Camptothecin analog ligand-drug conjugates, intermediates, methods for producing the same, pharmaceutical compositions, and uses thereof.

Abstract

The present disclosure relates to conjugates of novel camptothecin analogs and cell-binding molecules of formula (I). Also provided are methods for preparing the conjugates of camptothecin analogs and cell-binding agents, and methods for applying the conjugates in targeted cancer therapy.

Description

[Technical Field]

[0001] We provide a complex of a camptothecin analog and a cell surface receptor-binding molecule for targeted therapy, and a pharmaceutical composition containing said complex. We also provide camptothecin analogs, intermediates for the camptothecin analog complex, and methods for producing them. We also provide applications for targeted therapy of camptothecin analogs, camptothecin analog complexes, pharmaceutical compositions containing camptothecin analogs, and pharmaceutical compositions containing the camptothecin analog and cell-binding molecule complex.

[0002] [Cross-reference of related applications] This application claims the rights and priority of U.S. Provisional Application No. 63 / 336,995 (filed April 29, 2022), the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0003] Cancer is a leading cause of death worldwide. Surgery, chemotherapy, radiation therapy, and targeted therapy are standard treatments. Despite the widespread application of chemotherapy, its use is limited by undesirable side effects due to its effects on cells other than the tumor and its environment, resulting in systemic toxicity and a narrow therapeutic range. The discovery of the unique composition of cancer cell surfaces and the understanding of potent and selective interactions between antibodies and cell surface antigens have opened the way for the use of antibodies as targeted delivery agents for chemotherapy, including highly toxic drugs (Non-Patent Literature 1-4). The resulting molecular entities, also known as antibody-drug conjugates (ADCs), consist of three main parts: an antibody that selectively recognizes cancer cell surface antigens that can internalize the ADC; a drug payload that, upon release into the cell, kills cancer cells; and a linker that conjugates the antibody and the payload portion.

[0004] Antibody-drug conjugates (ADCs) combine selective targeting of tumor cells through antigen-directed recognition with potent cell killing by a cytotoxic payload, and have recently emerged as an effective treatment for various cancers (Non-Patent Literature 5). The first ADC (Mylotarg) was approved in 2000 (retracted in 2010 and re-approved in 2017), and the second ADC (Adcetris) received accelerated approval in 2011 and full approval in 2015.

[0005] The third ADC (Kadcyla) and the fourth ADC (Besponsa) were approved in 2013 and 2017, respectively. Kadcyla was the first ADC approved for the treatment of solid tumors. Since 2019, more than 10 ADCs have been approved, and there are more than 100 ADCs in clinical development.

[0006] The payload linker component of ADCs is known to make significant contributions to ADC homogeneity, circulatory stability, pharmacokinetic (PK) profile, tolerance, and overall therapeutic effect (Non-Patent Literature 6, 7). Despite extensive research to improve these profiles, most payloads used to date include DNA damaging agents (such as calichemycin, PBD, and duocalmycin), microtubule inhibitors (such as mytansins like DM1 and DM4, allistatins like MMAE and MMAF, and tubulicin), and topoisomerase inhibitors (such as camptothecins like Dxd and SN-38) (Non-Patent Literature 8-10).

[0007] Among these payloads, camptothecin has proven to be a promising choice with a broader range of therapeutic metrics than many other payloads for ADC construction. Of the approved ADCs, Enhertu and Trodelvy, which employ the camptothecin payload Dxd and SN-38 respectively, have demonstrated significant clinical efficacy (progression-free survival (PFS) and overall survival (OS)) against solid tumors in numerous clinical trials (Non-patent Literature 11, 12). Camptothecin can induce cell death by interacting with the DNA enzyme topoisomerase I and accumulating the reversible enzyme-camptothecin-DNA ternary complex. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International Publication No. 2021 / 212638 [Non-patent literature]

[0009] [Non-Patent Document 1] Drago, JZ et al., Nat. Rev. Clin. Oncol. 2021. [Non-Patent Document 2] Khongorzul, P. et al., Mol. Cancer Res. 2020, 18, 3-19. [Non-Patent Document 3] Joubert, N. et al.; The Last Decade. Pharmaceuticals 2020, 13, 245. [Non-Patent Document 4] Ravi VJ Chari et al., Angew. Chem. Int. Ed. 2014, 53, 3796 - 3827 [Non-Patent Document 5] Nature review Drug Discovery, 2013, 12, 329-332 [Non-Patent Document 6] Acchionea, M. et al., mAbs. 2012, 4, 362. [Non-Patent Document 7] Zhao, RY et al., J. Med. Chem. 2011, 54, 3606 [Non-Patent Document 8] Leung, D., et al., Antibodies (Basel).2020, 9, 2. [Non-Patent Document 9] Khongorzul, P., et al., Mol. Cancer. Res., 2020, 18, 3. [Non-Patent Document 10] Chau, CH, et al., Lancet. 2019, 394, 793. [Non-Patent Document 11] Ponde, N., et al., Curr Treat Options Oncol. 2019, 20, 37. [Non-Patent Document 12] Kaplon, H., et al., Mabs. 2020, 12, 1703531. [Non-Patent Document 13] Burke, P., et al. Bioconjugate Chem. 2009, 20, 6, 1242 [Non-Patent Document 14] Palakurthi,S., expert opin drug deliv.2015.,12(12),1911 [Disclosure of the Invention] [Problems that the invention aims to solve]

[0010] Camptothecin is a potent antitumor antibiotic isolated in 1958 from an extract of Camptothecinus sempervirens, a plant that has been widely used in traditional Chinese medicine for centuries. Numerous camptothecin analogs have been disclosed, as shown below.

[0011] [ka]

[0012] Most camptothecin and its analogues are highly insoluble in physiological buffers and have shown high rates of adverse drug reactions in preliminary clinical trials since the 1970s. The low solubility of camptothecin can lead to aggregation of ADC complexes (Non-Patent Literature 13), which poses a problem for scale-up manufacturing and can cause systematic side effects due to aggregation. To date, the U.S. FDA has approved only three water-soluble camptothecin analogues for cancer treatment: topotecan, irinotecan, and berotecan (Non-Patent Literature 14). Most camptothecin payloads used in ADC development have low solubility, further limiting drug-antibody ratios and resulting in lower efficacy.

[0013] The present invention provides a series of ligand-drug conjugates of camptothecin analogs. [Means for solving the problem]

[0014] This disclosure provides a complex of a camptothecin analog bound to a cell-binding molecule, a camptothecin analog-linker compound, and a camptothecin analog, as well as methods for producing and using them, and intermediates useful for their production. The camptothecin analog complex of this disclosure is water-soluble and stable in circulation, and when free camptothecin analogs or metabolites of the camptothecin analog-linker compound are released from the complex into the vicinity of or inside damaged cells, they generate high cytotoxicity.

[0015] Embodiment 1: The compound is of general formula I

[0016] [ka]

[0017] or having a pharmaceutically acceptable salt or solvate thereof, Eventually, Y and Z are independently selected from the group consisting of H, halo, hydroxy, cyano, C1-C8 alkyl, C1-C8 alkoxy, (C1-C8 alkoxy)-C1-C8 alkyl, amino, (C1-C8 alkyl)NHC(O)O-, (C3-C6 cycloalkyl)NHC(O)O-, (C1-C8 alkyl)NH-, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, (C1-C8 alkyl)C(O)O-, and (C1-C8 alkyl)C(O)NH-, or Y and Z, together with the atom to which they are attached, form a 5- to 8-membered heterocycloalkyl or 5- to 8-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, S, S(O) and S(O)2, wherein azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, 5- to 8-membered heterocycloalkyl, 5- to 8-membered heteroaryl, and each "C1-C8 alkyl" is independently optionally substituted with 1 to 3 R 9 and is optionally substituted with R 3 is selected from the group consisting of H, halo, hydroxy, cyano, C1-C8 alkyl, C1-C8 alkoxy, (C1-C8 alkoxy)-C1-C8 alkyl, amino, (C1-C8 alkyl)amino, (C1-C6 alkyl)NHC(O)O-, (C3-C6 cycloalkyl)NHC(O)O-, (C1-C6 alkyl)C(O)O-, (C1-C6 alkyl)C(O)NH-, aryl, heteroaryl, nitro, wherein "C1-C8 alkyl", cycloalkyl, aryl, heteroaryl are independently optionally substituted with 1 to 3 R 9 and is optionally substituted with each R 1 and each R 2 is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, or each pair of R 1 and R 2 forms, together with the atom to which they are attached, a 3- to 6-membered cycloalkyl or 4- to 8-membered heterocycloalkyl, wherein each R 1 , R 2 and R 1 / R 2Each ring group independently contains 1 to 4 R groups. 9 It is arbitrarily replaced with, n 3 is an integer selected from 0 to 6, X 1 It does not exist, or X 1 and R 8 Together with the atoms to which they are bonded, they form a 3-6 membered cycloalkyl or a 4-8 membered heterocycloalkyl, or X 1 and R 5 These atoms, together with the atoms to which they are bonded, form 3-6 membered cycloalkyl or 4-8 membered heterocycloalkyl groups, and the 3-6 membered cycloalkyl and 4-8 membered heterocycloalkyl groups independently have 1-3 R atoms. 9 It is arbitrarily replaced with, X 2 It comprises one or more groups independently selected from the group consisting of -O-, -S-, -NH-, C1-C6 alkylene, C3-C6 cycloalkylene, arylene, and heteroarylene, of which the group of formula (I)

[0018] [ka]

[0019] X connected 2 The terminal groups are O or S, and C1-C6 alkylenes, C3-C6 cycloalkylenes, arylenes, and heteroarylenes each independently have 1 to 3 R groups. 9 It is arbitrarily replaced with, R 4 , R 5 , R 6 , R 7 and R 8 At each occurrence, H is independently selected from the group consisting of halo, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, of which C1-C6 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl independently contain 1 to 4 R 9 It can be arbitrarily replaced with, or R 4 and R 5These, together with the atoms to which they are bonded, form a 3-6 member cycloalkyl or a 4-8 member heterocycloalkyl, or R 4 and R 7 These, together with the atoms to which they are bonded, form a 3-6 member cycloalkyl or a 4-8 member heterocycloalkyl, or R 6 and R 7 They form a 3-6 membered cycloalkyl group or a 4-8 membered heterocycloalkyl group with the atoms to which they are bonded, or R 7 and R 8 These, together with the atoms to which they are bonded, form oxo, 3-6 membered cycloalkyl, or 4-8 membered heterocycloalkyl groups, and of these, the 3-6 membered cycloalkyl and 4-8 membered heterocycloalkyl groups each independently have 1-4 R 9 It is arbitrarily replaced with the remaining R 4 , R 5 , R 6 , R 7 and R 8 At each occurrence, H is independently selected from the group consisting of halo, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, of which C1-C6 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl independently contain 1 to 4 R 9 It is arbitrarily replaced with, R 9 At each occurrence, the following are independently selected from the group consisting of halogen, oxo, hydroxy, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, aryl, and heteroaryl, or two R 9 When it bonds to an adjacent carbon, it forms a condensed C3-C6 cycloalkyl group with the carbon it is bonded to, or two R 9 When it bonds to an adjacent carbon, it forms a spiro-C3-C6 cycloalkyl group with the carbon it is bonded to, and each of these C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, aryl, heteroaryl, condensed C3-C6 cycloalkyl, and spiro-C3-C6 cycloalkyl groups can be independently optionally substituted with 1 to 3 fluoro or hydroxyl groups and C1-C3 alkyl groups. n 1 and n 2 n are integers independently selected from 0, 1, 2, 3, and 4, respectively. 1 + n 2 The condition is that is 2, 3, 4, or 5, and also, n is an integer selected from 0 and 1, and in some embodiments, one R 4 and one R 5 Together with the atoms to which they are bonded, they form a 3-6 membered cycloalkyl group or a 4-8 membered heterocycloalkyl group, R 4 and R 5 They are located on different but adjacent carbon atoms, and in some embodiments, one R 4 and one R 7 Together with the atoms to which they are bonded, they form a 3-6 membered cycloalkyl group or a 4-8 membered heterocycloalkyl group, R 6 and R 7 These are different but located on adjacent carbon atoms, and among them, 3-6 membered cycloalkyls and 4-8 membered heterocycloalkyls each independently have 1-4 R 9 It is arbitrarily replaced with, In some embodiments or aspects of the present invention, the composition or method is provided that the claim does not include any of the following substructures.

[0020] [ka]

[0021] Embodiment A: In some embodiments of the present disclosure, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is n 1 and n 2 n is an integer independently selected from 0, 1, and 2. 1 + n 2 Provided that is ≥ 2, all other variables are as defined in Embodiment 1.

[0022] Embodiment 2: In some embodiments of the present disclosure, the ligand-drug conjugate or its pharmaceutically acceptable salt or solvate is a compound of formula (II) or its ligand-drug conjugate or its pharmaceutically acceptable salt or solvate.

[0023] [ka]

[0024] Among them, Y, Z, R 3 , R 4 , R 5、 R 6、 R 7、 R 8、 X 1、 X 2、 n 1 , and n 2 This is defined by formula (I) in Embodiment 1, or as defined in Embodiment A.

[0025] Embodiment 2-A: In some embodiments of the present disclosure, the ligand-drug conjugate or a pharmaceutically acceptable salt or solvate thereof is a compound of formula (IIa) or a ligand-drug conjugate thereof or a pharmaceutically acceptable salt or solvate thereof.

[0026] [ka]

[0027] Among them, Y, Z, R 3 , each R 4 (Independently), each R 6 (Independently), R 5 , R 7 , R 8 , X 1 , and X 2 n is defined as shown in equation (I) of aspect 1, and 1 and n 2a n are integers independently selected from 0, 1, 2, 3, and 4, respectively. 1 + n 2a This is conditional on being 2, 3, or 4. In some embodiments, Y, Z, R3 、each R 4 (independently), each R 6 (independently), R 7 、R 9 、and X 2 is as defined in formula (I) of embodiment 1, and among them, X 1 does not exist, or, when R 4 and R 5 also do not form a ring, X 1 and R 5 together with the atom to which they are attached form a 3- to 6-membered cycloalkyl or a 4- to 8-membered heterocycloalkyl, among which the 3- to 6-membered cycloalkyl and the 4- to 8-membered heterocycloalkyl are optionally substituted with 1 to 3 R 9 s, and R 8 at each occurrence is independently selected from the group consisting of H, halo, hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, aryl and heteroaryl, among which C1-C6 alkyl, C3-C6 cycloalkyl, aryl and heteroaryl are independently optionally substituted with 1 to 4 R 9 s, and also n 1 and n 2a are each an integer independently selected from 0, 1, 2, 3, and 4, with the condition that n 1 + n 2a is 2, 3, or 4.

[0028] Embodiment 3: In some embodiments of the present disclosure, the ligand-drug complex or its pharmaceutically acceptable salt or solvate conforms to formula (III),

[0029]

Chemical formula

[0030] Among them, Y and Z are independently selected from the group consisting of H and halo, hydroxy, cyano, C1-C8 alkyl, C1-C8 alkoxy, (C1-C8 alkoxy)-C1-C8 alkyl, amino, (C1-C8 alkyl)NHC(O)O-, (C3-C6 cycloalkyl)NHC(O)O-, (C1-C8 alkyl)NH-, azetidine-1-yl, pyrrolidine-1-yl, piperidine-1-yl, azepan-1-yl, (C1-C8 alkyl)C(O)O-, and (C1-C8 alkyl)C(O)NH-, or Y and Z, together with the atom to which they are bonded, are N, O, S, S(O) and A 5-8 membered heterocycloalkyl or 5-8 membered heteroaryl is formed having 1-3 heteroatoms independently selected from S(O)2, of which azetidine-1-yl, pyrrolidine-1-yl, piperidine-1-yl, azepan-1-yl, 5-8 membered heterocycloalkyl, 5-8 membered heteroaryl, and each "C1-C8 alkyl" independently has 1-3 R 9 It is arbitrarily replaced with, R 3 The group is selected from H and halo, hydroxy, cyano, C1-C8 alkyl, C1-C8 alkoxy, (C1-C8 alkoxy)-C1-C8 alkyl, amino, (C1-C8 alkyl)amino, (C1-C8 alkyl)NHC(O)O-, (C3-C6 cycloalkyl)NHC(O)O-, (C1-C8 alkyl)C(O)O-, (C1-C8 alkyl)C(O)NH-, aryl, heteroaryl, and nitro, of which "C1-C8 alkyl" cycloalkyl, aryl, and heteroaryl independently have 1 to 3 R 9 It is arbitrarily replaced with, Each R 1 and each R 2 is independently selected from H, C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, or R 1 and R 2 Each pair, together with the atom to which they are bonded, forms a 3-6 membered cycloalkyl or a 4-8 membered heterocycloalkyl, of which each R 1 , R 2 , and R 1 / R 2Each ring group independently contains 1 to 4 R groups. 9 It is arbitrarily replaced with, n 3 is an integer selected from 0 to 6, X 1 It does not exist, or X 1 and R 8 Together with the atoms to which they are bonded, they form a 3-6 membered cycloalkyl or a 4-8 membered heterocycloalkyl, or X 1 and R 5 These atoms, together with the atoms to which they are bonded, form 3-6 membered cycloalkyl or 4-8 membered heterocycloalkyl groups, and the 3-6 membered cycloalkyl and 4-8 membered heterocycloalkyl groups independently have 1-3 R atoms. 9 It is arbitrarily replaced with, X 2 It comprises one or more groups independently selected from the group consisting of -O-, -S-, -NH-, C1-C8 alkylene, C3-C6 cycloalkylene, arylene, and heteroarylene, of which X is connected to L. 2 The terminal groups are O or S, and C1-C8 alkylenes, C3-C6 cycloalkylenes, arylenes, and heteroarylenes each independently have 1 to 3 R groups. 9 It is arbitrarily replaced with, R 4 , R 5 , R 6 , R 7 and R 8 At each occurrence, H is independently selected from the group consisting of halo, hydroxyl, C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, and of these, C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl each independently contain 1 to 4 R 9 It is arbitrarily replaced with, R 4 and R 5 These, together with the atoms to which they are bonded, form a 3-6 member cycloalkyl or a 4-8 member heterocycloalkyl, or R 4 and R 7 These, together with the atoms to which they are bonded, form a 3-6 member cycloalkyl or a 4-8 member heterocycloalkyl, or R6 and R 7 They form a 3-6 membered cycloalkyl group or a 4-8 membered heterocycloalkyl group together with the atoms to which they are bonded, or R 7 and R 8 These, together with the atoms to which they are bonded, form oxo, 3-6 membered cycloalkyl, or 4-8 membered heterocycloalkyl groups, and of these, the 3-6 membered cycloalkyl and 4-8 membered heterocycloalkyl groups each independently have 1-4 R 9 It is arbitrarily replaced with the remaining R 4 , R 5 , R 6 , R 7 and R 8 At each occurrence, H is independently selected from the group consisting of halo, hydroxyl, C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, of which C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl independently contain 1 to 4 R 9 It is arbitrarily replaced with, R 9 At each occurrence, the following are independently selected from the group consisting of halogen, oxo, hydroxy, cyano, C1-C8 alkyl, C3-C6 cycloalkyl, C1-C8 alkoxy, aryl, and heteroaryl, or two R 9 When it bonds to an adjacent carbon, it forms a condensed C3-C6 cycloalkyl group with the carbon it is bonded to, or two R 9 When it bonds to an adjacent carbon, it forms a spiro-C3-C6 cycloalkyl group with the carbon it is bonded to, and each of these C1-C8 alkyl, C3-C6 cycloalkyl, C1-C8 alkoxy, aryl, heteroaryl, condensed C3-C6 cycloalkyl, and spiro-C3-C6 cycloalkyl groups can be independently optionally substituted with 1 to 3 fluoro or hydroxyl groups and C1-C3 alkyl groups. n 1 and n 2 n are integers independently selected from 0, 1, 2, 3, and 4, respectively. 1 + n 2 The condition is that it is 2, 3, or 4, and also, n is an integer selected from 0 and 1. T is a targeting or binding ligand, L is a releaseable linker, M is an integer or fraction selected from 1 to 10.

[0031] Embodiment B: In some embodiments of the present disclosure, a compound of formula III, or a pharmaceutically acceptable salt or solvate thereof, is n 1 and n 2 n is an integer independently selected from 0, 1, and 2. 1 + n 2 Provided that is ≥ 2, all other variables are as defined in Embodiment 3.

[0032] Embodiment 3-A: In some embodiments of the present disclosure, the ligand-drug conjugate or a pharmaceutically acceptable salt or solvate thereof conforms to formula (IIIa).

[0033] [ka]

[0034] Among them, Y, Z, R 1 , R 2 , R 3 , each R 4 (Independently), each R 6 (Independently), R 5 , R 7 , R 8 , X 1、 X 2、 L, T, m, and n are defined in formula (III) of Embodiment 3, and n 1 and n 2a n are integers independently selected from 0, 1, 2, 3, and 4, respectively. 1 + n 2a This is conditional on being 2, 3, or 4. In some embodiments, Y, Z, R 1 , R 2 , R 3 , each R 4 (Independently), each R6 (Independently), R 7 , X 2、 L, T, m, and n are as defined by formula (III) of Embodiment 3, and of these, X 1 It does not exist, or R 4 and R 5 If X does not form a ring, 1 and R 5 These, together with the atoms to which they are bonded, form 3-6 membered cycloalkyl or 4-8 membered heterocycloalkyl groups, of which the 3-6 membered cycloalkyl and 4-8 membered heterocycloalkyl groups have 1-3 R atoms. 9 It is arbitrarily replaced with R 8 The group is selected from H and halo, hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, and of these, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl each independently contain 1 to 4 R 9 It is arbitrarily replaced by, and also, n 1 and n 2a n are integers independently selected from 0, 1, 2, 3, and 4, respectively. 1 + n 2a The condition is that R is 2, 3, or 4. In some embodiments, R 1 and R 2 These are hydrogen atoms, respectively.

[0035] Embodiment 3-B: In some embodiments of the present disclosure, the ligand-drug conjugate or its pharmaceutically acceptable salt or solvate conforms to formula (IIIb),

[0036] [ka]

[0037] Among them, Y, Z, R 1 , R 2 , R 3 , X 2 L, T, m, and n are as defined in formula (IIIa) of Embodiment 3-A and any embodiment thereof.4 and R 5 and R 6 and R 7 and R 8 each occurrence of R is independently selected from the group consisting of H, halo, hydroxy, C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, and among them, C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl are each independently optionally substituted with 1 to 4 R 9 and X 1 is absent, and n 1 and n 2a are each an integer independently selected from 0, 1, 2, 3, and 4, provided that n 1 + n 2aが is 2, 3, or 4. In some embodiments, R 1 and R 2 are each hydrogen, and

[0038]

Chemical formula

[0039] is

[0040]

Chemical formula

[0041] is.

[0042] In some embodiments of the present disclosure, the ligand-drug conjugate, or a pharmaceutically acceptable salt or solvate thereof, is any of formulas (I), (II), (IIa), (III), and (IIIa), and includes those defined in Aspect 1, Embodiment A, Aspect 2, Aspect 2-A, Aspect 3, Aspect 3-A, and Embodiment B, among which in Formulas I, II, and III

[0043]

Chemical formula

[0044] In IIa and IIIa,

[0045] [Chemical formula]

[0046] is a structure selected from the following structures.

[0047] [Chemical formula]

[0048] In some embodiments, the structure of any of formula (I), (II), (IIa), (III), and (IIIa), or a pharmaceutically acceptable salt or solvate thereof, includes those defined in Aspect 1, Embodiment A, Aspect 2, Aspect 2-A, Aspect 3, Aspect 3-A, and Embodiment B, among which, In formulas I, II, and III

[0049] [Chemical formula]

[0050] In IIa and IIIa

[0051] [Chemical formula]

[0052] is selected from the following.

[0053] [Chemical formula]

[0054] In some embodiments, any structure of formula (I), (II), (IIa), (III), and (IIIa), or a pharmaceutically acceptable salt or solvate thereof, includes those defined in Embodiment 1, Embodiment A, Embodiment 2, Embodiment 2-A, Embodiment 3, Embodiment 3-A, and Embodiment B, among which, In formulas I, II, and III

[0055] [ka]

[0056] In equations IIa and IIIa

[0057] [ka]

[0058] The following structures are selected.

[0059] [ka]

[0060] In some embodiments, any structure of formula (I), (II), (IIa), (III), and (IIIa), or a pharmaceutically acceptable salt or solvate thereof, includes those defined in Embodiment 1, Embodiment A, Embodiment 2, Embodiment 2-A, Embodiment 3, Embodiment 3-A, and Embodiment B, among which, In formulas I, II, and III

[0061] [ka]

[0062] In equations IIa and IIIa

[0063] [ka]

[0064] The following structures are selected.

[0065] [ka]

[0066] In some embodiments, any structure of formula (I), (II), (IIa), (III), and (IIIa), or a pharmaceutically acceptable salt or solvate thereof, includes those defined in Embodiment 1, Embodiment A, Embodiment 2, Embodiment 2-A, Embodiment 3, Embodiment 3-A, and Embodiment B, among which, In formulas I, II, and III

[0067] [ka]

[0068] In equations IIa and IIIa

[0069] [ka]

[0070] The following structures are selected.

[0071] [ka]

[0072] In another preferred embodiment of the present disclosure, the ligand-drug conjugate or pharmaceutically acceptable salt or solvate thereof according to the present disclosure includes any of formulas (I), (II), (IIa), (III), (IIIa), and (IIIb), as well as any embodiment thereof, including those defined in Embodiment 1, Embodiment A, Embodiment 2, Embodiment 2-A, Embodiment 3, Embodiment 3-A, and Embodiment B, wherein the linker unit L is -L 1 -L 2 -L 3 -L 4 -and among them, L1 teeth,

[0073] [ka]

[0074] -CH2-C(O)-NR 10 A selection is made from the group consisting of -WC(O)- and -C(O)-WC(O)-, and -W-, of which W and W 1 The L is independently selected from the group consisting of C1-C8 alkylene, -(C1-C8 alkylene)-cycloalkylene, arylene, heteroarylene, and linear heteroalkylene, of which linear heteroalkylene contains 1 to 8 carbon atoms and 1 to 3 heteroatoms selected from the group consisting of N, O, S, SO, and SO2, and of which -(C1-C8 alkylene)-cycloalkylene-linear heteroalkylene, arylene, and heteroarylene are each independently optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy, and cycloalkyl, and of which the L 1 Each left side of the base is connected to T, L 2 -NR 11 (CH2CH2O) p 1 CH2CH2C(O)-, -NR 11 (CH2CH2O) p 1 CH2CH2-, -NR 11 (CH2CH2O) p 1 CH2C(O)-, -S(CH2) p 1 Selected from the group consisting of C(O)- and chemical bonds, among them, p 1 L is an integer selected from 1 to 20 at each occurrence, and L 2 It is preferable that the bond is a chemical bond, and of which, L 2 The left side of each base is L 1 It is connected, L3 L is a peptide residue consisting of 2 to 7 amino acids, of which the amino acids are optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and cycloalkyl, and of which L 3 The left side of each base is L 2 It is connected, L 4 -NR 12 (CR 13 R 14 ) t -, -C(O)NR 12 -, -C(O)NR 12 (CH) t -,

[0075] [ka]

[0076] A selection is made from the group consisting of and chemical bonds, where t is an integer selected from 1 to 6 at each occurrence, and preferably L 4 -NR 12 (CR 13 R 14 ) t - And of which, L 4 The left side of each base is L 3 It is connected to the right side of the L 4 The right side of each base is X 2 It is connected, R 10 , R 11 and R 12 Each of these is independently selected from the group consisting of H, alkyl, haloalkyl, deuterated alkyl, and hydroxyalkyl. R 13 and R 14 Each of these is independently selected from the group consisting of H, halogen alkyl, haloalkyl, deuterated alkyl, and hydroxyalkyl, and also, R 15The channel is selected from -CH2CH2SO2CH3 and -CH2CH2N(CH3)2.

[0077] Another preferred embodiment of the present disclosure includes any of formulas (I), (II), (IIa), (III), (IIIa), and (IIIb), as well as any embodiment thereof, including those defined in Embodiment 1, Embodiment A, Embodiment 2, Embodiment 2-A, Embodiment 3, Embodiment 3-A, and Embodiment B, wherein the ligand-drug complex, or a pharmaceutically acceptable salt or solvate thereof, comprises a linker unit L 1 teeth,

[0078] [ka]

[0079] -CH2-C(O)-NR 10 -(CH2)s 3 -C(O)- (of which the left side of this group is connected to T), -C(O)-(CH2)s 4 -C(O)- (of which the left side of this group is connected to T), and -C6H4- are selected from the group, of which s 1 is an integer selected from 2 to 8, and s 2 is an integer selected from 1 to 3, and s 3 is an integer selected from 1 to 8, and s 4 is an integer selected from 1 to 8, of which s 1 =5 is preferable. L 2 -NR 11 (CH2CH2O) p 1 CH2CH2C(O)-, -NR 11 (CH2CH2O) p 1 CH2CH2-, -NR 11 (CH2CH2O) p 1 CH2C(O)-, -S(CH2) p 1 A selection from the group consisting of C(O)- and chemical bonds, among which, p1 L is an integer selected from 6 to 12 at each occurrence, and L 2 It is preferable that the bond is a chemical bond, and of which, L 2 The left side of each base is L 1 It is connected, L 3 L is a peptide residue consisting of 2 to 7 amino acids, of which the amino acids are selected from phenylalanine (F), glycine (G), valine (V), lysine (K), citrulline, serine (S), glutamic acid (E), and aspartic acid (N), preferably a peptide residue consisting of 1, 2 or more phenylalanine and glycine, more preferably a peptide residue consisting of 4 amino acids, most preferably a peptide residue consisting of GGFG, of which L 3 The left side of each base is L 2 It is connected, L 4 is -NR 12 (CR 13 R 14 )t- and R 12 is H or alkyl, and R 13 and R 14 Each is independently selected from H or alkyl, t is 1 or 2, and L 4 -NR (optional) 12 CR 13 R 14 - and, preferably, L 4 is -NHCH2, of which L 4 The left side of each base is L 3 It is connected to the right side of the L 4 The right side of each base is X 2 It is connected, R 10 , R 11 and R 12 Each of these is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, deuterated alkyl, and hydroxyalkyl, and R 13 and R 14Each of these is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, deuterated alkyl, and hydroxyalkyl.

[0080] Embodiment 4: In some embodiments of the present disclosure, a compound or a pharmaceutically acceptable salt or solvate thereof is provided as a tautomer, mesomer, racemic mixture, enantiomer, diastereomer, or mixture thereof, wherein the compound is represented by formula (IV).

[0081] [ka]

[0082] Among them, Y, Z, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X 1 , X 2 , L 2 , L 3 , L 4 , W, n 1 , n 2 , T, and m are as defined in formula (III) and any embodiment thereof, including those defined in embodiment B, and also n 3 This is an integer selected from 0 to 6.

[0083] Embodiment 4-A: In some embodiments of the present disclosure, a compound or a pharmaceutically acceptable salt or solvate thereof is provided, optionally as a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, of which the compound is represented by formula (IVa):

[0084] [ka]

[0085] Among them, Y, Z, R 3 , R 4 , R5 , R 6 , R 7 , R 8 , X 1 , X 2 , L 2 , L 3 , L 4 , W, n 1 , n 2a , T, and m are as defined in formula (IIIa) and any embodiment thereof, and also n 3 This is an integer selected from 0 to 6.

[0086] In some embodiments of the present disclosure, the ligand-drug conjugate or its pharmaceutically acceptable salt or solvate is represented by (IV) or (IVa), of which, Equation (IV)

[0087] [ka]

[0088] and equation (IVa)

[0089] [ka] This is a structure selected from the following structures.

[0090] [ka]

[0091] In some embodiments, the structure of either formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, among which, Equation (IV)

[0092] [ka]

[0093] and equation (IVa)

[0094] [ka]

[0095] The following structures are selected.

[0096] [ka]

[0097] In some embodiments, the structure of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, among which, Equation (IV)

[0098] [ka]

[0099] and equation (IVa)

[0100] [ka]

[0101] The following structures are selected.

[0102] [ka]

[0103] In some embodiments, the structure of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, among which, Equation (IV)

[0104] [ka]

[0105] and equation (IVa)

[0106] [ka]

[0107] The following structures are selected.

[0108] [ka]

[0109] In some embodiments, the structure of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, among which, Equation (IV)

[0110] [ka]

[0111] and equation (IVa)

[0112] [ka]

[0113] The following structures are selected.

[0114] [ka]

[0115] In some embodiments, the ligand-drug complex is

[0116] [ka]

[0117] [ka]

[0118]

change

[0119]

change

[0120]

change

[0121]

change

[0122]

change

[0123]

change

[0124]

change

[0125]

change

[0126]

change

[0127]

change

[0128]

change

[0129] [ka]

[0130] [ka]

[0131] [ka]

[0132] [ka]

[0133] [ka]

[0134] [ka]

[0135] or including, but not limited to, pharmaceutically acceptable salts or solvates thereof, Of these, T and m are as defined in formula (III) or (IIIa) and any embodiment thereof, including those defined in Embodiment B, of which further embodiments of T are provided below.

[0136] In some embodiments of this disclosure, ligand-drug conjugates or pharmaceutically acceptable salts or solvates thereof are provided, among which, T is a target antibody or ligand that binds to the antigen, and the antibody is selected from chimeric antibodies, humanized antibodies, and human antibodies, and optionally, T is a monoclonal antibody.

[0137] In some embodiments of this disclosure, ligand-drug conjugates or pharmaceutically acceptable salts or solvates thereof are provided, among which, T is selected from anti-Her2 (ErbB2) antibody, anti-EGFR antibody, anti-B7H3 antibody, anti-c-MET antibody, anti-Her3 (ErbB3) antibody, anti-Her4 (ErbB4) antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-MICI antibody, anti-Lewis Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-integrin antibody, anti-PSMA antibody, anti-tenascin C antibody, anti-SLC44A4 antibody or anti-mesothelin antibody, and anti-ROR1 antibody, or antigen-binding fragments.

[0138] In some embodiments of the present disclosure, ligand-drug conjugates or pharmaceutically acceptable salts or solvates thereof are provided, where T is selected from trastuzumab, pertuzumab, nimotuzumab, enobrituzumab, emibetuzumab, inotuzumab, pinatuzumab, brentuximab, gemtuzumab, vibatuzumab, lorbotuzumab, cBR96, and glenbatumumab, or antigen-binding fragments.

[0139] In some embodiments, the ligand-drug complex is

[0140] [ka]

[0141] [ka]

[0142] [ka]

[0143]

change

[0144]

change

[0145]

change

[0146]

change

[0147]

change

[0148]

change

[0149]

change

[0150]

change

[0151]

change

[0152]

change

[0153]

change

[0154] [ka]

[0155] [ka]

[0156] [ka]

[0157] [ka]

[0158] and,

[0159] [ka]

[0160] or including, but not limited to, pharmaceutically acceptable salts or solvates thereof, Of these, m is defined in formula (III) or (IIIa) and any embodiment thereof, and includes those defined in embodiment B.

[0161] Embodiment 5: In some embodiments of the present disclosure, a compound or a pharmaceutically acceptable salt or solvate thereof is provided as a tautomer, mesomer, racemic mixture, enantiomer, diastereomer, or combination thereof, wherein the compound is represented by formula (V),

[0162] [ka]

[0163] Among them, Y, Z, R 1 , R 2 , R 3 , R 4, R 5 , R 6 , R 7 , R 8 , X 1 , X 2 , n 1 , and n 2 This is as defined in formula (III) and any embodiment thereof, including as defined in embodiment B, and also L 2 -NR 11 (CH2CH2O) p 1 CH2CH2C(O)-, -NR 11 (CH2CH2O) p 1 CH2CH2-, -NR 11 (CH2CH2O) p 1 CH2C(O)-, -S(CH2) p 1 Selected from the group consisting of C(O)- and chemical bonds, among them, p 1 L is an integer selected from 1 to 20, and L 2 It is preferable that the bond is a chemical bond, and of which, L 2 The left side of each base is L 1 It is connected, L 3 L is a peptide residue consisting of 2 to 7 amino acids, of which the amino acids are optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and cycloalkyl, and of which L 3 The left side of each base is L 2 It is connected, L 4 -NR 12 (CR 13 R 14 )t-,-C(O)NR 12 -, -C(O)NR 12 (CH) t -,

[0164] [ka]

[0165] A selection from the group consisting of and chemical bonds, where t is an integer selected from 1 to 6, and preferably L 4 -NR 12 (CR 13 R 14 ) t - And of which, L 4 The left side of each base is L 3 It is connected to the right side of the L 4 The right side of each base is X 2 It is connected, R 11 and R 12 Each of these is independently selected from the group consisting of H, alkyl, haloalkyl, deuterated alkyl, and hydroxyalkyl. R 13 and R 14 Each of these is independently selected from the group consisting of H, halogen alkyl, haloalkyl, deuterated alkyl, and hydroxyalkyl, and also, R 15 The channel is selected from -CH2CH2SO2CH3 and -CH2CH2N(CH3)2. W is selected from the group consisting of C1-C8 alkylene, -(C1-C8 alkylene)-cycloalkylene, arylene, heteroarylene, and linear heteroalkylene, of which linear heteroalkylene contains 1 to 8 carbon atoms and 1 to 3 heteroatoms selected from the group consisting of N, O, S, SO, and SO2, and of which -(C1-C8 alkylene)-cycloalkylene-linear heteroalkylene, arylene, and heteroarylene are each independently optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy, and cycloalkyl. Also, n 3 is an integer selected from 0 to 6, and in some embodiments, L 2 -NR 11 (CH2CH2O)p 1 CH2CH2C(O)-, -NR 11 (CH2CH2O) p 1 CH2CH2-, -NR 11 (CH2CH2O) p 1 CH2C(O)-, -S(CH2) p 1 A selection from the group consisting of C(O)- and chemical bonds, among which, p 1 L is an integer selected from 6 to 12 at each occurrence, and L 2 It is preferable that the bond is a chemical bond, and of which, L 2 The left side of each base is L 1 It is connected, L 3 L is a peptide residue consisting of 2 to 7 amino acids, of which the amino acids are selected from phenylalanine (F), glycine (G), valine (V), lysine (K), citrulline, serine (S), glutamic acid (E), and aspartic acid (N), preferably a peptide residue consisting of 1, 2 or more phenylalanine and glycine, more preferably a peptide residue consisting of 4 amino acids, most preferably a peptide residue consisting of GGFG, of which L 3 The left side of each base is L 2 It is connected, L 4 is -NR 12 (CR 13 R 14 )t- and R 12 is H or alkyl, and R 13 and R 14 Each is independently selected from H or alkyl, t is 1 or 2, and L 4 -NR (optional) 12 CR 13 R 14 - and, preferably, L 4 is -NHCH2, of which L 4 The left side of each base is L 3 It is connected to the right side of the L 4The right side of each base is X 2 It is connected, R 11 and R 12 Each of these is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, deuterated alkyl, and hydroxyalkyl, and R 13 and R 14 Each of these is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, deuterated alkyl, and hydroxyalkyl.

[0166] Embodiment 5-A: In some embodiments of the present disclosure, a compound or a pharmaceutically acceptable salt or solvate thereof is provided as a tautomer, mesomer, racemic, enantiomer, diastereomer, or combination thereof, wherein the compound is represented by formula (Va),

[0167] [ka]

[0168] Among them, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X 1 , X 2 , n 1 , and n 2 L is defined as in formula (IIIa) and any embodiment thereof, and also L 2 , L 3 , L 4 , W and n 3 This is as defined in formula (V) and its embodiment in Embodiment 5.

[0169] In some embodiments of this disclosure, the ligand-drug conjugate or its pharmaceutically acceptable salt or solvate is represented by (V) or (Va), of which,

[0170] Equation (V)

[0171] [ka]

[0172] and equation (Va)

[0173] [ka]

[0174] This is a structure selected from the following structures.

[0175] [ka]

[0176] In some embodiments, the structure of formula (V) or (VA), or a pharmaceutically acceptable salt or solvate thereof, among which, Equation (V)

[0177] [ka]

[0178] and equation (Va)

[0179] [ka]

[0180] The following structures are selected.

[0181] [ka]

[0182] In some embodiments, the structure of formula (V) or (VA), or a pharmaceutically acceptable salt or solvate thereof, among which, Equation (V)

[0183] [ka]

[0184] and equation (Va)

[0185] [ka]

[0186] The following structures are selected.

[0187] [ka]

[0188] In some embodiments, the structure of formula (V) or (VA), or a pharmaceutically acceptable salt or solvate thereof, among which, Equation (V)

[0189] [ka]

[0190] and equation (Va)

[0191] [ka]

[0192] The following structures are selected.

[0193] [ka]

[0194] In some embodiments, the structure of formula (V) or (VA), or a pharmaceutically acceptable salt or solvate thereof, among which, Equation (V)

[0195] [ka]

[0196] and equation (Va)

[0197] [ka]

[0198] The following structures are selected.

[0199] [ka]

[0200] In some embodiments, the compound is

[0201] [ka]

[0202] [ka]

[0203] [ka]

[0204] [ka]

[0205] [ka]

[0206] This includes, but is not limited to, pharmaceutically acceptable salts or solvates thereof.

[0207] Embodiment 6: In some embodiments of the present disclosure, a compound or a pharmaceutically acceptable salt or solvate thereof is provided as a tautomer, mesomer, racemic, enantiomer, diastereomer, or combination thereof, wherein the compound is represented by formula (VI),

[0208] [ka]

[0209] Eventually, Y and Z consist of H and halo, hydroxy, cyano, C1-C8 alkyl, C1-C8 alkoxy, (C1-C8 alkoxy)-C1-C8 alkyl, amino, (C1-C8 alkyl)NHC(O)O-, (C3-C6 cycloalkyl)NHC(O)O-, (C1-C8 alkyl)NH-, azetidine-1-yl, pyrrolidine-1-yl, piperidine-1-yl, azepan-1-yl, C1-C8 alkyl)C(O)O-, and (C1-C8 alkyl)C(O)NH-. Independently selected from the group, or Y and Z, together with the atom to which they are bonded, form a 5-8 membered heterocycloalkyl or 5-8 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, S, S(O) and S(O)2, of which azetidine-1-yl, pyrrolidine-1-yl, piperidine-1-yl, azepan-1-yl, 5-8 membered heterocycloalkyl, 5-8 membered heteroaryl, and each "C1-C8 alkyl" independently has 1-3 R 9 It is arbitrarily replaced with, Each R 1 and each R 2 is independently selected from H, C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, or R 1 and R 2 Each pair, together with the atom to which they are bonded, forms a 3-6 membered cycloalkyl or a 4-8 membered heterocycloalkyl, of which each R 1 , R 2 , and R 1 / R2 Each ring group independently contains 1 to 4 R groups. 9 It is arbitrarily replaced with, n 3 is an integer selected from 0 to 6, R 3 The group is selected from H and halo, hydroxy, cyano, C1-C8 alkyl, C1-C8 alkoxy, (C1-C8 alkoxy)-C1-C8 alkyl, amino, (C1-C8 alkyl)amino, (C1-C8 alkyl)NHC(O)O-, (C3-C6 cycloalkyl)NHC(O)O-, (C1-C8 alkyl)C(O)O-, (C1-C8 alkyl)C(O)NH-, aryl, heteroaryl, and nitro, of which "C1-C8 alkyl" cycloalkyl, aryl, and heteroaryl independently have 1 to 3 R 9 It is arbitrarily replaced with, X 1 It does not exist, or X 1 and R 5 Together with the atoms to which they are bonded, they form a 3-6 membered cycloalkyl or a 4-8 membered heterocycloalkyl, or X 1 and R 8 These atoms, together with the atoms to which they are bonded, form 3-6 membered cycloalkyl or 4-8 membered heterocycloalkyl groups, and the 3-6 membered cycloalkyl and 4-8 membered heterocycloalkyl groups independently have 1-3 R atoms. 9 It is arbitrarily replaced with, X 2 It comprises one or more groups independently selected from the group consisting of -O-, -S-, -NH-, C1-C8 alkylene, C3-C6 cycloalkylene, arylene, and heteroarylene, of which -X 2 -X connected to H 2 The terminal groups are O or S, and C1-C8 alkylenes, C3-C6 cycloalkylenes, arylenes, and heteroarylenes each independently have 1 to 3 R groups. 9 It is arbitrarily replaced with, R 4 , R 5 , R 6 , R 7 and R 8At each occurrence, H is independently selected from the group consisting of halo, hydroxyl, C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, of which C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl independently contain 1 to 4 R 9 It can be arbitrarily replaced with, or R 4 and R 5 These, together with the atoms to which they are bonded, form a 3-6 member cycloalkyl or a 4-8 member heterocycloalkyl, or R 4 and R 7 These, together with the atoms to which they are bonded, form a 3-6 member cycloalkyl or a 4-8 member heterocycloalkyl, or R 6 and R 7 They form a 3-6 membered cycloalkyl group or a 4-8 membered heterocycloalkyl group with the atoms to which they are bonded, or R 7 and R 8 These, together with the atoms to which they are bonded, form oxo, 3-6 membered cycloalkyl, or 4-8 membered heterocycloalkyl groups, and of these, the 3-6 membered cycloalkyl and 4-8 membered heterocycloalkyl groups each independently have 1-4 R 9 It is arbitrarily replaced with the remaining R 4 , R 5 , R 6 , R 7 and R 8 At each occurrence, H is independently selected from the group consisting of halo, hydroxyl, C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, of which C1-C8 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl independently contain 1 to 4 R 9 It is arbitrarily replaced with, R 9 At each occurrence, the following are independently selected from the group consisting of halogen, oxo, hydroxy, cyano, C1-C8 alkyl, C3-C6 cycloalkyl, C1-C8 alkoxy, aryl, and heteroaryl, or two R 9 When it bonds to an adjacent carbon, it forms a condensed C3-C6 cycloalkyl group with the carbon it is bonded to, or two R9 When it bonds to an adjacent carbon, it forms a spiro-C3-C6 cycloalkyl group with the carbon it is bonded to, and each of these C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, aryl, heteroaryl, condensed C3-C6 cycloalkyl, and spiro-C3-C6 cycloalkyl groups can be independently optionally substituted with 1 to 3 fluoro or hydroxyl groups and C1-C3 alkyl groups. n 1 and n 2 n are integers independently selected from 0, 1, 2, 3, and 4, respectively. 1 + n 2 The condition is that it is 2, 3, or 4, and also, n is an integer selected from 0 and 1.

[0210] Embodiment C: In some embodiments of the present disclosure, a compound of formula VI, or a pharmaceutically acceptable salt or solvate thereof, is n 1 and n 2 n is an integer independently selected from 0, 1, and 2. 1 + n 2 Provided that is ≥ 2, all other variables are as defined in aspect 6.

[0211] Embodiment 6-A: In some embodiments of the present disclosure, a compound or a pharmaceutically acceptable salt or solvate thereof is provided as a tautomer, mesomer, racemate, enantiomer, diastereomer, or combination thereof, wherein the compound is represented by formula (VIa),

[0212] [ka]

[0213] Among them, Y, Z, R 1 , R 2 , R 3 , each R 4 (Independently), each R 6 (Independently), R 5 , R 7 , R8 , X 1、 and X 2 n is defined as in equation (VI) of aspect 6, and 3 n is an integer selected from 0 to 6, and also n 1 and n 2a n are integers independently selected from 0, 1, 2, 3, and 4, respectively. 1 + n 2aが The condition is that it is 2, 3, or 4. In some embodiments, Y, Z, R 1 , R 2 , R 3 , each R 4 (Independently), R 5 , each R 6 (Independently), R 7 , and X 2 This is defined by formula (VI) in aspect 6, and of which, X 1 It does not exist, or R 4 and R 5 If X does not form a ring, 1 and R 5 These, together with the atoms to which they are bonded, form 3-6 membered cycloalkyl or 4-8 membered heterocycloalkyl groups, of which the 3-6 membered cycloalkyl and 4-8 membered heterocycloalkyl groups have 1-3 R atoms. 9 It is arbitrarily replaced with R 8 The group is selected from H and halo, hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl, and of these, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl each independently contain 1 to 4 R 9 It is arbitrarily replaced by n 3 n is an integer selected from 0 to 6, and also n 1 and n 2a n are integers independently selected from 0, 1, 2, 3, and 4, respectively. 1 + n 2aが The condition is that it is 2, 3, or 4. In some embodiments, R 1 and R 2 These are hydrogen atoms, respectively.

[0214] Embodiment 7: In some embodiments of the present disclosure, a compound or a pharmaceutically acceptable salt or solvate thereof is provided as a tautomer, mesomer, racemate, enantiomer, diastereomer, or combination thereof, among which the compound of formula (VII) is,

[0215] [ka]

[0216] Among them, Y, Z, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X 1 , X 2 , n 1 and n 2 This is as defined by formula (VI), and includes those defined in Embodiment C.

[0217] Embodiment 7-A: In some embodiments of the present disclosure, a compound or a pharmaceutically acceptable salt or solvate thereof is provided, optionally as a tautomer, mesomer, racemate, enantiomer, diastereomer, or combination thereof, and is a compound of formula (VIIa),

[0218] [ka]

[0219] Among them, Y, Z, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X 1 , X 2 , n 1 and n 2a This is as defined by equation (VIa).

[0220] In some embodiments, the following compounds are excluded from the compounds of formulas (VI), (VIa), (VII), and (VIIa).

[0221] [ka]

[0222] In some embodiments of this disclosure, the structure of any of the formulas II, IIa, III, IIIa, IV, IVa, V, Va, VI, Via, VII, and VIIa, or a pharmaceutically acceptable salt or solvate thereof, Y and Z are independently selected from H, halo, C1-C8 alkyl, and C1-C8 alkoxy. R 3 The is selected from H, halo, C1-C8 alkyl, and C1-C8 alkoxy. X 1 It does not exist. X 2 is -O-, R 4 , R 5 , R 6 , R 7 , and R 8 At each occurrence, H, halo, and C1-C8 alkyl are independently selected. n 1 and n 2a n are integers independently selected from 0, 1, 2, and 3, respectively. 1 +n 2a A ligand-drug conjugate according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, characterized in that the condition is that is 2, 3, or 4.

[0223] Some embodiments of this disclosure provide compounds of any of formulas (VI), (VIa), (VII), and (VIIa), and any of those embodiments including Embodiment C, or pharmaceutically acceptable salts or solvates thereof, among which,

[0224] Equations (VI) and (VII)

[0225] [ka]

[0226] Equations (VIa) and VIIa)

[0227] [ka]

[0228] This is a structure selected from the following structures.

[0229] [ka]

[0230] Some embodiments of this disclosure provide compounds of any of formulas (VI), (VIa), (VII), and (VIIa), and any of those embodiments including Embodiment C, or pharmaceutically acceptable salts or solvates thereof, among which, Equations (VI) and (VII)

[0231] [ka]

[0232] Equations (VIa) and VIIa)

[0233] [ka]

[0234] The following structures are selected.

[0235] [ka]

[0236] Some embodiments of this disclosure provide compounds of any of formulas (VI), (VIa), (VII), and (VIIa), and any of those embodiments including Embodiment C, or pharmaceutically acceptable salts or solvates thereof, among which, Equations (VI) and (VII)

[0237] [ka]

[0238] Equations (VIa) and VIIa)

[0239] [ka]

[0240] The following structures are selected.

[0241] [ka]

[0242] Some embodiments of this disclosure provide compounds of any of formulas (VI), (VIa), (VII), and (VIIa), and any of those embodiments including Embodiment C, or pharmaceutically acceptable salts or solvates thereof, among which, Equations (VI) and (VII)

[0243] [ka]

[0244] Equations (VIa) and (VIIa)

[0245] [ka]

[0246] The following structures are selected.

[0247] [ka]

[0248] Some embodiments of this disclosure provide compounds of any of formulas (VI), (VIa), (VII), and (VIIa), and any of those embodiments including Embodiment C, or pharmaceutically acceptable salts or solvates thereof, among which, Equations (VI) and (VII)

[0249] [ka]

[0250] Equations (VIa) and VIIa)

[0251] [ka]

[0252] The following structures are selected.

[0253] [ka]

[0254] In some embodiments, compounds of any of formulas (VI), (VIa), (VII), and (VIIa), and any of those embodiments including Embodiment C, or pharmaceutically acceptable salts or solvates thereof are provided.

[0255] [ka]

[0256] [ka]

[0257] [ka]

[0258] [ka]

[0259] [ka]

[0260] Alternatively, tautomers, mesomers, racemates, enantiomers, diastereomers, or combinations thereof may be selected.

[0261] In another embodiment, the cell surface binding molecule T may be any type currently known or known cell-binding ligand, such as peptides or non-peptides. Generally, the cell-binding molecule T is an antibody, a single-chain antibody, an antibody fragment that binds to a target cell, a monoclonal antibody, a single-chain monoclonal antibody, or a monoclonal antibody fragment that binds to a target cell, a chimeric antibody, a chimeric antibody fragment that binds to a target cell, a domain antibody, a domain antibody fragment that binds to a target cell, an antibody-mimicking adnectin, DARPin, lymphokine, hormone, vitamin, growth factor, colony-stimulating factor, or nutrient transport molecule (transferrin), binding peptide, or protein, or a small affinity molecule attached to an antibody or albumin, polymer, dendrimer, liposome, nanoparticle, vesicle, or (viral) capsid. Preferably, the binding molecule T is a monoclonal antibody.

[0262] The present invention also provides compounds of any embodiment thereof, including those defined by formulas (I), (II), (IIa), (III), (IIIa), and (IIIb), as well as those defined in Embodiment 1, Embodiment A, Embodiment 2, Embodiment 2-A, Embodiment 3, Embodiment 3-A, and Embodiment B, or pharmaceutically acceptable salts or solvates thereof, wherein the compounds are tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof.

[0263] Another aspect of the present disclosure provides ligand-drug conjugates of formulas (I), (II), (IIa), (III), (IIIa), and (IIIb), as well as any embodiment thereof, or pharmaceutically acceptable salts or solvates thereof, and optionally methods for producing tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof.

[0264] Another aspect of the present disclosure further relates to 1) a ligand-drug conjugate or compound according to the present disclosure or a pharmaceutically acceptable salt or solvate thereof, and optionally a therapeutically effective amount of tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, and 2) a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0265] In another aspect of the present disclosure, further relating to the use of 1) ligand-drug conjugates or compounds according to the present disclosure, or pharmaceutically acceptable salts or solvates thereof, and optionally tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or 2) pharmaceutical compositions according to the present disclosure comprising thereof, in the manufacture of agents for treating or preventing tumors, preferably, the tumor being a cancer associated with the expression of HER2, HER3, or EGFR.

[0266] In another aspect of the present invention, further relating to the use of 1) the ligand-drug conjugate or compound, or a pharmaceutically acceptable salt or solvate thereof, and optionally tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or 2) pharmaceutical compositions comprising them according to the disclosure of the present invention, in the manufacture of agents for treating or preventing cancer, preferably, said cancer being breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, The following cancers are selected from the group consisting of gastric cancer, endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), colon cancer, rectal cancer, colorectal cancer, leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), bone cancer, skin cancer, thyroid cancer, pancreatic cancer, or lymphoma (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, and relapsed anaplastic large cell lymphoma).

[0267] The active compound can be formulated into a form suitable for administration via an appropriate route, preferably in the form of a unit dose or in a form that can be self-administered by a patient in a single dose. The unit dose form of the compound or composition of this disclosure may be a tablet, capsule, cachet, bottled, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation.

[0268] The dosage of the compound or composition in the therapeutic method disclosed herein generally varies depending on the severity of the disease, the patient's body weight, and the relative effect of the compound. However, as a general guideline, an appropriate unit dose is 0.1 to 1000 mg.

[0269] In addition to the active compound, the pharmaceutical composition of this disclosure may contain one or more auxiliary agents, including filters (diluents), binders, wetting agents, disintegrants, excipients, etc. Depending on the method of administration, the composition may contain the active compound in an amount of 0.1 to 99% by weight.

[0270] The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. The oral composition may be prepared according to any method known in the art for preparing pharmaceutical compositions. Such a composition may contain binders, fillers, lubricants, disintegrants, or pharmaceutically acceptable wetting agents. Such a composition may also contain one or more components selected from the group consisting of sweeteners, flavorings, colorants, and preservatives to provide a pleasant and palatable pharmaceutical formulation.

[0271] The aqueous suspension contains an active ingredient mixed with an excipient suitable for the production of an aqueous suspension. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavorings, and one or more sweeteners.

[0272] An oily suspension can be prepared by suspending the active ingredient in vegetable oil. The oily suspension may also contain a thickening agent. By adding the aforementioned sweeteners and flavorings, a formulation with a pleasant mouthfeel can be provided.

[0273] The pharmaceutical compositions of this disclosure may be in the form of an oil-in-water emulsion.

[0274] The pharmaceutical composition may be in the form of a sterile aqueous solution for injection. Acceptable media or solvents that can be used are water, Ringer's solution, or isotonic sodium chloride solution. The sterile injectable formulation may also be a sterile oil-in-water microemulsion for injection in which the active ingredient is dissolved in an oil phase. For example, the active ingredient may be dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerin and processed to form a microemulsion. The injection solution or microemulsion may be introduced into the patient's bloodstream by local bolus injection. Alternatively, the solution and microemulsion are preferably administered in such a way that the blood concentration of the compound of the present invention remains constant. A continuous intravenous delivery device can be used to maintain this constant concentration. An example of such a device is the Deltec CADD-PLUS. TM 5400 intravenous injection pumps are one example.

[0275] The pharmaceutical composition may be in the form of a sterile aqueous or oily suspension for intramuscular and subcutaneous administration. Such suspensions can be formulated using appropriate dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injection may also be a sterile injection solution or suspension prepared in a non-toxic, parenterally acceptable diluent or solvent. Furthermore, sterile fixative oils can be readily used as solvents or suspension media.

[0276] The compounds of this disclosure 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, thereby dissolving in the rectum and releasing the drug. Such materials include cocoa butter, glycerin gelatin, hydrogenated vegetable oils, and mixtures of polyethylene glycol and its fatty acid esters of various molecular weights.

[0277] It is well known to those skilled in the art that the dosage of a drug depends on a variety of factors, including but not limited to the activity of the particular compound, the patient's age, weight, overall health status, behavior, diet, timing of administration, route of administration, excretion rate, and drug combinations. Furthermore, the optimal treatment, such as the mode of treatment, the daily dose of the compound of formula (I), or the type of pharmaceutically acceptable salt thereof, can be verified according to conventional treatment plans. [Brief explanation of the drawing]

[0278] [Figure 1] The results of in vitro bystander killing tests of target cells SK-BR-3 and GFP-labeled tool cell flips are shown (Example 70). [Figure 2] The results of an in vitro plasma stability study of ADCs are shown (Example 71). [Figure 3] The results of the ADC efficacy study in NCI-N87 tumor-bearing nude mice are shown (Example 72). [Figure 4] The change in tumor size resulting from ADC treatment 21 days later is shown (Example 72). [Modes for carrying out the invention]

[0279] Unless otherwise specified, all technical and scientific terms used herein are consistent with the common understanding of those skilled in the art in which this disclosure pertains. Any methods and materials similar to or equivalent to those described herein may be used in carrying out or testing the disclosure, but preferred methods and materials are described herein. In describing and protecting this disclosure, the following terms shall be used according to their definitions below.

[0280] Unless otherwise specified, terms used in this specification and in the claims have the meanings set forth below.

[0281] As used herein, "one" means one or more unless otherwise explicitly indicated in the context.

[0282] A "ligand" refers to a compound that can recognize and bind to an antigen or receptor associated with a target cell. The role of a ligand is to deliver a drug to a population of target cells to which the ligand binds. These ligands include, but are not limited to, protein hormones, lectins, growth factors, antibodies, peptides, or other molecules that can bind to cells. In embodiments of this disclosure, the ligand is represented by T in trastuzumab. The ligand can form a bond with a linker via a heteroatom of the ligand. The ligand is preferably an antibody or its antigen-binding fragment. The antibody is selected from the group consisting of chimeric antibodies, humanized antibodies, fully humanized antibodies, or mouse antibodies, and is preferably a monoclonal antibody.

[0283] The term "drug" as defined herein refers to cytotoxic drugs, which are chemical molecules capable of potently inhibiting the normal growth of tumor cells. In principle, all cytotoxic drugs can kill tumor cells at sufficiently high concentrations. However, due to a lack of specificity, they may cause apoptosis in normal cells while killing tumor cells, leading to serious side effects.

[0284] "Linker," "linker unit," "link fragment," or "link unit" refers to a chemical structural fragment or bond in which one end is bound to a ligand and the other end is bound to a drug. In preferred embodiments of this disclosure, L and L 1 ~L 4 It is represented as, of which L 1 The end is bound to the ligand, and the L 4 The end is bound to the drug.

[0285] Linkers comprising extension units, spacer units, and amino acid units can be synthesized by methods known in the art, such as the method described in US 2005-0238649A1. The linker may be a “cleavable linker” or “releaseable linker” that promotes the release of drugs within cells. For example, acid-unstable linkers (e.g., hydrazone), protease-sensitive (e.g., peptidase-sensitive) linkers, photo-unstable linkers, dimethyl linkers, or disulfide-containing linkers can be used (Chari et al., Cancer Research 52: 127-131 (1992); US Pat. No. 5,208,020).

[0286] The term “ligand-drug complex” means that a biologically active drug is bound to a ligand as described herein via a stable link unit. In this disclosure, “ligand-drug complex” is preferably an antibody-drug complex (ADC), meaning that a toxic drug is bound to a biologically active monoclonal antibody or antibody fragment via a stable link unit.

[0287] The three-letter and one-letter amino acid codes used in this disclosure are as described in "J. Biol. Chem, 243, p 3558 (1968)".

[0288] The term "antibody" refers to immunoglobulins, which are four peptide chain structures linked by interchain disulfide bonds between two identical heavy chains and two identical light chains. Different immunoglobulin heavy chain constant regions exhibit different amino acid compositions and sequences, and therefore exhibit different antigenicity. Thus, immunoglobulins can be classified into five types, also called immunoglobulin isotypes, namely IgM, IgD, IgG, IgA, and IgE, each having a corresponding heavy chain |i, y, a, e|. Depending on the amino acid composition of the hinge region and the number and position of the heavy chain disulfide bonds, the same type of Ig can be further classified into different subtypes; for example, IgG can be classified into IgG1, IgG2, IgG3, and IgG4. The light chains can be classified into K or X chains based on different constant regions. Each of the five types of Ig can have either a K or an X chain. The antibodies described herein are preferably specific antibodies against cell surface antigens on target cells, and non-limiting examples include one or more of the following antibodies: anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cript0 antibody, anti-EphA 2 antibodies, anti-G250 antibody, anti-MUC1 antibody, anti-Lewis Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-integrin antibody, anti-PSMA antibody, anti-tenascin C antibody, anti-SLC44A4 antibody, or anti-mesoterin antibody, and preferably trastuzumab (trade name Herceptin), pertuzumab (also known as 2C4, trade name Pageta), nimotuzumab (trade name Taixin Shen), enobrituzumab, emibetuzumab, inotuzumab, pinatuzumab, brentuximab, gemtuzumab, vibatuzumab, rorbotuzumab, cBR96, and glenbatumumab.

[0289] The approximately 110-amino acid sequence adjacent to the N-terminus of the antibody's heavy or light chain is highly variable and is known as the variable region (Fv region), while the remaining amino acid sequence adjacent to the C-terminus is relatively stable and is known as the constant region. The variable region includes three hypervariable regions (HVRs) and four relatively conservative framework regions (FRs). The three hypervariable regions that determine the antibody's specificity are also known as complementarity-determining regions (CDRs). Each light chain variable region (LCVR) or each heavy chain variable region (HCVR) consists of three CDR regions and four FR regions, arranged in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 from the amino terminus to the carboxyl terminus. The three CDR regions of the light chain are LCDR1, LCDR2, and LCDR3, and the three CDR regions of the heavy chain are HCDR1, HCDR2, and HCDR3.

[0290] The antibodies of this disclosure include mouse antibodies, chimeric antibodies, humanized antibodies, and fully humanized antibodies, and are preferably humanized antibodies and fully humanized antibodies.

[0291] In this disclosure, “mouse antibody” means an antibody prepared from a mouse based on the knowledge and techniques of the art. During preparation, a subject is injected with a specific antigen, and a hybridoma expressing an antibody having a desired sequence or functional properties is isolated.

[0292] A "chimeric antibody" is an antibody obtained by condensing the variable region of a mouse antibody with the constant region of a human antibody, and can mitigate mouse antibody-induced immune responses. To establish chimeric antibodies, a hybridoma that secretes mouse-specific monoclonal antibodies is established, the variable region gene is cloned from the mouse hybridoma cells, then the constant region gene of a human antibody is cloned as needed, the human constant region gene is ligated with the mouse variable region gene to form a chimeric gene, this is then inserted into an expression vector, and finally the chimeric antibody molecule is expressed in a eukaryote or prokaryotic system.

[0293] The term "humanized antibody," also known as a CDR-transplanted antibody, refers to an antibody produced by transplanting a mouse CDR sequence into a human antibody variable region framework; in other words, an antibody produced with a different type of human germline antibody framework sequence. Humanized antibodies can overcome the immune response induced by multiple mouse protein components carried by chimeric antibodies. Such framework sequences can be obtained from publicly available DNA databases or publicly available references that cover germline antibody gene sequences. For example, germline DNA sequences of human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the World Wide Web at www.mrccpe.com.ac.uk / vbase) or in Kabat, EA, et al. 1991 Sequences of Proteins of Immunological Interest, 5th Ed. To avoid decreased activity due to reduced immunogenicity, the variable region framework sequences of human antibodies may undergo minimal reverse or reverse mutations to maintain activity. Humanized antibodies in this disclosure also include humanized antibodies that have undergone CDR affinity maturation by phage display. Documents further describing the use of mouse antibodies involved in humanization include, for example, Queen et al., Proc., Natl. Acad. Sci. USA, 88, 2869, 1991, and Winter and colleagues' method [Jones et al., Nature, 321, 522(1986), Riechmann et al., Nature, 332, 323-327(1988), Verhoeyen et al., Science, 239, 1534(1988)].

[0294] The term "fully humanized antibody," also known as "fully humanized monoclonal antibody," refers to an antibody in which both the variable and constant regions are derived from humans, eliminating immunogenicity and side effects. The development of monoclonal antibodies has progressed through four stages: mouse monoclonal antibodies, chimeric monoclonal antibodies, humanized monoclonal antibodies, and fully humanized monoclonal antibodies. The antibody disclosed herein is a fully humanized monoclonal antibody. Technologies related to the preparation of fully humanized antibodies mainly include human hybridoma technology, EBV-transformed B lymphocyte technology, phage display technology, transgenic mouse antibody preparation technology, and single B cell antibody preparation technology.

[0295] The term "antigen-binding fragment" refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that the function of binding to an antigen can be achieved using fragments of a full-length antibody. Examples of binding fragments in the term "antigen-binding fragment" include: (i) Fab fragments, which are monovalent fragments consisting of VL, VH, CL, and CH1 domains; (ii) F(ab')2 fragments, which are bivalent fragments containing two Fab fragments linked by a disulfide bond in the hinge region; (iii) Fd fragments, which consist of VH and CH: domains; (iv) Fv fragments, which consist of VH and VL domains of a single-arm antibody; (v) single-domain or dAb fragments consisting of a VH domain (Ward et al. (1989) Nature 341:544-546); and (vi) isolated complementarity-determining regions (CDRs), or (vii) combinations of two or more isolated CDRs arbitrarily linked by a synthetic linker. Furthermore, although the VL and VH domains of an Fv fragment are encoded by two separate genes, they can be linked together using a synthetic linker via recombinant DNA, thereby generating a single protein chain of a monovalent molecule formed by pairing the VL and VH domains. (This is called single-stranded Fv (scFv). See, e.g., Bird et al. (1988) Science: 242:423-426, and Huston et al. (1988) Proc. Natl. Acad. Sci USA 85:5879-5883). This single-stranded antibody is also intended to be included in the term "antigen-binding fragment" of an antibody. Such antibody fragments are obtained using conventional techniques known to those skilled in the art, and functional fragments are screened using the same methods as for intact antibodies. The antigen-binding site can be generated by recombinant DNA techniques or by enzymatic or chemical disruption of intact immunoglobulins.The antibody may be an antibody of a different isotype, for example, IgG (e.g., IgG1, IgG2, IgG3, or IgG4 subtype), IgAl, IgA2, IgD, IgE, or IgM antibody.

[0296] Fab is an antibody fragment obtained by treating an IgG antibody molecule with papain (which cleaves the amino acid residue at position 224 of the heavy chain). The Fab fragment has a molecular weight of approximately 50,000 and possesses antigen-binding activity, with approximately half of the N-terminal side of the heavy chain and the entire light chain bound via disulfide bonds.

[0297] The term "CDR" refers to the region of the six hypervariable domains within the variable region of an antibody that primarily contributes to antigen binding. One of the most commonly used definitions of the six CDRs is provided by Kabat EA et al. (1991) Sequences of protein of immunological interest. NIHPublication 91-3242. The Kabat CDR definition used here applies only to the light chain variable domains CDR1, CDR2, and CDR3 (CDR L1, CDR L2, CDR L3 or L1, L2, L3), and the heavy chain variable domains CDR2 and CDR3 (CDR H2, CDR H3 or H2, H3).

[0298] The term "antibody framework" refers to a portion of the variable domain (VL) or VH that forms the scaffold for the antigen-binding loop (CDR) of the variable domain. Essentially, it is a variable domain without a CDR.

[0299] The terms "specific binding," "selective binding," "selective binding," and "specifically binding" refer to an antibody binding to a specific epitope on an antigen. Typically, an antibody binds to approximately 10 times the epitope of an antigen. -7 M or less, for example, about 10 -8 M or less, 10 -9 M or 1O -10 It binds with affinity (KD) of M or less.

[0300] Methods for preparing and purifying antibodies and antigen-binding fragments are well known in the art and are described, for example, in Chapters 5–8 and 15 of the Cold Spring Harbor Antibody Technical Guide. Antigen-binding fragments can also be prepared by conventional methods. The antibodies or antigen-binding fragments of this disclosure are genetically engineered to have one or more human FR regions added to a non-human CDR region. Human FR germline sequences can be obtained from the ImMunoGeneTics (IMGT) website (http: / / imgt.cines.fr) or from the Journal of Immunoglobulins 20011SBN012441351 by aligning the IMGT Human Antibody Variable Germline Gene Database with MOE software.

[0301] The term "peptide" refers to a complex fragment between amino acids and proteins, consisting of two or more amino acid molecules linked together by peptide bonds. Peptides are structural and functional fragments of proteins. Hormones and enzymes are essentially peptides.

[0302] The term "toxin" refers to a substance that may have a harmful effect on cell growth or proliferation. Toxins are small molecule toxins and their derivatives derived from bacteria, fungi, plants, or animals, and include camptothecin derivatives such as exatecan, maytansinoids and their derivatives such as DM1, DM3, and DM4 (CN101573384), auristatin F(AF) and its derivatives such as MMAF, MMAE, 3024 (WO 2016 / 127790 Al, compound 7), diphtheria toxin, exotoxins, lysine A chain, abrin A chain, modesine, α-sarsine, aleuritesfordi toxic protein, dianthin toxic protein, pokeweed toxic protein (PAPI, PAPII, and PAP-S), momordica charantia inhibitors, curcin, crotin, Sapaonaria officinalis inhibitors, geronin, mitogenin, restrictosin, phenomycin, enomycin, and trichothecenes.

[0303] The term "chemotherapeutic drug" refers to compounds that can be used to treat tumors. This definition also includes anti-hormone agents that regulate, reduce, block, or inhibit the action of hormones that promote cancer growth, and these are often used in the form of systemic or holistic therapies. They may also be hormones. Examples of chemotherapeutic drugs include alkylating agents such as thiotepa, alkyl sulfonates such as cyclosphamide, busulfan, improsulfan, and piposulfan, aziridines such as benaodopa and uredepa, aziridines and methylmelamine including altoretamine, triethylenemelamine, and trimethylolmelamine, chlorambucil, nitrogen mustards such as chlornafadin, melphalan, and nobenbitin, nitrosoureas such as carmustine and chlorozotocin, and activator Lasinomycin, Actinomycin, Autoramycin, Azaserin, Bleomycin, Kakutinomycin C, Calicheamycin, Carabicin, Chromomycin, Cardinophilin, Actinomycin D, Daunorubicin, Detrubicin, Doxorubicin, Epirubicin, Esolubicin, Idarubicin, Mycophenolic acid, Nogaramycin, Olibomycin, Peplomycin, Potophyllomycin, Puromycin, Keramycin, Rhodolubicin, StreptonigrinAntibiotics such as streptozocin, tuberclocidine, ubenimex, dinostatin, and zolubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimethrexate; pterin analogs such as fludarabine, 6-mercaptothelin, thiomethopterin, and thioguanopterin; ancitabine, datrexate, 6-azuridine, and carmophil. Pyrimidine analogs such as doxilridine, enocitabine, and phloxuridine; androgens such as calstalon, dromostanol long propionate, epithiostanol, and testolactone; antiadrenergic drugs such as aminoglutethimide, mitotane, and trilostane; floric acid, acegraton, aldofsphamide glycoside, aminolevulinic acid, amsacrin, Bestrabusil, Biastoren, Defamin, Demecolsin, and Diazico Folic acid supplements such as 2-ethylhydrazide, procarbazine, razoxane, schizophyllan, spirogemanium, tenuazonic acid, triadicone, trichlorotriethylamine, urethane, erhomitin, eruptinium acetate, etoglucide, gallium nitrate, hydroxyurea, lentinan, ronidamin, mitoglucone, mitoxantrone, mopidamol, nitracrine, pintostatin, fenamet, pirarubicin, podophyllic acid, etc. This includes vindesine, dacarbazine, mannomustine, mitobronitol, dibromodulcitol, pipobromane, gasitosine, arabinoside, cyclophosphamide, thiotepa, taxanes such as paclitaxel and docetaxel, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, platinum analogs such as cisplatin and carboplatin, vinblastine, platinum, etoposide, ifbusfamide, mitomycin C, mitoxantrone, vincristine, vinorelbine, navelbine, novantrone, teniposide, daunorubicin, aminopterin, xeloda, ibandronate, topoisomerase inhibitor RFS2000, difluoromethylornithine, retinoic acid esperamicin, capecitabine, and any pharmaceutically acceptable salts, acids, or derivatives of any of the above substances. This definition also includes anti-hormone drugs.

[0304] The carbon atom content of various molecules, including hydrocarbons, is represented by prefixes indicating the minimum and maximum number of carbon atoms in the molecule. The prefix Ci-j represents carbon atom molecules from integer "i" to integer "j," and this numerical value is also included. For example, C 1-6 An alkyl group refers to an alkyl group having 1 to 6 carbon atoms.

[0305] As used herein, the term “alkyl” refers to a linear or branched saturated hydrocarbon substituent (i.e., a substituent obtained by removing hydrogen from a hydrocarbon), comprising 1 to 8 carbon atoms in one embodiment, 1 to 6 carbon atoms in another embodiment, and 1 to 3 carbon atoms in yet another embodiment. Non-limiting examples of such substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, isoamyl, hexyl, heptyl, octyl, and the like. In another embodiment, comprising 1 to 3 carbon atoms, consisting of methyl, ethyl, n-propyl and isopropyl. Each “C1-C8 alkyl” comprises 1 to 3 R 9 The phrase "arbitrarily substituted with" means that each of the listed "C1-C8 alkyl" groups in the group has 1 to 3 R 9 This means that substitution is permitted. For example, in the following list "C1-C8 alkyl, (C1-C8 alkyl)NHC(O)O-, (C1-C8 alkyl)NH-, (C1-C8 alkyl)C(O)O-", each C1-C8 alkyl may have 1 to 3 R 9 It may be replaced with.

[0306] As used herein, the term "alkylene" refers to a divalent alkyl group as defined herein.

[0307] As used herein, the term "-alkylene-cycloalkylene-" refers to an alkylene group, as defined herein, bonded to a cycloalkylene group, as defined herein.

[0308] The term "alkoxy" refers to an -OR group, where R is an alkyl group as defined herein (i.e., a substituent obtained by removing hydrogen from the OH group of a hydrocarbon alcohol), and in one embodiment, it contains 1 to 6 carbon atoms. Non-limiting examples of such substituents include methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy and tert-butoxy), pentoxy, hexoxy, and others. In another embodiment, it has 1 to 3 carbon atoms and consists of methoxy, ethoxy, n-propoxy, and isopropoxy. An alkoxy group bonded to an alkyl group is called an alkoxyalkyl group. An example of an alkoxyalkyl group is methoxymethyl.

[0309] As used herein, the term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group as defined herein.

[0310] The term "cycloalkyl" refers to a carbon ring substituent obtained by removing hydrogen from a saturated or partially unsaturated (but not aromatic) carbocyclic molecule, such as one having 3 to 7 carbon atoms. The term "cycloalkyl" includes monocyclic saturated carbocyclic molecules. "C3-C7, cycloalkyl" means a radical of a 3- to 7-membered ring system containing cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl groups. s -C s "Cycloalkyl" refers to a 3- to 6-membered ring radical containing cyclopropyl, cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, and cyclohexyl groups. The cycloalkyl group may be a bicyclic or spirocyclic carbocyclic. For example, "C3-C 12 "Cycloalkyl" refers to monocyclic carbocyclic and bicyclic and spirocyclic cycloalkyl moieties, including, for example, bicidapentyl, bicidohexyl, bicycloheptyl, bicyclooctyl, bicyclononyl, spiropentyl, spirohexyl, spiroheptyl, spirooctyl, spironanyl, etc.

[0311] "Cycloalkylene" means a divalent cycloalkyl group as defined herein.

[0312] "C3-C6 cycloalkoxy" refers to a 3- to 6-membered cycloalkyl group bonded to an oxygen radical. Examples include cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[0313] In some cases, the number of atoms in a cyclic substituent (i.e., heteroaryl or heterocycloalkyl) containing one or more heteroatoms is indicated by the prefix "x~y members," where x is the minimum number of atoms forming the cyclic portion of the substituent and y is the maximum number. Therefore, for example, "4~6 member heterocycloalkyl" refers to a heterocycloalkyl containing 4~6 atoms, with 1~3 heteroatoms in the cyclic portion. Similarly, "5~6 member heteroaryl" refers to a heteroaryl containing 5~6 atoms, and "5~10 member heteroaryl" refers to a heteroaryl containing 5~10 atoms, each with one or more heteroatoms in the cyclic portion. Furthermore, "5 member heteroaryl" and "6 member heteroaryl" refer to a 5-member heteroaromatic ring system and a 6-member heteroaromatic ring system, respectively. The heteroatoms present in these ring systems are selected from N, O, and S.

[0314] "Hydroxy" or "hydroxyl" refers to the -OH group. When used in combination with other terms, the prefix "hydroxy" indicates that the prefixed substituent is substituted with one or more hydroxy substituents. Compounds having a carbon atom with one or more hydroxy substituents include, for example, alcohols, enols, and phenols. Cyano and nitrile refer to the α-CN group. The term "oxo" means oxygen bonded to a carbon atom by a double bond (i.e., R 4 If R is an oxo, 4 (This is the C=O part, along with the carbon atom to which it is bonded.)

[0315] A hydroxyalkyl group is an alkyl group substituted with 1, 2, or 3 hydroxyl groups as defined herein.

[0316] The term "halo" or "halogen" refers to fluorine (may be written as -F), chlorine (may be written as -Cl), bromine (may be written as -Br), or iodine (may be written as -I).

[0317] A haloalkyl is an alkyl group substituted with one, two, three, four, five, or six halo groups as defined herein. In some embodiments, a haloalkyl includes a chloroalkyl group.

[0318] The term "heterocycloalkyl" refers to a substituent obtained by removing hydrogen from a saturated or partially saturated ring structure containing a total of a specified number of atoms, e.g., 4 to 6 ring atoms or 4 to 12 atoms, where at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining ring atoms are independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. The sulfur may or may not be oxidized (i.e., S(O) or S(O)2). In a group having a heterocycloalkyl substituent, the ring atom of the heterocycloalkyl substituent bonded to the group may be a nitrogen heteroatom or a cyclic carbon atom. Similarly, if the heterocycloalkyl substituent is substituted with a group or substituent, that group or substituent may be bonded to a nitrogen heteroatom or to a cyclic carbon atom. It is understood that the heterocyclic group may be monocyclic, bicyclic, polycyclic, or spirocyclic.

[0319] The term "aryl" refers to a monocyclic or bicyclic carbocyclic ring system, where a monocyclic ring is aromatic and a bicyclic ring contains at least one aromatic ring. 10"Aryl" refers to a carbocyclic system with 6 to 10 atoms, including phenyl, tetrahydronaphthyl, and naphthyl. In addition to any group specifically described in any embodiment or claim, in some embodiments, aryl is halo, -C1- 12 Alkyl (unsubstituted or substituted, one, two, or three halos in one embodiment), aryl, -OH, -OC 1-12 Alkyl, -S(O)nC 1-4 Alkyl (where n is 0, 1, or 2), -C 1-4 Alkyl NH2, -NHC 1-4 Alkyl, -C(=O)H, C(=O)OR a -OC(=O)R b , OC(=O)NR a R c , optionally substituted with 1 to 3 substituents independently selected from OC(=O) heteroaryl, OC(=O) (heterocyclic), and C=N-OR, of which R a , R c , and R d These are independently hydrogen or -C 1-4 It is alkyl, R b It is alkyl.

[0320] As used herein, the term "arylene" refers to a divalent aryl group as defined herein.

[0321] The term "heteroalkyl" refers to an alkyl group as defined herein, where one or more -CH2- groups are replaced with a group independently selected from -O-, -S-, -S(O)-, -S(O)2, and -NR-, where R is hydrogen or alkyl as defined herein, and / or, where one or more -CH3 groups are replaced with a group independently selected from -OH, -SH, and -NH, where each R is independently hydrogen or alkyl. Heteroalkyls include 2-thioethyl, 2-amino-proplu-1-yl, 2-hydroxy-ethyl-1-yl, N-methyl-amino-ethyl, etc. Hydroxyalkyls are a subset of heteroalkyls.

[0322] "Heteroalkylene" means a divalent heteroalkyl as defined herein.

[0323] A heteroaryl is an aromatic ring structure containing a specific number of ring atoms, where at least one of the ring atoms is a heteroatom (oxygen, nitrogen, and / or sulfur), and the remaining ring atoms are carbon. Heteroaryl substituents include six-membered heteroaryl rings such as pyridyl, pyrazyl, pyrimidinyl, and pyridadinyl, and five-melbea heteroaryl rings such as triazolyl, imidazolyl, furanil, thiophenyl, pyrazolyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, and isothiazolyl. The heteroaryl group may also be a bicyclic heteroaromatic group such as indolyl, benzofuranyl, benzothienyl, benzimidazoli, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, oxazolopyridinyl, imidazopyridinyl, and imidazopyrimidinyl. In a group having a heteroaryl ring, the ring atom of the heteroaryl ring bonded to the group may be a nitrogen atom or a cyclic carbon atom. Similarly, if the heteroaryl ring is substituted with a group or substituent, it may be bonded to a nitrogen atom or to a cyclic carbon atom. "Heteroaryl" also includes groups containing pyridyl N-oxide and pyridine N-oxide rings. Furthermore, the heteroaryl group may contain an oxo group, such as that present in a pyridone group. Other examples include furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, pyridine-2(1H)-onyl, pyridazine-2(1H)-onyl, pyrimidine-2(1H)-onyl, pyrazine-2(1H)-onyl, imidazo[1,2-a]pyridinyl, and pyrazolo[1,5-alpyridinyl]. Heteroaryls may be further substituted as defined herein.

[0324] Examples of monocyclic heteroaryls and heterocycloalkyls include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl, dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyraryl, pyrrolinil, pyrrolidinil, imidazolyl, isoimidazolyl, imidazolinil, imidazolidinil, pyrazolyl, pyrazolinil, pyrazalidinil, thiazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazalyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinil, isothiazolinil, thiazolidinil, isothiazolidinil, thiaoxadiazolyl, oxathiazolyl, dioxadiazolyl {oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl or 1,3,4-oxadiazolyl Contains {pillanil}, pyranyl (including 1,2-pyranyl or 1,4-pyranyl), dihydropyranyl, pyridinyl, piperidinyl, diazinyl (including pyridazinyl, pyrimidinyl, piperazinyl), triazinyl (including s-triazinyl, as-triazinyl, and v-triazinyl), oxazinyl (including 2H-1,2-oxazinyl, 6H-1,3-oxazinyl, or 2H-1,4-oxazinyl), isoxazidine (including O-isoxazinyl or p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiadinyl (including 1,2,5-oxathiadinyl or 1,2,6-oxathiadinyl), oxadiadinyl (including 2H1,2,4-oxadiadinyl or 2H1,2,5-oxadiadinyl), and morpholinyl.

[0325] The term "heteroaryl" also includes, when specified, ring systems having two rings, of which these rings may be fused, and of which one ring is aromatic and the other is not a complete part of a conjugated aromatic system (i.e., the heteroaromatic ring may be fused to a cycloalkyl or heterocycloalkyl ring). Non-limiting examples of such ring systems include 5,6,7,8-tetrahydroisoquinalinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 1,4,5,6-tetrahydrocyclopenta[cl-pyrazolyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 5,6-dihydro This product contains lo-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-b[1,2,4]triazolyl, 5,6,7,8-tetrahydro-[1,2.4]triazolo[1,5-a]pyridinyl, 4.5,6,7-tetrahydropyrazolo[1.5-a]pyridinyl, 4,5,6,7-tetrahydro-1H-indazolyl, and 4,5,6,7-tetrahydro-2H-indazolyl.

[0326] When a carbocyclic or heterocyclic moiety is bonded or connected to a designated group via different ring atoms without exhibiting specific bonding points, it should be understood that all possible points are intended, whether via carbon atoms or, for example, trivalent nitrogen atoms. For instance, the term "pyridyl" means 2-, 3-, or 4-pubridyl, and the term "thienyl" means 2- or 3-thienyl.

[0327] As used herein, the term "heteroarylene" refers to a divalent heteroaryl group as defined herein.

[0328] The term "amino protecting group" refers to a group that prevents an amino group from reacting even if other parts of the molecule react, and that can be easily removed. Non-limiting examples include 9-fluorenylmethyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl. These groups may be substituted with 1 to 3 substituents selected from the group consisting of halogens, alkoxy, and nitro. The amino protecting group is preferably 9-fluorenylmethyloxycarbonyl.

[0329] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, where alkyl is defined as described above.

[0330] In the context of the terms cycloalkyl, cycloalkylene, and heterocycle, the term "unsaturated" refers to a ring that is partially unsaturated but not aromatic.

[0331] The term "condensation" refers to a bicyclic, tricyclic, or polycyclic structure consisting of at least two carbocyclic or heterocyclic structures that share at least one chemical bond.

[0332] When a substituent is described as having two or more variables "independently," each example of the substituent is selected independently from the other from the list of available variables. Thus, each substituent may be identical or different from the other substituents.

[0333] When it is stated that a substituent is "independently selected" from the group, each example of a substituent is selected independently of the other groups. Therefore, each substituent may be identical or different from the other substituents.

[0334] "Optional" or "optionally" means that the event or situation described thereafter may occur, but is not necessarily required, and the description includes both cases in which the event or situation occurs and cases in which it does not occur. For example, "aryl group optionally single-substituted or disubstituted with an alkyl group" means that an alkyl group may be present, but is not required, and the description includes both cases in which the aryl group is single-substituted or disubstituted with an alkyl group and cases in which the aryl group is not substituted with an alkyl group.

[0335] "Substitution" refers to the independent substitution of one or more hydrogen atoms in a group, preferably up to five, more preferably one to three, by a corresponding number of substituents. Needless to say, substituents can only exist in chemically possible positions. Those skilled in the art can determine whether substitution is possible or not by experiment or theory without excessive effort. For example, combinations of amino or hydroxyl groups with free hydrogen and carbon atoms with unsaturated bonds (e.g., olefins) may be unstable.

[0336] As used herein, the term “compound of formula (I)” (or any other formula number) is defined to include all forms of the compound of formula I, including hydrates, solvates, isomers, crystalline and amorphous forms, isomorphs, polymorphs, and metabolites. For example, the compounds disclosed herein, or their medically acceptable salts, may exist in unsoluble and soluble forms. When the solvent or water is strongly bonded, the complex has a clear stoichiometry that is independent of humidity. However, when the solvent or water is weakly bonded, such as in channel solvates and hygroscopic compounds, the water / solvent content depends on humidity and dry conditions. In such cases, non-stoichiometry is the norm. Compounds that have the same molecular formula but differ in the nature or order of atomic bonding, or in the spatial arrangement of atoms, are called “isomers.” Isomers that differ in the spatial arrangement of atoms are called “stereoisomers.”

[0337] Stereoisomers that are not mirror images of each other are called "diastereomers," while stereoisomers that are mirror images of each other but cannot be superimposed are called "enantiomers." If a compound has an asymmetric center, for example, it can bond with four different groups, and a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described by Cahn and Prelog's (R)- and (S)- stereochemical rules, or by how the molecule rotates its plane of polarization, and are designated as dextrorotatory or levorotatory (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as single enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0338] The compounds described herein may have one or more asymmetric centers, and therefore such compounds may be produced as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise stated, the description or naming of specific compounds in the specification and claims is intended to include their individual enantiomers and mixtures, racemates or other forms. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 1992).

[0339] Substitution of hydrogen (H) or carbon (C) in compounds of formula I includes substitution with any isotope of each atom. Therefore, hydrogen (H) substitution may be required, for example, for specific therapeutic or diagnostic therapies, metabolic research applications, or for improving metabolic or chemical stability. 1 H, 2 H (deuterium), or 3 This includes H (tritium) isotope substitution. Optionally, the compounds of this disclosure may include radioisotopes known in the art, for example, 3 H, 15 O, 12 C, or 13The N isotope is incorporated, and each of the radiolabeled compounds of formula I is obtained.

[0340] "Pharmacopoeia-acceptable carrier" generally means a carrier that is safe, non-toxic, and free from other biologically undesirable elements, and is useful for preparing pharmaceutical compositions, including carriers useful for veterinary and human pharmaceuticals. As used herein and in the claims, "pharmacopoeia-acceptable carrier" includes one or more such carriers.

[0341] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically usable and possesses the pharmacological activity required of the parent compound. Such a salt is (1) Formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]octo-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary Acid addition salts formed with organic acids such as butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, or (2) The salts are formed when the acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or when combined with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, or N-methylglucamine.

[0342] The "treatment" of a disease is, (1) To prevent disease, that is, to prevent the progression of clinical symptoms of disease in mammals that may be exposed to or susceptible to the disease but have not experienced or shown symptoms of the disease. (2) Suppression of disease, that is, preventing or reducing the progression of disease or its clinical symptoms, (3) Relief of disease, that is, regression of the disease or its clinical symptoms.

[0343] The term "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or a physiologically / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism that promotes the absorption of the active ingredient in order to exhibit biological activity.

[0344] The term "solvate" refers to a pharmaceutically acceptable solvate formed by the ligand-drug conjugate of the present disclosure with one or more solvent molecules. Non-limiting examples of solvent molecules include water, ethanol, acetonitrile, isopropanol, DMSO, and ethyl acetate.

[0345] As used in the compositions of this disclosure, the term "carrier" refers to a system capable of altering the manner and distribution of a drug entering the human body, controlling the rate of drug release, and delivering the drug to a target organ. Drug carrier release and targeting systems can reduce drug degradation and loss, mitigate side effects, and improve bioavailability.

[0346] The term "excipient" refers to additives in pharmaceutical preparations other than the main ingredient, also known as adjuvants. Examples include adhesives, fillers, disintegrants, and lubricants in tablets; matrix components in semi-solid ointments and creams; and preservatives, antioxidants, flavorings, fragrances, cosolvents, emulsifiers, solubilizers, osmotic pressure regulators, and colorants in liquid preparations.

[0347] The term "diluent," also known as a filler, is primarily used to increase the weight and volume of tablets. Adding a diluent ensures a consistent volume, reduces variations in the dosage of the active ingredient, and improves the drug's compression profile. If the tablet contains oily components, an absorbent is added to maintain a "dry" state and facilitate tablet formation. Examples of diluents include starch, lactose, inorganic calcium salts, and microcrystalline cellulose.

[0348] The pharmaceutical composition may be in the form of a sterile aqueous solution for injection. Acceptable media or solvents that can be used are water, Ringer's solution, or an isotonic sodium chloride solution. The sterile injectable formulation may also be a sterile oil-in-water microemulsion for injection in which the active ingredient is dissolved in an oil phase. For example, the active ingredient may be dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerin and processed to form a microemulsion. The injection solution or microemulsion may be introduced into the patient's bloodstream by local bolus injection. Alternatively, the solution and microemulsion are preferably administered in such a way that the blood concentration of the compound of the present invention remains constant. A continuous intravenous delivery device can be used to maintain this constant concentration. An example of such a device is the Deltec CADD-PLUS. TM 5400 intravenous injection pumps are one example.

[0349] The pharmaceutical composition may be in the form of a sterile aqueous or oily suspension for intramuscular and subcutaneous administration. Such suspensions can be formulated using appropriate dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable preparation may be a sterile injectable solution or suspension prepared in a non-toxic, parenterally acceptable diluent or solvent, such as a solution prepared with 1,3-butanediol. Furthermore, sterile fixative oils can be readily used as solvents or suspension media. For this reason, any mixed fixative oil containing synthetic monoglycerides or diglycerides can be used. In addition, fatty acids such as oleic acid can also be used in the preparation of the injectable preparation.

[0350] "Drug load" refers to the average number of cytotoxic drugs loaded onto each ligand in the compound of formula (I), and can also be expressed as the ratio of the number of drugs to the number of antibodies. The drug load can range from 0 to 12, preferably 1 to 10, cytotoxic drugs per ligand. In embodiments of this disclosure, the drug load is represented as n, and exemplary values ​​may be the average of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. The average number of drugs per ADC molecule after the coupling reaction can be determined by conventional methods such as UV / visible spectroscopy, mass spectrometry, ELISA testing, and HPLC characterization.

[0351] The "therapeutic dose" refers to the amount of a compound administered to a mammal to treat a disease that is sufficient to have an effect on treating that disease. The therapeutic dose varies depending on the compound, the disease and its severity, the age and weight of the mammal being treated, etc.

[0352] The term "mammal" refers to all mammals, including humans, domesticated animals, and companion animals.

[0353] The compounds described in this application are typically named according to the IUPAC or CAS naming system. Abbreviations well known to those skilled in the art may be used (for example, "Ph" for phenyl group, "Me" for methyl group, "Et" for ethyl group, "h" for time, or "rt" or "rt" for room temperature).

[0354] Synthesis method of this disclosure Scheme I: A method for producing a compound represented by formula (VI) of this disclosure or a pharmaceutically acceptable salt or solvate thereof is:

[0355] [ka]

[0356] The process includes the step of reacting a compound represented by formula (D1) and a compound represented by formula (D2) under alkaline conditions to obtain a compound represented by formula (VI), Among them, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , n 1 , n 2 n is as defined in formula (VI) and any embodiment thereof.

[0357] Reagents that provide alkaline conditions include organic and inorganic bases. Organic bases include, but are not limited to, triethylamine, diethylamine, N-methylmorpholine, pyridine, hexahydropyridine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, tert-butoxide sodium, and tert-butoxide potassium. Inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and lithium hydroxide.

[0358] Scheme II: A method for producing a compound of formula (D7) according to formula (V) of the present invention, or a pharmaceutically acceptable salt or solvate thereof, comprises the following steps:

[0359] [ka]

[0360] Step 1 involves reacting the compound of formula (D1) and the compound of formula (D3) under optionally alkaline conditions to obtain the compound of formula (D4), Step 2 involves deprotecting the compound of formula (D4) to obtain the compound of formula (D5), Step 3 involves reacting the compound of formula (D5) and the compound of formula (D6) in the presence of a condensing agent or under basic conditions, or optionally under alkaline conditions, to obtain the compound of formula (D7). Eventually, PG is an amino protecting group, preferably benzyloxycarbonyl (Cbz), Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13、 R 14 S 1 , n 1 , n 2 n is as defined in formula (V) and any embodiment thereof.

[0361] Reagents that provide alkaline conditions include organic and inorganic bases. Organic bases include, but are not limited to, triethylamine, diethylamine, N-methylmorpholine, pyridine, hexahydropyridine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, tert-butoxide sodium, and tert-butoxide potassium. Inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and lithium hydroxide.

[0362] The aforementioned condensing agent is 4-(4.6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride, 1-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, A selection is made from the group consisting of O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, and benzotriazole-1-yloxytripyrrolidinylline hexafluorophosphate, preferably 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride, 1-hydroxybenzotriazole, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0363] Scheme III: A method for producing compounds of formula (D8) according to formula (IV) of the present disclosure and any embodiment thereof, or pharmaceutically acceptable salts or solvates thereof, comprises the following steps:

[0364] [ka]

[0365] The process includes the step of reducing T to bind with the compound of formula D7 to obtain the ligand-drug conjugate of formula (D8), wherein the reducing agent is preferably TCEP. Eventually, T is a ligand, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R6 , R 7 , R 8 , R 12 , R 13、 R 14 , W, n1, n 2 n and m are as defined in formula (IV) and any embodiment thereof.

[0366] The present disclosure will be further described with reference to the following embodiments, which will not limit the scope of the present disclosure.

[0367] In the examples of this disclosure, experimental methods for which specific conditions are not indicated were performed according to conventional conditions or conditions recommended by the manufacturer of the material or product. Reagents for which a specific supplier is not indicated are conventional reagents purchased from the market.

[0368] [Examples] Example 1

[0369] [ka]

[0370] 25 o NaN3 (120 mg, 1.85 mmol) was added in 14C. The reaction mixture was stirred with 25 NaN3 for 12 hours. LC-MS showed that 1-1 was completely consumed and the desired MS was detected. The reaction mixture was diluted with H2O (30 mL) and filtered. The solid was washed with H2O (15 mL x 3) and dried under reduced pressure to obtain crude 1-2 (240 mg, 0.551 mmol, yield 78.8%) as a yellow solid. LC-MS: 436.1 [M+H] + .

[0371] To a toluene (6 mL) solution of 1-2 (190 mg, 0.436 mmol), triethyl phosphite (181 mg, 1.09 mmol) was added at 25°C. The reaction mixture was heated to 120°C and stirred for 12 hours. After cooling the reaction mixture to 25°C, HCl / MeOH (4 mol / L, 3 mL) was added. The reaction mixture was heated to 80°C and stirred for 12 hours. TLC (PE / EA = 1 / 1) showed that 1-2 was completely consumed, and one new spot was detected by TLC. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was ground with EA (5.0 mL) at 25°C. 1-3 (80.0 mg, 0.179 mmol, yield 41.2%) was obtained as a yellow solid.

[0372] A mixture of 1-3 (50.0 mg, 0.112 mmol), 1-4 (70.9 mg, 0.224 mmol), and DIEA (28 μL, 0.168 mmol) in DCM (2 mL) was mixed with AcOH (0.016 mL, 0.280 mmol) and NaBH(OAc)3 (94.61 mg, 0.449 mmol) at 25°C under N2. The reaction mixture was stirred under N2 for 12 hours. LC-MS showed that 1-3 were completely consumed and the desired MS was detected. The reaction mixture was washed with brine (5 mL × 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC, and compound 1 (16.9 mg, 0.034 mmol, yield 30.5%) was obtained as a yellow solid.

[0373] [Table 1]

[0374] Example 2

[0375] [ka]

[0376] To a solution of 1-1 (30.00 mg, 0.07 mmol) in DMF (3.00 mL), pyrrolidine-3-ol (7.31 mg, 0.08 mmol) and DIEA (0.04 mL, 0.21 mmol) were added, and the mixture was stirred at 20°C for 12 hours. LC-MS indicated that the reaction was complete. The reaction mixture was purified by prep-HPLC, and compound 2 (2.87 mg, 0.01 mmol, yield 8.94%) was obtained as a yellow solid.

[0377] The following compounds were synthesized according to the procedure described in Example 2.

[0378] [Table 2A]

[0379] [Table 2B]

[0380] [Table 2C]

[0381] [Table 2D]

[0382] [Table 2E]

[0383] [Table 2F]

[0384] [Table 2G]

[0385] [Table 2H]

[0386] Table 2I

[0387]

Table 2J

[0388]

Table 2K

[0389]

Table 2L

[0390]

Table 2M

[0391] Example 36

[0392]

change

[0393] To a solution of boron trichloride (18.6 mL, 18.6 mmol) in DCE (5.00 mL) at 0°C, 36-1 (3.00 g, 19.85 mmol) was gradually added, and the mixture was stirred for 10 minutes. Then, 2-chloroacetonitrile (1.51 mL, 23.8 mmol) and AlCl3 (3.47 g, 26.0 mmol) were added. The mixture was stirred at 20°C for 20 minutes, then heated to 75°C and stirred for 11 hours. LC-MS showed that 36-1 was completely consumed and one main peak with the desired mass was detected. The reaction mixture was cooled to 0°C, adjusted to p=1 with 2N HCl, and stirred for 1 hour. The aqueous phase was extracted with DCM (50.0 mL × 3). The combined organic phase was washed with brine (30.0 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by prep-HPLC, and 36-2 (1.30 g, 5.71 mmol, yield 28.8%) was obtained as a yellow solid. LC-MS: 228.0 [M+H] + rt = 0.587 min.

[0394] Add 36-3 (231 mg, 0.879 mmol) and 4-methylbenzene-1-sulfonic acid (7.56 mg, 0.0440 mmol) to a toluene (5.00 ml) solution of 36-2 (200 mg, 1.12 mmol) and 4-methylbenzene-1-sulfonic acid (7.56 mg, 0.0440 mmol) in 25 ml of solution. o It was added with C. The mixture was stirred at 110°C for 12 hours. LC-MS showed that 36-2 was completely consumed and one main peak with the desired mass was detected. The reaction mixture was cooled to RT, filtered, and the solid was dried under reduced pressure. The crude product was ground with ethyl acetate (10 mL) at 25°C for 3 hours. 36-4 (380 mg, 0.835 mmol, 95.1% yield) was obtained as a brown solid. LC-MS: 455.1 [M+H] + rt = 0.844 min.

[0395] To a solution of 36-4 (50.0 mg, 0.110 mmol) in DMF (2.00 mL), (R)-1-(piperidine-4-yl)ethane-1-ol hydrochloride (21.5 mg, 0.13 mmol) and DIEA (77 μL, 0.440 mmol) were added at 0°C. The mixture was stirred at 25°C for 15 minutes. LC-MS showed that 36-4 was completely consumed and one main peak with the desired mass was detected. The mixture was purified by prep-HPLC. Compound 36 (13.7 mg, 0.0250 mmol, yield 22.8%) was obtained as a yellow solid.

[0396] The following compounds were synthesized according to the procedure described in Example 36.

[0397] [Table 3A]

[0398] [Table 3B]

[0399] [Table 3C]

[0400] Example 43

[0401] [ka]

[0402] 43-1 (110 mg, 0.29 mmol) was suspended in a mixture of CF3COOH (3.5 ml) and H2SO4 (1.2 ml). FeSO4·7H2O (0.21 g, 0.76 mmol) and H2O (6 ml) were added sequentially. After cooling to 5°C, HCONH2 (0.2 ml) was added. 65% (CH3)3COOH (0.1 ml, 0.68 mmol) was added dropwise to the mixture at 2°C. The mixture was stirred at 0°C for 1 hour, then poured into ice water. The precipitate in the solution was collected by aspirate, washed with water, and dried in vacuum. 43-2 was obtained as a yellow powder (0.100 g, yield: 96.1%).

[0403] A 2 mL DMSO solution of 43-2 (43 mg, 0.11 mmol) and piperidine-4-ylmethanol (75 mg, 0.65 mmol, 0.328 mol) was mixed with concentrated hydrochloric acid (0.1 mL), and the mixture was heated at 140 °C for 1 hour. H2O (4 mL) was added to the reaction mixture and filtered. The filtrate was loaded onto 4 mL of activated HP-20 resin and washed with H2O until the pH of the eluate reached 6. The product was then eluted with a 20% methanol-dichloromethane solution to obtain the product. The solvent was evaporated, and the residue was purified by SGC (DCM / MeOH = 10:1) to obtain 11 mg of compound 43 as a yellow solid (yield 21%).

[0404] [Table 4]

[0405] Example 49

[0406] [ka]

[0407] To a solution of 49-1 (15 g, 56.3 mmol) and Py (5.70 mL, 70.4 mmol) in THF (60 mL) and toluene (180 mL), Pb(OAc)4 (35.0 g, 78.9 mmol) was added at 25 °C, and the mixture was stirred at 80 °C for 12 hours. TLC (P / E = 0 / 1) showed that 49-1 was completely consumed. The reaction mixture was cooled to RT, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by SGC (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1). 49-2 (6.80 g, 24.3 mmol, yield 43.1%) was obtained as a pale yellow solid.

[0408] To 10 mL of DMF (DMF) solutions of 49-3 (1.00 g, 2.96 mmol) and 49-2 (1.08 g, 3.85 mmol), TosOH (0.03 g, 0.148 mmol) was added at 25°C. Reaction mixture 60 o The mixture was heated to 14°C and stirred for 12 hours. TLC (PE / EA = 0 / 1) showed that most of 49-3 was consumed, with one main spot detected. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was purified by SGC (petroleum ether / ethyl acetate = 50 / 1~1 / 1). 49-4 (1.00 g, 1.79 mmol, yield 60.5%) was obtained as a yellow solid.

[0409] To a 10 mL solution of 49-4 (1.00 g, 1.79 mmol) in DCM, diethylamine (1.86 mL, 17.9 mmol) was added at 25°C, and the mixture was stirred for 12 hours. LC-MS showed that 49-4 was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC. 49-5 (270 mg, 0.805 mmol, yield 44.9%) was obtained as a yellow oily substance.

[0410] DIEA (307 mg, 2.38 mmol) was added at 25°C to a mixture of 49-5 (340 mg, 0.793 mmol) and 1-1 (265.91 mg, 0.793 mmol) in DMF (3 mL). The reaction mixture was warmed to 25°C and stirred for 15 minutes. HPLC showed that 49-5 was completely consumed. The reaction mixture was purified by prep-HPLC. 49-6 (110 mg, 0.151 mmol, yield 19.1%) was obtained as a yellow solid.

[0411] To a solution of 49-6 (110 mg, 0.151 mmol) in 2,2,2-trifluoroethane-1-ol (5.0 mL), 2 Pd / C (30.0 mg, 0.282 mmol) was added under N2 at 5°C. The suspension was degassed, purged three times with H2 (15 psi), and then incubated under H2 (15 psi) for 25 minutes. o The mixture was stirred at 1C for 2 hours. LC-MS showed that 49-6 was completely consumed and the desired MS was detected. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC. 49-7 (30.0 mg, 0.042 mmol, 28.1% yield) was obtained as a yellow solid. LC-MS: 594.3 [M+H] + .

[0412] A mixture of compound 49-7 (30.0 mg, 0.042 mmol) and compound 49-8 (96.6 mg, 0.085 mmol) in DMF (2.0 mL) was mixed with DIEA (16.3 mg, 0.126 mmol) at 25°C, and the mixture was stirred for 12 hours. LC-MS showed that 49-7 were completely consumed and the desired MS was detected. The mixture was purified by prep-HPLC. Compound 49 (4.39 mg, 0.004 mmol, 9.88%) was obtained as a yellow solid.

[0413] The following compounds were synthesized according to the procedure described in Example 49.

[0414] [Table 5A]

[0415] [Table 5B]

[0416] [Table 5C]

[0417] [Table 5D]

[0418] [Table 5E]

[0419] [Table 5F]

[0420] [Table 5G]

[0421] Example 57

[0422] [Table 6A]

[0423] [Table 6B]

[0424] Example 61

[0425] [ka]

[0426] 61-7 was prepared in the same manner as 49-7.

[0427] To a solution of 61-1 (1.90 g, 4.32 mmol) in THF (30.0 mL), NaH (0.260 g, 6.48 mmol) was added at 0°C, and the mixture was stirred for 1 hour. Then, tert-butyl 2-bromoacetate (1.0 g, 5.19 mmol) was added. Reaction mixture 25 o The mixture was heated to 1°C and stirred for 2 hours. TLC (EA) showed that SM was completely consumed and one main spot was detected. The reaction mixture was quenched with saturated NH4Cl (50 mL) solution at 25°C, diluted with H2O (20 mL), and extracted with siRNA (30 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by SGC (petroleum ether / ethyl acetate = 100 / 1~0 / 1) to obtain 61-2 (1.30 g, 2.35 mmol, 54.3%) as a yellow oily substance.

[0428] To a 10.0 mL solution of 61-2 (1.00 g, 1.81 mmol) siRNA (SiO2), Pd / CPd / C (10%, 0.100 g, 0.903 mmol) was added under N2. The suspension was degassed under vacuum and purged several times with H2. The reaction mixture was heated under H2 (0.0400 g, 18.1 mmol) (15 psi) for 25 minutes. o The mixture was stirred at 1°C for 4 hours. LC-MS showed that the SM was completely consumed and the desired MS was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude 61-3 (900 mg, 1.71 mmol, 94.4%) as a yellow oily substance. LC-MS: 528.4 [M+H] + .

[0429] A mixture of 61-3 (900 mg, 1.706 mmol) and (1r,4r)-4-[(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)methyl]cyclohexane-1-carboxylic acid (486 mg, 2.05 mmol) in DCM (10.0 mL) is mixed with DIEA (0.9 mL, 661 mg, 5.12 mmol) and BOP (1.13 g, 2.56 mmol) for 25 minutes. o The mixture was added with 14C, and the reaction mixture was stirred for 12 hours. LC-MS showed that the SM was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified with prep-HPL (water (FA)-ACN, Phenomenex luna C18 (250*70mm, 15 um)) to obtain 61-4 (400 mg, 0.536 mmol, 31.4%) as a yellow oily substance. LC-MS: 747.35 [M+H] + .

[0430] A solution of 61-4 (400 mg, 0.536 mmol) in DCM (5.00 mL) and TFA (1.00 mL) was stirred at 25°C for 12 hours. LC-MS showed that the SM was completely consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to obtain 61-5 (370 mg, 0.536 mmol, crude) as a yellow oily substance. LC-MS: 691.35 [M+H] + .

[0431] To a solution of 61-5 (135 mg, 0.195 mmol) and HOSu (22.5 mg, 0.195 mmol) in DMF (5.00 mL), DIC (24.7 mg, 0.195 mmol) was added at 25°C. The mixture was stirred for 12 hours and then filtered. DIEA (50.5 mg, 0.391 mmol) and 61-6 (54.6 mg, 0.195 mmol) were added to the filtrate at 25°C, and the reaction mixture was stirred for 12 hours. LC-MS showed that SM was completely consumed and the desired MS was detected. The reaction mixture was purified by prep-HPLC (water (FA)-ACN, Phenomenex Luna C18 75*30 mm*3 μm) to obtain 61-7 (100 mg, 0.105 mmol, 53.7%) as a yellow oily substance. LC-MS: 952.4 [M+H] + .

[0432] To a mixture of 61-7 (35.0 mg, 0.037 mmol) and 61-6 (22.3 mg, 0.037 mmol) in DMF (3.00 mL), NMM (0.012 mL, 0.110 mmol) and DMTMMT (12.7 mg, 0.040 mmol) were added at 25°C, and the reaction mixture was stirred for 12 hours. LC-MS showed that SM was completely consumed and the desired MS was detected. The reaction mixture was purified by prep-HPLC (water (FA)-ACN, Phenomenex LunaC18 75*30 mm*3 μm). 61 (20.0 mg, 0.012 mmol, 32.6%) was obtained as an off-white solid.

[0433] The following compounds were synthesized according to the procedure described in Example 61.

[0434] [Table 7A]

[0435] [Table 7B]

[0436] [Table 7C]

[0437] [Table 7D]

[0438] Example 67 Preparation of antibody-drug conjugates (e.g., ADC-1) Antibodies of exemplary ADCs The antibodies against the ADC compounds in the examples were prepared according to conventional methods, including vector construction, eukaryotic cell transfection such as HEK2943 cells (Life Technologies Cat. No. 11625019), purification, and expression. The prepared antibodies included trastuzumab light chain (SEQ. ID NO. 1), trastuzumab heavy chain (SEQ. ID NO. 2), pertuzumab light chain (SEQ. ID NO. 3), pertuzumab heavy chain (SEQ. ID NO. 4), B7H3 antibody light chain (SEQ. ID NO. 5), and B7H3 antibody heavy chain (SEQ. ID NO. 6).

[0439] General process of compounding A combined aqueous solution of tris(2-carboxyethyl)phosphine (10 mM, 0.082 mL, 0.82 μmol) was added to a PBS-buffered solution of antibody (0.05 M PBS buffer solution, pH=6.5, 2.5 ml, 9.96 mg / ml, 0.168 μmol) at 37°C. The reaction solution was placed in a water bath shaker and shaken at 37°C for 3 hours to stop the reaction. The reaction solution was cooled to 25°C in a water bath and diluted to 5.0 mg / ml. 2.0 ml of the solution was taken for the next reaction.

[0440] Linker-camptothecin compound (2.1 mg, 2.02 umol) was dissolved in 0.10 mL of DMSO and added to 2.0 mL of the above solution. The reaction solution was placed in a water bath shaker and shaken at 25°C for 3 hours, after which the reaction was stopped. The reaction solution was desalted and purified using a Sephadex G25 gel column (elution phase: 0.05 M PBS buffered aqueous solution at pH=6.5 containing 0.001 M EDTA) to obtain a PBS buffered solution of exemplary product ADC, which was stored at 4°C.

[0441] [ka]

[0442] The drug load analysis of ADCs (UV method) was performed according to the method of U.S. Patent Application Publication No. US 2021 / 0353764 (i.e., paragraph

[0702] ).

[0443] The drug load analysis of ADCs (LC-MS method) was performed according to the method of U.S. Patent No. 11,572,414 (i.e., column 2, row 51 to column 3, row 15).

[0444] ADC aggregation levels were determined by size exclusion chromatography (SEC). All samples were filtered through a 0.22 μm filter prior to HPLC-SEC analysis.

[0445] The HPLC method was performed as follows. Equipment: Thermo Ultimate 3000 Column: Waters, XBridge BEH 200A SEC 3.5 μm (7.8 × 300 mm) Mobile phase: PBS containing 15% isopropanol, pH 7.4 Flow rate: 0.5ml / min, 30 min.

[0446] The following ADCs were synthesized according to the general procedure described in Example 67.

[0447] [Table 8A]

[0448] [Table 8B]

[0449] [Table 8C]

[0450] Example 68 In vitro cytotoxicity study of camptothecin payload The cytotoxicity of the small molecule fragments of the present invention was evaluated using the human lung adenocarcinoma cell line A549. A549 cells were seeded at 2000 cells per well in 96-well plates. After incubation overnight in 5% CO2 at 37°C, each dilution was added. Cell viability was assessed after 3 days using Promega Corp.'s CellTiter-Glo luminescent cell viability assay, according to the manufacturer's instructions. The results are shown in Table 9 below.

[0451] [Table 9]

[0452] As shown in Table 9, the potency of the compounds in Examples 15, 19, 22, 27, 31, 32, and 33 is 5 to 6 times higher than that of the comparative compound (Dxd). Surprisingly, some small structural changes can have a significant impact on cytotoxicity. For example, the lactam analog of Example 1 is less potent than most of the other amine analogs, even though the amide moiety is well acceptable in Dxd. The 3-OH substituted piperidine compound of Example 17 is the most potent of the other 4-membered, 5-membered, or 6-membered analogs in Examples 2, 9, and 16. The piperidine compounds with -CH2OH substituents in Examples 10, 11, and 12 are also less potent than that of Example 17. Furthermore, the S isomers of Examples 17 and 19 are also more potent than that of Example 17. Increasing lipophilicity, which can increase cell permeability, can also improve potency, as shown in Examples 15, 27, 31, 32, and 33. However, these molecules may have low solubility, and aggregation may increase during binding with antibodies, as evidenced by the high aggregation and low DAR values ​​in the synthesis of ADC-4 and ADC-5. The aggregation problem may be mitigated by using a linker such as hydrophilic PEG, but this may increase the difficulty of production and reduce potency. For example, Examples ADC-8 and ADC-9 in Table 2 have lower potency than Example ADC-3.

[0453] Example 69 In vitro cytotoxicity testing of ADCs The cytotoxicity of the ADCs of the present invention was tested using cancer cell lines with different Her2 expression levels, including NCI-N87, Calu-3, SK-BR-3, CAPAN-1, and CFPAC-1 cells. These cell lines were seeded in 96-well plates at 1000–4000 cells per well. After incubation overnight in 5% CO2 at 37°C, each dilution was added. Cell viability was assessed after 6 days using Promega Corp.'s CellTiter-Glo luminescent cell viability assay, according to the manufacturer's instructions. The results are shown in Table 10 below.

[0454] [Table 10]

[0455] Calu-3, NCI-N87, and SK-BR-3 are all Her2-highly expressing cancer cell lines, while CAPAN-1 and CFPAC-1 have been reported as Her2-lowly expressing cell lines. The ADC of the present invention, for example ADC-3, exhibits comparable cytotoxicity in Her2-highly expressing cancer cell lines, but surprisingly, it shows significantly higher efficacy in Her2-lowly expressing cell lines. Among similar analogues, ADC-3 is the most potent against the NCI-N87 cell line.

[0456] Example 70 ADC In Vitro Bystander Killing Target cells SK-BR-3 and 293mGFP-labeled tool cells Flip were seeded individually or mixed, cultured for 1 day, and treated with a 4-fold serial dilution of ADC-3 solution for 5 days. (Mixed cells were prepared by mixing these two cells and seeding at 40 μL / well, resulting in a final density of 750 cells / well for SK-BR-3 and 250 cells / well for 293mGFP-labeled Flip.) At the end of treatment, the number of viable Flip cells in 293mGFP cells was measured by high-content screening (HCS) assays for DPC and FITC channels. As shown in Figure 1, 293mGFP-labeled tool cells Flip stably expressed green fluorescent protein (GFP). When cells were seeded individually, no significant decrease in the number of 293mGFP Flip cells was observed. However, when cells were seeded in co-culture, the number of 293mGFP Flip cells decreased at the same concentration of ADC, demonstrating a bystander-killing effect.

[0457] Example 71 In vitro plasma stability study of ADCs A solution of ADC-3 was prepared at 1.6 mg / mL and added to human plasma, which was then incubated at 37°C. 40 μL samples were collected at 0, 6, 18, 24, 72, and 96 hours. After normal processing, the plasma samples were examined for free payload by LC-MSMS. As shown in Figure 2, the payload released from the ADC into the plasma was less than 0.5% up to 4 days, demonstrating the good stability of the ADC of this invention in human plasma.

[0458] The LCMSMS method has the following characteristics: Equipment:Thermo Orbitrap Exploris240 Column: ACQUITY UPLC (R) BEH C18 1.7 μm (2.1 × 150 mm) Mobile phase: 0.1% FA in ACN Flow rate: 0.3 ml / min

[0459] Example 72 In vitro efficacy study of ADC The NCI-N87 cell line was used to create a CDX (cell line-derived xenograft) NCI-N87 xenograft mouse model. Each 6-8 week postnatal nu / nu nude mouse received a subcutaneous injection of 107 cells in 200 μL of Matrigel-NCI-N87 cell suspension into its right flank. The injection site was measured with a digital caliper, and the average tumor size was 300 mm². 3 The animals were palpated up to three times a week until the tumor size was reached. The animals were randomly assigned to treatment groups. Both ADC-2 and ADC-3 were administered once by intravenous injection at a dose of 3 mg / kg. Tumor size was measured and recorded weekly.

[0460] As shown in Figure 3, treatment with ADC significantly suppressed tumor growth after treatment. Despite similar levels of in vitro cytotoxicity, ADC-3 demonstrated superior efficacy compared to ADC-2 in the NCI-N87 mouse model. Mice in the ADC-3 group achieved nearly two months of disease stability after a single treatment, which was much longer than that of the ADC-2 group. Importantly, in Figure 4, mice in the ADC-3 group (the last eight bars in the graph) showed a higher response rate and better tumor regression at day 21 than the ADC-2 group (the first eight bars in the graph). No tumor progression was observed in the ADC-3 group. Therefore, this dramatic improvement in the in vivo efficacy of the compound ADC-3 is entirely unexpected and quite surprising.

[0461] A comprehensive review of the representative data (Figures 3 and 4) reveals that the compounds described herein possess remarkably superior therapeutic effects, exhibiting unexpectedly beneficial advantages in the areas of potency, efficacy, and bystander killing. The dramatic and remarkable improvements in the in vivo efficacy of the ADCs provided herein result in significant advantages in the treatment of humans or mammals, including, but not limited to, improved clinical cure rates, reduced effective drug doses, and reduced potential side effects.

Claims

1. A ligand-drug conjugate having the structure of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, 【Chemistry 1】 Eventually, Y and Z are H, halogen, C 1 -C 8 Alkyl and C 1 -C 8 Independently selected from the group consisting of alkoxys, R 3 is selected from the group consisting of H, halogen, C 1 -C 8 -alkyl, and C 1 -C 8 -alkoxy, 【Chemistry 2】 teeth, 【Transformation 3】 That is, Ligand-drug conjugates, or pharmaceutically acceptable salts or solvates thereof.

2. A ligand-drug conjugate of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, 【Chemistry 4】 Eventually, R 1 and R 2 These are hydrogen atoms, T is a targeted or binding ligand, L is a releaseable linker, n is 0, and, m is an integer or fraction selected from 1 to 10. A ligand-drug conjugate according to claim 1, characterized in that, or a pharmaceutically acceptable salt or solvate thereof. 【Request Item 3】 【Chemistry 5】 teeth, 【Transformation 6】 The ligand-drug conjugate according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

4. The ligand-drug conjugate according to claim 2, or a pharmaceutically acceptable salt or solvate thereof, characterized in that m is an integer or fraction selected from 2 to 8.

5. L is -L 1 -L 2 -L 3 -L 4 - and among them, L 1 L is connected to the ligand, 4 is X 2 Connected to imaX 2 is -O-, and also, L 1 teeth, 【Transformation 7】 -CH 2 -C(O)-NR 10 A selection is made from the group consisting of -WC(O)- and -C(O)-WC(O)-, and -W-, of which W and W 1 Independently, C 1 -C 8 Alkylene, -(C 1 -C 8 The group consists of alkylene)-cycloalkylene, arylene, heteroarylene, and linear heteroalkylene, of which linear heteroalkylene consists of 1 to 8 carbon atoms and N, O, S, SO, and SO 2 It contains 1 to 3 heteroatoms selected from the group consisting of -(C 1 -C 8 Alkylene)-cycloalkylene, linear heteroalkylene, arylene and heteroarylene are each independently optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and cycloalkyl, among which the L 1 Each left side of the base is connected to T, L 2 -NR 11 (CH 2 CH 2 O) p 1 CH 2 CH 2 C(O)-, -NR 11 (CH 2 CH 2 O) p 1 CH 2 CH 2 -, -NR 11 (CH 2 CH 2 O) p 1 CH 2 C(O)-, -S(CH 2 ) p 1 Selected from the group consisting of C(O)- and chemical bonds, among them, p 1 L is an integer selected from 1 to 20 at each occurrence, of which L 2 The left side of each base is L 1 It is connected, L 3 L is a peptide residue consisting of 2 to 7 amino acids, of which the amino acids are optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy, and cycloalkyl, of which L 3 The left side of each base is L 2 It is connected, L 4 -NR 12 (CR 13 R 14 ) t -, -C(O)NR 12 -, 【Transformation 8】 and selected from the group consisting of chemical bonds, of which t is an integer selected from l to 6 at each occurrence, of which L 4 The left side of each base is L 3 It is connected to the right side of the L 4 The right side of each base is X 2 It is connected, R 10 , R 11 and R 12 Each of these is independently selected from the group consisting of H, alkyl, haloalkyl, deuterated alkyl, and hydroxyalkyl. R 13 and R 14 Each of these is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, deuterated alkyl, and hydroxyalkyl, and also, R 15 is, -CH 2 CH 2 SO 2 CH 3 , -CH 2 CH 2 N(CH 3 ) 2 Selected from, A ligand-drug conjugate according to claim 2, characterized in that, or a pharmaceutically acceptable salt or solvate thereof.

6. L 1 teeth, 【Chemistry 9】 -CH 2 -C(O)-NR 10 -(CH 2 )s 3 -C(O)-(where the left side of the group is connected to T), -C(O)-(CH 2 )s 4 -C(O)- (where the left side of the group is connected to T), and -C 6 H 4 -selected from the group consisting of, wherein s 1 is an integer selected from 2 to 8, s 2 is an integer selected from 1 to 3, s 3 is an integer selected from 1 to 8, s 4 is an integer selected from 1 to 8, and / or L 2 -NR 11 (CH 2 CH 2 O) p 1 CH 2 CH 2 C(O)-, -NR 11 (CH 2 CH 2 O) p 1 CH 2 CH 2 -, -NR 11 (CH 2 CH 2 O) p 1 CH 2 C(O)-, -S(CH) 2 ) p 1 Selected from the group consisting of C(O)- and chemical bonds, among them, p 1 is an integer selected from 6 to 12, and / or L 3 This is a peptide residue consisting of 2 to 7 amino acids, of which the amino acids are selected from phenylalanine (F), glycine (G), valine (V), lysine (K), citrulline, serine (S), glutamic acid (E), and aspartic acid (N), and / or L 4 -NR 12 (CR 13 R 14 ) t - and R 12 is H or alkyl, and R 13 and R 14 The ligand-drug conjugate according to claim 5, or a pharmaceutically acceptable salt or solvate thereof, characterized in that each is independently selected from H and alkyl, and t is 1 or 2.

7. L is -L 1 -L 2 -L 3 -L 4 -and, L 1 teeth, 【Chemistry 10】 And, L 2 It is a chemical bond, L 3 It is a peptide residue containing four amino acids, L 4 -NR 12 (CR 13 R 14 )t- and R 12 is H or alkyl, and R 13 and R 14 Each is independently either H or alkyl, and t is either 1 or 2. A ligand-drug conjugate according to any one of claims 2 to 6, characterized in that, or a pharmaceutically acceptable salt or solvate thereof.

8. L is -L 1 -L 2 -L 3 -L 4 -and, L 1 teeth, 【Chemistry 11】 And, L 2 -NR 11 (CH 2 CH 2 O) 9 CH 2 CH 2 C(O)-, L 3 It is a peptide residue containing four amino acids, L 4 -NR 12 (CR 13 R 14 )t- and R 12 is H or alkyl, and R 13 and R 14 Each is independently either H or alkyl, and t is either 1 or 2. A ligand-drug conjugate according to any one of claims 2 to 6, characterized in that, or a pharmaceutically acceptable salt or solvate thereof. 【Request Item 9】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 Selected from, m is an integer or fraction selected from 1 to 10. T is a target antibody or ligand that binds to an antigen, and the antibody is selected from chimeric antibodies, humanized antibodies, and human antibodies. A ligand-drug conjugate according to claim 1, characterized in that, or a pharmaceutically acceptable salt or solvate thereof.

10. The ligand-drug conjugate according to Claim 2, or a pharmaceutically acceptable salt or solvate thereof, characterized in that T is selected from anti-Her2 (ErbB2) antibody, anti-EGFR antibody, anti-B7H3 antibody, anti-c-MET antibody, anti-Her3 (ErbB3) antibody, anti-Her4 (ErbB4) antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-MICI antibody, anti-Lewis Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-integrin antibody, anti-PSMA antibody, anti-tenascin C antibody, anti-SLC44A4 antibody, anti-mesothelin antibody, and anti-ROR1 antibody.

11. The ligand-drug conjugate according to claim 2, or a pharmaceutically acceptable salt or solvate thereof, characterized in that T is selected from trastuzumab, pertuzumab, nimotuzumab, enobrituzumab, emibetuzumab, inotuzumab, pinatuzumab, brentuximab, gemtuzumab, vibatuzumab, lorbotuzumab, cBR96, and glenbatumumab.

12. The ligand-drug conjugate according to claim 9, or a pharmaceutically acceptable salt or solvate thereof, characterized in that T is selected from anti-Her2 (ErbB2) antibody, anti-EGFR antibody, anti-B7H3 antibody, anti-c-MET antibody, anti-Her3 (ErbB3) antibody, anti-Her4 (ErbB4) antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-MICI antibody, anti-Lewis Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-integrin antibody, anti-PSMA antibody, anti-tenascin C antibody, anti-SLC44A4 antibody, anti-mesothelin antibody, and anti-ROR1 antibody.

13. The ligand-drug conjugate according to claim 9, or a pharmaceutically acceptable salt or solvate thereof, characterized in that T is selected from trastuzumab, pertuzumab, nimotuzumab, enobrituzumab, emibetuzumab, inotuzumab, pinatuzumab, brentuximab, gemtuzumab, vibatuzumab, rorbotuzumab, cBR96, and glenbatumumab. 【Request Item 14】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 Selected from, m is an integer or fraction selected from 1 to 10. A ligand-drug conjugate according to claim 1, characterized in that, or a pharmaceutically acceptable salt or solvate thereof.

15. A compound of formula (Va), or a pharmaceutically acceptable salt or solvate thereof, 【Chemistry 42】 Of these, Y and Z are H, halogen, and C. 1 -C 8 Alkyl and C 1 -C 8 Selected from the group consisting of alkoxys, R 3 H, halogen, C 1 -C 8 Alkyl and C 1 -C 8 Selected from the group consisting of alkoxys, 【Chemistry 43】 teeth, 【Chemistry 44】 That is, Each R 1 and R 2 H is, n 3 is 1, W is C 1 -C 8 Alkylene, -(C 1 -C 8 The group consists of alkylene)-cycloalkylene, arylene, heteroarylene, and linear heteroalkylene, of which linear heteroalkylene consists of 1 to 8 carbon atoms and N, O, S, SO, and SO 2 It contains 1 to 3 heteroatoms selected from the group consisting of -(C 1 -C 8 Alkylene)-cycloalkylene-linear heteroalkylene, arylene, and heteroarylene are each independently optionally further substituted with one or more substituents selected from the group consisting of halogens, hydroxy, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy, and cycloalkyl. L 2 -NR 11 (CH 2 CH 2 O) p 1 CH 2 CH 2 C(O)-, -NR 11 (CH 2 CH 2 O) p 1 CH 2 CH 2 -, -NR 11 (CH 2 CH 2 O) p 1 CH 2 C(O)-, -S(CH 2 ) p 1 A group consisting of C(O)- and chemical bonds, among which p 1 This is an integer selected from 1 to 20 at each occurrence. L 3 This is a peptide residue consisting of 2 to 7 amino acids, of which the amino acids are optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, and deuterated alkyl. L 4 -NR 12 (CR 13 R 14 ) t -, -C(O)NR 12 -, 【Chemistry 45】 and selected from the group consisting of chemical bonds, of which t is an integer selected from 1 to 6 at each occurrence, and of which L 4 The left side of each is L 3 It is connected to the right side of the L 4 The right side of each is X 2 It is connected, R 11 and R 12 Each of these is independently selected from the group consisting of H, alkyl, haloalkyl, deuterated alkyl, and hydroxyalkyl. R 13 and R 14 Each of these is independently selected from the group consisting of H, halogen alkyl, haloalkyl, deuterated alkyl, and hydroxyalkyl, and also, R 15 is, -CH 2 CH 2 SO 2 CH 3 , -CH 2 CH 2 N(CH 3 ) 2 Selected from, A compound of formula (Va), or a pharmaceutically acceptable salt or solvate thereof, characterized by the above.

16. The compound according to claim 15, characterized in that it is selected from the following structures. 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】

17. A compound of formula (VIIa) or a pharmaceutically acceptable salt or solvate thereof, [Transformation 50] Optionally, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, Eventually, Y and Z are H, halogen, C 1 -C 8 Alkyl and C 1 -C 8 Independently selected from the group consisting of alkoxys, R 3 H, halogen, C 1 -C 8 Alkyl and C 1 -C 8 Selected from the group consisting of alkoxys, 【Chemistry 51】 teeth, 【Chemistry 52】 A compound of formula (VIIa), or a pharmaceutically acceptable salt or solvate thereof, characterized by being such. 【Request Item 18】 【Chemistry 53】 teeth, 【Chemistry 54】 The compound according to claim 17, or a pharmaceutically acceptable salt or solvate thereof, characterized in that it is such.

19. A compound according to claim 17 or 18, or a pharmaceutically acceptable salt or solvate thereof, characterized by being selected from the following structures. 【Transformation 55】

20. A pharmaceutical composition comprising a therapeutically effective amount of the ligand-drug conjugate described in claim 1, or a pharmaceutically acceptable salt or solvate thereof, or the compound described in claim 15, or a pharmaceutically acceptable salt or solvate thereof, or the compound described in claim 17, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

21. A ligand-drug conjugate for treating cancer, as described in claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, gastric cancer, endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, lung cancer, colon cancer, rectal cancer, colorectal cancer, leukemia, bone cancer, skin cancer, thyroid cancer, pancreatic cancer, and lymphoma.

22. A compound for treating cancer, the compound according to claim 15 or 17, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, gastric cancer, endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, lung cancer, colon cancer, rectal cancer, colorectal cancer, leukemia, bone cancer, skin cancer, thyroid cancer, pancreatic cancer, and lymphoma.

23. A pharmaceutical composition for treating cancer according to claim 20, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, stomach cancer, endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, lung cancer, colon cancer, rectal cancer, colorectal cancer, leukemia, bone cancer, skin cancer, thyroid cancer, pancreatic cancer, and lymphoma.

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