV0 C represents the tumor volume of the vehicle control group at the time of grouping (see Table 4).

[1047] [Table 5]

[1048] The results of the activity test showed that the ADCs prepared from the compounds of the present application all showed certain in vivo antitumor activity, and showed significantly stronger antitumor activity than the control ADC1. The tumor-bearing mice all tolerated the above drugs well, and did not experience symptoms such as weight loss.

[1049] In vivo antitumor effect measurement Calu-6 human lung cancer cells with low target expression in the logarithmic growth phase were taken, counted, and resuspended in EMEM medium at a cell concentration of 5 × 10 7 Adjust to cells / mL for later use. Use a syringe to subcutaneously inject the cells into female BALB / c nude mice, adding 100 μL (5 × 10 6 To establish a Calu-6 nude mouse transplant tumor model, inoculate 1000 cells / mouse (a × b). After the tumors have grown to a measurable size, use calipers to measure the long and short diameters of each tumor, and calculate the tumor volume according to the following formula: V = (a × b 2 ) / 2, where a represents the long axis of the tumor and b represents the short axis of the tumor.

[1050] The average tumor volume was approximately 150 mm 3 Once the tumors have grown to a tumor size of 100 mm, they are randomly divided into groups according to tumor volume and mouse weight. Tumor-bearing nude mice are injected intravenously with vehicle control (saline) or different doses of ADC (3 mg / kg or 10 mg / kg) once a week for a total of three injections. The length and short diameter of the tumor are measured twice a week, and the weight of the animals is recorded. The tumor volume of each group is counted, and the tumor growth inhibition rate (TGI) is calculated according to the following formula: TGI=100%×[1-(TVt T -TV0 T ) / (TVt C -TV0 C )], where TVt T represents the tumor volume of the administration group on the measurement day, and TV0 T represents the tumor volume of the treatment group at the time of grouping, and TVt C represents the tumor volume of the vehicle control group on the day of measurement, and TV0 C The tumor growth inhibition rate at the end of the experiment is shown in Table 5.

[1051] The experimental results show that the TROP2 antibody ADCI-Ia can inhibit the growth of subcutaneously implanted Calu-6 tumors at doses of 3 mg / kg and 10 mg / kg, and the inhibitory effect is superior to that of the control group ADC2 at a dose of 10 mg / kg.

[1052] [Table 6]

[1053] Example 5 Cell proliferation inhibition experiment KPL-4 tumor cells in logarithmic growth phase were taken, resuspended in fresh RPMI 1640 medium, counted, and the cell suspension was diluted to 2 × 10 4 Adjust to cells / mL. Inoculate the cell suspension into a 96-well cell culture plate at 100μL / well and place in a carbon dioxide incubator (37℃, 5%CO2) to culture overnight. The next day, take out one of the 96-well plates inoculated with cells and equilibrate to room temperature, then add 100μL of CellTiter-Glo Reagent (Promega, USA) pre-equilibrated to room temperature and well mixed to each well of the test plate, incubate in the dark for 30 minutes, read the luminescence value (recorded as G0 value) with a microplate reader, take another parallel plate, and add different concentrations of the test compound or DMSO (final concentration 0.5%) to the corresponding well of the test plate, and after 72 hours of culture in a carbon dioxide incubator, equilibrate the test plate to room temperature, and use CellTiter-Glo Reagent to detect cell activity, which is recorded as G3 value.

[1054] The cell proliferation rate is calculated according to the following formula: Cell proliferation rate (%) = (compound well G3 mean value - G0 mean value) / (DMSO control well G3 mean value - G0 mean value) x 100. The inhibition curves were fitted using Graphpad Prism software, and the GI 50 Calculate the values ​​(see the following table).

[1055] [Table 7]

[1056] [ka] corresponds to compound X (Example 1.6),

[1057] [ka] corresponds to compound Y (Example 1.6),

[1058] [ka] is DXd.

[1059] The foregoing detailed description has been provided by way of illustration and example, and is not intended to limit the scope of the appended claims. Various modifications to the embodiments described in the present application will be apparent to those skilled in the art and remain within the scope of the appended claims and their equivalents.

Claims

1. A ligand conjugate or a tautomer, mesomeric, racemic, enantiomer, diastereomeric, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof, The ligand conjugate comprises the structure shown in formula (I): 【Chemistry 1】 Here, R １ and R ２ are each independently a hydrogen atom, a deuterium atom, a halogen atom, an optionally substituted C １ -C ８ Alkyl groups, optionally substituted C １ -C ８ Haloalkyl groups and optionally substituted C １ -C ８ deuterated alkyl groups; or Or, R １ and R ２ together with the carbon atoms to which they are attached form a structure selected from the group consisting of optionally substituted alicyclic groups, optionally substituted aliphatic heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups; L is an optionally substituted linker; The ligand conjugate, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, characterized in that Ab is a ligand, a is a number greater than 0, and a is a decimal or integer.

2. The ligand conjugate of claim 1, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof, The ligand conjugate comprises a structure shown in formula (I-a) or (I-b): 【Chemistry 2】 Here, R １ and R ２ are each independently a hydrogen atom, a deuterium atom, a halogen atom, an optionally substituted C １ -C ８ Alkyl groups, optionally substituted C １ -C ８ Haloalkyl groups and optionally substituted C １ -C ８ deuterated alkyl groups; or Or, R １ and R ２ together with the carbon atoms to which they are attached form a structure selected from the group consisting of optionally substituted alicyclic groups, optionally substituted aliphatic heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups; L is an optionally substituted linker, and L is the linker -L 1 -L 2 -L 3 -L 4 -L 5 -; The ligand conjugate, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof, characterized in that Ab is a ligand, a is a number greater than 0, and a is a decimal or integer.

3. Said L １ is optionally replaced 【Chemistry 3】 and the L １ is directly linked to the Ab.

3. The ligand conjugate of claim 2, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

4. Said L ２ is an optionally substituted -(CH ２ ) ｍ１ -X １ - (CH ２ ) ｍ２ -C(O)-, optionally substituted -(CH ２ CH ２ O) ｎ -C(O)- and optionally substituted -(CH ２ ) ｐ is a group selected from the group consisting of -C(O)-, X １ is selected from the group consisting of -O-, optionally substituted -C(O)-NH-, optionally substituted aryl groups, optionally substituted heteroaryl groups, optionally substituted heteroalicyclic groups, and optionally substituted alicyclic groups; wherein m1, m2 and n are each independently selected from an integer of at least 0, and p is selected from an integer of 2 to 8.

4. The ligand conjugate of claim 2 or 3, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

5. Said L ２ is an optionally substituted -(CH ２ CH ２ O) ｎ is selected from the group consisting of -C(O)-, optionally substituted -(CH 2 ) m1 -X 1 -(CH 2 ) m2 -C(O)-, and optionally substituted -(CH 2 ) p -C(O)-; Preferably, n is 2, X 1 is selected from the group consisting of -O- and optionally substituted -C(O)-NH-; m1 is preferably 2, Preferably, m2 is 2; Alternatively, X 1 is selected from the group consisting of optionally substituted aryl groups and optionally substituted heteroaryl groups; Preferably, X 1 is an optionally substituted phenyl group or an optionally substituted pyridyl group; Preferably, m1 is 0, and / or m2 is 1; Alternatively, X 1 is optionally substituted 【Chemistry 4】 or an optionally substituted cyclohexyl group; Preferably, m1 is 1, and / or m2 is 0; Preferably, p is 5.

4. The ligand conjugate of claim 2 or 3, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

6. Said L ２ is optionally replaced 【Chemistry 5】 , optionally replaced 【Chemistry 6】 , optionally replaced 【Chemistry 7】 , optionally replaced 【Chemistry 8】 , optionally replaced 【Chemistry 9】 , optionally replaced 【Chemistry 10】 , optionally replaced 【Chemistry 11】 , optionally replaced 【Chemistry 12】 and optionally replaced 【Chemistry 13】 The structure is selected from the group consisting of 4. The ligand conjugate of claim 2 or 3, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

7. Said L ３ is a peptide residue, Preferably, L 3 is a peptide residue consisting of an amino acid selected from the group consisting of phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid and glycine; More preferably, L 3 is a peptide residue consisting of an amino acid selected from the group consisting of glycine, phenylalanine, valine and citrulline; Most preferably, said L 3 is a peptide residue selected from the group consisting of -glycine-phenylalanine-glycine-(-Gly-Phe-Gly-), -glycine-glycine-phenylalanine-glycine-(-Gly-Gly-Phe-Gly-) and -valine-citrulline-(-Val-Cit-); Most preferably, L 3 is 【Chemistry 14】 The structure is selected from the group consisting of 4. The ligand conjugate of claim 2 or 3, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

8. Said L ４ is an optionally substituted -L ４ａ -NR ４ -CH ２ -L ４ｂ - and Preferably, L ４ａ is not present or L ４ａ is optionally replaced 【Chemistry 15】 and L ４ｂ is not present or L ４ｂ is optionally replaced 【Chemistry 16】 and R ４ and R ５ are each independently selected from the group consisting of hydrogen and optionally substituted alkyl groups (preferably hydrogen and optionally substituted methyl groups); Preferably, L 4 is 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 and 【Chemistry 20】 is an optionally substituted group selected from the group consisting of More preferably, said L 4 is optionally substituted 【Chemistry 21】 , optionally replaced 【Chemical 22】 , optionally replaced 【Chemistry 23】 , optionally replaced 【Chemistry 24】 and optionally replaced 【Chemistry 25】 The structure is selected from the group consisting of 4. The ligand conjugate of claim 2 or 3, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

9. Said L ５ is optionally replaced 【Chemistry 26】 and the L ５ teeth, 【Chemistry 27】 is directly linked to the structure of the formula R ６ and R ７ are each independently selected from the group consisting of hydrogen, deuterium, optionally substituted alkyl groups, optionally substituted haloalkyl groups, optionally substituted cycloalkyl groups, and optionally substituted cycloalkylalkyl groups, or R ６ and R ７ together with the atom to which they are attached form an optionally substituted cycloalkyl group; where v is at least 0, preferably 0 or 1; Preferably, R 6 is selected from the group consisting of hydrogen or an optionally substituted methyl group (e.g. a methyl group), a methyl group substituted by fluorine (e.g. a trifluoromethyl group), an optionally substituted cycloalkyl group (e.g. a cyclopropyl group), and / or R 7 is hydrogen or R 6 and R 7 together with the atom to which they are attached form an optionally substituted cyclopropyl group or an optionally substituted cyclobutyl group; More preferably, said L 5 is optionally substituted 【Chemistry 28】 , optionally replaced 【Chemical 29】 , optionally replaced 【Chemistry 30】 , optionally replaced 【Chemistry 31】 , optionally replaced 【Chemistry 32】 , optionally replaced 【Chemical 33】 , optionally replaced 【Chemical 34】 and optionally replaced 【Chemistry 35】 The structure is selected from the group consisting of 4. The ligand conjugate of claim 2 or 3, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

10. the Ab is an antibody or an antigen-binding fragment thereof; Preferably, the antibody is selected from the group consisting of a murine antibody, a chimeric antibody, a humanized antibody and a fully human antibody; Preferably, the antibody is a monoclonal antibody, Preferably, the antigen-binding fragment is selected from the group consisting of Fab, Fab', Fv fragment, F(ab') 2 , F(ab) 2 , scFv, di-scFv, VHH and dAb. A ligand conjugate according to any one of claims 1 to 3, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

11. The Ab is characterized in that it contains a HER2 antibody and / or a TROP2 antibody. A ligand conjugate according to any one of claims 1 to 3, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

12. The Ab comprises HCDR1, HCDR2, and HCDR3 of a heavy chain variable region, wherein the HCDR1, HCDR2, and HCDR3 are defined in (1) or (2); (1) the amino acid sequence of the HCDR1 is as set forth in SEQ ID NO: 1, the amino acid sequence of the HCDR2 is as set forth in SEQ ID NO: 2, and the amino acid sequence of the HCDR3 is as set forth in SEQ ID NO: 3; and / or (2) The amino acid sequence of the HCDR1 is as shown in SEQ ID NO: 11, the amino acid sequence of the HCDR2 is as shown in SEQ ID NO: 12, and the amino acid sequence of the HCDR3 is as shown in SEQ ID NO: 13; the Ab comprises a LCDR1, LCDR2, and LCDR3 of a light chain variable region, wherein the LCDR1, LCDR2, and LCDR3 are defined in (i) or (ii); (i) the amino acid sequence of the LCDR1 is as set forth in SEQ ID NO:4, the amino acid sequence of the LCDR2 is as set forth in SEQ ID NO:5, and the amino acid sequence of the LCDR3 is as set forth in SEQ ID NO:6; and / or (ii) the amino acid sequence of the LCDR1 is as set forth in SEQ ID NO: 14, the amino acid sequence of the LCDR2 is as set forth in SEQ ID NO: 15, and the amino acid sequence of the LCDR3 is as set forth in SEQ ID NO: 16; Preferably, the Ab comprises a heavy chain variable region, the amino acid sequence of which is as set forth in any sequence selected from the group consisting of SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:17 and SEQ ID NO:19; and / or The Ab comprises a light chain variable region, and the amino acid sequence of the light chain variable region is as set forth in any sequence selected from the group consisting of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:18, and SEQ ID NO:

20. A ligand conjugate according to any one of claims 1 to 3, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

13. The ligand conjugate comprising: 【Chemical 36】 【change】 【change】 A structure selected from the group consisting of: A ligand conjugate according to any one of claims 1 to 3, characterized in that Ab is a ligand, a is a number greater than 0, and a is a decimal or integer number, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture form thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

14. A compound or a tautomer, mesomeric, racemic, enantiomer, diastereomeric, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof, The compound comprises the structure shown in formula (II): 【Chemical 37】 Where: R １ and R ２ are each independently a hydrogen atom, a deuterium atom, a halogen atom, an optionally substituted C １ -C ８ Alkyl groups, optionally substituted C １ -C ８ Haloalkyl groups and and optionally substituted C １ -C ８ deuterated alkyl groups; or Or, R １ and R ２ together with the carbon atoms to which they are attached form a structure selected from the group consisting of optionally substituted alicyclic groups, optionally substituted aliphatic heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups; Lx is a linking group, and the Lx is １ｘ -L ２ -L ３ -L ４ -L ５ -, and said L １ｘ can be directly linked to the ligand, Preferably, the compound comprises the structure shown in formula (II-a) or formula (II-b): 【Chemical 38】 【Chemical 39】 or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

15. Said L １ｘ is optionally replaced 【Chemistry 40】 characterized in that 15. A compound according to claim 14, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

16. Said L ２ is an optionally substituted -(CH ２ ) ｍ１ -X １ - (CH ２ ) ｍ２ -C(O)-, optionally substituted -(CH ２ CH ２ O) ｎ -C(O)- and optionally substituted -(CH ２ ) ｐ -C(O)-, Here, X １ is selected from the group consisting of -O-, optionally substituted -C(O)-NH-, optionally substituted aryl groups, optionally substituted heteroaryl groups, optionally substituted heteroalicyclic groups, and optionally substituted alicyclic groups; m1, m2 and n are each independently selected from an integer of at least 0, and p is selected from an integer of 2 to 8.

16. A compound according to claim 14 or 15, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

17. Said L ２ is an optionally substituted -(CH ２ CH ２ O) ｎ -C(O)-, -(CH 2 ) m1 -X 1 -(CH 2 ) m2 -C(O)-, or -(CH 2 ) p -X 1 -C(O)-, Preferably, n is 2, X 1 is selected from the group consisting of -O- and optionally substituted -C(O)-NH-; Preferably, m1 is 2, More preferably, m2 is 2; Alternatively, X 1 is selected from the group consisting of optionally substituted aryl groups (preferably, an optionally substituted phenyl group) and optionally substituted heteroaryl groups (preferably, an optionally substituted pyridyl group); Preferably, m1 is 0, More preferably, m2 is 1; Alternatively, X 1 is optionally substituted 【Chemistry 41】 or an optionally substituted cyclohexyl group; Preferably, m1 is 1, More preferably, m2 is 0, Preferably, p is 5.

16. A compound according to claim 14 or 15, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

18. Said L ２ is optionally replaced 【Chemistry 42】 , optionally replaced 【Chemistry 43】 , optionally replaced 【Chemistry 44】 , optionally replaced 【Chemistry 45】 , optionally replaced 【Chemistry 46】 , optionally replaced 【Chemistry 47】 , optionally replaced 【Chemistry 48】 , optionally replaced 【Chemistry 49】 and optionally replaced 【Chemistry 50】 The structure is selected from the following:

16. A compound according to claim 14 or 15, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

19. Said L ３ is a peptide residue, Preferably, L 3 is a peptide residue consisting of an amino acid selected from the group consisting of phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid and glycine; More preferably, L 3 is a peptide residue consisting of an amino acid selected from the group consisting of glycine, phenylalanine, valine and citrulline; Most preferably, said L 3 is a peptide residue selected from the group consisting of -glycine-phenylalanine-glycine-(-Gly-Phe-Gly-), -glycine-glycine-phenylalanine-glycine-(-Gly-Gly-Phe-Gly-) and -valine-citrulline-(-Val-Cit-); Most preferably, L 3 is 【Chemistry 51】 The structure is selected from the group consisting of 16. A compound according to claim 14 or 15, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

20. Said L ４ is an optionally substituted -L ４ａ -NR ４ -CH ２ -L ４ｂ - and Preferably, L ４ａ is not present or L ４ａ is optionally replaced 【Chemistry 52】 and L ４ｂ is not present or L ４ｂ is optionally replaced 【Chemistry 53】 and R ４ and R ５ are each independently selected from the group consisting of hydrogen and an optionally substituted alkyl group (preferably hydrogen or an optionally substituted methyl group); Preferably, L 4 is 【Chemical 54】 【Chemistry 55】 【Chemistry 56】 【Chemistry 57】 is an optionally substituted group selected from the group consisting of More preferably, said L 4 is optionally substituted 【Chemistry 58】 , optionally replaced 【Chemistry 59】 , optionally replaced 【Chemistry 60】 , optionally replaced 【Chemistry 61】 and optionally replaced 【Chemistry 62】 The structure is selected from the group consisting of 16. A compound according to claim 14 or 15, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

21. Said L ５ is optionally replaced 【Chemistry 63】 and the L ５ teeth, 【Chemistry 64】 is directly linked to the structure of the formula R ６ and R ７ are each independently selected from the group consisting of hydrogen, deuterium, optionally substituted alkyl groups, optionally substituted haloalkyl groups, optionally substituted cycloalkyl groups, and optionally substituted cycloalkylalkyl groups, or R ６ and R ７ together with the atom to which they are attached form an optionally substituted cycloalkyl group; where v is at least 0, preferably 0 or 1; Preferably, R 6 is selected from the group consisting of hydrogen, an optionally substituted methyl group, a methyl group substituted with fluorine, a trifluoromethyl group, an optionally substituted cycloalkyl group (e.g., a cyclopropyl group); and / or said R 7 is hydrogen; or R 6 and R 7 together with the atom to which they are attached form a group selected from the group consisting of an optionally substituted cyclopropyl group, or an optionally substituted cyclobutyl group; More preferably, said L 5 is optionally substituted 【Chemistry 65】 , optionally replaced 【Chemistry 66】 , optionally replaced 【Chemistry 67】 , optionally replaced 【Chemistry 68】 , optionally replaced 【Chemistry 69】 , optionally replaced 【Chemistry 70】 , optionally replaced 【Chemistry 71】 and optionally replaced 【Chemical 72】 The structure is selected from the group consisting of 16. A compound according to claim 14 or 15, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

22. The compound comprising: 【Chemical Formula 73】 【change】 【change】 16. A compound according to claim 14 or 15, characterized in that it is selected from the group consisting of: or a tautomer, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharma- ceutically acceptable salt or hydrate thereof.

23. 1. A pharmaceutical composition comprising:

16. A pharmaceutical composition comprising a ligand conjugate according to any one of claims 1 to 3, or a tautomer, mesomeric, racemic, enantiomer, diastereomeric or mixture thereof, or a pharma- ceutically acceptable salt, prodrug or solvate thereof, and / or a compound according to claim 14 or 15, and optionally a pharma- ceutically acceptable carrier.

24. A ligand conjugate according to any one of claims 1 to 3, or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharma- ceutically acceptable salt, prodrug or solvate thereof, and / or a compound according to claim 14 or 15, or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharma- ceutically acceptable salt or hydrate thereof, for use in the treatment and / or prophylaxis of a tumor, preferably said tumor is selected from tumors associated with expression of a target consisting of HER2 and TROP2, more preferably said tumor associated with expression of a target is a tumor with high expression of the target and / or a tumor with high expression of the target. and / or a compound selected from the group consisting of a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, and / or a compound selected from the group consisting of a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or hydrate ...

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