Novel dispirodiketopiperazine compound

Abstract

The present invention addresses the problem of providing a novel cytotoxic substance, in particular, a novel cytotoxic substance suitable as a payload of a ligand-drug conjugate, and a ligand-drug conjugate containing the cytotoxic substance. The present invention relates to a dispirodiketopiperazine compound represented by formula (VIII), or to a novel ligand-drug conjugate represented by formula (I), which contains the compound as a payload.

Description

Novel dispirodiketopiperazine compounds

[0001] The present invention relates to novel dispirodiketopiperazine compounds, ligand-drug conjugates containing the dispirodiketopiperazine compound or its derivatives, particularly antibody-drug conjugates (ADCs), pharmaceutical compositions containing the ligand-drug conjugate, methods for treating diseases (particularly cancer) characterized by administering the ligand-drug conjugate, and manufacturing intermediates for producing the ligand-drug conjugate.

[0002] An antibody-drug conjugate (ADC) is a combination of an antibody that binds to a specific target molecule and a physiologically active drug. In one embodiment, an ADC for cancer treatment is a combination of an antibody that binds to an antigen expressed on the surface of cancer cells, thereby internalizing the antigen into the cell, and a cytotoxic drug. ADCs are expected to efficiently deliver drugs to cancer cells, causing drug accumulation within the cancer cells and ultimately leading to cancer cell death. Examples of ADCs include Adcetris® (brentuximab vedotin), which is an anti-CD30 monoclonal antibody conjugated with monomethyl auristatin E (MMAE), and is approved for the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma. Additionally, Kadcyla® (trastuzumab emtansine), which is an anti-HER2 monoclonal antibody conjugated with emtansine, is used to treat HER2-positive advanced and recurrent breast cancer.

[0003] Known cytotoxic substances used as payloads for ADCs include tubulin polymerization inhibitors such as monomethyl auristatin E (MMAE) and maytansinoids (DM), and topoisomerase I inhibitors such as exatecan derivatives (DXd) (Non-Patent Literature 1, Non-Patent Literature 2).

[0004] Compounds possessing a dispirodiketopiperazine structure have been reported to have potent and cancer cell-selective cytotoxic activity (Patent Document 1). These compounds have been reported to highly selectively inhibit cell proliferation in cancer cells by stabilizing a complex containing NuMA1 and CKAP5 (Patent Document 2). However, it remains completely unknown whether compounds with a dispirodiketopiperazine structure can effectively function as payloads for ADCs.

[0005] International Publication No. 2020 / 246487, International Publication No. 2020 / 246488

[0006] Acta Pharm Sin B., 2023 Oct; 14(10): 4025-4059.Cancers (Basel), 2023 Feb; 15(3): 713.

[0007] The problem that the present invention aims to solve is to provide a novel ligand-dispirodiketopiperazine compound conjugate and a novel dispirodiketopiperazine compound. A further problem that the present invention aims to solve is to provide a novel pharmaceutical composition containing a ligand-dispirodiketopiperazine compound conjugate having antitumor activity. Another further problem that the present invention aims to solve is to provide a novel method for treating tumors using a ligand-dispirodiketopiperazine compound conjugate.

[0008] As a result of diligent research to solve the above problems, the present inventors discovered that a compound having a specific dispirodiketopiperazine structure is useful as a cytotoxic substance, and in particular is suitable as a payload for ligand-drug conjugates. Furthermore, they confirmed that a ligand-drug conjugate in which this compound is bound to a ligand exhibits suitable cytotoxic activity and antitumor effects, thus completing the present invention.

[0009] In other words, the present invention relates to, but is not limited to, the following: [1] Formula (I):

[0010]

[0011] [In the formula, m1 represents an integer from 1 to 20; Li represents a ligand; L represents a linker connecting Li and D; and D represents formula (II):

[0012]

[0013] (where the wavy line indicates the binding site with L, n 1 , n 2 , n 3 , and n 4 each independently represents an integer from 1 to 3, -X- represents -O-, -NH-, -S-, or -CH2-, -Y- represents -O-, -C(R 3 )(R 4 )-, or -N(R 5 )-, R 1 represents phenyl, 6-membered heteroaryl containing 1 or 2 nitrogen atoms as ring-constituting atoms, C 3-6 cycloalkyl, or C 5-8 bicycloalkyl (where the phenyl, 6-membered heteroaryl, C 3-6 cycloalkyl, and C 5-8 bicycloalkyl may each independently have 1 to 3 substituents selected from substituent group 1), R 2 represents phenyl, 6-membered heteroaryl containing 1 or 2 nitrogen atoms as ring-constituting atoms, or 9- or 10-membered bicyclic heteroaryl containing 1 or 2 heteroatoms each independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring-constituting atoms (where the phenyl, 6-membered heteroaryl, and 9- or 10-membered bicyclic heteroaryl may each independently have 1 to 3 substituents selected from substituent group 2), R 3 and R 4 each independently represent hydrogen, halogen, or ethynyl, or R 3 and R 4 are bonded to each other to form a 3- to 6-membered aliphatic heterocycle containing 1 or 2 nitrogen atoms as ring-constituting atoms together with the carbon atom to which they are bonded, and R 5 represents hydrogen or C 1-6This indicates alkyl. (Substituent group 1) Halogen, cyano, nitro, -NHC(=O)NH2, -NHC(=O)NHC(=O)NH2, -NHC(=O)-C 1-6 Alkyl, Carbamoyl, -C(=O)NH-C 1-6 Alkyl, -C(=O)NHOH, -C(=O)NHNH2, -C(=O)-C 1-6 Alkyl, carboxyl, -C(=O)OC 1-6 Alkyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -SC 1-6 Alkyl, -SC 3-6 Cycloalkyl, -S(=O)-C 1-6 Alkyl, -S(=O)-C 3-6 Cycloalkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)2-C 3-6 Cycloalkyl, C 1-6 Oxetanyl which may be alkyl-substituted, and 5-oxo-4H-1,2,4-oxadiazole-3-yl (in substituent group 1, the C 1-6 Alkyl and C 3-6 Cycloalkyls are, independently, halogen, hydroxyl, and -OC. 1-6 (May be further substituted with one or more groups selected from the group consisting of alkyl groups) (Substituent group 2) Halogen, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl (In substituent group 2, the C 1-6 Alkyl and C 3-6 The cycloalkyl group may be independently further substituted with one or more halogens.)) The compound represented by [ ] or a pharmaceutically acceptable salt thereof, or a solvate thereof (hereinafter sometimes referred to as "the ligand-drug conjugate of the present invention" or "the ligand-dispirodiketopiperazine compound conjugate of the present invention"). [2] m1 However, n is an integer from 1 to 12. 1 , n 2 , n 3 , and n 4 The compound described in [1] or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein each is independently 1 or 2, -X- is -O- or -NH-, and -Y- is -CF2- or -O-. [3] m 1 However, n is an integer from 1 to 10. 1 and n 2 However, both are 1, n 3 and n 4 However, both are 2, -X- is -O- or -NH-, -Y- is -CF2- or -O-, R 1 However, phenyl, a 6-membered heteroaryl containing one or two nitrogen atoms as ring constituent atoms, C 3-6 Cycloalkyl, or C 5-8 Bicycloalkyl (wherein the phenyl, 6-membered heteroaryl, C 3-6 Cycloalkyl, and C 5-8 Each bicycloalkyl group may independently have one or two substituents selected from substituent group 1', and R 2 However, the substituent is phenyl (wherein the phenyl substituent may have one or two substituents selected from substituent group 2'), or 3,4-methylenedioxyphenyl (substituent group 1') halogen, cyano, nitro, -NHC(=O)NH2, -NHC(=O)NHC(=O)NH2, -NHC(=O)-C 1-6 Alkyl, Carbamoyl, -C(=O)NH-C 1-6 Alkyl, -C(=O)NHOH, -C(=O)NHNH2, -C(=O)-C 1-6 Alkyl, carboxyl, -C(=O)OC 1-6 Alkyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -SC 1-6 Alkyl, -S(=O)-C 1-6 Alkyl, C 1-6Oxetanyl optionally substituted with alkyl, and 5-oxo-4H-1,2,4-oxadiazol-3-yl (in substituent group 1', the C 1-6 alkyl and C 3-6 cycloalkyl may each independently be further substituted with one or more groups selected from the group consisting of halogen, hydroxy, and -O-C 1-6 alkyl) (substituent group 2') halogen, -O-C 1-6 alkyl, and C 3-6 cycloalkyl (in substituent group 2', the C 1-6 alkyl and C 3-6 cycloalkyl may each independently be further substituted with one or more halogens), the compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, or a solvate thereof. [4] m 1 is an integer from 1 to 10, n 1 and n 2 are both 1, n 3 and n 4 are both 2, -X- is -O-, -Y- is -CF2-, R 1 is cyano, carbamoyl, -C(=O)-C 1-6 alkyl, -S-C 1-6 alkyl, -O-C 1-6 alkyl, and C 3-6 cycloalkyl, phenyl which may have one or two substituents selected from the group consisting of, and R 2 is phenyl which may have one or two substituents selected from the group consisting of halogen and -O-C 1-6 alkyl, the compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, or a solvate thereof. [5] D is of formula (III):

[0014]

[0015] (wherein the wavy line indicates the bonding site with L, R 1a represents cyano or carbamoyl, R 1b is -C(=O)-C 1-3 alkyl, -S-C1-3 alkyl, -O-C 1-3 alkyl, or C 3-4 cycloalkyl, and R 2a represents halogen, and R 2b represents -O-C 1-3 alkyl), and is a compound or a pharmaceutically acceptable salt thereof, or a solvate thereof as described in any one of [1] to [4]. [6] D is a formula (III-1), formula (III-2), or formula (III-3):

[0016]

[0017] [1] to [5] or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the group is represented by any of the following (wherein the formula, the wavy line indicates the binding site with L): [7] The compound according to any of the [1] to [6] (hereinafter sometimes referred to as "the antibody-drug conjugate of the present invention" or "the antibody-dispirodiketopiperazine compound conjugate of the present invention") or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Li is Ab (wherein Ab represents an antibody or an antigen-binding fragment thereof). [8] The compound according to [7] or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or an antigen-binding fragment thereof is an antibody or an antigen-binding fragment thereof that targets tumor cells. [9] The compound described in [7] or [8], or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or antigen-binding fragment thereof is an anti-B7-H3 antibody, an anti-CDH6 antibody, an anti-CD30 antibody, or an anti-CD70 antibody, or an antigen-binding fragment thereof.

[10] Anti-CDH6 antibody or antigen-binding fragment thereof, comprising: (1) an amino acid sequence CDRH1 represented by SEQ ID NO: 3, an amino acid sequence CDRH2 represented by SEQ ID NO: 4, an amino acid sequence CDRH3 represented by SEQ ID NO: 5, an amino acid sequence CDRL1 represented by SEQ ID NO: 8, an amino acid sequence CDRL2 represented by DAN, and an amino acid sequence CDRL3 represented by SEQ ID NO: 9; (2) an anti-CDH6 antibody or antigen-binding fragment thereof comprising an amino acid sequence CDRH1 represented by SEQ ID NO: 12, an amino acid sequence CDRH2 represented by SEQ ID NO: 13, an amino acid sequence CDRH3 represented by SEQ ID NO: 14, an amino acid sequence CDRL1 represented by SEQ ID NO: 17, an amino acid sequence CDRL2 represented by DAN, and an amino acid sequence CDRL3 represented by SEQ ID NO: 18; (3) An anti-B7-H3 antibody or its antigen-binding fragment, comprising the amino acid sequence CDRH1 represented by SEQ ID NO: 21, the amino acid sequence CDRH2 represented by SEQ ID NO: 22, the amino acid sequence CDRH3 represented by SEQ ID NO: 23, the amino acid sequence CDRL1 represented by SEQ ID NO: 26, the amino acid sequence CDRL2 represented by ATS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 27.(4) An anti-B7-H3 antibody or its antigen-binding fragment containing the amino acid sequence CDRH1 represented by SEQ ID NO: 30, the amino acid sequence CDRH2 represented by SEQ ID NO: 31, the amino acid sequence CDRH3 represented by SEQ ID NO: 32, the amino acid sequence CDRL1 represented by SEQ ID NO: 35, the amino acid sequence CDRL2 represented by ATS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 36; (5) An anti-CD30 antibody or its antigen-binding fragment containing the amino acid sequence CDRH1 represented by SEQ ID NO: 39, the amino acid sequence CDRH2 represented by SEQ ID NO: 40, the amino acid sequence CDRH3 represented by SEQ ID NO: 41, the amino acid sequence CDRL1 represented by SEQ ID NO: 44, the amino acid sequence CDRL2 represented by AAS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 45; (6) (7) An anti-CD70 antibody or its antigen-binding fragment containing the amino acid sequence CDRH1 represented by SEQ ID NO: 48, the amino acid sequence CDRH2 represented by SEQ ID NO: 49, the amino acid sequence CDRH3 represented by SEQ ID NO: 50, the amino acid sequence CDRL1 represented by SEQ ID NO: 53, the amino acid sequence CDRL2 represented by LAS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 54, (8) An anti-B7-H3 antibody or its antigen-binding fragment containing the amino acid sequence CDRH1 represented by SEQ ID NO: 57, the amino acid sequence CDRH2 represented by SEQ ID NO: 58, the amino acid sequence CDRH3 represented by SEQ ID NO: 59, the amino acid sequence CDRL1 represented by SEQ ID NO: 62, the amino acid sequence CDRL2 represented by ATS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 63, or (8) A compound described in any of [7] to [9], or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is an anti-B7-H3 antibody or an antigen-binding fragment thereof, comprising the amino acid sequence CDRH1 represented by SEQ ID NO: 66, the amino acid sequence CDRH2 represented by SEQ ID NO: 67, the amino acid sequence CDRH3 represented by SEQ ID NO: 68, the amino acid sequence CDRL1 represented by SEQ ID NO: 71, the amino acid sequence CDRL2 represented by ATS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 72. [10-1] The antibody or the antigen-binding fragment thereof,(1) An anti-CDH6 antibody or its antigen-binding fragment, comprising a heavy chain containing the amino acid sequence CDRH1 represented by SEQ ID NO: 3, the amino acid sequence CDRH2 represented by SEQ ID NO: 4, and the amino acid sequence CDRH3 represented by SEQ ID NO: 5, and a light chain containing the amino acid sequence CDRL1 represented by SEQ ID NO: 8, the amino acid sequence CDRL2 represented by DAN, and the amino acid sequence CDRL3 represented by SEQ ID NO: 9; (2) An anti-CDH6 antibody or its antigen-binding fragment, comprising a heavy chain containing the amino acid sequence CDRH1 represented by SEQ ID NO: 12, the amino acid sequence CDRH2 represented by SEQ ID NO: 13, and the amino acid sequence CDRH3 represented by SEQ ID NO: 14, and a light chain containing the amino acid sequence CDRL1 represented by SEQ ID NO: 17, the amino acid sequence CDRL2 represented by DAN, and the amino acid sequence CDRL3 represented by SEQ ID NO: 18; (3) (4) An anti-B7-H3 antibody or its antigen-binding fragment, comprising a heavy chain containing the amino acid sequence CDRH1 represented by SEQ ID NO: 21, the amino acid sequence CDRH2 represented by SEQ ID NO: 22, and the amino acid sequence CDRH3 represented by SEQ ID NO: 23, and a light chain containing the amino acid sequence CDRL1 represented by SEQ ID NO: 26, the amino acid sequence CDRL2 represented by ATS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 27, (5) An anti-B7-H3 antibody or its antigen-binding fragment, comprising a heavy chain containing the amino acid sequence CDRH1 represented by SEQ ID NO: 30, the amino acid sequence CDRH2 represented by SEQ ID NO: 31, and the amino acid sequence CDRH3 represented by SEQ ID NO: 32, and a light chain containing the amino acid sequence CDRL1 represented by SEQ ID NO: 35, the amino acid sequence CDRL2 represented by ATS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 36, An anti-CD30 antibody or its antigen-binding fragment, comprising a heavy chain containing the amino acid sequence CDRH1 represented by SEQ ID NO: 39, the amino acid sequence CDRH2 represented by SEQ ID NO: 40, and the amino acid sequence CDRH3 represented by SEQ ID NO: 41, and a light chain containing the amino acid sequence CDRL1 represented by SEQ ID NO: 44, the amino acid sequence CDRL2 represented by AAS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 45.(6) An anti-CD70 antibody or its antigen-binding fragment, comprising a heavy chain containing the amino acid sequence CDRH1 represented by SEQ ID NO: 48, the amino acid sequence CDRH2 represented by SEQ ID NO: 49, and the amino acid sequence CDRH3 represented by SEQ ID NO: 50, and a light chain containing the amino acid sequence CDRL1 represented by SEQ ID NO: 53, the amino acid sequence CDRL2 represented by LAS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 54; (7) An anti-B7-H3 antibody or its antigen-binding fragment, comprising a heavy chain containing the amino acid sequence CDRH1 represented by SEQ ID NO: 57, the amino acid sequence CDRH2 represented by SEQ ID NO: 58, and the amino acid sequence CDRH3 represented by SEQ ID NO: 59, and a light chain containing the amino acid sequence CDRL1 represented by SEQ ID NO: 62, the amino acid sequence CDRL2 represented by ATS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 63; or (8) An anti-B7-H3 antibody or antigen-binding fragment thereof, comprising a heavy chain containing the amino acid sequence CDRH1 represented by SEQ ID NO: 66, the amino acid sequence CDRH2 represented by SEQ ID NO: 67, and the amino acid sequence CDRH3 represented by SEQ ID NO: 68, and a light chain containing the amino acid sequence CDRL1 represented by SEQ ID NO: 71, the amino acid sequence CDRL2 represented by ATS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 72, is a compound according to any one of [7] to [9], or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[11] An antibody or its antigen-binding fragment comprises: (1) a) an amino acid sequence represented by SEQ ID NO: 2, or a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added, and an amino acid sequence represented by SEQ ID NO: 7, or a light chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) an anti-CDH6 antibody or its antigen-binding fragment comprising an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 2, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 7; (2) a)(3) a) an amino acid sequence represented by SEQ ID NO: 11, or a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added, and an amino acid sequence represented by SEQ ID NO: 16, or a light chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) an anti-CDH6 antibody or its antigen-binding fragment containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 11, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 16; (3) a) an amino acid sequence represented by SEQ ID NO: 20, or a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added, and an amino acid sequence represented by SEQ ID NO: 25, or a light chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) (4) a) an anti-B7-H3 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 20, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 25; or b) an anti-B7-H3 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 29, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 34; or b) an anti-B7-H3 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 29, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 34;(6) a) an amino acid sequence represented by SEQ ID NO: 38, or a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added, and an amino acid sequence represented by SEQ ID NO: 43, or a light chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) an anti-CD30 antibody or antigen-binding fragment thereof containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 38, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 43; (6) a) an amino acid sequence represented by SEQ ID NO: 47, or a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added, and an amino acid sequence represented by SEQ ID NO: 52, or a light chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) (7) a) an anti-CD70 antibody or antigen-binding fragment thereof containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 47, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 52; (8) a) an amino acid sequence represented by SEQ ID NO: 56, or a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added, and an amino acid sequence represented by SEQ ID NO: 61, or a light chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) an anti-B7-H3 antibody or antigen-binding fragment thereof containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 56, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 61; or (8) a)A compound described in any of [7] to [10-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof, comprising an amino acid sequence represented by SEQ ID NO: 65, or a heavy chain variable region of said amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added, and an amino acid sequence represented by SEQ ID NO: 70, or a light chain variable region of said amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 65, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 70. [11-1] An antibody or its antigen-binding fragment comprises: (1) a) a heavy chain containing a heavy chain variable region of an amino acid sequence represented by SEQ ID NO: 2, or an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added, and a light chain containing a light chain variable region of an amino acid sequence represented by SEQ ID NO: 7, or an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) an anti-CDH6 antibody or its antigen-binding fragment comprising a heavy chain containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 2, and a light chain containing a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 7; (2) a) (3) a) an anti-CDH6 antibody or antigen-binding fragment thereof comprising: a) an amino acid sequence represented by SEQ ID NO: 11, or a heavy chain containing a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) an anti-CDH6 antibody or antigen-binding fragment thereof comprising: a) an amino acid sequence represented by SEQ ID NO: 11, or a light chain containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 16;(4) a) an anti-B7-H3 antibody or its antigen-binding fragment comprising: an amino acid sequence represented by SEQ ID NO: 20, or a heavy chain containing a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) an anti-B7-H3 antibody or its antigen-binding fragment comprising: a) an amino acid sequence represented by SEQ ID NO: 20, or a heavy chain containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 20; or b) an anti-B7-H3 antibody or its antigen-binding fragment comprising: a) an amino acid sequence represented by SEQ ID NO: 29, or a heavy chain containing a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) an anti-B7-H3 antibody or its antigen-binding fragment comprising: a) an amino acid sequence represented by SEQ ID NO: 29, or a heavy chain containing a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) (5) a) an anti-B7-H3 antibody or its antigen-binding fragment, comprising a heavy chain containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 29, and a light chain containing a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 34, (6) a) an amino acid sequence represented by SEQ ID NO: 38, or a heavy chain containing a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added, and an amino acid sequence represented by SEQ ID NO: 43, or a light chain containing a light chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) an anti-CD30 antibody or its antigen-binding fragment, comprising a heavy chain containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 38, and a light chain containing a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 43, (6) a)(7) a) an anti-CD70 antibody or antigen-binding fragment thereof comprising: an amino acid sequence represented by SEQ ID NO: 47, or a heavy chain containing a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) an anti-CD70 antibody or antigen-binding fragment thereof comprising: a) an amino acid sequence represented by SEQ ID NO: 47, or a heavy chain containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 52; or b) an anti-CD70 antibody or antigen-binding fragment thereof comprising: a) an amino acid sequence represented by SEQ ID NO: 56, or a heavy chain containing a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) an anti-CD70 antibody or antigen-binding fragment thereof comprising: a heavy chain containing a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) (8) a) an anti-B7-H3 antibody or its antigen-binding fragment, comprising a heavy chain containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 56, and a light chain containing a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 61, or (8) a) a heavy chain containing a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added in the amino acid sequence represented by SEQ ID NO: 65, and a light chain containing a light chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added in the amino acid sequence represented by SEQ ID NO: 70; or b) An anti-B7-H3 antibody or an antigen-binding fragment thereof, comprising a heavy chain containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 65, and a light chain containing a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 70, is a compound according to any one of [7] to [10-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[12] The antibody or the antigen-binding fragment thereof,(1) An anti-CDH6 antibody or its antigen-binding fragment containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 2, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 7; (2) An anti-CDH6 antibody or its antigen-binding fragment containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 11, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 16; (3) An anti-B7-H3 antibody or its antigen-binding fragment containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 20, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 25; (4) (5) An anti-B7-H3 antibody or its antigen-binding fragment containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 29, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 34, (6) An anti-CD30 antibody or its antigen-binding fragment containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 38, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 43, (7) An anti-CD70 antibody or its antigen-binding fragment containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 47, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 52, (7) An anti-B7-H3 antibody or its antigen-binding fragment, comprising a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 56, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 61, or(8) An anti-B7-H3 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 65, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 70, the compound described in any of [7] to [11-1], a pharmaceutically acceptable salt thereof, or a solvate thereof. [12-1] Anti-CDH6 antibody or antigen-binding fragment thereof, (1) an anti-CDH6 antibody or antigen-binding fragment thereof comprising a heavy chain containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 2, and a light chain containing a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 7, (2) an anti-CDH6 antibody or antigen-binding fragment thereof comprising a heavy chain containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 11, and a light chain containing a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 16, (3) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 20, and a light chain containing a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 25, (4) (5) An anti-B7-H3 antibody or its antigen-binding fragment, comprising a heavy chain containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 29, and a light chain containing a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 34, (6) An anti-CD30 antibody or its antigen-binding fragment, comprising a heavy chain containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 38, and a light chain containing a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 43, (7) An anti-CD70 antibody or its antigen-binding fragment, comprising a heavy chain containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 47, and a light chain containing a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 52,(7) An anti-B7-H3 antibody or antigen-binding fragment thereof, comprising a heavy chain containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 56, and a light chain containing a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 61, or (8) An anti-B7-H3 antibody or antigen-binding fragment thereof, comprising a compound described in any of [7] to [11-1], a pharmaceutically acceptable salt thereof, or a solvate thereof.

[13] Antibodies or antigen-binding fragments thereof include: (1) an anti-CDH6 antibody or antigen-binding fragment thereof containing the heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 2 and the light chain variable region of the amino acid sequence represented by SEQ ID NO: 7; (2) an anti-CDH6 antibody or antigen-binding fragment thereof containing the heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 11 and the light chain variable region of the amino acid sequence represented by SEQ ID NO: 16; (3) an anti-B7-H3 antibody or antigen-binding fragment thereof containing the heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 20 and the light chain variable region of the amino acid sequence represented by SEQ ID NO: 25; (4) an anti-B7-H3 antibody or antigen-binding fragment thereof containing the heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 29 and the light chain variable region of the amino acid sequence represented by SEQ ID NO: 34; (5) an anti-CD30 antibody or antigen-binding fragment thereof containing the heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 38 and the light chain variable region of the amino acid sequence represented by SEQ ID NO: 43; (6) (7) an anti-CD70 antibody or its antigen-binding fragment containing the heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 47 and the light chain variable region of the amino acid sequence represented by SEQ ID NO: 52, or an anti-B7-H3 antibody or its antigen-binding fragment containing the heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 56 and the light chain variable region of the amino acid sequence represented by SEQ ID NO: 61, or(8) An anti-B7-H3 antibody or an antigen-binding fragment thereof, which is an anti-B7-H3 antibody or an antigen-binding fragment thereof, as described in any of [7] to [12-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof. [13-1] Antibodies or antigen-binding fragments thereof include: (1) an anti-CDH6 antibody or antigen-binding fragment thereof comprising a heavy chain containing a heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 2, and a light chain containing a light chain variable region of the amino acid sequence represented by SEQ ID NO: 7; (2) an anti-CDH6 antibody or antigen-binding fragment thereof comprising a heavy chain containing a heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 11, and a light chain containing a light chain variable region of the amino acid sequence represented by SEQ ID NO: 16; (3) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain containing a heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 20, and a light chain containing a light chain variable region of the amino acid sequence represented by SEQ ID NO: 25; (4) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain containing a heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 29, and a light chain containing a light chain variable region of the amino acid sequence represented by SEQ ID NO: 34; (5) (6) an anti-CD30 antibody or antigen-binding fragment thereof, comprising a heavy chain containing a heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 38 and a light chain containing a light chain variable region of the amino acid sequence represented by SEQ ID NO: 43; (7) an anti-CD70 antibody or antigen-binding fragment thereof, comprising a heavy chain containing a heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 47 and a light chain containing a light chain variable region of the amino acid sequence represented by SEQ ID NO: 52; (8) an anti-B7-H3 antibody or antigen-binding fragment thereof, comprising a compound according to any one of [7] to [12-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[14] The antibody or its antigen-binding fragment is(1) An anti-CDH6 antibody or its antigen-binding fragment containing a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 1, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 6, (2) An anti-CDH6 antibody or its antigen-binding fragment containing a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 10, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 15, (3) An anti-B7-H3 antibody or its antigen-binding fragment containing a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 19, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 24, (4) An anti-B7-H3 antibody or its antigen-binding fragment containing a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 28, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 33, (5) (6) An anti-CD30 antibody or its antigen-binding fragment containing a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 37, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 42, (7) An anti-CD70 antibody or its antigen-binding fragment containing a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 46, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 51, or (8) An anti-B7-H3 antibody or an antigen-binding fragment thereof, comprising a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 64, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 69, is a compound according to any one of [7] to [13-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[15] The antibody or the antigen-binding fragment thereof(1) An anti-CDH6 antibody or its antigen-binding fragment comprising a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 1, and having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 1, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 6, (2) An anti-CDH6 antibody or its antigen-binding fragment comprising a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 10, and having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 10, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 15, (3) (4) An anti-B7-H3 antibody or its antigen-binding fragment, comprising a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 19 and having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 19, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 24, (5) An anti-B7-H3 antibody or its antigen-binding fragment, comprising a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 28 and having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 28, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 33, (6) An anti-CD30 antibody or antigen-binding fragment thereof, comprising a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 37 and having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 37, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 42,(7) An anti-B7-H3 antibody or antigen-binding fragment thereof, which comprises a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 55 and having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 55, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 60, or (8) An anti-B7-H3 antibody or antigen-binding fragment thereof, which comprises a compound according to any one of [7] to

[14] , or a pharmaceutically acceptable salt thereof, or a solvate thereof. [15-1] Antibodies or antigen-binding fragments thereof include: (1) an anti-CDH6 antibody or antigen-binding fragment thereof containing a heavy chain of an amino acid sequence in which one or two amino acid residues are deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 1, and a light chain of an amino acid sequence represented by SEQ ID NO: 6; (2) an anti-CDH6 antibody or antigen-binding fragment thereof containing a heavy chain of an amino acid sequence in which one or two amino acid residues are deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 10, and a light chain of an amino acid sequence represented by SEQ ID NO: 15; (3) an anti-B7-H3 antibody or antigen-binding fragment thereof containing a heavy chain of an amino acid sequence in which one or two amino acid residues are deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 19, and a light chain of an amino acid sequence represented by SEQ ID NO: 24; (4) an anti-B7-H3 antibody or antigen-binding fragment thereof containing a heavy chain of an amino acid sequence in which one or two amino acid residues are deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 28, and a light chain of an amino acid sequence represented by SEQ ID NO: 33; (5) An anti-CD30 antibody or its antigen-binding fragment, comprising a heavy chain of an amino acid sequence having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 37, and a light chain of the amino acid sequence represented by SEQ ID NO: 42.(6) an anti-CD70 antibody or antigen-binding fragment thereof comprising a heavy chain of an amino acid sequence having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 46, and a light chain of the amino acid sequence represented by SEQ ID NO: 51; (7) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of an amino acid sequence having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 55, and a light chain of the amino acid sequence represented by SEQ ID NO: 60; or (8) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of an amino acid sequence having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 64, and a light chain of the amino acid sequence represented by SEQ ID NO: 69. The compounds described in any of [7] to

[14] , or pharmaceutically acceptable salts thereof, or solvates thereof.

[16] Antibodies or antigen-binding fragments thereof include: (1) an anti-CDH6 antibody or antigen-binding fragment thereof containing a heavy chain of the amino acid sequence represented by SEQ ID NO: 1 and a light chain of the amino acid sequence represented by SEQ ID NO: 6; (2) an anti-CDH6 antibody or antigen-binding fragment thereof containing a heavy chain of the amino acid sequence represented by SEQ ID NO: 10 and a light chain of the amino acid sequence represented by SEQ ID NO: 15; (3) an anti-B7-H3 antibody or antigen-binding fragment thereof containing a heavy chain of the amino acid sequence represented by SEQ ID NO: 19 and a light chain of the amino acid sequence represented by SEQ ID NO: 24; (4) an anti-B7-H3 antibody or antigen-binding fragment thereof containing a heavy chain of the amino acid sequence represented by SEQ ID NO: 28 and a light chain of the amino acid sequence represented by SEQ ID NO: 33; (5) an anti-CD30 antibody or antigen-binding fragment thereof containing a heavy chain of the amino acid sequence represented by SEQ ID NO: 37 and a light chain of the amino acid sequence represented by SEQ ID NO: 42; (6) an anti-CD70 antibody or antigen-binding fragment thereof containing a heavy chain of the amino acid sequence represented by SEQ ID NO: 46 and a light chain of the amino acid sequence represented by SEQ ID NO: 51. (7) An anti-B7-H3 antibody or its antigen-binding fragment, comprising the heavy chain of the amino acid sequence represented by SEQ ID NO: 55 and the light chain of the amino acid sequence represented by SEQ ID NO: 60, or(8) An anti-B7-H3 antibody or antigen-binding fragment thereof, comprising the heavy chain of the amino acid sequence represented by SEQ ID NO: 64 and the light chain of the amino acid sequence represented by SEQ ID NO: 69, or a compound according to any of [7] to

[14] , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[17] -L- is of the formula: -Lb-La-Lp-NH-CH2- ＊ [In the formula, * indicates a binding site with D, -Lp- indicates a divalent group consisting of 1 to 10 amino acid residues, and -La- indicates a single bond or formula: -(CH2)n 5 -C(=O)- ＊ ', -C(=O)-(CH2)n 6 -C(=O)- ＊ ', -(CH2CH2O)n 5 -(CH2)n 6 -C(=O)- ＊ ', -(CH2)n 6 -C(=O)NH-(CH2CH2O)n 8 -(CH2)n 7 -C(=O)- ＊ ', and -(CH2)n 6 -C(=O)NH-(CH2)n 8 -(CH2)n 7 -C(=O)- ＊ ' (In the formula, * indicates the binding site with Lp, n 5 n represents an integer from 1 to 10. 6 and n 7 Each of these independently represents an integer from 1 to 5, and n 8[1] The compound according to any one of [1] to

[16] or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein -Lp- represents any one divalent group selected from the group consisting of integers from 0 to 5, and -Lb- represents a divalent group linking La and Li, a divalent group linking La and Ab amino acid residues, or a divalent group linking La and Ab sugar chains, and is a linker represented by [1] to

[16] .

[18] The compound according to

[17] or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein -Lp- is a divalent group consisting of 2 to 7 amino acid residues.

[19] The compound according to

[17] or

[18] or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the amino acid residue of -Lp- is a natural amino acid residue.

[20] A compound according to any one of

[17] to

[19] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein -Lp- is a divalent group consisting of an amino acid residue selected from glycine (G), alanine (A), phenylalanine (F), citrulline (Cit), and leucine (L).

[21] -Lp- is a compound of the formula: -GGFG- ＊＊ ',-GGLCit- ＊＊ ',-GGACit- ＊＊ ',-GGGACit- ＊＊ ',-ACit- ＊＊ ', -GGGCit- ＊＊ ', and -CitGACit- ＊＊ A compound according to any one of

[17] to

[20] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is one divalent group selected from the group consisting of ' (wherein ** indicates a binding site with NH).

[22] -La- is of formula: -(CH2)2-C(=O)- ＊ ',-(CH2)5-C(=O)- ＊ ', -C(=O)-(CH2)2-C(=O)- ＊ ', -(CH2CH2O)4-(CH2)2-C(=O)- ＊ ',-(CH2CH2O)8-(CH2)2-C(=O)- ＊ ', -(CH2)2-C(=O)NH-(CH2CH2O)2-(CH2)2-C(=O)- ＊', and -(CH2)2-C(=O)NH-(CH2)2-C(=O)- ＊ A compound according to any one of

[17] to

[21] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is one divalent group selected from the group consisting of ' (wherein * indicates a binding site with Lp).

[23] -Lb- is of formula (V-1):

[0018]

[0019] A compound according to any of

[17] to

[22] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a divalent group represented by (wherein ** indicates a binding site with La, and the dashed line indicates a binding site with the sulfur atom of a cysteine ​​residue contained in Li or Ab).

[24] -Lb- is of formula (V-2) or formula (V-3):

[0020]

[0021] A compound according to any of

[17] to

[22] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a divalent group represented by the formula: (wherein ** indicates a binding site with La, and the wavy line indicates a binding site with a sugar chain of Li or Ab).

[25] -Lp- is a compound according to the formula: -CitGACit- ＊＊ 'or -GGACit- ＊＊ The divalent group represented by ' (wherein ** indicates the binding site with NH), -La- is represented by the formula: -(CH2)5-C(=O)- ＊ ' (wherein * indicates the binding site with Lp) is a divalent group represented by -Lb-, and -Lb- is given by formula (V-1):

[0022]

[0023]

[17] or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a divalent group represented by (wherein ** indicates a binding site with La, and the dashed line indicates a binding site with a sulfur atom of a cysteine ​​residue contained in Li or Ab).

[26] A compound according to any of [7] to

[22] and

[24] or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein L is bound to a sugar chain (N297 sugar chain) bound to Asn297 of Ab.

[27] A compound according to

[26] or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the N297 sugar chain is N297-(Fuc)MSG1 or N297-(Fuc)SG.

[28] A compound according to any one of [7] to

[23] and

[25] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein L is bound to one or more of the cysteine ​​residues at EU numbering 220 of the heavy chain, EU numbering 226 of the heavy chain, EU numbering 229 of the heavy chain, and EU numbering 214 of the light chain of Ab.

[29] -LD is of formula (XI-1) to (XI-6):

[0024]

[0025]

[0026] A compound according to any one of the groups [1] to

[16] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is selected from the group consisting of groups represented by (wherein the formula, the wavy line indicates the binding site with the sulfur atom of the cysteine ​​residue contained in Li or Ab).

[30] -LD is of formula (XI-2):

[0027]

[0028] (In the formula, the wavy line indicates the binding site with the sulfur atom of a cysteine ​​residue contained in the antibody represented by Ab or its antigen-binding fragment) and the group represented by m 1[7] The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is an integer from 1 to 8.

[31] The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is an antibody or an antigen-binding fragment thereof that targets tumor cells.

[32] The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is an antibody or an antigen-binding fragment thereof that is an anti-B7-H3 antibody or an antigen-binding fragment thereof.

[33] A compound according to any one of

[30] to

[32] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or antigen-binding fragment thereof is (1) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence represented by SEQ ID NO: 19 and a light chain of the amino acid sequence represented by SEQ ID NO: 24, or (2) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence in which one or two amino acid residues are deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 19 and a light chain of the amino acid sequence represented by SEQ ID NO: 24.

[34] A compound according to any one of

[30] to

[32] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or antigen-binding fragment thereof is (1) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence represented by SEQ ID NO: 28 and a light chain of the amino acid sequence represented by SEQ ID NO: 33, or (2) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 28 and a light chain of the amino acid sequence represented by SEQ ID NO: 33. [34-1] m 1 However, the compound described in any of

[30] to

[34] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, is 4. [34-2] m 1 However, the compound described in any of

[30] to

[34] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, is 6.

[35] -LD is of formula (XI-3):

[0029]

[0030] (In the formula, the wavy line indicates the binding site with the sulfur atom of a cysteine ​​residue contained in the antibody represented by Ab or its antigen-binding fragment) and m 1[7] The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is an integer from 1 to 8.

[36] The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is an antibody or an antigen-binding fragment thereof that targets tumor cells.

[37] The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is an antibody or an antigen-binding fragment thereof that is an anti-B7-H3 antibody or an antigen-binding fragment thereof.

[38] A compound according to any one of

[35] to

[37] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or antigen-binding fragment thereof is (1) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence represented by SEQ ID NO: 19 and a light chain of the amino acid sequence represented by SEQ ID NO: 24, or (2) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 19 and a light chain of the amino acid sequence represented by SEQ ID NO: 24.

[39] A compound according to any one of

[35] to

[37] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or antigen-binding fragment thereof is (1) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence represented by SEQ ID NO: 28 and a light chain of the amino acid sequence represented by SEQ ID NO: 33, or (2) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 28 and a light chain of the amino acid sequence represented by SEQ ID NO: 33.

[40] A compound according to any one of

[35] to

[37] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or antigen-binding fragment thereof is (1) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence represented by SEQ ID NO: 55 and a light chain of the amino acid sequence represented by SEQ ID NO: 60, or (2) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence in which one or two amino acid residues are deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 55 and a light chain of the amino acid sequence represented by SEQ ID NO: 60.

[41] The compound according to any one of

[35] to

[37] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or antigen-binding fragment thereof is (1) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence represented by SEQ ID NO: 64 and a light chain of the amino acid sequence represented by SEQ ID NO: 69, or (2) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence in which one or two amino acid residues are deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 64 and a light chain of the amino acid sequence represented by SEQ ID NO: 69. [41-1] m. 1 However, the compound described in any of

[35] to

[41] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, is 4. [41-2] m 1

[42] A pharmaceutical composition comprising a compound according to any one of

[35] to

[41] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, and at least one pharmaceutically acceptable additive.

[43] m 1A pharmaceutical composition according to

[42] , comprising two or more different compounds according to any one of [1] to

[41] or pharmaceutically acceptable salts thereof, or solvates thereof, wherein the average number of D bonds per Li or Ab unit in the compounds according to any one of [1] to

[41] or pharmaceutically acceptable salts thereof, or solvates thereof contained in the composition is 3 to 8.

[44] A pharmaceutical composition according to

[42] or

[43] for use in the treatment of cancer.

[45] The pharmaceutical composition according to

[44] , wherein the cancer is leukemia, malignant lymphoma, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, stomach cancer, appendiceal cancer, colorectal cancer, anal cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, gastrointestinal stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, bladder cancer, neuroendocrine tumor, neuroblastoma, glioblastoma, malignant melanoma, breast cancer, uterine cancer, cervical cancer, ovarian cancer, testicular cancer, osteosarcoma, soft tissue sarcoma, Kaposi's sarcoma, or myosarcoma.

[46] The pharmaceutical composition according to

[44] , wherein the cancer is leukemia, malignant lymphoma, brain tumor, head and neck cancer, esophageal cancer, lung cancer, neuroblastoma, glioblastoma, breast cancer, ovarian cancer, osteosarcoma, soft tissue sarcoma, Kaposi's sarcoma, or myosarcoma. [46-1] The pharmaceutical composition according to

[44] , wherein the cancer is ovarian cancer. [46-2] The pharmaceutical composition according to

[44] , wherein the cancer is breast cancer. [46-3] The pharmaceutical composition according to

[44] , wherein the cancer is lung cancer. [46-4] The pharmaceutical composition according to

[44] , wherein the cancer is sarcoma. [46-5] The pharmaceutical composition according to

[44] , wherein the cancer is esophageal cancer. [46-6] The pharmaceutical composition according to

[44] , wherein the cancer is prostate cancer. [46-7] The pharmaceutical composition according to

[44] , wherein the cancer is bladder cancer. [46-8] The pharmaceutical composition according to

[44] , wherein the cancer is head and neck cancer. [46-9] The pharmaceutical composition according to

[44] , wherein the cancer is uterine cancer. [46-10] The pharmaceutical composition according to

[44] , wherein the cancer is malignant melanoma. [46-11] The pharmaceutical composition according to

[44] , wherein the cancer is a solid tumor with a history of prior treatment. [46-12] The pharmaceutical composition according to

[44] , wherein the cancer is a solid tumor that has been treated with at least two lines of therapy. [46-13] The pharmaceutical composition according to

[44] , wherein the cancer is a solid tumor that has been treated with at least one line of therapy.[46-14] The pharmaceutical composition according to

[44] , wherein the cancer is an advanced solid tumor that is resistant to standard treatment or for which there is no standard treatment. [46-15] The pharmaceutical composition according to

[44] , wherein the cancer is ovarian cancer with a history of prior treatment. [46-16] The pharmaceutical composition according to

[44] , wherein the cancer is breast cancer with a history of prior treatment. [46-17] The pharmaceutical composition according to

[44] , wherein the cancer is sarcoma with a history of prior treatment. [46-18] The pharmaceutical composition according to

[44] , wherein the cancer is esophageal cancer with a history of prior treatment. [46-19] The pharmaceutical composition according to

[44] , wherein the cancer is prostate cancer with a history of prior treatment. [46-20] The pharmaceutical composition according to

[44] , wherein the cancer is bladder cancer with a history of prior treatment. [46-21] The pharmaceutical composition according to

[44] , wherein the cancer is head and neck cancer with a history of prior treatment. [46-22] The pharmaceutical composition according to

[44] , wherein the cancer is uterine cancer with a history of prior treatment. [46-23] The pharmaceutical composition according to

[44] , wherein the cancer is malignant melanoma with a history of prior treatment. [46-24] The pharmaceutical composition according to

[44] , wherein the cancer is characterized by amplification of the NuMA1 gene or overexpression of the NuMA1 protein. [46-25] The pharmaceutical composition according to [46-24], wherein the cancer is head and neck squamous cell carcinoma or esophageal squamous cell carcinoma.

[47] A compound according to any one of [1] to [41-2] or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in the treatment of cancer.

[48] A method for treating cancer, comprising the step of administering a therapeutically effective amount of a compound according to any one of [1] to [41-2] or a pharmaceutically acceptable salt thereof, or a solvate thereof, to a subject in need of treatment for cancer.

[49] Use of a compound according to any one of [1] to [41-2] or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the manufacture of a pharmaceutical for use in the treatment of cancer.

[50] Formula (VI):

[0031]

[0032] [where n 1 , n 2 , n 3 , and n 4 Each independently represents an integer from 1 to 3; -X- represents -O-, -NH-, -S-, or -CH2-; -Y- represents -O-, -C(R3 )(R 4 )-, or -N(R 5 )- indicates; R 1 phenyl, a six-membered heteroaryl containing one or two nitrogen atoms as ring atoms, C 3-6 Cycloalkyl, or C 5-8 Bicycloalkyl (wherein the phenyl, 6-membered heteroaryl, C 3-6 Cycloalkyl, and C 5-8 Each bicycloalkyl group may independently have 1 to 3 substituents selected from substituent group 1); R 2 R represents a 6-membered heteroaryl containing phenyl, one or two nitrogen atoms as ring constituent atoms, or a 9 or 10-membered bicyclic heteroaryl containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms (wherein the phenyl, 6-membered heteroaryl, and 9 or 10-membered bicyclic heteroaryl each independently may have one to three substituents selected from substituent group 2); R 3 and R 4 Each independently represents hydrogen, halogen, or ethynyl, or R 3 and R 4 They bond with each other, and together with the carbon atoms to which they bond, form a 3 to 6-membered aliphatic heterocycle containing one or two nitrogen atoms as ring constituent atoms; R 5 is hydrogen or C 1-6 Alkyl is indicated; and R L is a group represented by the formula: Cit-NH-CH2- or the formula: Lb'-La'-Lp'-NH-CH2- [wherein -Lp'- is the same as the formula: -GGFG-] ＊＊ '', -GGLCit- ＊＊ '', -GGACit- ＊＊ '', -GGGACit- ＊＊ '', -ACit- ＊＊ '', -GGGCit- ＊＊ '', and -CitGACit- ＊＊'' (wherein **'' indicates a binding site with NH) represents one divalent group selected from the group consisting of '', and -La'- represents the formula: -(CH2)2-C(=O)- ＊ '', -(CH2)5-C(=O)- ＊ '', -C(=O)-(CH2)2-C(=O)- ＊ '', -(CH2CH2O)4-(CH2)2-C(=O)- ＊ '', -(CH2CH2O)8-(CH2)2-C(=O)- ＊ '', -(CH2)2-C(=O)NH-(CH2CH2O)2-(CH2)2-C(=O)- ＊ '', and -(CH2)2-C(=O)NH-(CH2)2-C(=O)- ＊ '' (wherein *'' indicates the binding site with Lp') represents one divalent group selected from the group consisting of '' and Lb' is either formula (VII-1) or formula (VII-2):

[0033]

[0034] (In the formula, the wavy line indicates the bond site with La') indicates the group indicated by (substituent group 1) halogen, cyano, nitro, -NHC(=O)NH2, -NHC(=O)NHC(=O)NH2, -NHC(=O)-C 1-6 Alkyl, Carbamoyl, -C(=O)NH-C 1-6 Alkyl, -C(=O)NHOH, -C(=O)NHNH2, -C(=O)-C 1-6 Alkyl, carboxyl, -C(=O)OC 1-6 Alkyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -SC 1-6 Alkyl, -SC 3-6 Cycloalkyl, -S(=O)-C 1-6 Alkyl, -S(=O)-C 3-6 Cycloalkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)2-C 3-6 Cycloalkyl, C1-6 Oxetanyl which may be alkyl-substituted, and 5-oxo-4H-1,2,4-oxadiazole-3-yl (in substituent group 1, the C 1-6 Alkyl and C 3-6 Cycloalkyls are, independently, halogen, hydroxyl, and -OC. 1-6 (May be further substituted with one or more groups selected from the group consisting of alkyl groups) (Substituent group 2) Halogen, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl (In substituent group 2, the C 1-6 Alkyl and C 3-6 A compound represented by [the cycloalkyl group may be further independently substituted with one or more halogens] or a pharmaceutically acceptable salt thereof, or a solvate thereof (hereinafter sometimes referred to as "the drug linker of the present invention").

[51] n 1 and n 2 However, both are 1, n 3 and n 4 However, both are 2, -X- is -O- or -NH-, -Y- is -CF2- or -O-, R 1 However, phenyl, a 6-membered heteroaryl containing one or two nitrogen atoms as ring constituent atoms, C 3-6 Cycloalkyl or C 5-8 Bicycloalkyl (wherein the phenyl, 6-membered heteroaryl, C 3-6 Cycloalkyl, and C 5-8 Each bicycloalkyl group may independently have one or two substituents selected from substituent group 1', R 2 However, it is phenyl (wherein the phenyl may have one or two substituents selected from substituent group 2'), or 3,4-methylenedioxyphenyl, and R L However, the group represented by formula: Cit-NH-CH2-, or formula: Lb'-La'-Lp'-NH-CH2- [wherein -Lp'- is the same as formula: -GGFG-] ＊＊ '', -GGLCit-＊＊ '', -GGACit- ＊＊ '', -GGGACit- ＊＊ '', -ACit- ＊＊ '', -GGGCit- ＊＊ '', and -CitGACit- ＊＊ '' (wherein **'' indicates a binding site with NH) represents one divalent group selected from the group consisting of '', and -La'- represents the formula: -(CH2)2-C(=O)- ＊ '', -(CH2)5-C(=O)- ＊ '', -(CH2CH2O)4-(CH2)2-C(=O)- ＊ '', -(CH2CH2O)8-(CH2)2-C(=O)- ＊ '', -(CH2)2-C(=O)NH-(CH2CH2O)2-(CH2)2-C(=O)- ＊ '', and -(CH2)2-C(=O)NH-(CH2)2-C(=O)- ＊ '' (wherein *'' indicates the binding site with Lp') represents one divalent group selected from the group consisting of '', and Lb' is given by formula (VII-1):

[0035]

[0036] The group shown is indicated by (where the dashed line in the formula indicates the bonding site with La'). The group shown is (substituent group 1') halogen, cyano, nitro, -NHC(=O)NH2, -NHC(=O)NHC(=O)NH2, -NHC(=O)-C 1-6 Alkyl, Carbamoyl, -C(=O)NH-C 1-6 Alkyl, -C(=O)NHOH, -C(=O)NHNH2, -C(=O)-C 1-6 Alkyl, carboxyl, -C(=O)OC 1-6 Alkyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -SC 1-6 Alkyl, -S(=O)-C 1-6 Alkyl, C 1-6Oxetanyl which may be alkyl-substituted, and 5-oxo-4H-1,2,4-oxadiazole-3-yl (in substituent group 1', the C 1-6 Alkyl and C 3-6 Cycloalkyls are, independently, halogen, hydroxyl, and -OC. 1-6 (May be further substituted with one or more groups selected from the group consisting of alkyl groups) (Substituent group 2') Halogen, -OC 1-6 Alkyl and C 3-6 Cycloalkyl (in substituent group 2', the C 1-6 Alkyl and C 3-6 The cycloalkyl groups may each be independently further substituted with one or more halogens), the compounds described in

[50] or pharmaceutically acceptable salts thereof, or solvates thereof.

[52] Formulas (VI-6), (VI-9), (VI-12), (VI-15), (VI-24), and (VI-25):

[0037]

[0038]

[0039] Any one compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[53] Formulas (VI-5), (VI-8), and (VI-11):

[0040]

[0041] Any one compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[54] Formula (VIII):

[0042]

[0043] [where n 1 , n 2 , n 3 , and n 4 Each independently represents an integer from 1 to 3; -X- represents -O-, -NH-, -S-, or -CH2-; -Y- represents -O-, -C(R 3 )(R 4 )-, or -N(R 5)- indicates; R 1 phenyl, a six-membered heteroaryl containing one or two nitrogen atoms as ring atoms, C 3-6 Cycloalkyl, or C 5-8 Bicycloalkyl (wherein the phenyl, 6-membered heteroaryl, C 3-6 Cycloalkyl, and C 5-8 Each bicycloalkyl group may independently have 1 to 3 substituents selected from substituent group 1); R 2 R represents a 6-membered heteroaryl containing phenyl, one or two nitrogen atoms as ring constituent atoms, or a 9 or 10-membered bicyclic heteroaryl containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms (wherein the phenyl, 6-membered heteroaryl, and 9 or 10-membered bicyclic heteroaryl each independently may have one to three substituents selected from substituent group 2); R 3 and R 4 Each independently represents hydrogen, halogen, or ethynyl, or R 3 and R 4 They bond to each other, and together with the carbon atoms to which they bond, form a 3 to 6-membered aliphatic heterocycle containing one or two nitrogen atoms as ring constituent atoms; and R 5 is hydrogen or C 1-6 This indicates alkyl. (Substituent group 1) Halogen, cyano, nitro, -NHC(=O)NH2, -NHC(=O)NHC(=O)NH2, -NHC(=O)-C 1-6 Alkyl, Carbamoyl, -C(=O)NH-C 1-6 Alkyl, -C(=O)NHOH, -C(=O)NHNH2, -C(=O)-C 1-6 Alkyl, carboxyl, -C(=O)OC 1-6 Alkyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -SC 1-6 Alkyl, -SC 3-6Cycloalkyl, -S(=O)-C 1-6 Alkyl, -S(=O)-C 3-6 Cycloalkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)2-C 3-6 Cycloalkyl, C 1-6 Oxetanyl which may be alkyl-substituted, and 5-oxo-4H-1,2,4-oxadiazole-3-yl (in substituent group 1, the C 1-6 Alkyl and C 3-6 Cycloalkyls are, independently, halogen, hydroxyl, and -OC. 1-6 (May be further substituted with one or more groups selected from the group consisting of alkyl groups) (Substituent group 2) Halogen, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl (In substituent group 2, the C 1-6 Alkyl and C 3-6 The compounds represented by [the cycloalkyl group may be further independently substituted with one or more halogens] or pharmaceutically acceptable salts thereof, or solvates thereof (hereinafter sometimes referred to as "the dispirodiketopiperazine compounds of the present invention").

[55] n 1 and n 2 However, both are 1, n 3 and n 4 However, both are 2, -X- is -O- or -NH-, -Y- is -CF2- or -O-, R 1 However, phenyl, a 6-membered heteroaryl containing one or two nitrogen atoms as ring constituent atoms, C 3-6 Cycloalkyl, or C 5-8 Bicycloalkyl (wherein the phenyl, 6-membered heteroaryl, C 3-6 Cycloalkyl, and C 5-8 Each bicycloalkyl group may independently have one or two substituents selected from substituent group 1', and R 2However, the substituent is phenyl (wherein the phenyl substituent may have one or two substituents selected from substituent group 2') or 3,4-methylenedioxyphenyl (substituent group 1') halogen, cyano, nitro, -NHC(=O)NH2, -NHC(=O)NHC(=O)NH2, -NHC(=O)-C 1-6 Alkyl, Carbamoyl, -C(=O)NH-C 1-6 Alkyl, -C(=O)NHOH, -C(=O)NHNH2, -C(=O)-C 1-6 Alkyl, carboxyl, -C(=O)OC 1-6 Alkyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -SC 1-6 Alkyl, -S(=O)-C 1-6 Alkyl, C 1-6 Oxetanyl which may be alkyl-substituted, and 5-oxo-4H-1,2,4-oxadiazole-3-yl (in substituent group 1', the C 1-6 Alkyl and C 3-6 Cycloalkyls are, independently, halogen, hydroxyl, and -OC. 1-6 (may be further substituted with one or more groups selected from the group consisting of alkyls), (substituent group 2') halogen, -OC 1-6 Alkyl and C 3-6 Cycloalkyl (in substituent group 2', the C 1-6 Alkyl and C 3-6 The cycloalkyl groups may each be independently further substituted with one or more halogens), the compounds described in

[54] or pharmaceutically acceptable salts thereof, or solvates thereof.

[56] Formulas (VIII-22), (VIII-50), and (VIII-54):

[0044]

[0045] Any one compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[57] An antibody-drug conjugate in which a drug and an antibody or an antigen-binding fragment thereof are conjugated via a linker, the formula being:

[0046]

[0047] An antibody-drug conjugate comprising a linker represented by (wherein the formula, the wavy line indicates the binding site to the sulfur atom of a cysteine ​​residue contained in the antibody or its antigen-binding fragment, and * indicates the binding site to the drug).

[58] The antibody-drug conjugate according to

[57] , wherein the drug is an antitumor agent.

[59] The drug is represented by formula (III-1), formula (III-2), or formula (III-3):

[0048]

[0049] An antibody-drug conjugate according to

[57] or

[58] , wherein the group is represented by one of the following (wherein the formula, the wavy line indicates the binding site with the linker).

[60] An antibody-drug conjugate according to any one of

[57] to

[59] , wherein the antibody or its antigen-binding fragment is an antibody or its antigen-binding fragment that targets tumor cells.

[61] An antibody-drug conjugate according to any one of

[57] to

[60] , wherein the antibody or its antigen-binding fragment is an anti-B7-H3 antibody or its antigen-binding fragment.

[62] The following formula for obtaining an antibody-drug conjugate in which a drug and an antibody or its antigen-binding fragment are bound via a linker:

[0050]

[0051] A linker represented by formula (VI-24): (wherein the formula, the wavy line indicates the binding site to the sulfur atom of the cysteine ​​residue contained in the antibody or its antigen-binding fragment, and * indicates the binding site to the drug).

[63] After treating the antibody or its antigen-binding fragment under reducing conditions, formula (VI-24):

[0052]

[0053] The process involves reacting the compound shown in formula (XI-2):

[0054]

[0055] A method for producing an antibody-drug conjugate, wherein the structure represented by (wherein the formula, the wavy line indicates the binding site with the sulfur atom of a cysteine ​​residue contained in the antibody or its antigen-binding fragment) is conjugated to the antibody or its antigen-binding fragment.

[64] The method according to

[63] , wherein the antibody or its antigen-binding fragment is an antibody or its antigen-binding fragment that targets tumor cells.

[65] The method according to

[63] or

[64] , wherein the antibody or its antigen-binding fragment is an anti-B7-H3 antibody or its antigen-binding fragment.

[66] The method according to any one of

[63] to

[65] , wherein the antibody or its antigen-binding fragment is an anti-B7-H3 antibody or its antigen-binding fragment that includes a heavy chain of the amino acid sequence represented by SEQ ID NO: 19 and a light chain of the amino acid sequence represented by SEQ ID NO: 24.

[67] The method for producing an antibody or antigen-binding fragment thereof according to any one of

[63] to

[65] , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain of the amino acid sequence represented by SEQ ID NO: 28 and a light chain of the amino acid sequence represented by SEQ ID NO: 33.

[68] After treating the antibody or antigen-binding fragment thereof under reducing conditions, formula (VI-25):

[0056]

[0057] The process involves reacting the compound shown in formula (XI-3):

[0058]

[0059] A method for producing an antibody-drug conjugate, wherein the structure represented by (wherein the formula, the wavy line indicates the binding site with the sulfur atom of a cysteine ​​residue contained in the antibody or its antigen-binding fragment) is conjugated to the antibody or its antigen-binding fragment.

[69] The method for producing the antibody according to

[68] , wherein the antibody or its antigen-binding fragment is an antibody or its antigen-binding fragment that targets tumor cells.

[70] The method for producing the antibody according to

[68] or

[69] , wherein the antibody or its antigen-binding fragment is an anti-B7-H3 antibody or its antigen-binding fragment.

[71] The method for producing the antibody according to any one of

[68] to

[70] , wherein the antibody or its antigen-binding fragment is an anti-B7-H3 antibody or its antigen-binding fragment that includes a heavy chain of the amino acid sequence represented by SEQ ID NO: 19 and a light chain of the amino acid sequence represented by SEQ ID NO: 24.

[72] The method for producing an anti-B7-H3 antibody or its antigen-binding fragment, wherein the antibody or its antigen-binding fragment is an anti-B7-H3 antibody or its antigen-binding fragment, comprising a heavy chain of the amino acid sequence represented by SEQ ID NO: 28 and a light chain of the amino acid sequence represented by SEQ ID NO: 33.

[73] The method for producing an anti-B7-H3 antibody or its antigen-binding fragment, wherein the antibody or its antigen-binding fragment is an anti-B7-H3 antibody or its antigen-binding fragment, comprising a heavy chain of the amino acid sequence represented by SEQ ID NO: 55 and a light chain of the amino acid sequence represented by SEQ ID NO: 60.

[74] The method for producing an anti-B7-H3 antibody or its antigen-binding fragment, comprising a heavy chain of the amino acid sequence represented by SEQ ID NO: 64 and a light chain of the amino acid sequence represented by SEQ ID NO: 69. For example, if the item numbers are indicated as a range, such as "[7] to

[14] " above, and there are items within that range that include sub-numbers such as [10-1], [11-1], [12-1], and [13-1], then the items including those sub-numbers are also included in that range.

[0060] The ligand-dispirodiketopiperazine compound conjugate of the present invention has antitumor activity and is therefore useful as an antitumor agent. Furthermore, the dispirodiketopiperazine compound of the present invention has antitumor activity and is useful as a payload for antibody-dispirodiketopiperazine compound conjugates. Moreover, the present invention provides a pharmaceutical composition containing a ligand-dispirodiketopiperazine compound conjugate and a method for treating tumors using a ligand-dispirodiketopiperazine compound conjugate.

[0061] Figure 1 shows the antitumor effect of an anti-CDH6 antibody-drug conjugate (antibody-drug conjugate (IV-1a)) in mice subcutaneously transplanted with OVCAR-3 cells. The black circles in the figure represent the control group (vehicle administration group), the black squares represent the group administered antibody-drug conjugate (IV-1a) 3 mg / kg, and the black triangles represent the group administered antibody-drug conjugate (IV-1a) 10 mg / kg. The vertical axis represents tumor volume (mm²). 3 Figure 2 shows the horizontal axis representing the number of days after tumor transplantation. Each symbol represents the mean value of the tumor volume, and the error bars represent the standard error. Figure 2 shows the measured antitumor effect (Figure 1) of anti-CDH6 antibody-drug conjugate (antibody-drug conjugate (IV-1a)) in mice subcutaneously transplanted with OVCAR-3 cells. Figure 3 shows the antitumor effect of anti-CDH6 antibody-drug conjugate (antibody-drug conjugate (IV-2a), (IV-2b), and (IV-3b)) in mice subcutaneously transplanted with OVCAR-3 cells. In the figures, the black circles represent the control group (vehicle administration group), the black squares represent the antibody-drug conjugate (IV-2a) 3 mg / kg administration group, the black triangles represent the antibody-drug conjugate (IV-2b) 3 mg / kg administration group, and the black inverted triangles represent the antibody-drug conjugate (IV-3b) 3 mg / kg administration group. The vertical axis represents tumor volume (mm²). 3Figure 4 shows the horizontal axis of the graph, with the horizontal axis representing the number of days after tumor transplantation. Each symbol represents the mean value of the tumor volume, and the error bars represent the standard error. Figure 4 shows the measured antitumor effects (Figure 3) of anti-CDH6 antibody-drug conjugates (antibody-drug conjugates (IV-2a), (IV-2b), and (IV-3b)) in mice subcutaneously transplanted with OVCAR-3 cells. Figure 5 shows the antitumor effects of anti-CDH6 antibody-drug conjugates (antibody-drug conjugates (IV-5a) and (IV-6a)) in mice subcutaneously transplanted with OVCAR-3 cells. In the figure, the black circles represent the control group (vehicle administration group), the black squares represent the anti-CDH6 antibody 10 mg / kg administration group, the white circles represent the antibody-drug conjugate (IV-5a) 0.3 mg / kg administration group, the black diamonds represent the antibody-drug conjugate (IV-5a) 1 mg / kg administration group, the black inverted triangles represent the antibody-drug conjugate (IV-5a) 3 mg / kg administration group, the black triangles represent the antibody-drug conjugate (IV-5a) 10 mg / kg administration group, the white diamonds represent the antibody-drug conjugate (IV-6a) 0.3 mg / kg administration group, the white inverted triangles represent the antibody-drug conjugate (IV-6a) 1 mg / kg administration group, and the white triangles represent the antibody-drug conjugate (IV-6a) 3 mg / kg administration group. The graph shows the mg / kg dose groups, with the white square line indicating the antibody-drug conjugate (IV-6a) 10 mg / kg dose group. The vertical axis represents tumor volume (mm²). 3Figure 6 shows the values ​​of the tumor volume and the horizontal axis, respectively, and the horizontal axis represents the number of days after tumor transplantation. Each symbol represents the mean value of the tumor volume, and the error bars represent the standard error. Figure 6 shows the measured antitumor effects (Figure 5) of anti-CDH6 antibody-drug conjugates (antibody-drug conjugates (IV-5a) and (IV-6a)) in mice subcutaneously transplanted with OVCAR-3 cells. Figure 7 shows the antitumor effects of anti-B7-H3 antibody-drug conjugates (antibody-drug conjugates (IV-7a), (IV-7b), (IV-8a), (IV-5b), (IV-5c), (IV-6b), and (IV-6c)) in mice subcutaneously transplanted with Calu-6 cells. In the figure, the black circles represent the control group (vehicle administration group), the black triangles represent the antibody-drug conjugate (IV-7a) 3 mg / kg administration group, the black squares represent the antibody-drug conjugate (IV-7b) 3 mg / kg administration group, the white circles represent the antibody-drug conjugate (IV-8a) 3 mg / kg administration group, the black diamonds represent the antibody-drug conjugate (IV-5b) 3 mg / kg administration group, the black inverted triangles represent the antibody-drug conjugate (IV-5c) 3 mg / kg administration group, the white triangles represent the antibody-drug conjugate (IV-6b) 3 mg / kg administration group, and the white squares represent the antibody-drug conjugate (IV-6c) 3 mg / kg administration group. The vertical axis represents tumor volume (mm²). 3Figure 8 shows the values ​​of antitumor effects (Figure 7) of anti-B7-H3 antibody-drug conjugates (antibody-drug conjugates (IV-7a), (IV-7b), (IV-8a), (IV-5b), (IV-5c), (IV-6b), and (IV-6c)) in mice subcutaneously transplanted with Calu-6 cells. Figure 9 shows the antitumor effects of anti-B7-H3 antibody-drug conjugates (antibody-drug conjugates (IV-7a), (IV-7b), (IV-10a), and (IV-17a)) in mice subcutaneously transplanted with Calu-6 cells. In the figure, the black circles represent the control group (vehicle administration group), the black triangles represent the antibody-drug conjugate (IV-7a) 3 mg / kg administration group, the black squares represent the antibody-drug conjugate (IV-7b) 3 mg / kg administration group, the black diamonds represent the antibody-drug conjugate (IV-10a) 3 mg / kg administration group, and the black inverted triangles represent the antibody-drug conjugate (IV-17a) 3 mg / kg administration group. The vertical axis represents tumor volume (mm²). 3 Figure 10 shows the values ​​of antitumor effects (Figure 9) of anti-B7-H3 antibody-drug conjugates (antibody-drug conjugates (IV-7a), (IV-7b), (IV-10a), and (IV-17a)) in mice subcutaneously transplanted with Calu-6 cells. Figure 11 shows the antitumor effects of anti-B7-H3 antibody-drug conjugates (antibody-drug conjugate (IV-6d)) in mice subcutaneously transplanted with Calu-6 cells. In the figure, the black circles represent the control group (vehicle administration group), the black squares represent the anti-B7-H3 antibody 10 mg / kg administration group, the black diamonds represent the antibody-drug conjugate (IV-6d) 1 mg / kg administration group, the black inverted triangles represent the antibody-drug conjugate (IV-6d) 3 mg / kg administration group, and the black triangles represent the antibody-drug conjugate (IV-6d) 10 mg / kg administration group. The vertical axis represents tumor volume (mm²). 3Figure 12 shows the values ​​of the tumor volume and the horizontal axis, respectively, and the horizontal axis shows the number of days after tumor transplantation. Each symbol represents the mean value of the tumor volume, and the error bars represent the standard error. Figure 12 shows the measured antitumor effect (Figure 11) of anti-B7-H3 antibody-drug conjugates (antibody-drug conjugate (IV-6d)) in mice subcutaneously transplanted with Calu-6 cells. Figure 13 shows the antitumor effect of anti-B7-H3 antibody-drug conjugates (antibody-drug conjugate (IV-5d) and (IV-6d)) in mice subcutaneously transplanted with Calu-6 cells. In the figure, the black circles represent the control group (vehicle administration group), the black squares represent the antibody-drug conjugate (IV-5d) 1 mg / kg administration group, the black triangles represent the antibody-drug conjugate (IV-5d) 3 mg / kg administration group, the black inverted triangles represent the antibody-drug conjugate (IV-5d) 10 mg / kg administration group, the black diamonds represent the antibody-drug conjugate (IV-6d) 1 mg / kg administration group, the white circles represent the antibody-drug conjugate (IV-6d) 3 mg / kg administration group, and the white squares represent the antibody-drug conjugate (IV-6d) 10 mg / kg administration group. The vertical axis represents tumor volume (mm²). 3Figure 14 shows the values ​​of antitumor effects (Figure 13) of anti-B7-H3 antibody-drug conjugates (antibody-drug conjugates (IV-5d) and (IV-6d)) in mice subcutaneously transplanted with Calu-6 cells. Figure 15 shows the antitumor effects (Figure 13) of anti-B7-H3 antibody-drug conjugates (antibody-drug conjugates (IV-5d) and (IV-6d)) in mice subcutaneously transplanted with JIMT-1 cells. In the figure, the black circles represent the control group (vehicle administration group), the black squares represent the antibody-drug conjugate (IV-5d) 1 mg / kg administration group, the black triangles represent the antibody-drug conjugate (IV-5d) 3 mg / kg administration group, the black inverted triangles represent the antibody-drug conjugate (IV-5d) 10 mg / kg administration group, the black diamonds represent the antibody-drug conjugate (IV-6d) 1 mg / kg administration group, the white circles represent the antibody-drug conjugate (IV-6d) 3 mg / kg administration group, and the white squares represent the antibody-drug conjugate (IV-6d) 10 mg / kg administration group. The vertical axis represents tumor volume (mm²). 3Figure 16 shows the values ​​of antitumor effects (Figure 15) of anti-B7-H3 antibody-drug conjugates (antibody-drug conjugates (IV-5d) and (IV-6d)) in mice subcutaneously transplanted with JIMT-1 cells. Figure 17 shows the antitumor effects of anti-B7-H3 antibody-drug conjugates (antibody-drug conjugates (IV-6d), (IV-6f), and (IV-6g)) in mice subcutaneously transplanted with Calu-6 cells. In the figure, the black circles represent the control group (vehicle administration group), the black squares represent the antibody-drug conjugate (IV-6d) 1 mg / kg administration group, the black triangles represent the antibody-drug conjugate (IV-6d) 3 mg / kg administration group, the black inverted triangles represent the antibody-drug conjugate (IV-6d) 10 mg / kg administration group, the black diamonds represent the antibody-drug conjugate (IV-6f) 1 mg / kg administration group, the white circles represent the antibody-drug conjugate (IV-6f) 3 mg / kg administration group, the white squares represent the antibody-drug conjugate (IV-6f) 10 mg / kg administration group, the white triangles represent the antibody-drug conjugate (IV-6g) 1 mg / kg administration group, and the white inverted triangles represent the antibody-drug conjugate (IV-6g) 3 mg / kg administration group. The graph shows the mg / kg dose groups, and the white diamond line represents the antibody-drug conjugate (IV-6g) 10 mg / kg dose group. The vertical axis represents tumor volume (mm²). 3Figure 18 shows the antitumor effect (Figure 17) of anti-B7-H3 antibody-drug conjugates (antibody-drug conjugates (IV-6d), (IV-6f), and (IV-6g)) in mice subcutaneously transplanted with Calu-6 cells. Figure 19 shows the antitumor effect (Figure 17) of anti-B7-H3 antibody-drug conjugates (antibody-drug conjugates (IV-6d), (IV-6f), and (IV-6g)) in mice subcutaneously transplanted with JIMT-1 cells. In the figure, the black circles represent the control group (vehicle administration group), the black squares represent the antibody-drug conjugate (IV-6d) 1 mg / kg administration group, the black triangles represent the antibody-drug conjugate (IV-6d) 3 mg / kg administration group, the black inverted triangles represent the antibody-drug conjugate (IV-6d) 10 mg / kg administration group, the black diamonds represent the antibody-drug conjugate (IV-6f) 1 mg / kg administration group, the white circles represent the antibody-drug conjugate (IV-6f) 3 mg / kg administration group, the white squares represent the antibody-drug conjugate (IV-6f) 10 mg / kg administration group, the white triangles represent the antibody-drug conjugate (IV-6g) 1 mg / kg administration group, and the white inverted triangles represent the antibody-drug conjugate (IV-6g) 3 mg / kg administration group. The graph shows the mg / kg dose groups, and the white diamond line represents the antibody-drug conjugate (IV-6g) 10 mg / kg dose group. The vertical axis represents tumor volume (mm²). 3 Figure 20 shows the horizontal axis representing the number of days after tumor transplantation. Each symbol represents the mean tumor volume, and the error bars represent the standard error. Figure 20 shows the measured antitumor effects (Figure 19) of anti-B7-H3 antibody-drug conjugates (antibody-drug conjugates (IV-6d), (IV-6f), and (IV-6g)) in mice subcutaneously transplanted with JIMT-1 cells.

[0062] The following describes preferred embodiments for carrying out the present invention. The embodiments described below are merely examples of typical embodiments of the present invention, and this should not be interpreted as narrowing the scope of the invention.

[0063] <1. Definitions> Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. In the event of any conflict between the meaning of a term as defined herein and the meaning commonly understood by those skilled in the art, the meaning as defined herein shall prevail. Preferred methods and materials are described below, but similar or equivalent methods and materials may be used in carrying out or testing the present invention. All references (including patent and non-patent documents) cited herein are incorporated herein by reference in their entirety. The materials, methods and examples disclosed herein are illustrative and not intended to limit the scope of the invention.

[0064] In this specification, "halogen" means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0065] In this specification, “aliphatic heterocycle” means a non-aromatic ring containing one or more heteroatoms selected from atoms other than carbon atoms, such as nitrogen, oxygen, and sulfur atoms, as ring constituent atoms. Accordingly, in this specification, “a 3 to 6-membered aliphatic heterocycle containing one or two nitrogen atoms as ring constituent atoms” means a non-aromatic heterocycle containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms, and such non-aromatic heterocycle may contain only saturated bonds or may contain unsaturated bonds. Examples of "a 3- to 6-membered aliphatic heterocycle containing one or two nitrogen atoms as ring constituent atoms" include aziridine, azirine, diaziridine, diazirine, diazylene, azetidine, azeto, 1,2-diazetidine, 1,2-diazeto, 1,3-diazetidine, 1,3-diazeto, pyrrolidine, pyrroline, pyrazolidine, pyrazolin, imidazolidine, imidazoline, piperidine, piperidine, piperazine, and the like.

[0066] In this specification, "alkyl" means a linear or branched alkyl group. In this specification, "C 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms. 1-3"Alkyl" refers to an alkyl group having one to three carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl.

[0067] In this specification, "heteroaryl" means a monovalent group derived from a monocyclic or polycyclic ring in which at least one of the rings is an aromatic heterocycle, and which contains one or more heteroatoms selected from atoms other than carbon atoms, such as nitrogen, oxygen, and sulfur atoms, as ring constituent atoms. Accordingly, in this specification, "a six-membered heteroaryl having one or two nitrogen atoms in the ring" means a six-membered heteroaryl that contains one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms, and examples include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc.

[0068] In this specification, “cycloalkyl” means a group derived from a hydrocarbon ring that does not contain an unsaturated bond. “Cycloalkyl” may be a monocyclic cycloalkyl, a condensed cycloalkyl, a spirocycloalkyl, or a crosslinked cycloalkyl in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, but typically it means a monocyclic cycloalkyl. Thus, in one embodiment, in this specification, “cycloalkyl” is a monocyclic cycloalkyl. In this specification, “C 3-6 "Cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms, and examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0069] In this specification, "bicycloalkyl" means a bicyclic cycloalkyl, for example, a bicyclic condensed cycloalkyl, a spirocycloalkyl, or a cross-linked cycloalkyl. In this specification, "C 5-8"Bicycloalkyl" refers to bicycloalkyl compounds having 5 to 8 carbon atoms, and examples include bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.2.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.2.0]heptanyl, bicyclo[3.3.0]octanyl, bicyclo[2.2.2]octanyl, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.4]octanyl, and the like.

[0070] In this specification, "9 or 10-membered bicyclic heteroaryls comprising one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring constituent atoms" can be defined as, for example, 6 / 5-membered fused rings such as indolyl, isoindolyl, indazolyl, benzimidazolyl, imidazopyridinyl (including imidazo[1,2-a]pyridyl), benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzofuranil, isobenzofuranil, benzothiophenyl, benzothiadiazolyl, dihydrobenzofuranil, and methylenedioxyphenyl; and 6 / 6-membered fused rings such as quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, synnolinyl, phthalazinyl, clomenyl, isoclomenyl, chromanil, and ethylenedioxyphenyl.

[0071] In this specification, "pharmaceutically acceptable" means that it does not have significant toxicity and can be used as a pharmaceutical composition. Therefore, in this specification, "pharmaceutically acceptable salt" means a salt that does not have significant toxicity and can be used as a pharmaceutical composition.

[0072] In this specification, “solvate” means a complex of the dispirodiketopiperazine compound or a salt thereof, a drug linker, a ligand-drug conjugate, or an intermediate for the manufacture thereof, with one or more solvent molecules. When one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate may be isolated. Therefore, the term “solvate” encompasses both solution-phase solvates and solvable solvates.

[0073] In this specification, "natural amino acid residue" means the constituent unit derived from each amino acid (the group obtained by removing water from an amino acid) when naturally occurring amino acids are linked by peptide bonds. Examples of "naturally occurring amino acids" include glycine (Gly; G), valine (Val; V), alanine (Ala; A), phenylalanine (Phe; F), glutamic acid (Glu; E), isoleucine (Ile; I), proline (Pro; P), citrulline (Cit), leucine (Leu; L), methionine (Met; M), serine (Ser; S), lysine (Lys; K), and aspartic acid (Asp; D).

[0074] In this specification, “treatment” includes the cure of a disease, improvement of the pathology of a disease (e.g., one or more symptoms), suppression of the progression of a disease (or its severity), prevention of recurrence, prevention of the onset of a disease, delay of the onset of a disease, and prevention of the development of a pathology.

[0075] In this specification, “effective dose” or “therapeutic dose” means an amount effective in treating, preventing progression of, or alleviating the existing symptoms of the subject being treated. The effective dose may be determined appropriately in accordance with conventional methods, taking into account the desired therapeutic effect and side effects.

[0076] In this specification, "subject" means a subject to which a pharmaceutical (pharmaceutical composition) containing an effective amount of active ingredients necessary to treat a disease or the pathophysiological condition of a disease is administered. Examples of such "subjects" include humans and non-human animals, and in particular mammals (e.g., humans, mice, rats, guinea pigs, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, etc.).

[0077] In this specification, “cancer” means any type of cancer, malignant neoplasm, or malignant tumor found in mammals, particularly humans. As used herein, “cancer” and “tumor” are used synonymously and in the singular or plural form. This includes not only primary cancers but also metastatic cancers, as well as any cells derived from cancer stem cells, cancer progenitor cells, or the ancestors of cancer cells.

[0078] <2. Ligand-drug conjugate of the present invention> In one embodiment, the present invention relates to the following formula (I):

[0079]

[0080] This relates to compounds indicated by or pharmaceutically acceptable salts thereof, or solvates thereof.

[0081] In formula (I), m 1 m represents the number of drug-bound ligand molecules in the ligand-drug conjugate. In one embodiment, m 1 represents an integer from 1 to 20, preferably an integer from 1 to 10, more preferably an integer from 1 to 8, even more preferably an integer from 3 to 8, and even more preferably 4 or 6.

[0082] In the manufacture of ligand-drug conjugates, reaction conditions such as the amount of raw materials and reagents used are specified so that the number of drug molecules bound is constant. However, unlike the chemical reactions of low-molecular-weight compounds, ligand-drug conjugates with different numbers of drugs bound (i.e., m 1 It is usually obtained as a mixture of two or more different ligand-drug conjugates. Therefore, although the ligand-drug conjugate of the present invention has an integer number of drug bindings per molecule, it may also be specified by its average value, i.e., the average number of drug bindings (drug-antibody binding ratio: DAR), in which case it is not necessarily described as an integer. One embodiment of the DAR is a number from 1 to 20, preferably from 1 to 10, more preferably from 1 to 8, and even more preferably from 3 to 8. Another embodiment of the DAR may be a number from 3 to 5 or from 5 to 7.

[0083] In formula (I), Li represents the ligand, L represents the linker that connects Li and D, and D represents the payload (drug). These will be described in detail below.

[0084] <2-1. Ligands> In the present invention, “ligand” means a structural unit that binds to a specific receptor, antigen, or other receptor site (target molecule). Ligands may be molecules that bind to components of a cell population that is to be therapeutically or biologically modified. Ligands play a role in transporting a drug (a structural unit represented by “D” in formula (I) of the present invention, which may also be referred to herein as the “payload”) to a specific target cell population to which the ligand binds. The binding of a ligand to its target molecule is typically a reversible reaction formed by ionic bonds, covalent bonds, van der Waals interactions, and / or hydrogen bonds, and such reactions can be measured and evaluated by various known techniques. Such ligands include, but are not limited to, large molecular weight proteins such as full-length antibodies and antibody fragments, small molecular weight proteins, polypeptides or peptides, lectins, and cells.

[0085] The ligands of the present invention are linked to a drug by a linker (meaning the structural unit represented by "L" in formula (I) of the present invention). In one embodiment, the ligands of the present invention can form a bond with stretcher units or amino acid units of the linker. In one embodiment, the ligand can form a bond with the linker via heteroatoms present in the ligand. Heteroatoms that may be present on the ligand include sulfur (in one embodiment, from the sulfhydryl group of the ligand), oxygen (in one embodiment, from the carbonyl, carboxy, or hydroxyl group of the ligand), and nitrogen (in one embodiment, from the primary or secondary amino group of the ligand). These heteroatoms may be present on the ligand in its natural state or may be introduced into the ligand through chemical modification.

[0086] In a preferred embodiment, the ligand has a sulfhydryl group (-SH), and the ligand is bonded to the linker via the sulfur atom of the sulfhydryl group. In other embodiments, the ligand may have one or more groups that can be chemically modified to have one or more sulfhydryl groups. Maleimide groups are, but are not limited to, reaction sites on the linker that can react with sulfhydryl groups present on or introduced on the ligand.

[0087] In another embodiment, the ligand may have one or more groups that, when oxidized, yield an aldehyde group (-CHO) (see Laguzza et al., J. Med. Chem., 1989, 32(3), 548-555). The aldehyde group present on or introduced on the ligand forms a bond with the reaction site on the linker. Examples of reaction sites on the linker that can react with the aldehyde group or carbonyl group on the ligand include, but are not limited to, hydrazine and hydroxylamine.

[0088] In yet another embodiment, the ligand can also be linked to the linker using click chemistry. For example, the azide group present in or introduced in the ligand can be reacted with the alkyne moiety present in or introduced in the linker to link the ligand and the linker via a 1,2,3-triazole ring.

[0089] In one embodiment, the ligand of the present invention is a non-immunoreactive protein, polypeptide, or peptide ligand, and examples include, but are not limited to, transferrin; epidermal growth factor (EGF); bombesin; gastrin; gastrin-releasing peptide; platelet-derived growth factor; IL-2; IL-6; transforming growth factors (TGF) such as TGF-α and TGF-β; vaccinia growth factor (VGF); insulin and insulin-like growth factors I and II; lectins and apolipoproteins from low-density lipoproteins.

[0090] <2-2. Antibodies> In one embodiment of the present invention, the ligand (Li) is an antibody or an antigen-binding fragment thereof. In this specification, unless otherwise specified, an antibody or an antigen-binding fragment thereof will be denoted as "Ab". Therefore, in one embodiment of the present invention, the ligand-drug conjugate of the present invention is the following formula (IV), where Li in formula (I) is Ab:

[0091]

[0092] (In the formula, Ab represents an antibody or its antigen-binding fragment, L represents a linker that connects Ab and D, and D and m 1 The compound represented by (wherein it is the same as the definition of each group specified for formula (I) above), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0093] The antibody used in the antibody-drug conjugate of the present invention refers to an immunoglobulin, which is a molecule containing an antigen-binding site that specifically binds to an antigen. The antibody used in the antibody-drug conjugate of the present invention may be any of the classes IgG, IgE, IgM, IgD, IgA, and IgY, but IgG is preferred. Furthermore, the subclass of IgG may be any of IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2, but IgG1, IgG2, or IgG4 is preferred. Therefore, in one embodiment, the antibody used in the antibody-drug conjugate of the present invention is IgG1, IgG2, or IgG4, and the antigen-binding fragment of the antibody used in the antibody-drug conjugate of the present invention is an antigen-binding fragment of IgG1, IgG2, or IgG4.

[0094] It is known that the constant region of an antibody can have multiple allotypes. For example, G1m17, G1m3, G1m1, and G1m2 can be listed as allotypes of IgG1.

[0095] The antibody used in the antibody-drug conjugate of the present invention may originate from any species, but is preferably derived from humans, monkeys, rats, mice, rabbits, camels, alpacas, or llamas. If derived from a species other than humans, it is preferable to chimerize or humanize it using well-known techniques. Therefore, in one embodiment, the antibody used in the antibody-drug conjugate of the present invention is a human antibody, a chimeric antibody, or a humanized antibody, and is preferably a human antibody or a humanized antibody. The antibody of the present invention may be a polyclonal antibody or a monoclonal antibody, but monoclonal antibodies are preferred, and may be a monospecific antibody or a polyspecific antibody (dispecific antibody, trispecific antibody, etc.).

[0096] In the present invention, "antigen-binding fragment of an antibody" means a partial fragment of an antibody having antigen-binding activity or a fusion polypeptide containing an antigen-binding site of an antibody (variable region of the light chain and / or heavy chain or CDR, etc., contained in said variable region), and includes Fab, F(ab')2, Fv, scFv, VHH (variable domain of heavy chain of heavy-chain antibody) antibody, diabody, linear antibody, antibody or multispecific antibody formed from its antigen-binding fragment, and fusion proteins in which antigen-binding ability is conferred by linking scFv to the functional domain of another protein. Furthermore, Fab', a monovalent fragment of the variable region of an antibody obtained by treating F(ab')2 under reducing conditions, is also included in antibody antigen-binding fragments. However, the invention is not limited to these molecules as long as they have the ability to bind to an antigen. In addition, these antigen-binding fragments include not only full-length antibody molecules treated with appropriate enzymes, but also proteins produced in appropriate host cells using genetically modified antibodies or genes encoding their antigen-binding sites. In one embodiment of the present invention, the antigen-binding fragment of the antibody is selected from the group consisting of Fab, F(ab')2, Fab', Fv, scFv, VHH, and scFv-containing fusion proteins.

[0097] In one embodiment of the present invention, the antigen-binding fragment includes a functional fragment that retains asparagine (Asn297 or N297) and surrounding amino acids that are modified by well-conserved N-linked glycans in the Fc region of the IgG heavy chain, and that has the ability to bind to an antigen.

[0098] Whether the antibody or its antigen-binding fragment used in the antibody-drug conjugate of the present invention specifically binds to a particular antigen can be determined by known methods, such as flow cytometry.

[0099] The antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention is not particularly limited, but may target tumor cells, immune cells, or stromal cells, but is not limited to these. In one embodiment, the antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention is an antibody or antigen-binding fragment that targets tumor cells.

[0100] The antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention preferably possesses at least one of the following properties: the ability to recognize cells expressing a target antigen, the ability to bind to cells expressing a target antigen, the ability to be taken up and internalized within cells expressing a target antigen, and the ability to damage cells expressing a target antigen. Whether the antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention has the ability to recognize cells expressing a target antigen or the ability to bind to cells expressing a target antigen can be determined by known methods, such as flow cytometry.

[0101] In one embodiment, the antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention has the ability to be internalized into cells, preferably into cells expressing the target antigen in tumor cells and / or cells in their midstium (e.g., cancer-associated fibroblasts: CAFs, vascular endothelial cells, vascular pericytes, immune cells, etc.). The internalization of antibodies or their antigen-binding fragments into cells can be confirmed using known methods such as (1) an assay that visualizes antibodies or their antigen-binding fragments taken into cells using a fluorescence microscope with a secondary antibody (fluorescently labeled) that binds to the antibody or its antigen-binding fragment (Cell Death and Differentiation, 2008, 15, 751-761), (2) an assay that measures the amount of fluorescence taken into cells using a secondary antibody (fluorescently labeled) that binds to the antibody or its antigen-binding fragment (Molecular Biology of the Cell, 2004, 15, 5268-5282), (3) an assay that evaluates the growth inhibitory activity against a cell line using an antibody-drug conjugate in which a compound having cytotoxic activity is conjugated to the antibody or its antigen-binding fragment via a linker, and (4) the Mab-ZAP assay (Bio Techniques, 2000, 28: 162-165).

[0102] In one embodiment, the antibody or its antigen-binding fragment used in the antibody-drug conjugate of the present invention has the property of damaging cells expressing the target antigen. In particular, when an antibody targeting tumor cells is used in the antibody-drug conjugate of the present invention, the antibody itself may have antitumor activity. Antitumor activity of an antibody refers to cytotoxic activity against tumor cells, activity that brings about tumor regression, etc. The property of damaging cells and the antitumor activity described above can be confirmed using known in vitro or in vivo evaluation systems, cytotoxicity tests using antigen-positive cells as in Test Examples 1 to 6, and antitumor tests using mice transplanted with tumor cells as in Test Examples 8 to 17.

[0103] When IgG1 is used as the antibody in the antibody-drug conjugate of the present invention, the effector function can be adjusted by substituting a portion of the amino acid residues in the constant region. In one embodiment, antibody-dependent cytotoxicity (ADCC) can be enhanced or reduced, antibody-dependent cell-mediated phagocytosis (ADCP) can be enhanced or reduced, or complement-dependent cytotoxicity (CDC) can be enhanced or reduced. One example of a variant of IgG1 that reduces or weakens the effector function is the substitution of leucine at position 234 and 235 of the amino acid sequence in the constant region of wild-type human IgG1, as identified by the EU index (Proc. Natl. Acad. Sci. USA, 1969, 63(1), 78-85), with alanine and alanine, respectively (LALA mutation); the substitution of leucine at position 234, 235, and aspartic acid at position 265, as identified by the EU index, with alanine, alanine, and glycine, respectively (LALADG mutation); or the substitution of leucine at position 234, 235, and proline at position 329, as identified by the EU index, with alanine, alanine, and alanine, respectively (LALAPA mutation). Accordingly, in one embodiment, the antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention comprises the Fc region of the IgG1 heavy chain or a fragment thereof, and the Fc region of the IgG1 heavy chain or the fragment thereof has an effector function, in particular a mutation that affects ADCC, ADCP and / or CDC, for example, a LALA mutation, a LALADG mutation or a LALAPA mutation.

[0104] It is known that both the heavy and light chains of antibodies have three complementarity determining regions (CDRs). CDRs, also known as hypervariable regions, are areas within the variable regions of the heavy and light chains of antibodies that exhibit particularly high variability in their primary structure. They are separated into three distinct locations on the primary structure of the polypeptide chains of both the heavy and light chains. In this specification, the CDRs of the heavy chain are denoted as CDRH1, CDRH2, and CDRH3, starting from the amino-terminal end of the heavy chain amino acid sequence, and the CDRs of the light chain are denoted as CDRL1, CDRL2, and CDRL3, starting from the amino-terminal end of the light chain amino acid sequence. These regions are in close proximity to each other in terms of three-dimensional structure and determine the specificity for the antigen to which they bind. In this specification, unless otherwise specified, amino acid sequences are determined according to the IMGT definition (Developmental and Comparative Immunology, 2003, 27, 55-77).

[0105] Examples of antibodies or antigen-binding fragments used in the antibody-drug conjugate of the present invention include anti-CDH6 antibody, anti-B7-H3 antibody, anti-CD30 antibody, anti-CD70 antibody, anti-HER3 antibody, anti-DLL3 antibody, anti-FAP antibody, anti-CDH11 antibody, anti-A33 antibody, anti-CanAg antibody, anti-CD19 antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD33 antibody, anti-CD56 antibody, anti-CD98 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, and anti-Tenascin. Examples include anti-C antibody, anti-SLC44A4 antibody, anti-Mesothelin antibody, anti-ENPP3 antibody, anti-CD47 antibody, anti-EGFR antibody, anti-GPR20 antibody, or anti-DR5 antibody or its antigen-binding fragment. Preferably, examples include anti-CDH6 antibody, anti-B7-H3 antibody, anti-CD30 antibody, or anti-CD70 antibody or its antigen-binding fragment. More preferably, examples include anti-CDH6 antibody or anti-B7-H3 antibody or its antigen-binding fragment. Even more preferably, examples include anti-B7-H3 antibody, but the definition is not limited to these.

[0106] In one embodiment, the antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention is: (1) an anti-CDH6 antibody or antigen-binding fragment thereof comprising the amino acid sequence CDRH1 represented by SEQ ID NO: 3, the amino acid sequence CDRH2 represented by SEQ ID NO: 4, the amino acid sequence CDRH3 represented by SEQ ID NO: 5, the amino acid sequence CDRL1 represented by SEQ ID NO: 8, the amino acid sequence CDRL2 represented by DAN, and the amino acid sequence CDRL3 represented by SEQ ID NO: 9; (2) an anti-CDH6 antibody or antigen-binding fragment thereof comprising the amino acid sequence CDRH1 represented by SEQ ID NO: 12, the amino acid sequence CDRH2 represented by SEQ ID NO: 13, the amino acid sequence CDRH3 represented by SEQ ID NO: 14, the amino acid sequence CDRL1 represented by SEQ ID NO: 17, the amino acid sequence CDRL2 represented by DAN, and the amino acid sequence CDRL3 represented by SEQ ID NO: 18; (3) (4) An anti-B7-H3 antibody or its antigen-binding fragment containing the amino acid sequence CDRH1 represented by SEQ ID NO: 21, the amino acid sequence CDRH2 represented by SEQ ID NO: 22, the amino acid sequence CDRH3 represented by SEQ ID NO: 23, the amino acid sequence CDRL1 represented by SEQ ID NO: 26, the amino acid sequence CDRL2 represented by ATS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 27; (5) An anti-B7-H3 antibody or its antigen-binding fragment containing the amino acid sequence CDRH1 represented by SEQ ID NO: 30, the amino acid sequence CDRH2 represented by SEQ ID NO: 31, the amino acid sequence CDRH3 represented by SEQ ID NO: 32, the amino acid sequence CDRL1 represented by SEQ ID NO: 35, the amino acid sequence CDRL2 represented by ATS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 36; (6) An anti-CD30 antibody or its antigen-binding fragment containing the amino acid sequence CDRH1 represented by SEQ ID NO: 39, CDRH2 represented by SEQ ID NO: 40, CDRH3 represented by SEQ ID NO: 41, CDRL1 represented by SEQ ID NO: 44, CDRL2 represented by AAS, and CDRL3 represented by SEQ ID NO: 45.(6) an anti-CD70 antibody or its antigen-binding fragment containing the amino acid sequence CDRH1 represented by SEQ ID NO: 48, the amino acid sequence CDRH2 represented by SEQ ID NO: 49, the amino acid sequence CDRH3 represented by SEQ ID NO: 50, the amino acid sequence CDRL1 represented by SEQ ID NO: 53, the amino acid sequence CDRL2 represented by LAS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 54; (7) an anti-B7-H3 antibody or its antigen-binding fragment containing the amino acid sequence CDRH1 represented by SEQ ID NO: 57, the amino acid sequence CDRH2 represented by SEQ ID NO: 58, the amino acid sequence CDRH3 represented by SEQ ID NO: 59, the amino acid sequence CDRL1 represented by SEQ ID NO: 62, the amino acid sequence CDRL2 represented by ATS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 63; or (8) This is an anti-B7-H3 antibody or its antigen-binding fragment, containing the amino acid sequence CDRH1 represented by SEQ ID NO: 66, the amino acid sequence CDRH2 represented by SEQ ID NO: 67, the amino acid sequence CDRH3 represented by SEQ ID NO: 68, the amino acid sequence CDRL1 represented by SEQ ID NO: 71, the amino acid sequence CDRL2 represented by ATS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 72.

[0107] In another embodiment, the antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention optionally includes the combination of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 as defined above, and includes: (1) an anti-CDH6 antibody or antigen-binding fragment thereof containing a heavy chain variable region of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 2, and a light chain variable region of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 7; (2) an anti-CDH6 antibody or antigen-binding fragment thereof containing a heavy chain variable region of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 11, and a light chain variable region of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 16; (3) (4) An anti-B7-H3 antibody or its antigen-binding fragment containing a heavy chain variable region of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 20, and a light chain variable region of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 25, (5) An anti-B7-H3 antibody or its antigen-binding fragment containing a heavy chain variable region of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 29, and a light chain variable region of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 34, (6) An anti-CD30 antibody or its antigen-binding fragment containing a heavy chain variable region of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 38, and a light chain variable region of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 43, (6) (7) An anti-CD70 antibody or its antigen-binding fragment containing a heavy chain variable region of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 47, and a light chain variable region of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 52, or (8) An anti-B7-H3 antibody or its antigen-binding fragment containing a heavy chain variable region of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 56, and a light chain variable region of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 61, or(8) An anti-B7-H3 antibody or its antigen-binding fragment, comprising a heavy chain variable region of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 65, and a light chain variable region of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 70. In the above, examples of sequence identity of 80% or more include 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100% sequence identity. Preferably, the sequence identity is 90% or more (e.g., 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100%).

[0108] In yet another embodiment, the antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention optionally includes the combination of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 as defined above and / or the combination of heavy chain variable region and light chain variable region identified above, and: (1) an anti-CDH6 antibody or antigen-binding fragment thereof comprising a heavy chain of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 1, and a light chain of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 6; (2) an anti-CDH6 antibody or antigen-binding fragment thereof comprising a heavy chain of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 10, and a light chain of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 15; (3) (4) An anti-B7-H3 antibody or its antigen-binding fragment containing a heavy chain of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 19, and a light chain of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 24, (5) An anti-CD30 antibody or its antigen-binding fragment containing a heavy chain of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 33, and a light chain of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 42, (6) An anti-CD70 antibody or its antigen-binding fragment containing a heavy chain of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 46, and a light chain of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 51, (7) An anti-B7-H3 antibody or its antigen-binding fragment, comprising a heavy chain of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 55, and a light chain of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 60, or(8) An anti-B7-H3 antibody or its antigen-binding fragment, comprising a heavy chain of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 64, and a light chain of an amino acid sequence having 80% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 69. In the above, examples of sequence identity of 80% or more include 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100% sequence identity. Preferably, the sequence identity is 90% or more (e.g., 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100%).

[0109] In the present invention, the identity between amino acid sequences can be evaluated based on any known method. In one embodiment, sequence identity in the present invention refers to the percentage of identical amino acids per total number of amino acids (including gaps) when two amino acid sequences are aligned to maximize the degree of amino acid similarity. In another embodiment, sequence identity in the present invention can be determined, for example, by aligning sequences using the default parameters of ClustalW version 2 (Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R, Thompson JD, Gibson TJ and Higgins DG, “Clustal W and Clustal X version 2.0”, Bioinformatics, 2007, 23(21): 2947-2948).

[0110] Furthermore, by combining amino acid sequences in which one to several amino acid residues are substituted, deleted, inserted, and / or added in the heavy chain and / or light chain amino acid sequences, it is possible to select antibodies with various effects equivalent to those of the antibodies described above. Accordingly, in one embodiment, the antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention includes an antibody or antigen-binding fragment which is a combination of a heavy chain containing an amino acid sequence in which one to several amino acid residues are substituted, deleted, inserted and / or added in the amino acid sequence of the heavy chain defined above, and a light chain defined above; an antibody or antigen-binding fragment which is a combination of a heavy chain defined above and a light chain containing an amino acid sequence in which one to several amino acid residues are substituted, deleted, inserted and / or added in the amino acid sequence of the light chain defined above; or an antibody or antigen-binding fragment which is a combination of a heavy chain containing an amino acid sequence in which one to several amino acid residues are substituted, deleted, inserted and / or added in the amino acid sequence of the heavy chain defined above and a light chain containing an amino acid sequence in which one to several amino acid residues are substituted, deleted, inserted and / or added in the amino acid sequence of the light chain defined above. Furthermore, in one embodiment, the antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention includes an antibody or antigen-binding fragment which is a combination of a heavy chain including a heavy chain variable region which includes an amino acid sequence in which one to several amino acid residues are substituted, deleted, inserted and / or added in the amino acid sequence of the heavy chain variable region as defined above, and a light chain as defined above; an antibody or antigen-binding fragment which is a combination of a heavy chain as defined above and a light chain including a light chain variable region which includes an amino acid sequence in which one to several amino acid residues are substituted, deleted, inserted and / or added in the amino acid sequence of the light chain variable region as defined above; or an antibody or antigen-binding fragment which is a combination of a heavy chain including a heavy chain variable region which includes an amino acid sequence in which one to several amino acid residues are substituted, deleted, inserted and / or added in the amino acid sequence of the heavy chain variable region as defined above, and a light chain including a light chain variable region which includes an amino acid sequence in which one to several amino acid residues are substituted, deleted, inserted and / or added in the amino acid sequence of the light chain variable region as defined above.The number of amino acid residues substituted, deleted, inserted and / or added is generally 10 amino acid residues or less, preferably 5 to 6 amino acid residues or less, more preferably 2 to 3 amino acid residues or less, and even more preferably 1 amino acid residue.

[0111] In one embodiment, the antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention is: (1) an anti-CDH6 antibody or antigen-binding fragment thereof comprising a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 1 and having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 1, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 6; (2) an anti-CDH6 antibody or antigen-binding fragment thereof comprising a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 10 and having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 10, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 15; (3) (4) An anti-B7-H3 antibody or its antigen-binding fragment, comprising a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 19 and having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 19, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 24, (5) An anti-B7-H3 antibody or its antigen-binding fragment, comprising a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 28 and having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 28, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 33, An anti-CD30 antibody or its antigen-binding fragment, comprising a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 37, and having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 37, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 42,(6) An anti-CD70 antibody or its antigen-binding fragment containing a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 46 and having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 46, and an amino acid sequence containing a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 51, (7) An anti-B7-H3 antibody or its antigen-binding fragment containing a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 55 and having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 55, and an amino acid sequence containing a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 60, or (8) This is an anti-B7-H3 antibody or its antigen-binding fragment, comprising a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 64, and having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 64, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 69.

[0112] In another embodiment, the antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention is: (1) an anti-CDH6 antibody or antigen-binding fragment thereof comprising a heavy chain of an amino acid sequence in which one or two amino acid residues are deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 1, and a light chain of an amino acid sequence represented by SEQ ID NO: 6; (2) an anti-CDH6 antibody or antigen-binding fragment thereof comprising a heavy chain of an amino acid sequence in which one or two amino acid residues are deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 10, and a light chain of an amino acid sequence represented by SEQ ID NO: 15; (3) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of an amino acid sequence in which one or two amino acid residues are deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 19, and a light chain of an amino acid sequence represented by SEQ ID NO: 24; (4) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of an amino acid sequence in which one or two amino acid residues are deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 28, and a light chain of an amino acid sequence represented by SEQ ID NO: 33; (5) (6) An anti-CD30 antibody or its antigen-binding fragment containing a heavy chain of an amino acid sequence in which one or two amino acid residues are deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 37, and a light chain of the amino acid sequence represented by SEQ ID NO: 42; (7) An anti-CD70 antibody or its antigen-binding fragment containing a heavy chain of an amino acid sequence in which one or two amino acid residues are deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 46, and a light chain of the amino acid sequence represented by SEQ ID NO: 51; (8) An anti-B7-H3 antibody or its antigen-binding fragment containing a heavy chain of an amino acid sequence in which one or two amino acid residues are deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 55, and a light chain of the amino acid sequence represented by SEQ ID NO: 60; or (9) An anti-B7-H3 antibody or its antigen-binding fragment containing a heavy chain of an amino acid sequence in which one or two amino acid residues are deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 64, and a light chain of the amino acid sequence represented by SEQ ID NO: 69.

[0113] In the present invention, amino acid substitutions are preferably conservative amino acid substitutions. A conservative amino acid substitution is a substitution that occurs within an amino acid group having the same properties. Preferred amino acid groups are as follows: The acidic group includes aspartic acid and glutamic acid; the basic group includes lysine, arginine, and histidine; the nonpolar group includes alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, and tryptophan; and the uncharged polar group includes glycine, asparagine, glutamine, cysteine, serine, threonine, and tyrosine. Other preferred amino acid groups are as follows: The aliphatic hydroxyl group includes serine and threonine; the amide-containing group includes asparagine and glutamine; the aliphatic group includes alanine, valine, leucine, and isoleucine; and the aromatic group includes phenylalanine, tryptophan, and tyrosine. Such amino acid substitutions are preferably carried out within a range that does not degrade the properties of the substance having the original amino acid sequence.

[0114] It is known that antibodies produced in mammalian cultured cells lose a lysine residue at the carboxyl terminus of their heavy chain (Journal of Chromatography A, 1995, 705: 129-134), and that two amino acid residues, glycine and lysine, at the carboxyl terminus of the heavy chain are also lost, with a proline residue newly located at the carboxyl terminus being amidated (Analytical Biochemistry, 2007, 360: 75-83). However, these deletions or modifications of the heavy chain sequence do not affect the antigen-binding ability or effector function (such as complement activation or antibody-dependent cytotoxicity) of the antibody. Therefore, the antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention may include antibodies or antigen-binding fragments that have undergone such deletions or modifications. Thus, in one embodiment, the antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention includes a heavy chain in which one or more amino acid residues at the carboxyl terminus are lost. In this context, "one or more amino acid residues" preferably means 1 to 10 amino acid residues, 1 to 9 amino acid residues, 1 to 8 amino acid residues, 1 to 7 amino acid residues, 1 to 6 amino acid residues, 1 to 5 amino acid residues, 1 to 4 amino acid residues, 1 to 3 amino acid residues, 1 or 2 amino acid residues, or 1 amino acid residue, preferably 1 or 2 amino acid residues, more preferably 1 amino acid residue. In one embodiment, the antibody or its antigen-binding fragment used in the antibody-drug conjugate of the present invention also includes deletions in which one or two amino acid residues are deleted at the heavy chain carboxyl terminus, and amidated deletions (for example, a heavy chain in which a proline residue at the carboxyl terminus is amidated). However, the deletions of the carboxyl terminus of the heavy chain contained in the antibody or its antigen-binding fragment used in the antibody-drug conjugate of the present invention are not limited to the above types, as long as the deletion or modification (amidation) of the carboxyl terminus does not significantly affect the antigen-binding ability.The two heavy chains constituting the antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention may be one of the full-length heavy chains and heavy chains selected from the group consisting of the above-mentioned deletions, or a combination of either two. The ratio of each deletion may be affected by the type of mammalian cultured cell producing the antibody and the culture conditions, but the antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention preferably has one or two amino acid residues deleted at the carboxyl terminus of both heavy chains, more preferably has one amino acid residue deleted at the carboxyl terminus of both heavy chains.

[0115] The antibodies or antigen-binding fragments used in the antibody-drug conjugates of the present invention also include modified antibodies. Such modified antibodies are those that have undergone chemical or biological modification. Chemically modified antibodies include those with chemical moieties attached to the amino acid backbone, and those with chemical modifications to N- or O-linked carbohydrate chains. Biologically modified antibodies include those with post-translational modifications (e.g., glycosylation of N- or O-linked bonds, processing of amino- or carboxyl-terminals, deamidation, isomerization of aspartic acid, oxidation of methionine, or pyroglutamine oxidation of amino-terminal glutamine or amino-terminal glutamic acid), and those with methionine residues added to the amino-terminus by expression using prokaryotic host cells. Furthermore, labeled antibodies or antigen-binding fragments used in the antibody-drug conjugates of the present invention, such as enzyme-labeled, fluorescently labeled, or affinity-labeled antibodies, are also included as such modified antibodies. Such modified antibodies may be useful for improving antibody stability and blood retention, reducing antigenicity, and for detecting or isolating antibodies or antigens.

[0116] Furthermore, by modifying the glycosylation (glycosylation, defucose, etc.) of the antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention, it is possible to enhance or reduce antibody-dependent cell-mediated cytotoxicity (ADCC), enhance or reduce antibody-dependent cell-mediated phagocytosis (ADCP), or enhance or reduce complement-dependent cell-mediated cytotoxicity (CDC). Known techniques for modifying antibody glycosylation include, but are not limited to, International Publication Nos. 1999 / 54342, 2000 / 61739, 2002 / 31140, and 2007 / 133855. The antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention also includes antibodies or antigen-binding fragments with modified glycosylation.

[0117] The antibodies or antigen-binding fragments used in the antibody-drug conjugate of the present invention can be obtained by immunizing animals with an antigenic polypeptide using methods commonly practiced in the art, and then collecting, purifying, and / or cleaving the antibodies produced in vivo. The antigen is not limited to human origin; animals can also be immunized with antigens derived from non-human animals such as cynomolgus monkeys, mice, and rats. In this case, antibodies applicable to human diseases can be selected by testing the cross-reactivity between the obtained heterologous antigen and the human antigen.

[0118] Furthermore, monoclonal antibodies can also be obtained by establishing hybridomas and fusing antibody-producing cells that produce antibodies against an antigen with myeloma cells, following known methods (e.g., Kohler and Milstein, Nature, 1975, 256, 495-497; Kennett, R.ed., Monoclonal Antibodies, 1980, p.365-367, Plenum Press, NY).

[0119] Antigens can be obtained by known methods, for example, by introducing a gene encoding an antigen protein into a host cell through genetic engineering and expressing that gene in the host cell. Specifically, for example, a vector capable of expressing the antigen gene can be created, introduced into a host cell to express the gene, and the expressed antigen can be purified. Antibodies can also be obtained by immunizing animals with antigen-expressing cells obtained through the above genetic engineering, or with cell lines expressing the antigen. Furthermore, antibodies can also be obtained by incorporating the cDNA of the antigen protein into an expression vector and administering it to an immunized animal, causing the immunized animal to express the antigen protein and produce antibodies against the antigen protein.

[0120] In one embodiment, the antibody or antigen-binding fragment used in the antibody-drug conjugate of the present invention can be obtained by known methods (e.g., Proc. Natl. Acad. Sci. USA, 1984, 81, 6851-6855; Nature, 1986, 321, 522-525; International Publication No. 90 / 07861).

[0121] One example of a desirable method for obtaining antibodies is DNA immunoassay. DNA immunoassay is a technique that induces immunity to an antigen by introducing an antigen expression plasmid into an animal, such as a mouse or rat, and then expressing the antigen within the animal. Methods of gene introduction include directly injecting the plasmid into the muscle, intravenously injecting introduction reagents such as liposomes or polyethyleneimine, using viral vectors, injecting gold particles with the plasmid attached using a Gene Gun, and the Hydrodynamic method, which involves rapidly injecting a large amount of plasmid solution intravenously. Regarding gene transfer methods by intramuscular injection of expression plasmids, a technique called in vivo electroporation, in which the plasmid is injected intramuscularly and then electroporated at the same site, is known as a method to improve expression levels (Aihara H, Miyazaki J, Nat Biotechnol., 1998 Sep; 16(9): 867-870 or Mir LM, Bureau MF, Gehl J, Rangara R, Rouy D, Caillaud JM, Delaere P, Branellec D, Schwartz B, Scherman D, Proc Natl Acad Sci USA, 1999 Apr 13; 96(8): 4262-4267).

[0122] Specific examples of obtaining monoclonal antibodies include the following: (a) By incorporating the cDNA of the target antigen into an expression vector (e.g., pcDNA3.1: manufactured by Thermo Fisher Scientific), and directly administering the vector to immune animals (e.g., rats or mice) using methods such as electroporation or a gene gun, the target antigen can be expressed in the animal's body, thereby inducing an immune response. (b) The administration of the vector by electroporation or the like may be done once or multiple times, preferably multiple times, if necessary to increase the antibody titer; (c) Tissue containing antibody-producing cells (e.g., lymph nodes) is collected from the aforementioned animals from which an immune response has been induced; (d) Myeloma cells (hereinafter referred to as "myeloma") (e.g., mouse myeloma SP2 / 0-ag14 cells) are prepared; (e) Cell fusion of antibody-producing cells and myeloma is performed; (e) Selection of hybridoma groups that produce the target antibody; (f) Division into single-cell clones (cloning); (g) If necessary, culture of hybridomas for the mass production of monoclonal antibodies, or rearing of animals transplanted with hybridomas; and / or (h) Examination of the physiological activity (internalization activity) and binding specificity of the monoclonal antibodies produced in this manner, or testing of their properties as labeling reagents.

[0123] Examples of antibody titer measurement methods used here include, but are not limited to, flow cytometry or Cell-ELISA.

[0124] When an antibody gene is isolated and then introduced into a suitable host to produce an antibody, a suitable host and expression vector combination can be used. A specific example of an antibody gene is a combination of a gene encoding the heavy chain sequence and a gene encoding the light chain sequence of the antibody described herein. When transforming host cells, the heavy chain sequence gene and the light chain sequence gene may be inserted into the same expression vector, or into separate expression vectors. Furthermore, to promote antibody secretion or expression, a signal sequence may be introduced upstream or downstream of the gene encoding the heavy chain sequence or the gene encoding the light chain sequence. As a signal sequence introduced upstream or downstream of the gene encoding the heavy chain sequence, a nucleotide sequence encoding the amino acid sequence represented by SEQ ID NO: 73 may be used. As a signal sequence introduced upstream or downstream of the gene encoding the light chain sequence, a nucleotide sequence encoding the amino acid sequence represented by SEQ ID NO: 74 may be used.

[0125] When using eukaryotic cells as hosts, for example, animal cells, plant cells, and eukaryotic microorganisms can be used. In particular, animal cells include mammalian cells such as monkey cells (COS cells, Gluzman, Y, Cell, 1981, 23, 175-182; ATCC No.CRL-1650), mouse fibroblast cells NIH3T3 (ATCC No.CRL-1658), and dihydrofolate reductase-deficient strains of Chinese hamster ovary cells (CHO cells, ATCC No.CCL-61) (Urlaub, G and Chasin, LA, Proc. Natl. Acad. Sci. USA, 1980, 77, 4126-4220), FreeStyle 293F cells (Invitrogen), and Expi293 cells (Thermo Fisher Scientific).

[0126] When using prokaryotic cells, for example, E. coli, Bacillus subtilis, etc., can be used.

[0127] Antibodies can be obtained by introducing the target antibody gene into these cells by transformation and culturing the transformed cells in vitro. In this culture, the yield may differ depending on the antibody sequence, and it is possible to select antibodies that are easy to produce as pharmaceuticals from among antibodies with equivalent binding activity, using yield as an indicator. Therefore, the antibodies of the present invention also include antibodies obtained by a method for producing antibodies, which is characterized by including the steps of culturing the transformed host cells and collecting the target antibody or its antigen-binding fragment from the culture obtained in the step.

[0128] <2-3. Payload> The payload (D) used in the ligand-drug conjugate or antibody-drug conjugate of the present invention is the following formula (II):

[0129]

[0130] (In the formula, the wavy line indicates the bonding site with L, n) 1 , n 2 , n 3 , and n 4 Each of these independently represents an integer from 1 to 3, where X represents -O-, -NH-, -S-, or -CH2-, and Y represents -O-, -C(R 3 )(R 4 )-, or -N(R 5 )- indicates R 1 phenyl, a six-membered heteroaryl containing one or two nitrogen atoms as ring atoms, C 3-6 Cycloalkyl, or C 5-8 Bicycloalkyl (phenyl, 6-membered heteroaryl, C 3-6 Cycloalkyl, and C 5-8 Each bicycloalkyl group may independently have one or two substituents selected from substituent group 1, and R 2This represents a 6-membered heteroaryl containing phenyl, one or two nitrogen atoms as ring constituent atoms, or a 9 or 10-membered bicyclic heteroaryl containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms (the phenyl, the 6-membered heteroaryl, and the 9 or 10-membered bicyclic heteroaryl may each independently have one or two substituents selected from substituent group 2), R 3 and R 4 Each independently represents hydrogen, halogen, or ethynyl group, or R 3 and R 4 They bond to each other, and together with the carbon atoms to which they bond, form a 3 to 6-membered aliphatic heterocycle containing one or two nitrogen atoms as ring constituent atoms, and R 5 is hydrogen or C 1-6 This indicates alkyl. (Substituent group 1) Halogen, cyano, nitro, -NHC(=O)NH2, -NHC(=O)NHC(=O)NH2, -NHC(=O)-C 1-6 Alkyl, Carbamoyl, -C(=O)NH-C 1-6 Alkyl, -C(=O)NHOH, -C(=O)NHNH2, -C(=O)-C 1-6 Alkyl, carboxyl, -C(=O)OC 1-6 Alkyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -SC 1-6 Alkyl, -SC 3-6 Cycloalkyl, -S(=O)-C 1-6 Alkyl, -S(=O)-C 3-6 Cycloalkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)2-C 3-6 Cycloalkyl, C 1-6 Oxetanyl which may be alkyl-substituted, and 5-oxo-4H-1,2,4-oxadiazole-3-yl (in substituent group 1, the C 1-6 Alkyl and C 3-6Cycloalkyls are, independently, halogen, hydroxyl, and -OC. 1-6 (May be further substituted with one or more groups selected from the group consisting of alkyl groups) (Substituent group 2) Halogen, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl (In substituent group 2, the C 1-6 Alkyl and C 3-6 Each cycloalkyl group may be independently further substituted with one or more halogens. ) (This is represented by ).

[0131] In one embodiment of the present invention, n in formula (II) above 1 , n 2 , n 3 , and n 4 Each of these independently represents an integer of 1 or 2, preferably n 1 and n 2 However, it is 1, and n 3 and n 4 However, the answer is 2.

[0132] In one embodiment of the present invention, -X- in formula (II) above represents -O-, -NH-, or -S-, or -O-, -NH-, or -CH2-, preferably -X- is -O- or -NH-, and particularly preferably -O-.

[0133] In one embodiment of the present invention, -Y- in formula (II) above is -O- or -C(R 3 )(R 4 )- indicates, preferably -Y- is -C(R 3 )(R 4 )- (particularly preferably -CF2-).

[0134] In one embodiment of the present invention, R in formula (II) above 1 phenyl, a six-membered heteroaryl containing one or two nitrogen atoms as ring atoms, C 3-6 Cycloalkyl or C 5-8 It exhibits a bicycloalkyl structure, preferably R 1R in formula (II) above is phenyl, pyridyl, or bicyclopentyl, more preferably phenyl or pyridyl, and even more preferably phenyl. 1 It may have 1 to 3 substituents (preferably 1 or 2) selected from the substituent group 1, substituent group 1', substituent group 1'', substituent group 1''', or substituent group 1''''.

[0135] (Substituent group 1) Halogen, cyano, nitro, -NHC(=O)NH2, -NHC(=O)NHC(=O)NH2, -NHC(=O)-C 1-6 Alkyl, Carbamoyl, -C(=O)NH-C 1-6 Alkyl, -C(=O)NHOH, -C(=O)NHNH2, -C(=O)-C 1-6 Alkyl, carboxyl, -C(=O)OC 1-6 Alkyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -SC 1-6 Alkyl, -SC 3-6 Cycloalkyl, -S(=O)-C 1-6 Alkyl, -S(=O)-C 3-6 Cycloalkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)2-C 3-6 Cycloalkyl, C 1-6 Oxetanyl may be alkyl-substituted (preferably one C 1-6 Oxetanyl (which may be alkyl-substituted), and 5-oxo-4H-1,2,4-oxadiazole-3-yl (in substituent group 1, the C 1-6 Alkyl and C 3-6 Cycloalkyls are, independently, halogen, hydroxyl, and -OC. 1-6 (It may be further substituted with one or more groups selected from the group consisting of alkyl groups.)

[0136] (Substituent group 1') Halogen, Cyano, Nitro, -NHC(=O)NH2, -NHC(=O)NHC(=O)NH2, -NHC(=O)-C 1-6 Alkyl, Carbamoyl, -C(=O)NH-C 1-6 Alkyl, -C(=O)NHOH, -C(=O)NHNH2, -C(=O)-C 1-6 Alkyl, carboxyl, -C(=O)OC 1-6 Alkyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -SC 1-6 Alkyl, -S(=O)-C 1-6 Alkyl, 1 C 1-6 Oxetanyl which may be alkyl-substituted, and 5-oxo-4H-1,2,4-oxadiazole-3-yl (in substituent group 1', the C 1-6 Alkyl and C 3-6 Cycloalkyls are, independently, halogen, hydroxyl, and -OC. 1-6 (It may be further substituted with one or more groups selected from the group consisting of alkyl groups.)

[0137] (Substituent group 1'') Cyano, Carbamoyl, -C(=O)-C 1-6 Alkyl, -SC 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 Cycloalkyl

[0138] (Substituent group 1''') Cyano, Carbamoyl, -C(=O)-C 1-3 Alkyl, -SC 1-3 Alkyl, -OC 1-3 Alkyl and C 3-4 Cycloalkyl

[0139] (Substituent group 1'''') Carbamoyl, -S-methyl, -O-methyl, and cyclopropyl

[0140] In one embodiment of the present invention, R in formula (II) above 1 The substituent group 1 is given by the following equation (IX):

[0141]

[0142] This represents the group represented by the above formula (IX). 1a This represents cyano or carbamoyl, preferably R 1a However, it is carbamoyl. 1b is -C(=O)-C 1-3 Alkyl, -SC 1-3 Alkyl, -OC 1-3 Alkyl, or C 3-4 It exhibits cycloalkyl properties, preferably R 1b However, -SC 1-3 Alkyl, -OC 1-3 Alkyl, or C 3-4 It is a cycloalkyl group, more preferably -S-methyl, -O-methyl, or cyclopropyl group.

[0143] In one embodiment of the present invention, R in formula (II) above 2 This represents a 6-membered heteroaryl containing phenyl, one or two nitrogen atoms as ring constituent atoms, or a 9 or 10-membered bicyclic heteroaryl containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring constituent atoms, preferably R 2 However, R in formula (II) above is phenyl or 3,4-methylenedioxyphenyl, and more preferably phenyl. 2 It may have 1 to 3 substituents (preferably 1 or 2) selected from the substituent group 2, substituent group 2', substituent group 2'', or substituent group 2''' below.

[0144] (Substituent group 2) Halogen, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl (In substituent group 2, the C 1-6 Alkyl and C 3-6 Each cycloalkyl group may be independently further substituted with one or more halogens.

[0145] (Substituent group 2') Halogen, -OC 1-6Alkyl and C 3-6 Cycloalkyl (in substituent group 2', the C 1-6 Alkyl and C 3-6 Each cycloalkyl group may be independently further substituted with 1 to 3 halogens.

[0146] (Substituent group 2'') Halogens, and -OC 1-6 Alkyl

[0147] (Substituent group 2''') Fluorine atom and -O-methyl

[0148] In one embodiment of the present invention, R in formula (II) above 2 The substituent group 2 is given by the following equation (X):

[0149]

[0150] The group shown is represented by the above formula (X). 2a represents a halogen, preferably R 2a However, it is a fluorine atom. 2b is, -OC 1-6 It represents alkyl, preferably R 2b However, -OC 1-3 It is alkyl, and more preferably -O-methyl.

[0151] In one embodiment of the present invention, R in formula (II) above 3 and R 4 Each independently represents hydrogen, halogen, or ethynyl, preferably R 3 and R 4 However, each is independently a halogen, and more preferably R 3 and R 4 However, both are fluorine.

[0152] In another embodiment of the present invention, R in formula (II) above 3 and R 4 These atoms bond with each other, and together with the carbon atoms to which they bond, form a 3 to 6-membered aliphatic heterocycle containing one or two nitrogen atoms as ring constituent atoms. Diazirine is a preferred example of such an aliphatic heterocycle.

[0153] In one embodiment of the present invention, R in formula (II) above 5 is hydrogen or C 1-6 It represents alkyl, preferably R 5 However, hydrogen or C 1-3 Alkyl, more preferably R 5 However, it is hydrogen, methyl, or ethyl, and more preferably R 5 However, it is methyl.

[0154] In one embodiment of the present invention, in formula (II), n 1 , n 2 , n 3 , and n 4 However, each is independently 1 or 2, -X- is -O- or -NH-, -Y- is -CF2- or -O-, R 1 However, phenyl, a 6-membered heteroaryl containing one or two nitrogen atoms as ring constituent atoms, C 3-6 Cycloalkyl or C 5-8 Bicycloalkyl (wherein the phenyl, 6-membered heteroaryl, C 3-6 Cycloalkyl, and C 5-8 Each bicycloalkyl group may independently have one or two substituents selected from the substituent group 1, and R 2 However, the compound is a 6-membered heteroaryl containing phenyl, one or two nitrogen atoms as ring constituent atoms, or a 9 or 10-membered bicyclic heteroaryl containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring constituent atoms (the phenyl, the 6-membered heteroaryl, and the 9 or 10-membered bicyclic heteroaryl may each independently have one or two substituents selected from the substituent group 2).

[0155] In another embodiment of the present invention, in formula (II), n 1 and n 2 However, it is 1, and n 3 and n 4 However, 2, -X- is -O- or -NH-, -Y- is -CF2- or -O-, R 1However, phenyl, a 6-membered heteroaryl containing one or two nitrogen atoms as ring constituent atoms, C 3-6 Cycloalkyl, or C 5-8 Bicycloalkyl (wherein the phenyl, 6-membered heteroaryl, C) 3-6 Cycloalkyl, and C 5-8 Each bicycloalkyl group may independently have one or two substituents selected from the substituent group 1, and R 2 However, the compound is phenyl (which may have one or two substituents selected from substituent group 2) or 3,4-methylenedioxyphenyl.

[0156] In another embodiment of the present invention, in formula (II), n 1 and n 2 However, it is 1, and n 3 and n 4 , is 2, -X- is -O-, -Y- is -CF2-, R 1 However, it represents a phenyl which may have one or two substituents selected from the substituent group 1'', and R 2 However, it is a phenyl compound that may have one or two substituents selected from the substituent group 2''.

[0157] In another embodiment of the present invention, D is the following formula (III):

[0158]

[0159] (In the formula, the dashed line indicates the bonding site with L, and R 1a R indicates cyano or carbamoyl. 1b is -C(=O)-C 1-3 Alkyl, -SC 1-3 Alkyl, -OC 1-3 Alkyl, or C 3-4 R indicates a cycloalkyl group. 2a This indicates a halogen, and R 2b is, -OC 1-6 It indicates an alkyl group.

[0160] In yet another aspect of the present invention, D is represented by any of the following formulas (III-1), (III-2), and (III-3).

[0161]

[0162] (In the formula, the wavy line indicates the bond site with L.)

[0163] <2-4. Linker> The linker (L in formula (I)) that binds the payload to the ligand in the ligand-drug conjugate of the present invention will now be described. The linker used in the ligand-drug conjugate of the present invention is not particularly limited as long as it is understood by those skilled in the art as a linker that connects the ligand and the payload. Examples of linkers used in the ligand-drug conjugate of the present invention include, but are not limited to, those described in Protein Cell, 2018, 9(1): 33-46; Pharm Res, 2015, 32: 3526-3540; or Int. J. Mol. Sci., 2016, 17, 561. The linker may be a linker that is cleaved in vivo or a linker that is not cleaved in vivo, but is preferably a linker that is cleaved in vivo. Examples of linkers cleaved in living organisms include, but are not limited to, linkers cleaved by acids, linkers cleaved by light, linkers cleaved by peptidases, linkers cleaved by esterases, and linkers cleaved by disulfide bond cleavage.

[0164] In one embodiment, the linker used in the ligand-drug conjugate of the present invention is a linker that conjugates the payload to any amino acid residue (e.g., a cysteine ​​residue or a lysine residue) contained in the ligand (e.g., a linker described in International Publication No. 2014 / 057687), and examples include a linker that forms a thioether bond with the sulfhydryl group (-SH) of cysteine ​​contained in the ligand (sometimes referred to herein as a "cysteine ​​conjugation linker") or a linker that forms an amide bond with the amino group (-NH2) of lysine contained in the ligand, preferably a cysteine ​​conjugation linker. Alternatively, the linker used in the ligand-drug conjugate of the present invention is a linker that binds to a glycan contained in the ligand (typically, if the ligand is Ab, to the glycan of the Fc portion of Ab) (e.g., described in International Publication No. 2018 / 003983).

[0165] A preferred linker used in the ligand-drug conjugate of the present invention is of the formula: -Lb-La-Lp-NH-CH2- ＊ (In the formula, * indicates the binding site with D) is shown as follows: -Lp- indicates a bivalent group consisting of an amino acid sequence that can be cleaved in the target cell, and -La- indicates a single bond, or as shown in the formula below: -(CH2)n 5 -C(=O)- ＊ ', -C(=O)-(CH2)n 6 -C(=O)- ＊ ', -(CH2CH2O)n 5 -(CH2)n 6 -C(=O)- ＊ ', -(CH2)n 6 -C(=O)NH-(CH2CH2O)n 8 -(CH2)n 7 -C(=O)- ＊ ', and -(CH2)n 6 -C(=O)NH-(CH2)n 8 -(CH2)n 7 -C(=O)- ＊ ' (In the formula, * indicates the binding site with Lp, n 5 n represents an integer from 1 to 10.6 and n 7 Each of these independently represents an integer from 1 to 5, and n 8 represents one divalent group selected from the group consisting of integers from 0 to 5, where -Lb- represents a divalent group that links La and Li, a divalent group that links amino acid residues of La and Ab, or a divalent group that links the sugar chain of La and Ab.

[0166] First, let's explain -Lp-. -Lp- represents a divalent group consisting of an amino acid sequence that can be cleaved in target cells, and is cleaved by enzymes such as peptidases and esterases. -Lp- is a peptide composed of 1 to 10 (preferably 2 to 7, more preferably 2 to 6, even more preferably 2 to 5, and particularly preferably 2 to 4) amino acid residues. At its amino terminus, -Lp- forms an amide bond with the carbonyl group at the right end of -La- or -Lb-, which will be described later, and at its carboxyl terminus, it forms an amide bond with an amino group (-NH-). The amide bond on the carboxyl terminus side of -Lp- is cleaved by enzymes such as peptidases. In one embodiment, -Lp- is a divalent group consisting of a peptide composed of native amino acid residues.

[0167] The amino acid residues constituting -Lp- are not particularly limited, but for example, they are L-amino acid residues or D-amino acid residues, and preferably L-amino acid residues. In addition to α-amino acid residues, they may also be amino acid residues with structures such as β-alanine residues, ε-aminocaproic acid residues, and γ-aminobutyric acid residues, and may even be unnatural amino acid residues such as N-methylated amino acid residues. The amino acid sequence of -Lp- is not particularly limited, but examples of constituent amino acids include glycine (Gly; G), valine (Val; V), alanine (Ala; A), phenylalanine (Phe; F), glutamic acid (Glu; E), isoleucine (Ile; I), proline (Pro; P), citrulline (Cit), leucine (Leu; L), methionine (Met; M), serine (Ser; S), lysine (Lys; K), and aspartic acid (Asp; D). Preferably, the amino acids are glycine (Gly; G), valine (Val; V), alanine (Ala; A), phenylalanine (Phe: F), citrulline (Cit), isoleucine (Ile; I), proline (Pro; P), and leucine (Leu; L), and more preferably, glycine (Gly; G), alanine (Ala; A), phenylalanine (Phe: F), citrulline (Cit), and leucine (Leu; L). These amino acids may be duplicated, and the amino acid sequence may include any selected amino acids. Furthermore, the sequence of amino acids used for -Lp- can be used to control whether or not the linker is cleaved in vivo, at what site in vivo the linker is cleaved, and the rate at which the linker is cleaved in vivo.

[0168] A concrete example of -Lp- is, for instance, the formula: -GGFG- ＊＊ ',-GGPI- ＊＊ ',-GGVA- ＊＊ ',-GGFM- ＊＊ ',-GGVCit- ＊＊ ', -GGFCit- ＊＊ ',-GGICit- ＊＊ ',-GGPL- ＊＊ ',-GGAQ- ＊＊ ',-GGPP-＊＊ ', -GGLCit- ＊＊ ',-GGACit- ＊＊ ',-GGGACit- ＊＊ ',-ACit- ＊＊ ',-GGGCit- ＊＊ ', or -CitGACit- ＊＊ Examples include a divalent group consisting of amino acid residues represented by ' (wherein ** indicates the binding site with NH), and among these, preferably, formula: -GGFG- ＊＊ ',-GGLCit- ＊＊ ',-GGACit- ＊＊ ',-GGGACit- ＊＊ ',-ACit- ＊＊ ', -GGGCit- ＊＊ ', or -CitGACit- ＊＊ It is a divalent group consisting of amino acid residues represented by ' (the symbols in the formula indicate the same meaning as above).

[0169] Next, let's explain -La-. -La- represents a single bond, or as shown in the following equation: -(CH2)n 5 -C(=O)- ＊ ', -C(=O)-(CH2)n 6 -C(=O)- ＊ ', -(CH2CH2O)n 5 -(CH2)n 6 -C(=O)- ＊ ', -(CH2)n 6 -C(=O)NH-(CH2CH2O)n 8 -(CH2)n 7 -C(=O)- ＊ ', and -(CH2)n 6 -C(=O)NH-(CH2)n 8 -(CH2)n 7 -C(=O)- ＊ ' (In the formula, * indicates the binding site with Lp, n 5 n represents an integer from 1 to 10. 6 and n 7 Each of these independently represents an integer from 1 to 5, and n 8 (where represents integers from 0 to 5) indicates one divalent base selected from this group.

[0170] In one embodiment, the formula is: -(CH2)n 5 -C(=O)- ＊ ', -C(=O)-(CH2)n 6 -C(=O)- ＊ ', -(CH2CH2O)n 5 -(CH2)n 6 -C(=O)- ＊ ', -(CH2)n 6 -C(=O)NH-(CH2CH2O)n 8 -(CH2)n 7 -C(=O)- ＊ ', and -(CH2)n 6 -C(=O)NH-(CH2)n 8 -(CH2)n 7 -C(=O)- ＊ In -La- represented by ', n 5 n is an integer from 1 to 10, specifically, n 5 n represents an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, preferably an integer from 2 to 8, more preferably 2, 4, 5, or 8. 6 , n 7 and n 8 Each of these independently represents an integer from 1 to 5, specifically, n 6 , n 7 , and n 8 Each independently represents an integer of 1, 2, 3, 4, or 5, preferably an integer from 1 to 4, more preferably an integer from 1 to 3, and even more preferably 2.

[0171] In one embodiment, -La- is preferably of the formula: -(CH2)n 5 -C(=O)- ＊ ', -C(=O)-(CH2)n 6 -C(=O)- ＊ ', -(CH2CH2O)n 5 -(CH2)n 6 -C(=O)- ＊ ', -(CH2)n 6 -C(=O)NH-(CH2CH2O)n 8 -(CH2)n 7 -C(=O)- ＊', and -(CH2)n 6 -C(=O)NH-(CH2)n 8 -(CH2)n 7 -C(=O)- ＊ ' (In the formula, * indicates the binding site with Lp, n 5 n represents an integer from 2 to 8 (preferably 2, 4, 5, or 8), and n 6 and n 7 Each of these independently represents an integer from 1 to 4 (preferably an integer from 1 to 3), and n 8 represents any one divalent group selected from the group consisting of integers from 1 to 4 (preferably integers from 1 to 3), more preferably the formula: -(CH2)2-C(=O)- ＊ ',-(CH2)5-C(=O)- ＊ ', -C(=O)-(CH2)2-C(=O)- ＊ ', -(CH2CH2O)4-(CH2)2-C(=O)- ＊ ',-(CH2CH2O)8-(CH2)2-C(=O)- ＊ ', -(CH2)2-C(=O)NH-(CH2CH2O)2-(CH2)2-C(=O)- ＊ ', and -(CH2)2-C(=O)NH-(CH2)2-C(=O)- ＊ ' (wherein * indicates the binding site with Lp) represents one divalent group selected from the following.

[0172] Next, -Lb- will be explained. -Lb- represents a divalent group that links La with Li or Ab. The divalent group used as -Lb- is not particularly limited as long as it is understood by those skilled in the art as a polyfunctional (especially difunctional) chemical moiety capable of linking La with Li or Ab, and in particular a polyfunctional, especially difunctional, chemical moiety capable of linking amino acid residues of La and Ab or a sugar chain of Ab. Preferably, examples include a divalent group used as a linker in cysteine ​​conjugation and a divalent group used as a linker in sugar chain conjugation.

[0173] <When -Lb- is a divalent group used as a linker in cysteine ​​conjugations> When -Lb- is a divalent group used as a linker in cysteine ​​conjugations, Lb is not particularly limited, but for example, formula (V-1):

[0174]

[0175] Examples of divalent groups can be given by (wherein the formula, ** indicates the binding site with La, and the dashed line indicates the binding site with the sulfur atom of the cysteine ​​residue contained in Li or Ab).

[0176] <When Lb is a divalent group used as a linker in a glycan conjugation> When Lb is a divalent group used as a linker in a glycan conjugation, Lb is not particularly limited, but for example, formulas (V-2) and (V-3):

[0177]

[0178] , formula (V-4), formula (V-5):

[0179]

[0180] , equation (V-6), and equation (V-7):

[0181]

[0182] Any one divalent group selected from the group consisting of (in each of the above formulas, ** indicates a binding site with La, and the wavy line indicates a binding site with a sugar chain of Li or Ab) can be mentioned, preferably any one divalent group represented by formula (V-2), formula (V-3), formula (V-6), or formula (V-7), more preferably a divalent group represented by formula (V-2) or formula (V-3).

[0183] In the divalent groups represented by formulas (V-2) to (V-7) above, the triazole ring moiety contains either one of two geometric isomers or a mixture thereof. The ligand-drug conjugate of the present invention can conjugate multiple payloads to one ligand molecule. When multiple payloads are conjugated to one ligand molecule, there will also be multiple Lb groups. When Lb is a divalent group represented by any one of formulas (V-2) to (V-7), and there are multiple linkers (L) for one ligand molecule (for example, m 1 However, if the Lb is an integer from 2 to 20, in each Lb constituting the linker (L), the triazole ring moiety contains either one of two geometric isomers or a mixture thereof.

[0184] Preferred linker used in the ligand-drug conjugate of the present invention (L;-Lb-La-Lp-NH-CH2- ＊ ) If the binding mode between ligand (Li) and payload (D) is cysteine ​​conjugation, then -Lp- is given by the formula: -GGFG- ＊＊ ',-GGLCit- ＊＊ ',-GGACit- ＊＊ ',-GGGACit- ＊＊ ',-ACit- ＊＊ ', -GGGCit- ＊＊ ', or -CitGACit- ＊＊ ' (wherein the formula ** indicates the binding site with NH) is a divalent group consisting of amino acid residues, where -La- is represented by the formula: -(CH2)2-C(=O)- ＊ ',-(CH2)5-C(=O)- ＊ ',-(CH2CH2O)4-(CH2)2-C(=O)- ＊ ', -(CH2CH2O)8-(CH2)2-C(=O)- ＊ ', -(CH2)2-C(=O)NH-(CH2CH2O)2-(CH2)2-C(=O)- ＊ ', and -(CH2)2-C(=O)NH-(CH2)2-C(=O)- ＊Examples of linkers include one divalent group selected from ' (wherein * indicates a binding site with Lp), and -Lb- is a divalent group represented by formula (V-1), more preferably -Lp- is a linker of formula: -GGFG- ＊＊ ',-GGLCit- ＊＊ ',-GGACit- ＊＊ ',-GGGACit- ＊＊ ',-ACit- ＊＊ ', -GGGCit- ＊＊ ', or -CitGACit- ＊＊ ' (wherein the formula ** indicates the binding site with NH) is a divalent group consisting of amino acid residues, where -La- is represented by the formula: -(CH2)5-C(=O)- ＊ Linkers can be given in which -Lb- is a divalent group represented by formula (V-1), and -Lp- is a divalent group represented by formula (V-1), and more preferably -Lp- is a linker represented by formula: -GGACit- ＊＊ ', or -CitGACit- ＊＊ ' (wherein the formula ** indicates the binding site with NH) is a divalent group consisting of amino acid residues, where -La- is represented by the formula: -(CH2)5-C(=O)- ＊ Linkers can be given in which -Lb- is a divalent group represented by formula (V-1), and -Lp- is a divalent group represented by formula (V-1), and particularly preferably -Lp- is a linker represented by formula: -CitGACit- ＊＊ ' (wherein the formula ** indicates the binding site with NH) is a divalent group consisting of amino acid residues, where -La- is represented by the formula: -(CH2)5-C(=O)- ＊ A linker can be described as having a divalent group represented by ' (wherein * indicates the bonding site with Lp), and -Lb- being the divalent group represented by formula (V-1).

[0185] A more preferred linker used in the ligand-drug conjugate of the present invention (L;-Lb-La-Lp-NH-CH2- ＊) If the binding mode between ligand (Li) and payload (D) is a glycosylation, then -Lp- is given by the formula: -GGFG- ＊＊ ',-GGLCit- ＊＊ ',-GGACit- ＊＊ ',-GGGACit- ＊＊ ',-ACit- ＊＊ ', -GGGCit- ＊＊ ', or -CitGACit- ＊＊ ' (wherein the formula ** indicates the binding site with NH) is a divalent group consisting of amino acid residues, and -La- is represented by the formula: -C(=O)-(CH2)2-C(=O)- ＊ ', or -(CH2)5-C(=O)- ＊ Linkers can be given in which -Lb- is a divalent group represented by formula (V-2) or formula (V-3), and more preferably -Lp- is a divalent group represented by formula: -GGACit- ＊＊ ', or -CitGACit- ＊＊ ' (wherein the formula ** indicates the binding site with NH) is a divalent group consisting of amino acid residues, and -La- is represented by the formula: -C(=O)-(CH2)2-C(=O)- ＊ ', or -(CH2)5-C(=O)- ＊ Linkers can be given in which -Lb- is a divalent group represented by formula (V-2) or formula (V-3), and -Lp- is a divalent group represented by formula (V-2) or formula (V-3), and particularly preferably -Lp- is a linker represented by formula: -GGACit- ＊＊ ', or -CitGACit- ＊＊ ' (wherein the formula ** indicates the binding site with NH) is a divalent group consisting of amino acid residues, where -La- is represented by the formula: -(CH2)5-C(=O)- ＊ Linkers can be described as having a divalent group represented by ' (wherein * indicates the binding site with Lp), and -Lb- being a divalent group represented by formula (V-2) or formula (V-3).

[0186] The ligand-drug conjugate of the present invention is preferably of the following formulas: (IV-3), (IV-5), (IV-6), (IV-7), (IV-8), and (IV-10):

[0187]

[0188]

[0189] (In the formula, m 1 A is any one compound selected from the group consisting of (where a is an integer from 1 to 10, and Ab represents an antibody or an antigen-binding fragment thereof), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0190] <2-5. Binding site between ligand and drug linker> <Cysteine ​​conjugation> When the ligand is an antibody or its antigen-binding fragment (Ab), and the binding mode between the ligand (Li) and the drug linker (a complex of payload (D) and linker (L)) is cysteine ​​conjugation, the linker can be linked to any cysteine ​​residue contained in Ab, but preferably it binds to one or more of the following: the cysteine ​​residue at EU numbering position 220 of the heavy chain of Ab, the cysteine ​​residue at EU numbering position 226 of the heavy chain, the cysteine ​​residue at EU numbering position 229 of the heavy chain, and the cysteine ​​residue at EU numbering position 214 of the light chain.

[0191] <Glycan Conjugation> When the ligand is an antibody or its antigen-binding fragment (Ab), and the binding mode between the ligand and the drug linker is glycan conjugation, the linker can be linked to any glycan contained in Ab, but preferably to a glycan that binds to the 297th asparagine residue in the Fc region of the heavy chain of Ab (hereinafter referred to as "Asn297" or "N297") (hereinafter referred to as "Asn297 glycan" or "N297 glycan"). IgG has a well-conserved N-linked glycan at Asn297, which is known to contribute to the activity and kinetics of the antibody (Eon-Duval, A. et al, Biotechnol. Prog. 2012, 28, 608-622, Sanglier-Cianferani, S., Anal. Chem. 2013, 85, 715-736). The amino acid sequence in the constant region of IgG is well conserved, and in the report by Edelman et al. (Proc. Natl. Acad. Sci. USA, 1969, 63, 78-85), each amino acid was identified using EU numbering (EU INDEX). For example, Asn297, to which an N-linked glycan is attached in the Fc region, is at position 297 in EU numbering. Even if the actual amino acid position changes due to molecular fragmentation or region deletion, the amino acid can be uniquely identified by representing it with EU numbering.

[0192] In the present invention, the N297 glycan may be a glycan originally present in the antibody, or it may be a "remodeled glycan" in which the original glycan has been removed by enzymatic means or the like, and then a desired glycan has been introduced. In one embodiment, the N297 glycan is a remodeled glycan.

[0193] In one embodiment, the N297 glycan used in the antibody-drug conjugate of the present invention is N297-(Fuc)SG or N297-(Fuc)MSG1.

[0194] N297-(Fuc)SG is represented by the following structural formula or sequence formula.

[0195]

[0196]

[0197] In the above formula, the wavy line indicates that Ab is bonded to Asn297, and -L(PEG)- represents -(CH2-CH2-O)n 9 -CH2-CH2-NH- is represented, and the amino group of -L(PEG)- is amide-bonded to the carboxyl group at position 2 of the sialic acid at the non-reducing end of the β-Man branched chain of the N297 sugar chain, * indicates the bonding site with the linker (L), preferably the bonding site with the nitrogen atom at position 1 or 3 on the 1,2,3-triazole ring of Lb in the linker (L), and n 9 This represents an integer from 2 to 5 (preferably an integer from 2 to 4, more preferably 3 or 4, and particularly preferably 3).

[0198] N297-(Fuc)MSG1 is represented by the following structural formula or sequence formula.

[0199]

[0200]

[0201] In the above formula, the wavy line indicates that Ab is bonded to Asn297, and -L(PEG)- represents -(CH2-CH2-O)n 9 -CH2-CH2-NH- is represented, and the amino group of -L(PEG)- is amide-bonded to the carboxyl group at position 2 of the sialic acid at the non-reducing end of the β-Man branched chain on the 1-3 chain side of the N297 sugar chain, * indicates the bonding site with the linker (L), preferably the bonding site with the nitrogen atom at position 1 or 3 on the 1,2,3-triazole ring of Lb in the linker (L), and n 9 This represents an integer from 2 to 5 (preferably an integer from 2 to 4, more preferably 3 or 4, and particularly preferably 3).

[0202] In the antibody-drug conjugate of the present invention, if the N297 glycan of the antibody is N297-(Fuc)SG, the antibody-drug conjugate is a compound (m) in which one Ab is bound to four linkers (L) and four payloads (D). 1=4). In the antibody-drug conjugate of the present invention, if the N297 glycan of the antibody is N297-(Fuc)MSG1, the antibody-drug conjugate is a compound (m) to which two linkers (L) and two payloads (D) are bound to one Ab. 1 =2)

[0203] <3. Dispirodiketopiperazine Compound of the Present Invention> In one embodiment of the present invention, the following formula (VIII):

[0204]

[0205] (In the formula, n 1 , n 2 , n 3 , n 4 X, Y, R 1 , and R 2 Compounds represented by (wherein the definitions of each group are the same as those specified for formula (II) above), or pharmaceutically acceptable salts thereof, or solvates thereof are provided. Furthermore, specific preferred embodiments of the compound of formula (VIII) can be similar to those in formula (II), except that the wavy lines are replaced with hydrogen atoms.

[0206] In one embodiment of the present invention, the compound represented by formula (VIII) or a pharmaceutically acceptable salt thereof, or a solvate thereof, is preferably the following formula (VIII-A):

[0207]

[0208] (R in the formula) 1a , R 1b , R 2a , and R 2b The compound represented by (wherein it is the same as the definition of each group specified for formula (III) above), or a pharmaceutically acceptable salt thereof, or a solvate thereof, more preferably the following formulas (VIII-22), (VIII-50), and (VIII-54):

[0209]

[0210] It is one compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0211] As shown in Test Example 7, the compound represented by formula (VIII) has been confirmed to inhibit the proliferation of CD57-positive cells among human neuroblastoma SK-N-SH cells when added, i.e., it exhibits cell proliferation inhibitory activity. It is presumed that the compound represented by formula (VIII) inhibits cell proliferation of cancer cells with high selectivity by stabilizing a complex containing NuMA1 and CKAP5. Therefore, the compound represented by formula (VIII) can be used as a novel cell proliferation inhibitor with high selectivity for cancer cells and low toxicity.

[0212] Furthermore, the compound represented by formula (VIII) can be used as a payload in ligand-drug conjugates, particularly antibody-drug conjugates, linked to a ligand that binds to target cells (e.g., tumor cells) via a suitable linker. In this case, the compound represented by formula (VIII) can be used as a raw material or intermediate for producing the ligand-drug conjugate, or as a free drug after being cleaved in vivo. In such embodiments, the linking position of the compound represented by formula (VIII) with the linker is not limited as long as the desired effect is achieved, but preferably, a nitrogen atom bonded to a hydrogen atom on the piperazine ring can be mentioned.

[0213] <4. Intermediate> In one embodiment of the present invention, the following formula (VI):

[0214]

[0215] (where n 1 , n 2 , n 3 , n 4 X, Y, R 1 , and R 2 This indicates the same meaning as the definitions of each group specified in formula (II) above, and R L This is the group represented by the formula: Cit-NH-CH2-, or the formula: Lb'-La'-Lp'-NH-CH2- (where -Lp'- is the same as the formula: -GGFG-) ＊＊ '', -GGLCit- ＊＊ '', -GGACit-＊＊ '', -GGGACit- ＊＊ '', -ACit- ＊＊ '', -GGGCit- ＊＊ '', and -CitGACit- ＊＊ '' (wherein **'' indicates a binding site with NH) represents one divalent group selected from the group consisting of '', and -La'- represents the formula: -(CH2)2-C(=O)- ＊ '', -(CH2)5-C(=O)- ＊ '', -C(=O)-(CH2)2-C(=O)- ＊ '', -(CH2CH2O)4-(CH2)2-C(=O)- ＊ '', -(CH2CH2O)8-(CH2)2-C(=O)- ＊ '', -(CH2)2-C(=O)NH-(CH2CH2O)2-(CH2)2-C(=O)- ＊ '', and -(CH2)2-C(=O)NH-(CH2)2-C(=O)- ＊ '' (wherein *'' indicates the binding site with Lp') represents one divalent group selected from the group consisting of '', where Lb' is represented by formulas (VII-1) and (VII-2):

[0216]

[0217] A compound represented by (in the formula, the wavy line indicates the bonding site with La') or a pharmaceutically acceptable salt thereof, or a solvate thereof is provided (hereinafter, the compound of formula (VI) or a pharmaceutically acceptable salt thereof, or a solvate thereof may be referred to as "the drug linker of the present invention"). Also, R in formula (VI) L Each other group, i.e., n 1 , n 2 , n 3 , n 4 X, Y, R 1 , and R 2 As for specific preferred embodiments, examples of compounds similar to the preferred embodiments of each group defined in formula (II) can be given.

[0218] In one embodiment of the present invention, in formula (VI), R Lis a group represented by the formula: Lb'-La'-Lp'-NH-CH2-, where -Lp'- is represented by the formula: -GGFG- ＊＊ '', -GGLCit- ＊＊ '', -GGACit- ＊＊ '', -GGGACit- ＊＊ '', -ACit- ＊＊ '', -GGGCit- ＊＊ '', and -CitGACit- ＊＊ One divalent group selected from the group consisting of '' (wherein **'' indicates a binding site with NH) (preferably -Lp'- is the same as formula: -GGACit- ＊＊ ', or -CitGACit- ＊＊ A divalent group consisting of amino acid residues represented by ' (wherein ** indicates a binding site with NH), more preferably -Lp'- is represented by formula: -CitGACit- ＊＊ ' (wherein the formula ** indicates the binding site with NH) is a divalent group consisting of amino acid residues, and -La'- is represented by the formula: -(CH2)2-C(=O)- ＊ '', -(CH2)5-C(=O)- ＊ ''-(CH2CH2O)4-(CH2)2-C(=O)- ＊ '', -(CH2CH2O)8-(CH2)2-C(=O)- ＊ '', -(CH2)2-C(=O)NH-(CH2CH2O)2-(CH2)2-C(=O)- ＊ '', and -(CH2)2-C(=O)NH-(CH2)2-C(=O)- ＊ One divalent group selected from the group consisting of '' (wherein *'' indicates the binding site with Lp') (preferably -La'- is of the formula: -(CH2)5-C(=O)- ＊ '' (wherein *'' indicates the binding site with Lp') is a divalent group, and Lb' is represented by formula (VII-1):

[0219]

[0220] This is the group represented by (in the formula, the wavy line indicates the bonding site with La').

[0221] In one embodiment of the present invention, in formula (VI), n 1 and n 2 However, both are 1, n 3 and n 4 However, both are 2, -X- is -O- or -NH-, and -Y- indicates -CF2- or -O-, R 1 However, phenyl, a 6-membered heteroaryl containing one or two nitrogen atoms as ring constituent atoms, C 3-6 Cycloalkyl or C 5-8 Bicycloalkyl (wherein the phenyl, 6-membered heteroaryl, C 3-6 Cycloalkyl, and C 5-8 Each bicycloalkyl group may independently have one or two substituents selected from substituent group 1', R 2 However, it is phenyl (wherein the phenyl may have one or two substituents selected from substituent group 2'), or 3,4-methylenedioxyphenyl, and R L However, it represents a group represented by the formula: Cit-NH-CH2- or a group represented by the formula: Lb'-La'-Lp'-NH-CH2-, where -Lp'- is represented by the formula: -GGFG- ＊＊ '', -GGLCit- ＊＊ '', -GGACit- ＊＊ '', -GGGACit- ＊＊ '', -ACit- ＊＊ '', -GGGCit- ＊＊ '', and -CitGACit- ＊＊ '' (wherein **'' indicates a binding site with NH) represents one divalent group selected from the group consisting of '', and La' represents the formula: -(CH2)2-C(=O)- ＊ '', -(CH2)5-C(=O)- ＊ ''-(CH2CH2O)4-(CH2)2-C(=O)- ＊ '', -(CH2CH2O)8-(CH2)2-C(=O)- ＊ '', -(CH2)2-C(=O)NH-(CH2CH2O)2-(CH2)2-C(=O)- ＊'', and -(CH2)2-C(=O)NH-(CH2)2-C(=O)- ＊ '' (wherein *'' indicates the binding site with Lp') represents one divalent group selected from the group consisting of '', where Lb' is given by the following formula (VII-1):

[0222]

[0223] A compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a group represented by the formula (wherein the wavy line indicates the bonding site with La'), is provided as a drug linker, most preferably of the following formulas (VI-6), (VI-9), (VI-12), (VI-15), (VI-24), and (VI-25):

[0224]

[0225]

[0226] Any one compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or the following formulas (VI-5), (VI-8), and (VI-11):

[0227]

[0228] A single compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is provided as a drug linker.

[0229] Since the compound of formula (VI) or its pharmaceutically acceptable salts, or solvates thereof, is a complex of the dispirodiketopiperazine compound of the present invention and a linker moiety, it can be used as a manufacturing intermediate, i.e., a drug linker, when producing ligand-drug conjugates containing the dispirodiketopiperazine compound of the present invention, particularly antibody-drug conjugates.

[0230] <5. Salts, solvates, isomers, prodrugs, etc.>

[0231] If the dispirodiketopiperazine compound, drug linker, ligand-drug conjugate, antibody-drug conjugate, and their manufacturing intermediates of the present invention have a basic group such as an amino group, they can optionally be pharmaceutically acceptable salts. Examples of such salts include hydrohalides such as hydrochloride and hydroiodide; inorganic salts such as nitrates, perchlorates, sulfates, and phosphates; lower alkanesulfons such as methanesulfonates, trifluoromethanesulfons, and ethanesulfons; allylsulfons such as benzenesulfons and p-toluenesulfons; organic salts such as formate, acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, and maleate; and amino acid salts such as ornithine, glutamate, and aspartate.

[0232] If the dispirodiketopiperazine compound, drug linker, ligand-drug conjugate, antibody-drug conjugate, and intermediates for their production according to the present invention have an acidic group such as a carboxyl group, they can optionally be pharmaceutically acceptable salts. Examples of such salts include alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; inorganic salts such as ammonium salts; and organic amine salts such as dibenzylamine salt, morpholine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, diethanolamine salt, N-benzyl-N-(2-phenylethoxy)amine salt, piperazine salt, tetramethylammonium salt, and tris(hydroxymethyl)aminomethane salt.

[0233] The dispirodiketopiperazine compounds, drug linkers, ligand-drug conjugates, antibody-drug conjugates, and their manufacturing intermediates, or pharmaceutically acceptable salts thereof, of the present invention may also exist as solvates. The solvates of the present invention are not particularly limited as long as they are pharmaceutically acceptable, but specifically, hydrates, methanol hydrates, ethanol hydrates, 2-propanol hydrates, etc., are preferred. In one embodiment, the dispirodiketopiperazine compounds, drug linkers, ligand-drug conjugates, antibody-drug conjugates, and their manufacturing intermediates, or pharmaceutically acceptable salts thereof, may absorb moisture by being left in the air or by recrystallization, resulting in adsorbed water or the formation of hydrates, and such hydrates or their pharmaceutically acceptable salts are also included in the present invention. Furthermore, if a nitrogen atom is present in the dispirodiketopiperazine compound, drug linker, ligand-drug conjugate, antibody-drug conjugate, and their manufacturing intermediates, or their pharmaceutically acceptable salts, they may be in the form of an N-oxide, and such N-oxide is also included within the scope of the present invention. Furthermore, if a sulfur atom is present in the dispirodiketopiperazine compound, drug linker, ligand-drug conjugate, antibody-drug conjugate, and their manufacturing intermediates, or their pharmaceutically acceptable salts, they may be in the form of a sulfoxide and a sulfone, and such sulfoxide and sulfone are also included within the scope of the present invention.

[0234] Furthermore, the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes. The dispirodiketopiperazine compounds, drug linkers, ligand-drug conjugates, antibody-drug conjugates, and their manufacturing intermediates, or their pharmaceutically acceptable salts, may also contain non-natural proportions of atomic isotopes in one or more of the atoms constituting them. Examples of atomic isotopes include deuterium ( 2 H), tritium ( 3 H), Iodine-125( 125 I), Carbon-14 ( 14 Examples include C). Furthermore, the above-mentioned compounds in the present invention include, for example, tritium ( 3 H), Iodine-125(125 I), Carbon-14 ( 14 The compounds can be radiolabeled with radioactive isotopes such as C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents (e.g., assay reagents), and diagnostic agents (e.g., in vivo imaging agents). All isotopic variants of the above compounds in this invention, whether radioactive or not, are included in the scope of this invention.

[0235] The dispirodiketopiperazine compounds, drug linkers, ligand-drug conjugates, antibody-drug conjugates, and their manufacturing intermediates, or their pharmaceutically acceptable salts, or their solvates, of the present invention may contain stereoisomers, or optical isomers derived from chiral carbon atoms, geometric isomers, tautomers, or optical isomers such as d-isomers, l-isomers, and atropisomers. Any of these isomers, optical isomers, or mixtures thereof are included in the present invention. Mixtures of these isomers can be separated by known separation methods.

[0236] Furthermore, the present invention also includes prodrugs of the dispirodiketopiperazine compounds, drug linkers, ligand-drug conjugates, antibody-drug conjugates, and their manufacturing intermediates, or pharmaceutically acceptable salts thereof, or solvates thereof. A prodrug is a compound having a group that can be converted to an amino group, hydroxyl group, carboxyl group, etc., by hydrolysis or under physiological conditions. Examples of groups that form such prodrugs include those described in Prog. Med., 1985, 5, 2157-2161, etc. More specifically, examples of such prodrugs include: (1) If the compound contains an amino group, the amino group has been acylated, alkylated, or phosphorylated (for example, compounds in which the amino group has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, or tert-butylated); and (2) If the compound contains a hydroxyl group, the hydroxyl group has been acylated, alkylated, phosphorylated, or borated (for example, compounds in which the hydroxyl group has been acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumalylated, alanylated, or dimethylaminomethylcarbonylated). (3) If a carboxyl group is present in the compound, examples include compounds in which the carboxyl group has been esterified or amidized (for example, compounds in which the carboxyl group has been ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, amidized or methylamidized).

[0237] <6. Compositions and Pharmaceutical Uses> In one embodiment of the present invention, a pharmaceutical composition is provided comprising the dispirodiketopiperazine compound of the present invention, a ligand-drug conjugate, or an antibody-drug conjugate, and at least one pharmaceutically acceptable additive.

[0238] In the present invention, "pharmaceutical composition" means a composition used to treat any disease. Since the ligand-drug conjugate of the present invention can target a wide variety of antigens or cells depending on the type of ligand, there are no particular limitations on the diseases that can be treated with the pharmaceutical composition of the present invention, however, examples include cancer and immune diseases. In one embodiment, the disease that can be treated with the pharmaceutical composition of the present invention is cancer. Such cancers are not particularly limited, but examples include leukemia, malignant lymphoma, multiple myeloma, brain tumors (including brain metastases), head and neck cancers (head and neck squamous cell carcinoma, etc.), esophageal cancers (esophageal squamous cell carcinoma, etc.), gastric cancer, appendiceal cancer, colorectal cancer, anal cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, gastrointestinal stromal tumors, lung cancers (non-small cell lung cancer (squamous cell carcinoma, adenocarcinoma), small cell lung cancer, etc.), liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, bladder cancer, neuroendocrine tumors, neuroblastoma, glioblastoma, and malignant cancers. Examples of diseases that can be treated with the pharmaceutical composition of the present invention are solid tumors with a history of prior treatment. Here, "solid tumors" are not particularly limited to any solid cancer, but include, for example, ovarian cancer, breast cancer, sarcoma, esophageal cancer, prostate cancer, bladder cancer, head and neck cancer, uterine cancer, and malignant melanoma. "Prior treatment" is not particularly limited to any treatment for solid tumors, but includes, for example, standard treatment for that cancer. For esophageal squamous cell carcinoma and small cell lung cancer, this would include chemotherapy including platinum-based drugs or treatment with immune checkpoint inhibitors, and for castration-resistant prostate cancer, it would include treatment with one or two androgen receptor signaling inhibitors (hormone therapy). Solid tumors with a history of at least one line (first line) or two lines (second line) of prior treatment are eligible for treatment.Furthermore, cancers that have become resistant to standard treatments and advanced solid tumors for which there are no standard treatments are also targets for treatment. The compound represented by formula (VIII) in the present invention is presumed to inhibit cell proliferation of cancer cells with high selectivity by stabilizing a complex containing NuMA1 and CKAP5. Therefore, diseases that can be treated with the pharmaceutical composition of the present invention include cancers in which amplification of the NuMA1 gene or overexpression of the NuMA1 protein occurs. Cancers with a high frequency of NuMA1 gene amplification or overexpression of the NuMA1 protein include head and neck squamous cell carcinoma and esophageal squamous cell carcinoma.

[0239] The route of administration of such pharmaceutical compositions to humans or other animals may be oral administration in the form of tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration in the form of injections, suppositories, eye drops, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches, inhalants, etc., for intra-articular, intravenous, or intramuscular administration. However, if the molecular weight of the ligand-drug conjugate of the present invention (e.g., antibody-drug conjugate) is large, parenteral administration by injection for intravenous administration, etc., is preferred.

[0240] Examples of solid compositions for oral administration include tablets, powders, granules, etc. Such solid compositions contain, in addition to the dispirodiketopiperazine compound or ligand-drug conjugate of the present invention, at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminometasilicate, etc. Such solid compositions may further contain inert additives (e.g., lubricants such as magnesium stearate; disintegrants such as sodium carboxymethyl starch; stabilizers; solubilizers, etc.) according to conventional methods. Tablets or pills may, if necessary, be coated with sugar or a film of gastric-soluble or enteric-soluble material.

[0241] Examples of liquid compositions for oral administration include pharmaceutically acceptable emulsifiers, solutions, suspensions, syrups, elixirs, etc. Such liquid compositions may contain commonly used inert diluents (e.g., purified water or ethanol). In addition to inert diluents, such liquid compositions may further contain auxiliary agents such as solubilizers and wetting agents; sweeteners; flavoring agents; fragrances; preservatives, etc.

[0242] Examples of injectable preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of aqueous solvents include distilled water for injection and physiological saline. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such injectable compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and / or solubilizers. These injectable compositions can be sterilized, for example, by filtration through a bacterial retention filter, by adding a bactericide, or by irradiation. Alternatively, these injectable compositions can be prepared as sterile solid compositions and dissolved or suspended in sterile water or a sterile solvent for injection before use.

[0243] Examples of topical preparations include ointments, plasters, creams, gels, poultices, sprays, lotions, eye drops, and eye ointments. These topical preparations may contain commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, etc. For example, examples of ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, bleached beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, and sorbitan sesquioleate.

[0244] Transmucosal preparations such as inhalants and nasal preparations may be used in solid, liquid, or semi-solid form and can be manufactured according to conventionally known methods. For example, known excipients may be added as appropriate, along with pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, etc. For these transmucosal preparations, a suitable inhalation or blowing device can be used as the method of administration. For example, the dispirodiketopiperazine compound or ligand-drug conjugate of the present invention can be administered alone or as a powder in a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using a known device such as a metered inhalation device or a sprayer. Dry powder inhalers may be for single or multiple doses, and can use dry powder or powder-containing capsules. Alternatively, a suitable excipient may be used. For example, it may be in the form of a pressurized aerosol spray using a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, or carbon dioxide.

[0245] The pharmaceutical composition of the present invention may contain other active ingredients, or may be used in combination with another pharmaceutical composition containing other active ingredients. This combination may involve simultaneous administration, separate and consecutive administration, or administration at desired time intervals. The simultaneous administration formulation may be a combination formulation or formulated separately.

[0246] The amount of the dispirodiketopiperazine compound or ligand-drug conjugate of the present invention to be filled into a pharmaceutical composition, or the amount administered to a subject, is not particularly limited as long as it is an effective amount to achieve the objective, and can be appropriately selected according to the purpose of use, the subject's age, weight, symptoms, health condition, disease progression, etc. There are also no particular restrictions on the frequency of administration, and can be appropriately selected according to the purpose; for example, the daily dose may be administered once a day, or divided into multiple doses.

[0247] The pharmaceutical compositions of the present invention typically contain two or more ligand-drug conjugates or pharmaceutically acceptable salts thereof, or solvates thereof. In the ligand-drug conjugates of the present invention, the number of drug molecules bound to one ligand molecule is an important factor affecting their efficacy and safety. The production of ligand-drug conjugates is carried out by specifying reaction conditions, such as the amount of raw materials and reagents used to react, so that the number of drug molecules bound is constant. However, unlike the chemical reactions of low-molecular-weight compounds, ligand-drug conjugates with different numbers of drugs bound (i.e., m 1 It is usually obtained as a mixture of two or more different ligand-drug conjugates. The number of drug molecules bound to one ligand molecule can be specified as an average value, i.e., the average drug binding number (drug-antibody binding ratio: DAR). The number of drug linkers bound to the ligand is controllable, and the average drug binding number per ligand can range from 1 to 20, but is preferably 1 to 10, more preferably 1 to 8, even more preferably 3 to 8, and particularly preferably 3 to 5 or 5 to 7. Thus, in one embodiment, the pharmaceutical composition of the present invention comprises two or more ligand-drug conjugates or pharmaceutically acceptable salts thereof, or solvates thereof, wherein the average number of D bound per unit of Li or Ab in the ligand-drug conjugates or pharmaceutically acceptable salts thereof, or solvates thereof contained in the composition is 1 to 20, preferably 1 to 10, more preferably 1 to 8, even more preferably 3 to 8, and even more preferably 3 to 5 or 5 to 7.

[0248] Furthermore, those skilled in the art can design a method for binding the required number of drugs to a ligand, and obtain ligands (typically antibodies) with controlled drug binding numbers.

[0249] In one aspect of the present invention, a compound represented by formula (I) or formula (IV) or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in the treatment of cancer is provided; in another aspect of the present invention, a method for treating cancer is provided, comprising the step of administering a therapeutically effective amount of a compound represented by formula (I) or formula (IV) or a pharmaceutically acceptable salt thereof, or a solvate thereof, to a subject in need of treatment for cancer; in yet another aspect of the present invention, the use of a compound represented by formula (I) or formula (IV) or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the manufacture of a pharmaceutical for use in the treatment of cancer, or an antitumor agent containing a compound represented by formula (I) or formula (IV) or a pharmaceutically acceptable salt thereof, or a solvate thereof, is provided.

[0250] <7. Combined Use> The dispirodiketopiperazine compound or ligand-drug conjugate of the present invention, or a pharmaceutical composition or antitumor agent containing either of these, may be used in combination with other antitumor agents. Other antitumor agents used for this purpose may be administered to an individual simultaneously with, separately from, or consecutively with the dispirodiketopiperazine compound or ligand-drug conjugate of the present invention, or a pharmaceutical composition or antitumor agent containing either of these, or with varying administration intervals. Examples of such antitumor agents include platinum-based drugs such as cisplatin, oxaliplatin, and carboplatin; taxane compounds such as paclitaxel and docetaxel; antimetabolites such as 5-fluorouracil and gemcitabine; antiestrogens such as tamoxifen; aromatase inhibitors such as letrozole; androgen receptor antagonists such as enzalutamide; tyrosine kinase inhibitors such as imatinib, sunitinib, and lenvatinib; CDK4 / 6 inhibitors such as palbociclib; PARP inhibitors such as olaparib; HSP90 inhibitors such as pimitespib; MEK inhibitors such as cabozantinib; and BRAF inhibitors such as dabrafenib. Examples of antitumor agents include KRAS inhibitors such as adagrab; FGFR inhibitors such as futivatinib; EGFR inhibitors such as gefitinib, erlotinib, osimertinib, and afatinib; cytokines such as IL-2, IFN-γ, and G-CSF; angiogenesis inhibitors such as bevacizumab; monoclonal antibodies targeting tumor antigens or marker antigens such as trastuzumab, rituximab, and panitumumab; antibody-drug conjugates such as trastuzumab deruxtecan; and immune checkpoint inhibitors such as nivolumab, ipilimumab, and relatrimab. However, the list is not limited to drugs with antitumor activity. Furthermore, the dispirodiketopiperazine compound or ligand-drug conjugate of the present invention, or a pharmaceutical composition containing either thereof, may be used in combination with an antibody-drug conjugate (ADC) containing the above-mentioned antitumor agent as a payload, or a TPD (Targeted Protein Degrader) using the above-mentioned antitumor agent as a POI (Protein Of Interest) ligand.

[0251] The dispirodiketopiperazine compound or ligand-drug conjugate of the present invention, or a pharmaceutical composition containing either of these, may be administered simultaneously or separately with the above-mentioned co-administered drug, and may be provided as a combination or kit formulation.

[0252] <8. Manufacturing Method> Next, a typical manufacturing method for the dispirodiketopiperazine compound, drug linker, antibody-drug conjugate, or intermediate for their manufacture according to the present invention will be described. In the following, the compound number shown in each reaction formula will be used to indicate the compound. That is, it will be referred to as "compound of formula (1)", "compound (1)", etc. Compounds with other numbers will also be described in the same manner. When using a ligand other than an antibody, the desired ligand-drug conjugate can be manufactured in accordance with the manufacturing method described below and / or by using a conventional method as appropriate.

[0253] <8-1. Manufacturing Method 1> Compound (VIII) of the present invention can be manufactured according to methods A to C described below.

[0254]

[0255] Methods A through C are methods for producing the dispirodiketopiperazine compound (VIII) and its synthetic intermediate according to the present invention. Method D is a method for producing the drug linker according to the present invention. Each step of Methods A through D below can be carried out using known organic chemical techniques to achieve the desired reaction. The solvent used in each step of Methods A through D below is not particularly limited as long as it does not inhibit the reaction, does not adversely affect the reaction, and dissolves the starting materials to some extent. In each step of Methods A through D below, the reaction temperature will vary depending on the solvent, starting materials, reagents, etc., and the reaction time will also vary depending on the solvent, starting materials, reagents, reaction temperature, etc.

[0256] If the products of each step in Methods A to D below, or their intermediates in production, have basic groups such as amino groups, they can be pharmaceutically acceptable salts as desired. Examples of such salts include hydrohalides such as hydrochloride, hydrobromide, and hydroiodide; inorganic salts such as nitrates, perchlorates, sulfates, and phosphates; lower alkanesulfons such as methanesulfonates, trifluoromethanesulfons, and ethanesulfons; allylsulfons such as benzenesulfonates and p-toluenesulfonates; organic salts such as formates, acetates, malates, fumarates, succinates, citrates, tartrates, oxalates, and maleates; and amino acid salts such as ornithines, glutamates, and aspartates.

[0257] If the products of each step in Methods A to D below, or their intermediates in their production, have an acidic group such as a carboxyl group, they may be pharmaceutically acceptable salts as desired. Examples of such salts include alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; inorganic salts such as ammonium salts; and organic amine salts such as dibenzylamine salt, morpholine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, diethanolamine salt, N-benzyl-N-(2-phenylethoxy)amine salt, piperazine salt, tetramethylammonium salt, and tris(hydroxymethyl)aminomethane salt.

[0258] The products or intermediates produced by each step of the following methods A to D may, depending on the type and combination of substituents, exist as various isomers, such as geometric isomers (including cis and trans isomers), tautomers, atrop isomers, and optical isomers (including enantiomers and diastereomers) (including d and l isomers). Unless otherwise specified, all of these isomers, stereoisomers, and mixtures of these isomers and stereoisomers in any ratio are included in the present invention. These mixtures of isomers can be separated by known separation methods.

[0259] In the reactions of each step from Method A to Method D described below, after the reaction is complete, each target compound is collected from the reaction mixture according to conventional methods. For example, the reaction mixture is neutralized as appropriate, and if insoluble matter is present, it is removed by filtration. Then, an immiscible solvent such as water and ethyl acetate or water and dichloromethane is added to separate the organic layer containing the target compound. After washing with water, the target compound is dried with anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., filtered, and the solvent is removed by distillation to obtain the target compound. The obtained target compound can be separated and purified by conventional methods, if necessary, such as recrystallization, reprecipitation, chromatography (for example, adsorption column chromatography using carriers such as silica gel, alumina, magnesium silica gel-based Florisil, amino-silica (manufactured by Fuji Silysia Chemical Co., Ltd.); partition column chromatography using carriers such as Sephadex LH-20 (manufactured by Pharmacia Co., Ltd.), Amberlite XAD-11 (manufactured by Rohm & Haas Co., Ltd.), Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation), etc., using synthetic adsorbents; ion exchange chromatography; normal-phase and reverse-phase column chromatography using silica gel or alkylated silica gel (preferably high-performance liquid chromatography), etc., in appropriate combinations, and eluted with an appropriate eluent); chiral column chromatography using carriers where the stationary phase is a chiral compound, such as polysaccharide derivatives (manufactured by Daicel Corporation), etc., in appropriate combinations of methods commonly used for the separation and purification of organic compounds. For target compounds insoluble in solvent, the obtained crude solid product can be purified by washing with a solvent. Alternatively, the target compound from each step can be used directly in the next reaction without purification.

[0260] In the reactions of each step from Method A to Method D below, n 1 , n 2 , n 3 , n 4 X, Y, R 1 , R 2 , R 1a , R 1b , La, and Lp indicate the same meaning as above.

[0261] PRO 1The group represents an amino group protecting group, preferably a tert-butoxycarbonyl group, a benzyloxycarbonyl group, or a 9-fluorenylmethyloxycarbonyl (FMOC) group.

[0262] PRO 2 This represents a hydroxyl group protecting group used in the field of organic synthesis chemistry, and preferably includes benzyl group, acetyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, tert-butyl group, etc.

[0263] W represents a leaving group used in the field of organic synthesis chemistry, and is preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethylsulfonyloxy group, etc.

[0264] M represents alkali metals such as lithium, sodium, and potassium. + This represents a monovalent cation of an alkali metal.

[0265] Z is CH, N, or CR 6 It represents.

[0266] R 6 These include halogens, cyano, nitro, -NHC(=O)NH2, -NHC(=O)NHC(=O)NH2, -NHC(=O)-C1-6 alkyl, carbamoyl, and -C(=O)NH-C 1-6 Alkyl, -C(=O)NHOH, -C(=O)NHNH2, -C(=O)-C 1-6 Alkyl, carboxyl, -C(=O)OC 1-6 Alkyl, one hydroxyl, or one -OC 1-6 C may be substituted with alkyl. 1-6 Alkyl, may be substituted with 1 to 3 halogens - OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -SC 1-6 Alkyl, -SC 3-6 Cycloalkyl, -S(=O)-C 1-6 Alkyl, -S(=O)-C 3-6 Cycloalkyl, -S(=O)2-C 1-6Alkyl, -S(=O)2-C 3-6 Cycloalkyl, C 1-6 This represents oxetanyl, which may be substituted with alkyl, or 5-oxo-4H-1,2,4-oxadiazole-3-yl.

[0267] R 7 This represents a methyl group, ethyl group, benzyl group, or tert-butyl group.

[0268] R 8 These are hydroxy, amino, 1 to 3 hydroxy or 1-OC 1-6 C may be substituted with alkyl. 1-6 Alkyl, possibly substituted with 1 to 3 amino groups C 1-6 Alkyl, may be substituted with 1 to 3 halogens - OC 1-6 Alkyl, or C 3-6 Represents cycloalkyl. The amino group and hydroxyl group are represented as PRO, respectively. 1 and PRO 2 This includes those protected by a protective agent.

[0269] R 9 This represents a side chain of an amino acid residue, preferably a side chain of a native amino acid residue, and more preferably a side chain of glycine, alanine, phenylalanine, citrulline, or leucine.

[0270] Furthermore, amino groups and / or hydroxyl groups that are not explicitly protected in methods A through D may be protected with protecting groups as needed. They may also be deprotected as needed, or they may be protected, then deprotected, and replaced with other protecting groups.

[0271] Method A is a method for producing compound (VIIIa) and compound (VIIIb) from compound (VIII).

[0272]

[0273]

[0274] Step A-1 is a process in which compound (2a) is produced by carrying out a trifluoroacetylation reaction on compound (1a).

[0275] Compound (1a) is added to a solvent (methanol, ethanol, tert-butyl alcohol, dichloromethane, diethyl ether, toluene, 1,4-dioxane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), tetrahydrofuran (THF), acetonitrile, dimethyl sulfoxide (DMSO), water, etc., or a mixture thereof) with a base (potassium methoxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, pyridine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.) and stirred at -20°C to the boiling point of the solvent used in the reaction, preferably from 20°C to 60°C, for 1 minute to 1 hour, preferably from 5 minutes to 30 minutes, and then reacted with a trifluoroacetylating agent such as ethyl trifluoroethyl acetate. The base and trifluoroacetylating agent are used in amounts ranging from 1 mole to an excess mole per mole of compound (1a). The reaction temperature is from -20°C to the boiling point of the solvent used in the reaction, preferably in the range of 20°C to 60°C. The reaction time is from 5 minutes to 12 hours, preferably from 30 minutes to 6 hours.

[0276] Step A-2 is a process in which compound (5a) is produced by carrying out a Strecker reaction using compound (3a) and compound (4a).

[0277] Compound (3a) is reacted with compound (4a) in a solvent (methanol, ethanol, tert-butyl alcohol, dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, DMSO, water, etc., or a mixture thereof). Then, an acid (acetic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, etc.) is added, and the mixture is stirred from -20°C to the boiling point of the solvent used in the reaction, preferably from 20°C to 60°C, for 1 minute to 1 hour, preferably from 5 minutes to 30 minutes, before being reacted with MCN (potassium cyanide, sodium cyanide, etc.). For every mole of compound (3a), 1 to 10 moles, preferably 1 to 2 moles, of compound (4a) is used, 0.1 to 10 moles, preferably 1 to 5 moles, of acid (acetic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, etc.) is used, and 1 to 10 moles, preferably 1 to 2 moles, of MCN is used. The reaction temperature is from -20°C to the boiling point of the solvent used in the reaction, preferably from 20°C to 60°C. The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

[0278] Step A-3 is a process in which compound (6a) is produced by carrying out a hydrolysis reaction on compound (5a).

[0279] Compound (5a) is reacted in a solvent (methanol, ethanol, tert-butyl alcohol, dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, DMSO, water, etc., or a mixture thereof), preferably DMSO, in the presence of hydrogen peroxide, by adding a base (potassium carbonate, potassium tert-butoxide, potassium methoxide, sodium methoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.). For every mole of compound (5a), 1 to 10 moles, preferably 1 to 5 moles, of hydrogen peroxide are used, and 1 to 10 moles, preferably 1 to 5 moles, of the base are used. The reaction temperature is from 0°C to the boiling point of the solvent used in the reaction, preferably from 0°C to 60°C. The reaction time is from 10 minutes to 240 hours, preferably from 1 hour to 120 hours.

[0280] Step A-4 is a process in which compound (7a) is produced by performing a hydrolysis reaction on compound (6a).

[0281] Compound (6a) is reacted with an aqueous solution of a base (potassium tert-butoxide, potassium methoxide, sodium methoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.) in a solvent (methanol, ethanol, tert-butyl alcohol, dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, DMSO, water, etc., or a mixture thereof), preferably ethanol. For every mole of compound (6a), 1 to 10 moles of base are used, preferably 1 to 5 moles. The reaction temperature is from 0°C to the boiling point of the solvent used in the reaction, preferably 60°C to 120°C. The reaction time is from 10 minutes to 100 hours, preferably 1 hour to 48 hours.

[0282] Step A-5 is a process in which compound (8a) is produced by carrying out a dispirodiketopiperazine construction reaction using compound (7a) and compound (2a).

[0283] Compound (2a) is stirred in a solvent (dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, etc., or a mixture thereof), preferably dichloromethane, in the presence of oxalyl chloride and DMF, from -20°C to the boiling point of the solvent used in the reaction, preferably from 4°C to 50°C, for 10 minutes to 24 hours, preferably from 30 minutes to 6 hours. The solvent is removed under reduced pressure, and the mixture is dried under reduced pressure. Next, compound (7a) is added dropwise to a solvent (dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, etc., or a mixture thereof) preferably DMF, in the presence of a base (pyridine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.), after which a solution of the previously synthesized acid chloride in DMF is added dropwise. The mixture is then stirred from -20°C to the boiling point of the solvent used in the reaction, preferably from 4°C to 50°C, for 10 minutes to 48 hours, preferably from 1 hour to 24 hours. Subsequently, 1,1'-carbonyldiimidazole is added, and the reaction is carried out from -20°C to the boiling point of the solvent used in the reaction, preferably from 20°C to 100°C, for 10 minutes to 48 hours, preferably from 1 hour to 24 hours. For every 1 mole of compound (7a), 1 to 2 moles, preferably 1 to 1.5 moles, of compound (2a) are used. For every mole of compound (7a), 1 to 2 moles, preferably 1 to 1.5 moles, of oxalyl chloride are used. For every mole of compound (2a), 0.01 to 1 mole, preferably 0.05 to 0.2 moles, of DMF are used. For every mole of compound (7a), 1 to 10 moles, preferably 1 to 5 moles, of a base (pyridine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.) are used. For every mole of compound (7a), 1 to 10 moles, preferably 1 to 2 moles, of 1,1'-carbonyldiimidazole are used.

[0284] Step A-6 is a process in which compound (9a) is produced by carrying out a deprotection reaction on compound (8a).

[0285] Protecting agent to use (PRO1 Depending on the type of group (tert-butoxycarbonyl group, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, etc.), deprotection can be carried out by known methods. 1 However, in the case of a tert-butoxycarbonyl group, compound (8a) is reacted with an acid (trifluoroacetic acid, hydrochloric acid, hydrogen chloride-dioxane, sulfuric acid, etc.) in a solvent (methanol, ethanol, tert-butyl alcohol, dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, DMSO, water, etc., or a mixture thereof) at a temperature from -20°C to the boiling point of the solvent used in the reaction, preferably from 0°C to 30°C. The acid (trifluoroacetic acid, hydrochloric acid, hydrogen chloride-dioxane, sulfuric acid, etc.) is used in an amount of 0.5 moles to an excess mole per mole of compound (8a). The reaction time is 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

[0286] Step A-7 is a process for producing compound (VIIIa) and compound (VIIIb) by carrying out a transition metal-catalyzed cross-coupling reaction using compound (9a) and compound (10a).

[0287] Compound (9a) and compound (10a) are mixed in a solvent (methanol, ethanol, tert-butyl alcohol, dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, DMSO, water, etc., or a mixture thereof) with a transition metal catalyst (tris(dibenzylideneacetone)dipalladium(0), palladium(II) acetate, dichlorobis(benzonitrile)palladium(II), etc.) and phosphine compound The reaction is carried out in the presence of a ligand (such as dicyclohexyl[3,6-dimethoxy-2',4',6'-tri(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, etc.) and a base (such as potassium methoxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, etc.) at a temperature of -20°C to 200°C, preferably 20°C to 120°C, for 10 minutes to 72 hours, preferably 1 hour to 24 hours. If the reaction is carried out above the boiling point of the solvent used, a microwave synthesis apparatus or the like is used. For every mole of compound (9a), 1 to 5 moles, preferably 1 to 2 moles, of compound (10a) are used. For every mole of compound (9a), 0.01 to 1 mole, preferably 0.05 to 0.5 moles, of a transition metal catalyst (such as tris(dibenzylideneacetone)dipalladium(0), palladium(II) acetate, or dichlorobis(benzonitrile)palladium(II)) are used. For every mole of compound (9a), 0.01 to 1 mole, preferably 0.02 to 0.5 moles, of the phosphine ligand (dicyclohexyl[3,6-dimethoxy-2',4',6'-tri(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphine, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, etc.) is used.For every mole of compound (9a), 1 to 5 moles, preferably 1 to 2 moles, of a base (potassium methoxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, etc.) are used.

[0288] Method B is a method for producing compound (VIIIc) and compound (VIIId) from compound (VIII).

[0289]

[0290]

[0291] Step B-1 is a process in which compound (3b) is produced by carrying out a Strecker reaction using compound (1b) and compound (2b), and is carried out in accordance with step A-2 of Method A.

[0292] Step B-2 is a process in which compound (4b) is produced by hydrolysis of compound (3b), and is carried out in accordance with step A-3 of Method A.

[0293] Step B-3 is a process in which compound (5b) is produced by hydrolysis of compound (4b), and is carried out in accordance with step A-4 of Method A.

[0294] Step B-4 is the process of producing compound (6b) by carrying out a dispirodiketopiperazine construction reaction using compound (5b) and compound (2a), and is carried out in accordance with step A-5 of Method A.

[0295] Step B-5 is a process in which compound (6b) is produced by carrying out a dispirodiketopiperazine construction reaction using compound (5b) and compound (2a).

[0296] Compound (2a) is stirred in a solvent (dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, etc., or a mixture thereof), preferably dichloromethane, in the presence of oxalyl chloride and DMF, from -20°C to the boiling point of the solvent used in the reaction, preferably from 4°C to 50°C, for 10 minutes to 24 hours, preferably from 30 minutes to 2 hours. Next, DMA is added, followed by compound (5b), and the mixture is stirred from -20°C to the boiling point of the solvent used in the reaction, preferably from 4°C to 50°C, for 1 minute to 12 hours, preferably from 1 minute to 1 hour. Subsequently, a base (1-methylpiperidine, pyridine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.) is added, and the mixture is stirred from -20°C to the boiling point of the solvent used in the reaction, preferably from 4°C to 50°C, for 1 minute to 12 hours, preferably from 30 minutes to 6 hours. Subsequently, 1,1'-carbonyldiimidazole is added, and the reaction is carried out by stirring from -20°C to the boiling point of the solvent used in the reaction, preferably from 20°C to 100°C, for 1 minute to 12 hours, preferably from 30 minutes to 6 hours. For every mole of compound (5b), 1 to 2 moles, preferably 1 to 1.5 moles, of compound (2a) are used. For every mole of compound (5b), 1 to 2 moles, preferably 1 to 1.5 moles, of oxalyl chloride are used. For every mole of compound (2a), 0.01 to 1 mole, preferably 0.05 to 0.2 moles, of DMF are used. For every mole of compound (5b), 1 to 10 moles, preferably 1 to 5 moles, of a base (1-methylpiperidine, pyridine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.) are used. For every mole of compound (5b), 1 to 10 moles, preferably 1 to 2 moles, of 1,1'-carbonyldiimidazole are used.

[0297] Step B-6 is a process in which compound (7b) is produced by carrying out a deprotection reaction on compound (6b).

[0298] Protecting agent to use (PRO 2Depending on the type of group (benzyl group, acetyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, tert-butyl group, etc.), deprotection can be carried out by known methods. 2 However, in the case of a benzyl group, the reaction is carried out by catalytic hydrogenation of compound (6b) in a solvent (ethanol, propanol, methanol, ethyl acetate, THF, 1,4-dioxane, etc., or a mixture thereof) in the presence of a transition metal catalyst (palladium-carbon, etc.) from 0°C to the boiling point of the solvent used in the reaction, preferably from 0°C to 50°C. This step is usually carried out under a hydrogen atmosphere, but if necessary, cyclohexene, 1,4-cyclohexadiene, etc. may be used as a hydrogen donor. For 1 mole of compound (6b), 0.01 moles to 10 moles, preferably 0.01 moles to 1 mole of transition metal catalyst (palladium-carbon, etc.) are used. For 1 mole of compound (6b), 1 moles to 1000 moles, preferably 1 moles to 100 moles of hydrogen donor (cyclohexene, 1,4-cyclohexadiene, etc.) are used. The reaction time is 10 minutes to 100 hours, preferably 30 minutes to 72 hours.

[0299] Step B-7 is a process in which compound (8b) is produced by carrying out an oxidation reaction with compound (7b).

[0300] Compound (7b) is reacted with an oxidizing agent (chlorosulfonium salt, des-martin periodinane, tetrabutylammonium lutenate, pyridinium chlorochromate, nitroxyl radical oxidation catalyst, etc.) in a solvent (dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, acetone, pyridine, etc., or a mixture thereof) at a temperature from -78°C to the boiling point of the solvent used in the reaction, preferably from -78°C to 30°C. If necessary, a base (triethylamine, N,N-diisopropylethylamine, sodium bicarbonate, sodium carbonate, sodium hydroxide, etc.) and a reoxidizing agent (N-methylmorpholine N-oxide, iodobenzene diacetate, sodium hypochlorite, etc.) or additive (tetrabutylammonium bromide, potassium bromide, etc.) are added. For every mole of compound (7b), the amount of oxidizing agent used is 0.01 moles to an excess mole, preferably 0.01 moles to 10 moles. Furthermore, 1 to 10 moles of a base (triethylamine, N,N-diisopropylethylamine, sodium bicarbonate, sodium carbonate, sodium hydroxide, etc.) or a reoxidizing agent, and 0.01 to 1 mole of an additive are added to 1 mole of compound (7b). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

[0301] Step B-8 is a process in which compounds (VIIIc) and (VIIId) are produced by carrying out a reductive amination reaction using compounds (8b) and (9b).

[0302] Compound (8b) and compound (9b) are reacted with a reducing agent (sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, 2-picolineborane, pyridineborane, etc.) in a solvent (methanol, ethanol, tert-butyl alcohol, dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, DMSO, water, etc., or a mixture thereof) at a temperature from -78°C to the boiling point of the solvent used in the reaction, preferably from 0°C to 80°C. If necessary, an acid (acetic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, etc.) is added. For every mole of compound (8b), 1 to 10 moles, preferably 1 to 2 moles, of compound (9b) are used. For every mole of compound (8b), 1 mole to an excess mole, preferably 1 to 5 moles, of the reducing agent are used. Furthermore, 0.01 to 10 moles of acid (acetic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, etc.) are added to 1 mole of compound (8b). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 48 hours.

[0303] Method C is a method for producing compound (VIIIe), compound (VIIIf), compound (VIIIg), compound (VIIIh), and compound (VIIIi) of compound (VIII), in which the -X- is -O-.

[0304]

[0305]

[0306]

[0307] Step C-1 is a process in which compounds (VIIIe) and (VIIIf) are produced by carrying out a coupling reaction using compounds (7b) and (1c).

[0308] Compound (7b) is reacted with compound (1c) and a base (potassium methoxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, sodium hydride, sodium bis(trimethylsilyl)amide, etc.) in a solvent (dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, DMSO, water, etc., or a mixture thereof) in which compound (7b) is reacted first in a solvent (dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, DMSO, water, etc., or a mixture thereof). The reaction temperature is from 0°C to 200°C, preferably from 20°C to 150°C. If the reaction is carried out above the boiling point of the solvent used, a microwave synthesizer or the like is used. For every mole of compound (7b), 1 to 10 moles, preferably 1 to 2 moles, of compound (1c) are used. For every mole of compound (7b), 1 to 10 moles, preferably 1 to 2 moles, of a base (such as potassium methoxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, sodium hydride, sodium bis(trimethylsilyl)amide, etc.) are used. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

[0309] Step C-2 is a process in which compound (2c) is produced by carrying out a reduction reaction with compound (8b).

[0310] The reaction is carried out by treating compound (8b) with a reducing agent (lithium aluminum hydride, diborane, lithium borohydride, sodium borohydride, borane-tetrahydrofuran complex, sodium bis(2-methoxyethoxy)aluminum hydride, etc.) in a solvent (methanol, ethanol, tert-butyl alcohol, dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, DMSO, water, etc., or a mixture thereof) at a temperature from -78°C to the boiling point of the solvent used in the reaction, preferably from -78°C to 50°C. The reducing agent is used at a temperature of 1 mole to an excess mole, preferably from 1 mole to 5 moles, per mole of compound (8b). If necessary, Lewis acids (such as lithium chloride, calcium chloride, tin chloride, trifluoroborane ether complexes, (S)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine, (R)-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine, etc.) may be added. The reaction time is from 1 minute to 72 hours, preferably from 5 minutes to 24 hours.

[0311] Step C-3 is a process in which compound (VIIIf) is produced by carrying out a coupling reaction using compound (2c) and compound (1c), and is carried out in accordance with step C-1 of Method C.

[0312] C-4 This step involves compound (VIIIf, R 1a This is a process to produce compound (VIIIg) by performing a hydrolysis reaction on (=CN), and is carried out in accordance with step A-3 of method A.

[0313] C-5 This step involves compound (VIIIf, R 1a This is a process to produce compound (VIIIg) by performing a hydrolysis reaction on (=CN). Compound (VIIIf, R 1aThe reaction is carried out by reacting compound (=CN) with a base (potassium tert-butoxide, potassium methoxide, sodium methoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.), preferably potassium tert-butoxide, in a solvent (methanol, ethanol, tert-butyl alcohol, dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, DMSO, water, etc., or a mixture thereof), preferably a mixed solvent of tert-butyl alcohol and toluene. Compound (VIIIf, R 1a For every mole of CN, 1 to 10 moles, preferably 2 to 5 moles, of the base are used. The reaction temperature is from 20°C to the boiling point of the solvent used in the reaction, preferably from 20°C to 60°C. The reaction time is from 1 hour to 240 hours, preferably from 2 hours to 120 hours.

[0314] C-6 This step involves compound (VIIIf, R 1a =CO2R 7 This is a process for producing compound (VIIIh) by carrying out a hydrolysis reaction on ).

[0315] Compound (VIIIf, R 1a =CO2R 7 The reaction is carried out by reacting the compound (VIIIf, R) with an aqueous solution of a base (lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, etc.) in a solvent (acetonitrile, THF, 1,4-dioxane, DMF, methanol, ethanol, water, etc., or a mixture thereof) at a temperature from 0°C to the boiling point of the solvent used in the reaction, preferably from 20°C to 120°C. The base (lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, etc.) is compound (VIIIf, R 1a =CO2R 7 For every 1 mole of ), 1 mole to an excess mole is used, and the reaction time is from 30 minutes to 120 hours, preferably from 1 hour to 72 hours. 7 If it is a tert-butyl group, the compound (VIIIf, R 1aThe reaction is carried out using an acid (trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc.) in a solvent (dichloromethane, chloroform, 1,4-dioxane, DMF, THF, etc., or a mixture thereof) at a temperature from -20°C to the boiling point of the solvent used in the reaction, preferably from 0°C to 50°C. The acid (trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc.) is a compound (VIIIf, R 1a For every mole of CO2t-Bu, 1 mole to an excess mole is used, and the reaction time is from 1 minute to 24 hours, preferably from 30 minutes to 12 hours.

[0316] Step C-7 is a process in which compound (VIIIi) is produced by carrying out an amidation reaction using compound (VIIIh) and compound (3c).

[0317] The reaction is carried out by reacting compound (VIIIh) with compound (3c) in a solvent (dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, DMSO, etc., or a mixture thereof) at a temperature from -20°C to the boiling point of the solvent used in the reaction, preferably from 0°C to 50°C, in the presence of a condensing agent (N,N-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride, etc.). For every mole of compound (VIIIh), 1 to 5 moles, preferably 1 to 3 moles, of compound (3c) are used, and 1 to an excess mole, preferably 1 to 3 moles, of the coupling agent. Additionally, a base (triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.) and an additive (1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, etc.) are added as needed. For every mole of compound (VIIIh), a catalytic amount to an excess mole of base is used, preferably 0.2 to 3 moles. For every mole of compound (VIIIh), a catalytic amount to an excess amount of additive is used, preferably 0.05 to 3 moles. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 48 hours. The R of compound (3c) 8 PRO 1 and PRO 2 If the protected amino group or hydroxyl group is present, it can be deprotected by known methods.

[0318] Method D is a typical drug linker for conjugating dispirodiketopiperazine compounds to antibodies. The peptide residue represented by the general formula Lp can be produced by an amino acid condensation reaction. When using a linker other than the typical linkers listed below, the desired drug linker can be produced by following the production method described below and / or by using a conventional method as appropriate.

[0319]

[0320]

[0321]

[0322] Step D-1 is a process in which compound (2d) is produced by carrying out a condensation reaction with compound (1d).

[0323] When using compound (1d) and succinate ester ((maleimido-N-yl)-La-OSu), compound (1d) is reacted with succinate ester ((maleimido-N-yl)-La-OSu) in a solvent (methanol, ethanol, tert-butyl alcohol, dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, DMSO, water, etc., or a mixture thereof) at a temperature from -20°C to the boiling point of the solvent used in the reaction, preferably from 0°C to 50°C. A base (triethylamine, diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.) may be added as needed. For every mole of compound (1d), 1 to 5 moles, preferably 1 to 3 moles, of succinate ester ((maleimido-N-yl)-La-OSu) are used. For every mole of compound (1d), the amount of base used ranges from a catalytic amount to an excess mole, preferably 0.2 to 3 moles. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 48 hours.

[0324] When the reaction is carried out using compound (1d) and a carboxylic acid ((maleimido-N-yl)-La-OH), compound (1d) is heated in a solvent (methanol, ethanol, tert-butyl alcohol, dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, DMSO, water, etc., or a mixture thereof) from -20°C to the boiling point of the solvent used in the reaction, preferably from 0°C to 50°C, using a condensing agent (N,N-dicyclohexyl carboxylate). The reaction is carried out by reacting a carboxylic acid ((maleimido-N-yl)-La-OH) in the presence of mid, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride, etc. For every mole of compound (1d), 1 to 5 moles, preferably 1 to 3 moles, of the carboxylic acid ((maleimido-N-yl)-La-OH) is used, and 1 to an excess mole, preferably 1 to 3 moles, of the coupling agent. Furthermore, bases (triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.) and additives (1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, etc.) may be added as needed. For every mole of compound (1d), a catalytic amount to an excess mole of base is used, preferably 0.2 to 3 moles. For every mole of compound (1d), a catalytic amount to an excess amount of additive is used, preferably 0.05 to 3 moles. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 48 hours.

[0325] When a condensation reaction is carried out to convert a carboxylic acid ((maleimido-N-yl)-La-OH) into an acid halide, compound (1d) is reacted with the acid halide of the carboxylic acid ((maleimido-N-yl)-La-OH) in a solvent (benzene, toluene, diethyl ether, dichloromethane, THF, dichloromethane, etc., or a mixture thereof) at a temperature from -78°C to the boiling point of the solvent used in the reaction, preferably from -20°C to 100°C, in the presence of a base (triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.). For every mole of compound (1d), 0.3 to 5 moles, preferably 1 to 3 moles, of the acid halide are used, and the amount of base is used in a catalytic amount to an excess mole, preferably 0.3 to 5 moles. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

[0326] To prepare acid halogen compounds of carboxylic acid ((maleimido-N-yl)-La-OH), the carboxylic acid ((maleimido-N-yl)-La-OH) is treated with oxalyl chloride, thionyl chloride, etc., in a solvent (benzene, toluene, dichloromethane, dichloroethane, etc., or a mixture thereof) from 0°C to the boiling point of the solvent used in the reaction, preferably from 0°C to 100°C. If necessary, a catalytic amount of DMF, etc., is added. For 1 mole of carboxylic acid ((maleimido-N-yl)-La-OH), 1 mole to an excess mole, preferably 1 mole to 10 moles, of oxalyl chloride or thionyl chloride is used. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

[0327] Step D-2 is a process in which compound (2d) is produced by performing solid-phase synthesis on compound (3d).

[0328] Compound (1d) is synthesized by solid-phase synthesis, such as the Fmoc solid-phase synthesis method, using 2-chlorotrityl chloride resin (3d, where Po represents resin (polymer)). This compound is then synthesized in which the resin is bonded to the OH group of the H-Lp-OH of compound (1d). Compound (2d) is then synthesized by this compound in which the resin is bonded to the OH group of compound (2d) according to step D-1. Compound (2d) is produced by treating this compound with an acid (trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, etc.), preferably trifluoroacetic acid, from -20°C to the boiling point of the solvent used in the reaction, preferably from 0°C to 50°C. Additives (tri(propane-2-yl)silane, triethylsilane, etc.) may be added as needed. The reaction may also be carried out in a solvent (methanol, ethanol, tert-butyl alcohol, dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, DMSO, water, etc., or a mixture thereof) as needed. For every mole of compound (3d), 1 mole to an excess mole of acid is used, preferably 10 moles to 500 moles. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

[0329] Step D-3 is a process in which compound (5d) is produced by carrying out a decarboxylation acetoxylation reaction on compound (4d).

[0330] Compound (4d) is reacted with lead(IV) acetate in a solvent (dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, etc., or a mixture thereof) at a temperature from -78°C to the boiling point of the solvent used in the reaction, preferably from 0°C to 100°C. Acetic acid may be added as needed. A base (pyridine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.) may be added as needed. Additives (copper(II) acetate, sodium acetate, etc.) may be added as needed. For every mole of compound (4d), 1 to 10 moles, preferably 1 to 3 moles, of lead(IV) acetate are used. For every mole of compound (4d), 0.05 moles to an excess mole, preferably 0.1 to 10 moles, of acetic acid, a base (pyridine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.), and an additive (copper(II) acetate, sodium acetate, etc.) are used. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

[0331] Step D-4 is a process in which compound (6d) is produced by carrying out a coupling reaction using compound (VIIIj) and compound (5d).

[0332] Compound (VIIIj) obtained by the above methods A to C or other methods is stirred in a solvent (dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, etc., or a mixture thereof) at a temperature from -78°C to the boiling point of the solvent used in the reaction, preferably from 0°C to 100°C, in the presence of a base (potassium methoxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, sodium hydride, sodium bis(trimethylsilyl)amide, etc.), preferably sodium hydride, for 1 minute to 12 hours, preferably from 1 minute to 2 hours. Next, compound (5d) is added and the reaction is carried out at a temperature from -78°C to the boiling point of the solvent used in the reaction, preferably from 0°C to 100°C. Additives (sodium iodide, tetrabutylammonium iodide, etc.) may be added as needed. For every mole of compound (VIIIj), 1 to 10 moles, preferably 1 to 3 moles, of compound (5d) are used. For every mole of compound (VIIIj), 1 to 5 moles, preferably 1 to 3 moles, of a base (such as potassium methoxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, sodium hydride, sodium bis(trimethylsilyl)amide, etc.) are used. For every mole of compound (VIIIj), 0.01 moles to an excess mole, preferably 0.05 moles to 3 moles, of an additive (such as sodium iodide, tetrabutylammonium iodide, etc.) are used. The reaction time is 10 minutes to 72 hours, preferably 1 hour to 24 hours.

[0333] Step D-5 is a process in which compound (VIa) is produced by carrying out a deprotection reaction on compound (6d).

[0334] Protecting agent to use (PRO 1 Depending on the type of group (tert-butoxycarbonyl group, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, etc.), deprotection can be carried out by known methods.1 However, in the case of the 9-fluorenylmethyloxycarbonyl group, compound (7d) is reacted with a base (pyrrolidine, piperidine, 1,8-diazabicyclo[5.4.0]-7-undecene, etc.) in a solvent (methanol, ethanol, tert-butyl alcohol, dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, DMSO, water, etc., or a mixture thereof) from -20°C to the boiling point of the solvent used in the reaction, preferably from 0°C to 30°C, to carry out deprotection. For 1 mole of compound (6d), 0.5 moles to an excess mole of base (pyrrolidine, piperidine, 1,8-diazabicyclo[5.4.0]-7-undecene, etc.) is used. The reaction time is 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

[0335] Step D-6 is a process in which compound (VIa) is produced by carrying out a coupling reaction and a deprotection reaction using compound (VIIIj) and compound (5d).

[0336] PRO 1 However, in the case of the 9-fluorenylmethyloxycarbonyl group, compound (VIa) is produced by performing step D-4 followed by step D-5 in a single pot.

[0337] Step D-7 is a process in which compound (VIb) is produced by carrying out an amidation reaction using compound (VIa) and compound (2d).

[0338] The reaction is carried out by reacting compound (VIa) with compound (2d) in a solvent (dichloromethane, diethyl ether, toluene, 1,4-dioxane, DMF, DMA, THF, acetonitrile, DMSO, etc., or a mixture thereof) at a temperature from -20°C to the boiling point of the solvent used in the reaction, preferably from 0°C to 50°C, in the presence of a condensing agent (N,N-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride, etc.). For every mole of compound (VIa), 1 to 5 moles, preferably 1 to 3 moles, of compound (2d) are used, and 1 to an excess mole, preferably 1 to 3 moles, of the coupling agent. Additionally, a base (triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.) and an additive (1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, etc.) are added as needed. For every mole of compound (VIa), a catalytic amount to an excess mole of base is used, preferably 0.2 to 3 moles. For every mole of compound (VIa), a catalytic amount to an excess amount of additive is used, preferably 0.05 to 3 moles. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 48 hours.

[0339] When compound (2d) is converted to a succinate ester through a condensation reaction, compound (VIa) is reacted with the succinate ester of compound (2d) in a solvent (benzene, toluene, DMF, diethyl ether, dichloromethane, THF, dichloromethane, etc., or a mixture thereof) at a temperature from -78°C to the boiling point of the solvent used in the reaction, preferably from -20°C to 100°C, in the presence of a base (triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.). For every mole of compound (VIa), 0.5 to 5 moles, preferably 1 to 3 moles, of succinate ester are used, and the amount of base is from a catalytic amount to an excess mole, preferably 0.3 to 5 moles. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

[0340] To prepare the succinate ester of compound (2d), compound (2d) is treated in a solvent (benzene, toluene, DMF, dichloromethane, dichloroethane, etc., or a mixture thereof) at a temperature from 0°C to the boiling point of the solvent used in the reaction, preferably from 0°C to 80°C, in the presence of N-hydroxysuccinimide and a condensing agent (N,N-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, etc.). For every mole of compound (2d), 1 mole to an excess mole, preferably 1 to 3 moles, of N-hydroxysuccinimide is used. For every mole of compound (2d), 1 mole to an excess mole, preferably 1 to 3 moles, of the condensing agent (N,N-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, etc.) is used. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

[0341] When compound (2d) is converted to an acid halide and condensed, compound (VIa) is reacted with the acid halide of compound (2d) in a solvent (benzene, toluene, DMF, diethyl ether, dichloromethane, THF, dichloromethane, etc., or a mixture thereof) at a temperature from -78°C to the boiling point of the solvent used in the reaction, preferably from -20°C to 100°C, in the presence of a base (triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.). For every mole of compound (VIa), 0.3 to 5 moles, preferably 1 to 3 moles, of the acid halide are used, and the amount of base is a catalytic amount to an excess mole, preferably 0.3 to 5 moles. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

[0342] To prepare the acid halogen compound of compound (2d), compound (2d) is treated with oxalyl chloride, thionyl chloride, etc., in a solvent (benzene, toluene, dichloromethane, dichloroethane, etc., or a mixture thereof) at a temperature from 0°C to the boiling point of the solvent used in the reaction, preferably from 0°C to 100°C. If necessary, a catalytic amount of DMF, etc., is added. For 1 mole of compound (2d), oxalyl chloride or thionyl chloride is used in an excess of 1 mole, preferably from 1 mole to 10 moles. The reaction time is 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

[0343] D-8 This step involves compound (VIIIf, R 1a =CN) and compound (5d, PRO 1 This is a step to produce compound (7d) by carrying out a coupling reaction using FMOC, and is performed in accordance with step D-4 of method D.

[0344] Step D-9 is a process in which compound (VIc) is produced by hydrolysis and deprotection reactions of compound (7d), and is carried out in accordance with step A-3 of Method A.

[0345] Step D-10 is a process in which compound (VIc) is produced by hydrolysis and deprotection reactions of compound (7d), and is carried out in accordance with step C-5 of Method C.

[0346] Step D-11 is a process in which compound (VId) is produced by carrying out a coupling reaction using compound (VIc) and compound (2d), and is carried out in accordance with step D-7 of Method D.

[0347] <8-2. Manufacturing Method 2> Next, a typical manufacturing method for the antibody-drug conjugate (IV) of the present invention, or its manufacturing intermediate, will be described. In the following, the compound numbers shown in each reaction formula will be used to indicate the compounds. For example, they will be referred to as "compound of formula (VIb)", "compound (VIb)", etc. Compounds with other numbers will also be described in the same manner.

[0348] The antibodies used in this invention can be obtained by known methods. Specific examples of antibody preparation methods used in the examples described later are given below as reference examples, but are not limited to these.

[0349] (Reference Example 1) Preparation of Anti-CDH6 Antibody 1 An antibody containing the heavy chain of the amino acid sequence described in SEQ ID NO: 1 and the light chain of the amino acid sequence described in SEQ ID NO: 6 was prepared by a known method, and the obtained antibody was designated as "Anti-CDH6 Antibody 1".

[0350] (Reference Example 2) Preparation of Anti-CDH6 Antibody 2 An antibody containing the heavy chain of the amino acid sequence described in SEQ ID NO: 10 and the light chain of the amino acid sequence described in SEQ ID NO: 15 was prepared by a known method, and the obtained antibody was designated as "Anti-CDH6 Antibody 2".

[0351] (Reference Example 3) Preparation of Anti-B7-H3 Antibody 1 An antibody containing the heavy chain of the amino acid sequence described in SEQ ID NO: 19 and the light chain of the amino acid sequence described in SEQ ID NO: 24 was prepared by a known method, and the obtained antibody was designated as "Anti-B7-H3 Antibody 1".

[0352] (Reference Example 4) Preparation of Anti-B7-H3 Antibody 2 An antibody containing the heavy chain of the amino acid sequence described in SEQ ID NO: 28 and the light chain of the amino acid sequence described in SEQ ID NO: 33 was prepared by a known method, and the obtained antibody was designated as "Anti-B7-H3 Antibody 2".

[0353] (Reference Example 5) Preparation of Anti-CD30 Antibody 1 An antibody containing the heavy chain of the amino acid sequence described in SEQ ID NO: 37 and the light chain of the amino acid sequence described in SEQ ID NO: 42 was prepared by a known method, and the obtained antibody was designated as "Anti-CD30 Antibody 1".

[0354] (Reference Example 6) Preparation of Anti-CD70 Antibody 1 An antibody containing the heavy chain of the amino acid sequence described in SEQ ID NO: 46 and the light chain of the amino acid sequence described in SEQ ID NO: 51 was prepared by a known method, and the obtained antibody was designated as "Anti-CD70 Antibody 1".

[0355] (Reference Example 7) Preparation of Anti-B7-H3 Antibody 3 An antibody containing the heavy chain of the amino acid sequence described in SEQ ID NO: 55 and the light chain of the amino acid sequence described in SEQ ID NO: 60 was prepared by a known method, and the obtained antibody was designated as "Anti-B7-H3 Antibody 3".

[0356] (Reference Example 8) Preparation of Anti-B7-H3 Antibody 4 An antibody containing the heavy chain of the amino acid sequence described in SEQ ID NO: 64 and the light chain of the amino acid sequence described in SEQ ID NO: 69 was prepared by a known method, and the obtained antibody was designated as "Anti-B7-H3 Antibody 4".

[0357] Among the antibody-drug conjugates represented by formula (IV), those in which Ab and the linker structure are bound via a thioether (antibody-drug conjugate (IVa)) can be produced, for example, by reacting an antibody having a sulfhydryl group or its antigen-binding fragment (1e) (hereinafter sometimes referred to as "Ab") with a compound (VIb). Note that in the following reaction formula, m 1 This represents an integer from 1 to 20.

[0358]

[0359] Antibodies (1e) having sulfhydryl groups can be obtained by methods well known to those skilled in the art (Hermanson, GT, Bioconjugate Techniques, pp. 56-136, pp. 456-493, Academic Press (1996)). For example, methods include, but are not limited to, reacting the amino group of the antibody with Traut's reagent; reacting the amino group of the antibody with N-succinimidyl 3-acetylthioalkanoates followed by hydroxylamine; reacting the antibody with N-succinimidyl 3-(pyridyldithio)propionate followed by a reducing agent; or reacting the antibody with reducing agents such as dithiothreitol, 2-mercaptoethanol, or tris(2-carboxyethyl)phosphine hydrochloride (TCEP) to reduce the disulfide bond in the hinge region of the antibody and generate a sulfhydryl group.

[0360] Specifically, by using TCEP as a reducing agent in an amount of 0.3 to 3 molar equivalents per mole of hinge disulfide in the antibody, and reacting it with the antibody in a buffer containing a chelating agent, an antibody in which the hinge disulfide in the antibody is partially or completely reduced can be obtained. Examples of chelating agents include ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA), which can be used at concentrations of 1 mM to 20 mM. As a buffer, sodium phosphate, sodium borate, sodium acetate solution, etc. Specifically, by reacting the antibody with TCEP at 4°C to 37°C for 1 to 24 hours, an antibody (1e) having partially or completely reduced sulfhydryl groups can be obtained.

[0361] Here, a reaction is carried out to add a sulfhydryl group to the drug linker portion, thereby allowing the drug linker portion to be bonded via a thioether bond.

[0362] An antibody-drug conjugate (IVa) can be produced in which 2 to 8 drug molecules are bound to each antibody by using 2 to 20 molar equivalents of compound (9d) per mole of antibody (1e) containing a sulfhydryl group. Specifically, the reaction is carried out by adding a solution in which compound (VIb) is dissolved to a buffer containing antibody (1e) containing a sulfhydryl group. Here, sodium acetate solution, sodium phosphate solution, sodium borate solution, etc. can be used as the buffer. The pH during the reaction is 5 to 9, more preferably around pH 7. Organic solvents such as DMSO, DMF, DMA, N-methyl-2-pyrrolidone (NMP), acetone, and propylene glycol (PG) can be used as the solvent to dissolve compound (VIb).

[0363] The compound (VIb) is dissolved in a solution and then reacted by adding 0.5 to 50% v / v of the solution to a buffer containing the sulfhydryl antibody (1e). The reaction temperature is 4°C to 37°C, more preferably 10°C to 25°C, and the reaction time is 30 minutes to 2 hours. If necessary, the reaction can be terminated by deactivating the reactivity of unreacted compound (VIb) with a thiol-containing reagent. Examples of thiol-containing reagents include cysteine ​​or N-acetyl-L-cysteine ​​(NAC). More specifically, the reaction can be terminated by adding 1 to 2 molar equivalents of NAC to compound (VIb) and incubating at room temperature for 10 to 30 minutes.

[0364] The manufactured antibody-drug conjugates (IVa) can be identified by the following common procedures: concentration, buffer exchange, purification, measurement of antibody concentration and average number of drug conjugates per antibody molecule.

[0365] Common Procedure A: Concentration of Antibody Aqueous Solution The antibody or antibody-drug conjugate solution is placed in an Amicon® Ultra centrifugal filter device (30,000 or 50,000 NMWL, Merck Millipore Ltd.), and the antibody and antibody-drug conjugate solution are concentrated by centrifugation (2000G to 4000G for 5 minutes to 1 hour) using an Allegra X-15R centrifuge (Beckman Coulter, Inc.).

[0366] Common Procedure B: Antibody Concentration Measurement Using a UV meter (Nanodrop 1000, Thermo Fisher Scientific, Inc. or DS-11 DeNovix, Inc.), measure the antibody concentration according to the manufacturer's specified method. At that time, use the 280nm extinction coefficient (1.3 mL mg) which differs for each antibody. -1 cm -1 From 1.8 mL mg -1 cm -1 Use ).

[0367] Common Procedure C: Antibody Buffer Exchange NAP columns using Sephadex G-25 support (NAP-5, NAP-10, NAP-25 (Cytiva)) are equilibrated with phosphate buffer (PBS, 5mM EDTA solution (NACALAI TESQUE, INC.)) containing sodium chloride (137mM) and ethylenediaminetetraacetic acid (EDTA, 5mM) according to the manufacturer's instructions. 2.5 mL of antibody aqueous solution is placed on each NAP-25 column, and then eluted with 3.5 mL of PBS, 5mM EDTA solution (NACALAI TESQUE, INC.). The resulting fraction (3.5 mL) is collected. This fraction is concentrated using Common Procedure A, and the antibody concentration is measured using Common Procedure B. Finally, the antibody concentration is adjusted to approximately 10 mg / mL using PBS, 5mM EDTA solution (NACALAI TESQUE, INC.).

[0368] Common Procedure D: Purification of Antibody-Drug Conjugate (Gel Filtration Chromatography) Equilibrate an NAP column (NAP-5, NAP-10, NAP-25 (Cytiva)) with acetate buffer (10 mM Acetate Buffer, 5% Sorbitol, pH 5.5; referred to herein as ABS) or another suitable buffer. Charge the NAP column with the antibody-drug conjugate reaction solution, allow the manufacturer's specified amount of buffer to flow by gravity, and separate the antibody fraction. Charge this fraction back into the NAP column, allow the manufacturer's specified amount of buffer to flow by gravity, and separate the antibody fraction. Repeat this procedure a total of two to three times to obtain an antibody-drug conjugate free of unbound drug linkers, DMSO, propylene glycol, NAC, and TCEP. Adjust the concentration of the antibody-drug conjugate solution as needed using Common Procedures A and C.

[0369] Common Procedure E: Measurement of antibody concentration and average number of drug molecules bound per antibody molecule in antibody-drug conjugates (UV method) The concentration of bound drug in an antibody-drug conjugate can be calculated by first measuring the absorbance of the antibody-drug conjugate aqueous solution at two wavelengths, 280 nm and 260 nm, 320 nm, or 250 nm (other wavelengths may also be used) using an absorbance spectrometer (UV / VIS Spectrometer Lambda 25 or Lambda 465, PerkinElmer, Inc.), and then performing the following calculation when using 280 nm and 260 nm. Since the total absorbance at a given wavelength is equal to the sum of the absorbances of all absorbing chemical species present in the system (additive properties of absorbance), assuming that there is no change in the molar extinction coefficients of the antibody and drug before and after conjugation, the antibody concentration and drug concentration in the antibody-drug conjugate aqueous solution are given by the following relational equation.

[0370]

[0371] Here, A 280 This shows the absorbance of the antibody-drug conjugate aqueous solution at 280 nm, A 260 This shows the absorbance of the antibody-drug conjugate aqueous solution at 260 nm, AA , 280 This shows the absorbance of the antibody at 280 nm, A A , 260 This shows the absorbance of the antibody at 260 nm, A D , 280 This shows the absorbance of the conjugate precursor at 280 nm, A D , 260 This shows the absorbance of the conjugate precursor at 260 nm, and ε A , 280 This indicates the molar extinction coefficient of the antibody at 280 nm, and ε A , 260 This indicates the molar extinction coefficient of the antibody at 260 nm, and ε D , 280 This shows the molar extinction coefficient of the conjugate precursor at 280 nm, and ε D , 260 This shows the molar extinction coefficient of the conjugate precursor at 260 nm, and C A C indicates the antibody concentration in the antibody-drug conjugate. D Here, ε represents the drug concentration in the antibody-drug conjugate. A , 280 , ε A , 260 , ε D , 280 , ε D , 260 For this, a pre-prepared value (calculated estimate or measured value) is used. For example, ε A , 280 This can be estimated from the amino acid sequence of the antibody using a known calculation method (Protein Science, 1995, vol. 4, 2411-2423). ε A , 260 This is the measured value obtained from UV measurement of the antibody and ε A , 280 The value calculated from the estimated value is used. In the example, when 260 nm was used, the molar extinction coefficient of anti-CDH6 antibody 1 is ε A , 280 = 220400 and ε A , 260 = Use 116812. The molar extinction coefficient of anti-CDH6 antibody 2 is ε A ,280 = 223400 and ε A , 260 = 118290 is used. The molar absorption coefficient of anti-B7-H3 antibody 1 is ε A , 280 = 235300 and ε A , 260 = 121580 is used. The molar absorption coefficient of anti-B7-H3 antibody 2 is ε A , 280 = 235320 and ε A , 260 = 115004 is used. The molar absorption coefficient of anti-B7-H3 antibody 3 is ε A , 280 = 235070 is used. The molar absorption coefficient of anti-B7-H3 antibody 4 is ε A , 280 = 235070 is used. The molar absorption coefficient of anti-CD30 antibody is ε A , 280 = 234400 and ε A , 260 = 122662 is used. The molar absorption coefficient of anti-CD70 antibody is ε A , 280 = 226380 and ε A , 260 = 118487 is used. ε D , 280 and ε D , 260 and ε can be obtained by measuring the absorbance of a solution in which the conjugate precursor to be used is dissolved at a certain molar concentration and applying Lambert-Beer's law (absorbance = molar concentration × molar absorption coefficient × cell optical path length). The molar absorption coefficient of the conjugate precursor in the examples is obtained by UV measurement each time. In the case of cysteine conjugation, the measured value of the compound obtained by reacting each drug linker with mercaptoethanol or N-acetylcysteine to convert the maleimide group to a succinimide thioether is used. Measure A 280 and A 260 of the antibody-drug conjugate aqueous solution, substitute these values into equations (1) and (2), and solve the simultaneous equations to obtain C A and C D . Furthermore, C D ABy dividing by this, the average number of drug-bound molecules per antibody can be determined.

[0372] Common procedure F: Measurement of antibody concentration and average number of drug molecules bound per antibody molecule in antibody-drug conjugates (reverse-phase high-performance liquid chromatography: RP-HPLC) The antibody concentration and average number of drug molecules bound per antibody molecule in antibody-drug conjugates can be determined by high-performance liquid chromatography analysis using the following method, in addition to the common procedure E described above.

[0373] [F-1. Preparation of Sample for HPLC Analysis (Reduction of Antibody-Drug Conjugate)] Mix antibody-drug conjugate solution (approximately 1 mg / mL, 60 μL) with dithiothreitol (DTT) aqueous solution (100 mM, 15 μL). Incubate the mixture at 37°C for 30 minutes to cleave the disulfide bond between the L and H chains of the antibody-drug conjugate. Use this reaction solution directly for HPLC analysis.

[0374] [F-2. HPLC Analysis] Typical analytical conditions are as follows: HPLC system: Agilent 1290 HPLC system (Agilent Technologies) Detector: UV absorbance meter (measurement wavelength: 280 nm) Column: Acquity BEH Phenyl (2.1 × 50 mm, 1.7 μm, Waters) Column temperature: 75°C Flow rate: 0.8 mL / min Sample injection volume: 10 μL Mobile phase A: 0.1% trifluoroacetic acid (TFA), 15% isopropyl alcohol aqueous solution Mobile phase B: 0.075% TFA, 15% isopropyl alcohol acetonitrile solution Gradient program (Mobile phase B): 14%–36% (0 min–15 min), 36%–80% (15 min–17 min), 80%–14% (17 min–17.1 min), 14%–14% (17.1 min–23 min)

[0375] [F-3. Data Analysis] [F-3-1] Compared to the light chain (L0) and heavy chain (H0) of an antibody that is not bound to a drug, the light chain (L1) and heavy chain (H3) bound to a drug (L1) and heavy chain (H1), which are bound to a drug (H2), which are bound to two drug molecules (H1), which are bound to three drug molecules (H3), become more hydrophobic and retain longer in proportion to the number of bound drug molecules. Therefore, in principle, they are eluted in the order of L0, L1, H0, H1, H2, and H3.

[0376] [F-3-2] Because drug linkers have UV absorption, the peak area is corrected according to the following formula using the molar extinction coefficients of the L chain, H chain, and drug linkers, depending on the number of drug linkers.

[0377]

[0378]

[0379] Here, the molar extinction coefficients (280 nm) of the light chain and heavy chain for each antibody are estimated values ​​calculated using the known calculation method described in Common Operation E. For anti-CDH6 antibody 1, 31710 is used as the molar extinction coefficient of the light chain and 78500 as the molar extinction coefficient of the heavy chain. For anti-CDH6 antibody 2, 31712 is used as the molar extinction coefficient of the light chain and 79988 as the molar extinction coefficient of the heavy chain. For anti-B7-H3 antibody 1, 30220 is used as the molar extinction coefficient of the light chain and 87440 as the molar extinction coefficient of the heavy chain. For anti-B7-H3 antibody 2, 30222 is used as the molar extinction coefficient of the light chain and 87438 as the molar extinction coefficient of the heavy chain. For anti-B7-H3 antibody 3, 30160 is used as the molar extinction coefficient of the light chain and 87375 as the molar extinction coefficient of the heavy chain. For anti-B7-H3 antibody 4, 30160 is used as the molar extinction coefficient of the light chain and 87375 as the molar extinction coefficient of the heavy chain. For anti-CD30 antibody, 30222 is used as the molar extinction coefficient of the light chain and 86978 as the molar extinction coefficient of the heavy chain. For anti-CD70 antibody, 30222 is used as the molar extinction coefficient of the light chain and 82968 as the molar extinction coefficient of the heavy chain. For cysteine ​​conjugation, the molar extinction coefficient (280 nm) of the drug linker is measured using the measured value of the compound obtained by reacting each drug linker with mercaptoethanol or N-acetylcysteine ​​and converting the maleimide group to succinimidothioether.

[0380] [F-3-3] Calculate the ratio (%) of each chain's peak area to the sum of the peak area correction values ​​according to the following formula.

[0381]

[0382] [F-3-4] The average number of drug bindings per antibody molecule in an antibody-drug conjugate (drug-antibody binding ratio: DAR) is calculated according to the following formula.

[0383]

[0384] [F-3-5] The antibody concentration in the antibody-drug conjugate is calculated according to the following formula.

[0385]

[0386] Here, the absorbance (280 nm) of the antibody-drug conjugate is measured using the actual value of the antibody-drug conjugate aqueous solution. The dilution factor indicates how many times the antibody-drug conjugate aqueous solution was diluted when measuring the absorbance, and is usually 4-fold. The molar extinction coefficient (280 nm) of the antibody is an estimated value calculated using the known calculation method described in Common Operation E. The average number of drug conjugates is the value obtained in [F-3-4]. For cysteine ​​conjugation, the molar extinction coefficient (280 nm) of the drug linker is measured using the actual value of the compound obtained by reacting each drug linker with mercaptoethanol or N-acetylcysteine ​​and converting the maleimide group to succinimidothioether.

[0387] Common Operation G: Measurement of antibody concentration and average number of drug bounds per antibody molecule in antibody-drug conjugates (hydrophobic interaction - high-performance liquid chromatography: HI-HPLC) The antibody concentration and average number of drug bounds per antibody molecule in antibody-drug conjugates can be determined by high-performance liquid chromatography analysis using the following method, in addition to the common operations E and F described above.

[0388] [G-1. Preparation of Sample for HPLC Analysis] The antibody-drug conjugate solution (approximately 1 mg / mL, 60 μL) is used directly for HPLC analysis.

[0389] [G-2. HPLC Analysis] Typical analytical conditions are as follows: HPLC system: SHIMADZU CBM-20A (Shimadzu Corporation) Detector: UV absorbance meter (measurement wavelength: 280 nm) Column: TSK-gel Butyl-NPR (4.6 × 100 mm, 2.5 μm, manufactured by TOSOH) Column temperature: Constant temperature around 30°C Mobile phase A: 25 mM phosphate buffer containing 1.5 M ammonium sulfate (pH = 7.0) Mobile phase B: 25 mM phosphate buffer (pH = 7.0) / isopropyl alcohol mixture (3:1) Flow rate: 0.8 mL / min Sample injection volume: 10 μL Gradient program (mobile phase B): 15%–15% (0 min–5 min), 15%–100% (5 min–20 min)

[0390] [G-3. Data Analysis] [G-3-1] Since hydrophobicity increases in proportion to the number of drugs bound to the antibody, and retention time increases, in principle, the antibodies, ADCs with 2 drug bindings per antibody, ADCs with 4 drug bindings per antibody, ADCs with 6 drug bindings per antibody, and ADCs with 8 drug bindings per antibody are eluted in that order. By comparing the retention time with that of the antibody, the detection peaks can be assigned to ADCs with 2 drug bindings per antibody, ADCs with 4 drug bindings per antibody, ADCs with 6 drug bindings per antibody, and ADCs with 8 drug bindings per antibody. Depending on the type of antibody and drug linker, peaks may also be detected for ADCs with 1 drug binding per antibody, ADCs with 3 drug bindings per antibody, ADCs with 5 drug bindings per antibody, and ADCs with 7 drug bindings per antibody. The number of drugs bound to each antibody in the detected peak can sometimes be estimated by fractionating the peak using HI-HPLC and then measuring the mass spectrum.

[0391] [G-3-2] Because drug linkers have UV absorption, the peak area value is corrected according to the following formula using the molar extinction coefficients of the antibody and drug linkers, depending on the number of drug linkers bound.

[0392]

[0393] Here, the molar extinction coefficient (280 nm) of the antibody is the estimated value calculated using the known calculation method described in Common Operation E. The molar extinction coefficient (280 nm) of the drug linker is the measured value of the conjugate precursor. In the case of cysteine ​​conjugation, the measured value of the compound obtained by reacting each drug linker with mercaptoethanol or N-acetylcysteine ​​and converting the maleimide group to succinimidothioether is used.

[0394] [G-3-3] Calculate the ratio (%) of antibody peak area to the total peak area correction value according to the following formula.

[0395]

[0396] [G-3-4] The average number of drug conjugates per antibody molecule in an antibody-drug conjugate is calculated according to the following formula.

[0397]

[0398] [G-3-5] The antibody concentration in the antibody-drug conjugate is calculated according to the formula described in [F-3-5]. In this calculation, the average number of drug conjugates is the value obtained in [G-3-4].

[0399] The present invention will be described in detail by the following embodiments, but will not be limited thereto.

[0400] Nuclear magnetic resonance spectrum (hereinafter, 1 For 1H-NMR (resonance frequency 400 MHz or 500 MHz), tetramethylsilane was used as the standard substance, or the chemical shift value of the deuterated solvent used was used as the reference value, and the chemical shift value was expressed as a δ value (ppm).

[0401] The following abbreviations may also be used: Boc: tert-butoxycarbonyl Bn: benzyl DMA: N,N-dimethylacetamide DMSO: dimethyl sulfoxide DMF: N,N-dimethylformamide FMOC: 9-fluorenylmethyloxycarbonyl THF: tetrahydrofuran CDCl3: deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide CD3OD: deuterated methanol 1H-NMR: Proton nuclear magnetic resonance s: singlet d: doublet dd: doublet of doublets t: triplet q: quartet m: multiplet br: broad J: coupling constant Hz: Hertz CDI: 1,1'-carbonyldiimidazole HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate EDC・HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride TCEP: tris(2-carboxyethyl)phosphine hydrochloride NAC: N-acetylcysteine ​​DVB: divinylbenzene ESI: electrospray ionization

[0402] Unless otherwise specified, the reagents, solvents, and equipment used in the following examples are commercially available. Furthermore, unless otherwise specified, the starting compounds are known compounds, commercially available, or synthesized and identified according to known or equivalent methods. Unless otherwise specified, the PBS, 5mM EDTA solution used was from NACALAI TESQUE, INC. Unless otherwise specified, the tris(2-carboxyethyl)phosphine hydrochloride (TCEP) used was from Tokyo Chemical Industry Co., Ltd. Unless otherwise specified, the N-acetylcysteine ​​(NAC) and 1M dipotassium hydrogen phosphate aqueous solution used were from Sigma-Aldrich Co. LLC.

[0403] Example 1: Synthesis of dispirodiketopiperazine (compound (VIII-1) and compound (VIII-2))

[0404]

[0405] (Step 1): tert-butyl (3-cyano-3-{[(3-fluoro-4-methoxyphenyl)methyl]amino}cyclobutyl)carbamate

[0406] 2.0 g of tert-butyl (3-oxocyclobutyl)carbamate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was dissolved in 20 mL of methanol, and 1.51 mL of 1-(3-fluoro-4-methoxyphenyl)methaneamine (Angene International Limited) was added. Then, 3.09 mL of acetic acid was added, and the mixture was stirred at room temperature for 10 minutes. After that, 0.72 g of potassium cyanide was added to the reaction mixture at room temperature, and the mixture was stirred at 60°C for 21 hours. After concentrating the reaction mixture under reduced pressure, water was added to the residue and the mixture was stirred. The precipitated solid was filtered, washed with water, and the resulting solid was dried under reduced pressure to obtain the title compound (3.66 g). 1 H-NMR(CDCl3)δ:7.19-6.89(3H,m),4.56-4.25(1H,m),3.91(3H,s),3.80-3.74(2H,m),2.9 9-2.90(1H,m),2.64-2.54(1H,m),2.45-2.35(1H,m),2.15-2.04(1H,m),1.50-1.42(9H,m).

[0407] (Step 2): tert-butyl (3-carbamoyl-3-{[(3-fluoro-4-methoxyphenyl)methyl]amino}cyclobutyl)carbamate

[0408] The compound obtained in step 1 above (3.66 g) was dissolved in DMSO (20 mL), hydrogen peroxide solution (34.5%, 1.73 mL) was added, and then potassium carbonate (4.36 g) was added under ice cooling. After raising the temperature to room temperature, the mixture was stirred for 20 hours. Water was slowly added to the reaction mixture, the solid was filtered off, and the title compound (3.69 g) was obtained by drying under reduced pressure. 1 H-NMR(DMSO-d6)δ:7.30-6.89(5H,m),4.12-3.75(1H,m),3.81(3H,s),3.42-3.34( 2H,m),2.62-2.53(1H,m),2.17-2.04(2H,m),1.93-1.82(1H,m),1.38-1.35(9H,m).

[0409] (Step 3): 3-[(tert-butoxycarbonyl)amino]-1-{[(3-fluoro-4-methoxyphenyl)methyl]amino}cyclobutane-1-carboxylic acid

[0410] The compound (3.69 g) obtained in the above step 2 was suspended in ethanol (100 mL), an aqueous potassium hydroxide solution (8 mol / L, 5.02 mL) was added, and the mixture was stirred at 80 °C for 11 hours. After the reaction solution was concentrated under reduced pressure, the residue was diluted with water, hydrochloric acid (2 mol / L, 20.6 mL) was added under ice-cooling, the precipitated solid was collected by filtration and washed with water. The obtained solid was dried under reduced pressure to obtain the title compound (1.81 g). 1 1H-NMR (DMSO-d6) δ: 7.33 - 7.08 (3H, m), 4.23 - 3.92 (1H, m), 3.83 (1.25H, s), 3.82 (1.75H, s), 3.78 - 3.73 (0.83H, m), 3.69 - 3.62 (1.17H, m), 2.63 - 2.44 (1H, m), 2.37 - 2.09 (3H, m), 1.39 - 1.33 (9H, m).

[0411] (Step 4): tert-Butyl {10,10-difluoro-5-[(3-fluoro-4-methoxyphenyl)methyl]-6,14-dioxo-5,13-diazadispiro[3.2.5 7 .2 4 [tetradecane-2-yl]}carbamate

[0412] ​4,4-difluoro-1-(2,2,2-trifluoroacetamide)cyclohexane-1-carboxylic acid (896 mg), synthesized according to the method described in International Publication No. 2020 / 246487, was suspended in dichloromethane (20 mL), oxalyl chloride (0.303 mL) and DMF (0.1 mL) were added, and the mixture was stirred at room temperature for 2 hours. After removing the solvent under reduced pressure, the mixture was dried under reduced pressure using a vacuum pump to obtain the corresponding acid chloride. The compound obtained in step 3 (1.00 g) was placed in another round-bottom flask, and N,N-diisopropylethylamine (0.929 mL) dissolved in DMF (20 mL) was added. Then, the solution of the previously obtained acid chloride in DMF (10 mL) was added dropwise under ice cooling, and the mixture was stirred overnight at room temperature. CDI (1.32 g) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 5 minutes, followed by stirring at 80°C for 2 hours. After adding saturated ammonium chloride aqueous solution and water to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (786 mg). MS(ESI)m / z:512(M+H) + ; 1 H-NMR(CDCl3)δ:8.46-8.32(0.5H,br s),8.29-8.16(0.5H,br s),7.02-6.88(3H,m),5.69-5.58(1H,m),5.18-4.74(2H,m),4.45-4.29(0.5H,m),3.99-3.84(0.5H,m),3 .90(1.5H,s),3.89(1.5H,s),3.15-2.61(4H,m),2.47-2.10(6H,m),1.90-1.77(2H,m),1.51-1.41(9H,m).

[0413] (Step 5): 2-amino-10,10-difluoro-5-[(3-fluoro-4-methoxyphenyl)methyl]-5,13-diazadispiro[3.2.5 7 .2 4 Tetradecane-6,14-dione monohydrochloride

[0414] The compound obtained in step 4 above (786 mg) was dissolved in dichloromethane (10 mL), and hydrogen chloride / 1,4-dioxane solution (4 mol / L, 5 mL) was added under ice cooling. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was suspended in ethyl ether, filtered, washed with ethyl ether, and dried under reduced pressure to obtain the title compound (664 mg). MS(ESI)m / z:412(M+H) + .

[0415] (Step 6): (2s,4s)-10,10-difluoro-5-[(3-fluoro-4-methoxyphenyl)methyl]-2-(4-methoxyanilino)-5,13-diazadispiro[3.2.5 7 .2 4 ]Tetradecane-6,14-dione (compound (VIII-1)), (2r,4r)-10,10-difluoro-5-[(3-fluoro-4-methoxyphenyl)methyl]-2-(4-methoxyanilino)-5,13-diazadispiro[3.2.5 7 .2 4 Tetradecane-6,14-dione (compound (VIII-2))

[0416] The compound obtained in step 5 above (100 mg), 1-bromo-4-methoxybenzene (56 μL), dicyclohexyl[3,6-dimethoxy-2',4',6'-tri(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane (10.8 mg), tris(dibenzylideneacetone)dipalladium (8.2 mg), and sodium tert-butoxide (42.9 mg) were mixed with 1,4-dioxane (1 mL), and the mixture was stirred at 100°C for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by aminosilica gel column chromatography (hexane / ethyl acetate), and the resulting compounds were purified by chiral preparative chromatography (CHIRALPAK IA (registered trademark; manufactured by Daicel Corporation), ethanol / hexane) to obtain compound (VIII-1) (30.1 mg) and compound (VIII-2) (14.7 mg).

[0417] Compound (VIII-1) MS(ESI)m / z:518(M+H) + ; 1 H-NMR(CDCl3)δ:8.96-8.86(1H,br s),6.97-6.89(3H,m),6.83-6.77(2H,m),6.57-6.51(2H,m),4.93-4.83(2H,m),4.05-3.93 (1H,m),3.89(3H,s),3.77(3H,s),3.16-3.05(2H,m),2.51-2.19(8H,m),1.93-1.81(2H,m).

[0418] Compound (VIII-2) MS(ESI)m / z:518(M+H) + ; 1 H-NMR(CDCl3)δ:8.58-8.49(1H,br s),7.02-6.92(3H,m),6.82-6.75(2H,m),6.55-6.47(2H,m),4.90-4.83(2H,m),4.18-4.03(1H,m),3 .91(3H,s),3.75(3H,s),2.94-2.85(2H,m),2.77-2.68(2H,m),2.47-2.17(6H,m),1.88-1.78(2H,m).

[0419] Example 2: Synthesis of dispirodiketopiperazine (compound (VIII-3) and compound (VIII-4))

[0420]

[0421] (Step 1): (2s,4s)-10,10-difluoro-2-(2-fluoro-4-methoxyanilino)-5-[(3-fluoro-4-methoxyphenyl)methyl]-5,13-diazadispiro[3.2.5 7 .2 4 ]Tetradecane-6,14-dione (compound (VIII-3)), (2r,4r)-10,10-difluoro-2-(2-fluoro-4-methoxyanilino)-5-[(3-fluoro-4-methoxyphenyl)methyl]-5,13-diazadispiro[3.2.5 7 .2 4 Tetradecane-6,14-dione (compound (VIII-4))

[0422] The compound obtained in step 5 of Example 1 (100 mg), 1-bromo-2-fluoro-4-methoxybenzene (91.6 mg), dicyclohexyl[3,6-dimethoxy-2',4',6'-tri(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane (21.6 mg), tris(dibenzy...

Claims

1. Formula (I): [wherein, m 1 represents an integer from 1 to 20; Li represents a ligand; L represents a linker connecting Li and D; and D represents Formula (II): (wherein, the wavy line indicates the binding site with L, and n 1 , n 2 , n 3 , and n 4 each independently represents an integer from 1 to 3, -X- represents -O-, -NH-, -S-, or -CH2-, -Y- represents -O-, -C(R 3 )(R 4 )-, or -N(R 5 )-, R 1 represents phenyl, 6-membered heteroaryl containing 1 or 2 nitrogen atoms as ring-constituting atoms, C 3-6 cycloalkyl, or C 5-8 bicycloalkyl (wherein, the phenyl, 6-membered heteroaryl, C 3-6 cycloalkyl, and C 5-8 bicycloalkyl may each independently have 1 to 3 substituents selected from Substituent Group 1), R 2 represents phenyl, 6-membered heteroaryl containing 1 or 2 nitrogen atoms as ring-constituting atoms, or 9- or 10-membered bicyclic heteroaryl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring-constituting atoms (wherein, the phenyl, 6-membered heteroaryl, and 9- or 10-membered bicyclic heteroaryl may each independently have 1 to 3 substituents selected from Substituent Group 2), R 3 and R 4 each independently represent hydrogen, halogen, or ethynyl, or R 3 and R 4 are bonded to each other to form, together with the carbon atom to which they are bonded, a 3- to 6-membered aliphatic heterocyclic ring containing 1 or 2 nitrogen atoms as ring-constituting atoms, and R 5 represents hydrogen or C 1-6 This indicates alkyl. (Substituent group 1) Halogen, cyano, nitro, -NHC(=O)NH2, -NHC(=O)NHC(=O)NH2, -NHC(=O)-C 1-6 Alkyl, Carbamoyl, -C(=O)NH-C 1-6 Alkyl, -C(=O)NHOH, -C(=O)NHNH2, -C(=O)-C 1-6 Alkyl, carboxyl, -C(=O)OC 1-6 Alkyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -SC 1-6 Alkyl, -SC 3-6 Cycloalkyl, -S(=O)-C 1-6 Alkyl, -S(=O)-C 3-6 Cycloalkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)2-C 3-6 Cycloalkyl, C 1-6 Oxetanyl which may be alkyl-substituted, and 5-oxo-4H-1,2,4-oxadiazole-3-yl (in substituent group 1, the C 1-6 Alkyl and C 3-6 Cycloalkyls are, independently, halogen, hydroxyl, and -OC. 1-6 (May be further substituted with one or more groups selected from the group consisting of alkyl groups) (Substituent group 2) Halogen, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl (In substituent group 2, the C 1-6 Alkyl and C 3-6 Compounds represented by [the cycloalkyl group, which may each be independently further substituted with one or more halogens] or pharmaceutically acceptable salts thereof, or solvates thereof.

2. m 1 However, n is an integer from 1 to 12. 1 , n 2 , n 3 , and n 4 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein each is independently 1 or 2, -X- is -O- or -NH-, and -Y- is -CF2- or -O-.

3. m 1 However, n is an integer from 1 to 10. 1 and n 2 However, both are 1, n 3 and n 4 However, both are 2, -X- is -O- or -NH-, -Y- is -CF2- or -O-, R 1 However, phenyl, a 6-membered heteroaryl containing one or two nitrogen atoms as ring constituent atoms, C 3-6 Cycloalkyl, or C 5-8 Bicycloalkyl (wherein the phenyl, 6-membered heteroaryl, C 3-6 Cycloalkyl, and C 5-8 Each bicycloalkyl group may independently have one or two substituents selected from substituent group 1', and R 2 However, the substituent is phenyl (wherein the phenyl substituent may have one or two substituents selected from substituent group 2'), or 3,4-methylenedioxyphenyl (substituent group 1') halogen, cyano, nitro, -NHC(=O)NH2, -NHC(=O)NHC(=O)NH2, -NHC(=O)-C 1-6 Alkyl, Carbamoyl, -C(=O)NH-C 1-6 Alkyl, -C(=O)NHOH, -C(=O)NHNH2, -C(=O)-C 1-6 Alkyl, carboxyl, -C(=O)OC 1-6 Alkyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -SC 1-6 Alkyl, -S(=O)-C 1-6 Alkyl, C 1-6 Oxetanyl which may be alkyl-substituted, and 5-oxo-4H-1,2,4-oxadiazole-3-yl (in substituent group 1', the C 1-6 Alkyl and C 3-6 Cycloalkyls are, independently, halogen, hydroxyl, and -OC. 1-6 (May be further substituted with one or more groups selected from the group consisting of alkyl groups) (Substituent group 2') Halogen, -OC 1-6 Alkyl and C 3-6 Cycloalkyl (in substituent group 2', the C 1-6 Alkyl and C 3-6 The cycloalkyl group may be independently further substituted with one or more halogens), the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

4. m 1 However, n is an integer from 1 to 10. 1 and n 2 However, both are 1, n 3 and n 4 However, both are 2, -X- is -O-, -Y- is -CF2-, R 1 However, cyano, carbamoyl, -C(=O)-C 1-6 Alkyl, -SC 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 A phenyl which may have one or two substituents selected from the group consisting of cycloalkyls, and R 2 However, halogens and -OC 1-6 A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a phenyl having one or two substituents selected from the group consisting of alkyl groups.

5. D is a group represented by formula (III): (In the formula, the wavy line indicates the bonding site with L, and R 1a represents cyano or carbamoyl, R 1b represents -C(=O)-C 1-3 alkyl, -S-C 1-3 alkyl, -O-C 1-3 alkyl, or C 3-4 cycloalkyl, R 2a represents halogen, and R 2b represents -O-C 1-3 alkyl), the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or a solvate thereof.

6. D is equation (III-1), equation (III-2), or equation (III-3): A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a group represented by any one of the following (wherein the formula, the wavy line indicates the bonding site with L).

7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Li is Ab (wherein Ab represents an antibody or an antigen-binding fragment thereof).

8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or antigen-binding fragment thereof is an antibody or antigen-binding fragment thereof that targets tumor cells.

9. The compound according to claim 7 or 8, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or its antigen-binding fragment is an anti-B7-H3 antibody, an anti-CDH6 antibody, an anti-CD30 antibody, or an anti-CD70 antibody, or an antigen-binding fragment thereof.

10. The antibody or its antigen-binding fragment is: (1) an anti-CDH6 antibody or its antigen-binding fragment containing the amino acid sequence CDRH1 represented by SEQ ID NO: 3, the amino acid sequence CDRH2 represented by SEQ ID NO: 4, the amino acid sequence CDRH3 represented by SEQ ID NO: 5, the amino acid sequence CDRL1 represented by SEQ ID NO: 8, the amino acid sequence CDRL2 represented by DAN, and the amino acid sequence CDRL3 represented by SEQ ID NO: 9; (2) an anti-CDH6 antibody or its antigen-binding fragment containing the amino acid sequence CDRH1 represented by SEQ ID NO: 12, the amino acid sequence CDRH2 represented by SEQ ID NO: 13, the amino acid sequence CDRH3 represented by SEQ ID NO: 14, the amino acid sequence CDRL1 represented by SEQ ID NO: 17, the amino acid sequence CDRL2 represented by DAN, and the amino acid sequence CDRL3 represented by SEQ ID NO: 18; (3) (4) An anti-B7-H3 antibody or its antigen-binding fragment containing the amino acid sequence CDRH1 represented by SEQ ID NO: 21, the amino acid sequence CDRH2 represented by SEQ ID NO: 22, the amino acid sequence CDRH3 represented by SEQ ID NO: 23, the amino acid sequence CDRL1 represented by SEQ ID NO: 26, the amino acid sequence CDRL2 represented by ATS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 27; (5) An anti-B7-H3 antibody or its antigen-binding fragment containing the amino acid sequence CDRH1 represented by SEQ ID NO: 30, the amino acid sequence CDRH2 represented by SEQ ID NO: 31, the amino acid sequence CDRH3 represented by SEQ ID NO: 32, the amino acid sequence CDRL1 represented by SEQ ID NO: 35, the amino acid sequence CDRL2 represented by ATS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 36; (6) An anti-CD30 antibody or its antigen-binding fragment containing the amino acid sequence CDRH1 represented by SEQ ID NO: 39, CDRH2 represented by SEQ ID NO: 40, CDRH3 represented by SEQ ID NO: 41, CDRL1 represented by SEQ ID NO: 44, CDRL2 represented by AAS, and CDRL3 represented by SEQ ID NO: 45.(6) an anti-CD70 antibody or its antigen-binding fragment containing the amino acid sequence CDRH1 represented by SEQ ID NO: 48, the amino acid sequence CDRH2 represented by SEQ ID NO: 49, the amino acid sequence CDRH3 represented by SEQ ID NO: 50, the amino acid sequence CDRL1 represented by SEQ ID NO: 53, the amino acid sequence CDRL2 represented by LAS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 54; (7) an anti-B7-H3 antibody or its antigen-binding fragment containing the amino acid sequence CDRH1 represented by SEQ ID NO: 57, the amino acid sequence CDRH2 represented by SEQ ID NO: 58, the amino acid sequence CDRH3 represented by SEQ ID NO: 59, the amino acid sequence CDRL1 represented by SEQ ID NO: 62, the amino acid sequence CDRL2 represented by ATS, and the amino acid sequence CDRL3 represented by SEQ ID NO: 63; or (8) A compound according to any one of claims 7 to 9, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is an anti-B7-H3 antibody or antigen-binding fragment thereof comprising the amino acid sequence CDRH1 represented by SEQ ID NO: 66, the amino acid sequence CDRH2 represented by SEQ ID NO: 67, the amino acid sequence CDRH3 represented by SEQ ID NO: 68, the amino acid sequence CDRL1 represented by SEQ ID NO: 71, the amino acid sequence CDRL2 represented by ATS, and the amino acid sequence CDRL3 represented by SEQ ID NO:

72.

11. An antibody or its antigen-binding fragment comprises: (1) a) the amino acid sequence represented by SEQ ID NO: 2, or a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added, and the amino acid sequence represented by SEQ ID NO: 7, or a light chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) an anti-CDH6 antibody or its antigen-binding fragment comprising a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 2, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 7; (2) a) the amino acid sequence represented by SEQ ID NO: 11, or a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added, and the amino acid sequence represented by SEQ ID NO: 16, or a light chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) (3) an anti-CDH6 antibody or its antigen-binding fragment, comprising a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 11, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 16; (4) a) an amino acid sequence represented by SEQ ID NO: 20, or a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; and an amino acid sequence represented by SEQ ID NO: 25, or a light chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added;(4) a) an anti-B7-H3 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 20, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 25; (5) a) an amino acid sequence represented by SEQ ID NO: 29, or a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added, and an amino acid sequence represented by SEQ ID NO: 34, or a light chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) an anti-B7-H3 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 29, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 34; (6) a) (6) an amino acid sequence represented by SEQ ID NO: 38, or a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added, and an amino acid sequence represented by SEQ ID NO: 43, or a light chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) an anti-CD30 antibody or antigen-binding fragment thereof containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 38, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 43; (6) a) an amino acid sequence represented by SEQ ID NO: 47, or a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added, and an amino acid sequence represented by SEQ ID NO: 52, or a light chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added;or b) an anti-CD70 antibody or its antigen-binding fragment containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 47, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 52, (7) a) an amino acid sequence represented by SEQ ID NO: 56, or a heavy chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added, and an amino acid sequence represented by SEQ ID NO: 61, or a light chain variable region of an amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) an anti-B7-H3 antibody or its antigen-binding fragment containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 56, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 61, or (8) a) A compound according to any one of claims 7 to 10, or a pharmaceutically acceptable salt thereof, or a solvate thereof, comprising an amino acid sequence represented by SEQ ID NO: 65, or a heavy chain variable region of said amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added, and an amino acid sequence represented by SEQ ID NO: 70, or a light chain variable region of said amino acid sequence in which one to several amino acids are substituted, deleted, inserted, or added; or b) an anti-B7-H3 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 65, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO:

70.

12. Antibodies or antigen-binding fragments thereof include: (1) an anti-CDH6 antibody or antigen-binding fragment thereof containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 2, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 7; (2) an anti-CDH6 antibody or antigen-binding fragment thereof containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 11, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 16; (3) an anti-B7-H3 antibody or antigen-binding fragment thereof containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 20, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 25; (4) (5) An anti-B7-H3 antibody or its antigen-binding fragment containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 29, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 34, (6) An anti-CD30 antibody or its antigen-binding fragment containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 38, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 43, (7) An anti-CD70 antibody or its antigen-binding fragment containing a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 47, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 52, (7) An anti-B7-H3 antibody or its antigen-binding fragment, comprising a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 56, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 61, or(8) An anti-B7-H3 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 65, and a light chain variable region of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 70, the compound according to any one of claims 7 to 11, a pharmaceutically acceptable salt thereof, or a solvate thereof.

13. The antibody or its antigen-binding fragment is: (1) an anti-CDH6 antibody or its antigen-binding fragment containing the heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 2 and the light chain variable region of the amino acid sequence represented by SEQ ID NO: 7; (2) an anti-CDH6 antibody or its antigen-binding fragment containing the heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 11 and the light chain variable region of the amino acid sequence represented by SEQ ID NO: 16; (3) an anti-B7-H3 antibody or its antigen-binding fragment containing the heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 20 and the light chain variable region of the amino acid sequence represented by SEQ ID NO: 25; (4) an anti-B7-H3 antibody or its antigen-binding fragment containing the heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 29 and the light chain variable region of the amino acid sequence represented by SEQ ID NO: 34; (5) an anti-CD30 antibody or its antigen-binding fragment containing the heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 38 and the light chain variable region of the amino acid sequence represented by SEQ ID NO: 43; (6) (7) an anti-CD70 antibody or antigen-binding fragment thereof comprising a heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 47 and a light chain variable region of the amino acid sequence represented by SEQ ID NO: 52; (8) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 56 and a light chain variable region of the amino acid sequence represented by SEQ ID NO: 61; or (9) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain variable region of the amino acid sequence represented by SEQ ID NO: 65 and a light chain variable region of the amino acid sequence represented by SEQ ID NO: 70; or a pharmaceutically acceptable salt thereof, or a solvate thereof.

14. Antibodies or antigen-binding fragments thereof include: (1) an anti-CDH6 antibody or antigen-binding fragment thereof containing a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 1, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 6; (2) an anti-CDH6 antibody or antigen-binding fragment thereof containing a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 10, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 15; (3) an anti-B7-H3 antibody or antigen-binding fragment thereof containing a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 19, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 24; (4) (5) An anti-B7-H3 antibody or its antigen-binding fragment containing a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 28, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 33, (6) An anti-CD30 antibody or its antigen-binding fragment containing a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 37, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 42, (7) An anti-CD70 antibody or its antigen-binding fragment containing a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 46, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 51, (8) An anti-B7-H3 antibody or antigen-binding fragment thereof, comprising a heavy chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 64, and a light chain of an amino acid sequence having 90% or more sequence identity with the amino acid sequence represented by SEQ ID NO: 69, or a compound according to any one of claims 7 to 13, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

15. Antibodies or antigen-binding fragments thereof include: (1) an anti-CDH6 antibody or antigen-binding fragment thereof containing a heavy chain of an amino acid sequence in which one or two amino acid residues are deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 1, and a light chain of an amino acid sequence represented by SEQ ID NO: 6; (2) an anti-CDH6 antibody or antigen-binding fragment thereof containing a heavy chain of an amino acid sequence in which one or two amino acid residues are deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 10, and a light chain of an amino acid sequence represented by SEQ ID NO: 15; (3) an anti-B7-H3 antibody or antigen-binding fragment thereof containing a heavy chain of an amino acid sequence in which one or two amino acid residues are deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 19, and a light chain of an amino acid sequence represented by SEQ ID NO: 24; (4) an anti-B7-H3 antibody or antigen-binding fragment thereof containing a heavy chain of an amino acid sequence in which one or two amino acid residues are deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 28, and a light chain of an amino acid sequence represented by SEQ ID NO: 33; (5) (6) an anti-CD30 antibody or antigen-binding fragment thereof, comprising a heavy chain of an amino acid sequence having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 37, and a light chain of the amino acid sequence represented by SEQ ID NO: 42; (7) an anti-CD70 antibody or antigen-binding fragment thereof, comprising a heavy chain of an amino acid sequence having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 46, and a light chain of the amino acid sequence represented by SEQ ID NO: 51; (8) an anti-B7-H3 antibody or antigen-binding fragment thereof, comprising a heavy chain of an amino acid sequence having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 55, and a light chain of the amino acid sequence represented by SEQ ID NO: 60; or (9) an anti-B7-H3 antibody or antigen-binding fragment thereof, comprising a heavy chain of an amino acid sequence having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 64, and a light chain of the amino acid sequence represented by SEQ ID NO:

69.

16. The antibody or its antigen-binding fragment is: (1) an anti-CDH6 antibody or its antigen-binding fragment containing the heavy chain of the amino acid sequence represented by SEQ ID NO: 1 and the light chain of the amino acid sequence represented by SEQ ID NO: 6; (2) an anti-CDH6 antibody or its antigen-binding fragment containing the heavy chain of the amino acid sequence represented by SEQ ID NO: 10 and the light chain of the amino acid sequence represented by SEQ ID NO: 15; (3) an anti-B7-H3 antibody or its antigen-binding fragment containing the heavy chain of the amino acid sequence represented by SEQ ID NO: 19 and the light chain of the amino acid sequence represented by SEQ ID NO: 24; (4) an anti-B7-H3 antibody or its antigen-binding fragment containing the heavy chain of the amino acid sequence represented by SEQ ID NO: 28 and the light chain of the amino acid sequence represented by SEQ ID NO: 33; (5) an anti-CD30 antibody or its antigen-binding fragment containing the heavy chain of the amino acid sequence represented by SEQ ID NO: 37 and the light chain of the amino acid sequence represented by SEQ ID NO: 42; (6) an anti-CD70 antibody or its antigen-binding fragment containing the heavy chain of the amino acid sequence represented by SEQ ID NO: 46 and the light chain of the amino acid sequence represented by SEQ ID NO:

51. (7) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence represented by SEQ ID NO: 55 and a light chain of the amino acid sequence represented by SEQ ID NO: 60, or (8) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence represented by SEQ ID NO: 64 and a light chain of the amino acid sequence represented by SEQ ID NO: 69, or a compound according to any one of claims 7 to 14, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

17. -L- is the formula: -Lb-La-Lp-NH-CH2- ＊ [In the formula, * indicates a binding site with D, -Lp- indicates a divalent group consisting of 1 to 10 amino acid residues, and -La- indicates a single bond or formula: -(CH2)n 5 -C(=O)- ＊ ', -C(=O)-(CH2)n 6 -C(=O)- ＊ ', -(CH2CH2O)n 5 -(CH2)n 6 -C(=O)- ＊ ', -(CH2)n 6 -C(=O)NH-(CH2CH2O)n 8 -(CH2)n 7 -C(=O)- ＊ ', and -(CH2)n 6 -C(=O)NH-(CH2)n 8 -(CH2)n 7 -C(=O)- ＊ ' (In the formula, * indicates the binding site with Lp, n 5 n represents an integer from 1 to 10. 6 and n 7 Each of these independently represents an integer from 1 to 5, and n 8 The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the linker is represented by [where is an integer from 0 to 5, and -Lb- represents a divalent group that links La and Li, a divalent group that links La and Ab amino acid residues, or a divalent group that links La and Ab sugar chains].

18. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein -Lp- is a divalent group consisting of 2 to 7 amino acid residues.

19. The compound according to claim 17 or 18, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the -Lp- amino acid residue is a natural amino acid residue.

20. The compound according to any one of claims 17 to 19, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein -Lp- is a divalent group consisting of an amino acid residue selected from glycine (G), alanine (A), phenylalanine (F), citrulline (Cit), and leucine (L).

21. -Lp- is the formula: -GGFG- ＊＊ ',-GGLCit- ＊＊ ',-GGACit- ＊＊ ',-GGGACit- ＊＊ ',-ACit- ＊＊ ', -GGGCit- ＊＊ ', and -CitGACit- ＊＊ A compound according to any one of claims 17 to 20, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is one divalent group selected from the group consisting of ' (wherein ** indicates a binding site with NH).

22. -La- is the formula: -(CH2)2-C(=O)- ＊ ',-(CH2)5-C(=O)- ＊ ', -C(=O)-(CH2)2-C(=O)- ＊ ', -(CH2CH2O)4-(CH2)2-C(=O)- ＊ ',-(CH2CH2O)8-(CH2)2-C(=O)- ＊ ', -(CH2)2-C(=O)NH-(CH2CH2O)2-(CH2)2-C(=O)- ＊ ', and -(CH2)2-C(=O)NH-(CH2)2-C(=O)- ＊ A compound according to any one of claims 17 to 21, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is one divalent group selected from the group consisting of ' (wherein * indicates a binding site with Lp).

23. -Lb- is given by equation (V-1): A compound according to any one of claims 17 to 22, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a divalent group represented by (wherein ** indicates a binding site with La, and the dashed line indicates a binding site with a sulfur atom of a cysteine ​​residue contained in Li or Ab).

24. -Lb- is given by equation (V-2) or equation (V-3): A compound according to any one of claims 17 to 22, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a divalent group represented by (wherein ** indicates a binding site with La, and the wavy line indicates a binding site with a sugar chain of Li or Ab).

25. -Lp- is the formula: -CitGACit- ＊＊ 'or -GGACit- ＊＊ The divalent group represented by ' (wherein ** indicates the binding site with NH), -La- is represented by the formula: -(CH2)5-C(=O)- ＊ ' (wherein * indicates the binding site with Lp) is a divalent group represented by -Lb-, and -Lb- is given by formula (V-1): The compound according to claim 17, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a divalent group represented by (wherein ** indicates a binding site with La, and the dashed line indicates a binding site with a sulfur atom of a cysteine ​​residue contained in Li or Ab).

26. A compound according to any one of claims 7 to 22 and 24, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein L is bonded to a sugar chain (N297 sugar chain) attached to Asn297 of Ab.

27. The compound according to claim 26, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the N297 glycan is N297-(Fuc)MSG1 or N297-(Fuc)SG.

28. The compound according to any one of claims 7 to 23 and 25, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein L is bound to one or more of the cysteine ​​residues at EU numbering 220 of the heavy chain, EU numbering 226 of the heavy chain, EU numbering 229 of the heavy chain, and EU numbering 214 of the light chain of Ab.

29. -LD is obtained from equation (XI-1) to (XI-6): A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is selected from the group consisting of groups represented by (wherein the formula, the dashed line indicates the binding site with the sulfur atom of a cysteine ​​residue contained in Li or Ab).

30. -LD is given by equation (XI-2): (In the formula, the wavy line indicates the binding site with the sulfur atom of a cysteine ​​residue contained in the antibody represented by Ab or its antigen-binding fragment) and m 1 The compound according to claim 7, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is an integer from 1 to 8.

31. The compound according to claim 30, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or antigen-binding fragment thereof is an antibody or antigen-binding fragment thereof that targets tumor cells.

32. The compound according to claim 30 or 31, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or its antigen-binding fragment is an anti-B7-H3 antibody or its antigen-binding fragment.

33. A compound according to any one of claims 30 to 32, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or antigen-binding fragment thereof is (1) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence represented by SEQ ID NO: 19 and a light chain of the amino acid sequence represented by SEQ ID NO: 24, or (2) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 19 and a light chain of the amino acid sequence represented by SEQ ID NO:

24.

34. A compound according to any one of claims 30 to 32, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or antigen-binding fragment thereof is (1) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence represented by SEQ ID NO: 28 and a light chain of the amino acid sequence represented by SEQ ID NO: 33, or (2) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 28 and a light chain of the amino acid sequence represented by SEQ ID NO:

33.

35. -LD is given by equation (XI-3): (In the formula, the wavy line indicates the binding site with the sulfur atom of a cysteine ​​residue contained in the antibody represented by Ab or its antigen-binding fragment) and m 1 The compound according to claim 7, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is an integer from 1 to 8.

36. The compound according to claim 35, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or antigen-binding fragment thereof is an antibody or antigen-binding fragment thereof that targets tumor cells.

37. The compound according to claim 35 or 36, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or its antigen-binding fragment is an anti-B7-H3 antibody or its antigen-binding fragment.

38. A compound according to any one of claims 35 to 37, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or antigen-binding fragment thereof is (1) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence represented by SEQ ID NO: 19 and a light chain of the amino acid sequence represented by SEQ ID NO: 24, or (2) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 19 and a light chain of the amino acid sequence represented by SEQ ID NO:

24.

39. A compound according to any one of claims 35 to 37, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or antigen-binding fragment thereof is (1) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence represented by SEQ ID NO: 28 and a light chain of the amino acid sequence represented by SEQ ID NO: 33, or (2) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 28 and a light chain of the amino acid sequence represented by SEQ ID NO:

33.

40. A compound according to any one of claims 35 to 37, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or antigen-binding fragment thereof is (1) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence represented by SEQ ID NO: 55 and a light chain of the amino acid sequence represented by SEQ ID NO: 60, or (2) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 55 and a light chain of the amino acid sequence represented by SEQ ID NO:

60.

41. A compound according to any one of claims 35 to 37, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the antibody or antigen-binding fragment thereof is (1) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence represented by SEQ ID NO: 64 and a light chain of the amino acid sequence represented by SEQ ID NO: 69, or (2) an anti-B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain of the amino acid sequence having one or two amino acid residues deleted from the carboxyl terminus of the amino acid sequence represented by SEQ ID NO: 64 and a light chain of the amino acid sequence represented by SEQ ID NO:

69.

42. A pharmaceutical composition comprising a compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, or a solvate thereof, and at least one pharmaceutically acceptable additive.

43. m 1 The pharmaceutical composition according to claim 42, comprising two or more different compounds according to any one of claims 1 to 41 or pharmaceutically acceptable salts thereof, or solvates thereof, wherein the average number of D bonds per Li or Ab unit in the compounds according to any one of claims 1 to 41 or pharmaceutically acceptable salts thereof, or solvates thereof contained in the composition is 3 to 8.

44. The pharmaceutical composition according to claim 42 or 43 for use in the treatment of cancer.

45. The pharmaceutical composition according to claim 44, wherein the cancer is leukemia, malignant lymphoma, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, stomach cancer, appendiceal cancer, colorectal cancer, anal cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, gastrointestinal stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, bladder cancer, neuroendocrine tumor, neuroblastoma, glioblastoma, malignant melanoma, breast cancer, uterine cancer, cervical cancer, ovarian cancer, testicular cancer, osteosarcoma, soft tissue sarcoma, Kaposi's sarcoma, or myosarcoma.

46. ​​The pharmaceutical composition according to claim 44, wherein the cancer is leukemia, malignant lymphoma, brain tumor, head and neck cancer, esophageal cancer, lung cancer, neuroblastoma, glioblastoma, breast cancer, ovarian cancer, osteosarcoma, soft tissue sarcoma, Kaposi's sarcoma, or myosarcoma.

47. A compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in the treatment of cancer.

48. A method for treating cancer, comprising the step of administering a therapeutically effective amount of a compound according to any one of claims 1 to 41, a pharmaceutically acceptable salt thereof, or a solvate thereof, to a subject in need of cancer treatment.

49. Use of a compound according to any one of claims 1 to 41, a pharmaceutically acceptable salt thereof, or a solvate thereof, in the manufacture of a pharmaceutical for use in the treatment of cancer.

50. Equation (VI): [where n 1 , n 2 , n 3 , and n 4 Each independently represents an integer from 1 to 3; -X- represents -O-, -NH-, -S-, or -CH2-; -Y- represents -O-, -C(R 3 )(R 4 )-, or -N(R 5 )- indicates; R 1 phenyl, a six-membered heteroaryl containing one or two nitrogen atoms as ring atoms, C 3-6 Cycloalkyl, or C 5-8 Bicycloalkyl (wherein the phenyl, 6-membered heteroaryl, C 3-6 Cycloalkyl, and C 5-8 Each bicycloalkyl group may independently have 1 to 3 substituents selected from substituent group 1); R 2 R represents a 6-membered heteroaryl containing phenyl, one or two nitrogen atoms as ring constituent atoms, or a 9 or 10-membered bicyclic heteroaryl containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms (wherein the phenyl, 6-membered heteroaryl, and 9 or 10-membered bicyclic heteroaryl each independently may have one to three substituents selected from substituent group 2); R 3 and R 4 Each independently represents hydrogen, halogen, or ethynyl, or R 3 and R 4 They bond with each other, and together with the carbon atoms to which they bond, form a 3 to 6-membered aliphatic heterocycle containing one or two nitrogen atoms as ring constituent atoms; R 5 is hydrogen or C 1-6 Alkyl is indicated; and R L This is the group represented by the formula: Cit-NH-CH2-, or the formula: Lb'-La'-Lp'-NH-CH2- (where -Lp'- is the same as the formula: -GGFG-) ＊＊ '', -GGLCit- ＊＊ '', -GGACit- ＊＊ '', -GGGACit- ＊＊ '', -ACit- ＊＊ '', -GGGCit- ＊＊ '', and -CitGACit- ＊＊ '' (wherein **'' indicates a binding site with NH) represents one divalent group selected from the group consisting of '', and -La'- represents the formula: -(CH2)2-C(=O)- ＊ '', -(CH2)5-C(=O)- ＊ '', -C(=O)-(CH2)2-C(=O)- ＊ '', -(CH2CH2O)4-(CH2)2-C(=O)- ＊ '', -(CH2CH2O)8-(CH2)2-C(=O)- ＊ '', -(CH2)2-C(=O)NH-(CH2CH2O)2-(CH2)2-C(=O)- ＊ '', and -(CH2)2-C(=O)NH-(CH2)2-C(=O)- ＊ '' (wherein *'' indicates the binding site with Lp') represents one divalent group selected from the group consisting of '' and Lb' is either formula (VII-1) or formula (VII-2): (In the formula, the wavy line indicates the bond site with La') indicates the group indicated by (substituent group 1) halogen, cyano, nitro, -NHC(=O)NH2, -NHC(=O)NHC(=O)NH2, -NHC(=O)-C 1-6 Alkyl, Carbamoyl, -C(=O)NH-C 1-6 Alkyl, -C(=O)NHOH, -C(=O)NHNH2, -C(=O)-C 1-6 Alkyl, carboxyl, -C(=O)OC 1-6 Alkyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -SC 1-6 Alkyl, -SC 3-6 Cycloalkyl, -S(=O)-C 1-6 Alkyl, -S(=O)-C 3-6 Cycloalkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)2-C 3-6 Cycloalkyl, C 1-6 Oxetanyl which may be alkyl-substituted, and 5-oxo-4H-1,2,4-oxadiazole-3-yl (in substituent group 1, the C 1-6 Alkyl and C 3-6 Cycloalkyls are, independently, halogen, hydroxyl, and -OC. 1-6 (May be further substituted with one or more groups selected from the group consisting of alkyl groups) (Substituent group 2) Halogen, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl (In substituent group 2, the C 1-6 Alkyl and C 3-6 Compounds represented by [the cycloalkyl group may be further substituted with one or more halogens independently] or pharmaceutically acceptable salts thereof, or solvates thereof.

51. n 1 and n 2 However, both are 1, n 3 and n 4 However, both are 2, -X- is -O- or -NH-, -Y- is -CF2- or -O-, R 1 However, phenyl, a 6-membered heteroaryl containing one or two nitrogen atoms as ring constituent atoms, C 3-6 Cycloalkyl, or C 5-8 Bicycloalkyl (wherein the phenyl, 6-membered heteroaryl, C 3-6 Cycloalkyl, and C 5-8 Each bicycloalkyl group may independently have one or two substituents selected from substituent group 1', R 2 However, it is phenyl (wherein the phenyl may have one or two substituents selected from substituent group 2'), or 3,4-methylenedioxyphenyl, and R L However, the group represented by formula: Cit-NH-CH2-, or formula: Lb'-La'-Lp'-NH-CH2- [wherein -Lp'- is the same as formula: -GGFG-] ＊＊ '', -GGLCit- ＊＊ '', -GGACit- ＊＊ '', -GGGACit- ＊＊ '', -ACit- ＊＊ '', -GGGCit- ＊＊ '', and -CitGACit- ＊＊ '' (wherein **'' indicates a binding site with NH) represents one divalent group selected from the group consisting of '', and -La'- represents the formula: -(CH2)2-C(=O)- ＊ '', -(CH2)5-C(=O)- ＊ '', -(CH2CH2O)4-(CH2)2-C(=O)- ＊ '', -(CH2CH2O)8-(CH2)2-C(=O)- ＊ '', -(CH2)2-C(=O)NH-(CH2CH2O)2-(CH2)2-C(=O)- ＊ '', and -(CH2)2-C(=O)NH-(CH2)2-C(=O)- ＊ '' (wherein *'' indicates the binding site with Lp') represents one divalent group selected from the group consisting of '', and Lb' is given by formula (VII-1): The group shown is indicated by (where the dashed line in the formula indicates the bonding site with La'). The group shown is (substituent group 1') halogen, cyano, nitro, -NHC(=O)NH2, -NHC(=O)NHC(=O)NH2, -NHC(=O)-C 1-6 Alkyl, Carbamoyl, -C(=O)NH-C 1-6 Alkyl, -C(=O)NHOH, -C(=O)NHNH2, -C(=O)-C 1-6 Alkyl, carboxyl, -C(=O)OC 1-6 Alkyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -SC 1-6 Alkyl, -S(=O)-C 1-6 Alkyl, C 1-6 Oxetanyl which may be alkyl-substituted, and 5-oxo-4H-1,2,4-oxadiazole-3-yl (in substituent group 1', the C 1-6 Alkyl and C 3-6 Cycloalkyls are, independently, halogen, hydroxyl, and -OC. 1-6 (May be further substituted with one or more groups selected from the group consisting of alkyl groups) (Substituent group 2') Halogen, -OC 1-6 Alkyl and C 3-6 Cycloalkyl (in substituent group 2', the C 1-6 Alkyl and C 3-6 The compound according to claim 50, or a pharmaceutically acceptable salt thereof, or a solvate thereof, (each cycloalkyl group may be independently further substituted with one or more halogens).

52. Equations (VI-6), (VI-9), (VI-12), (VI-15), (VI-24), and (VI-25): Any one compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

53. Equations (VI-5), (VI-8), and (VI-11): Any one compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

54. Formula (VIII): [In the formula, n 1 , n 2 , n 3 , and n 4 Each independently represents an integer from 1 to 3; -X- represents -O-, -NH-, -S-, or -CH2-; -Y- represents -O-, -C(R 3 )(R 4 )-, or -N(R 5 )- indicates; R 1 phenyl, a six-membered heteroaryl containing one or two nitrogen atoms as ring atoms, C 3-6 Cycloalkyl, or C 5-8 Bicycloalkyl (wherein the phenyl, 6-membered heteroaryl, C 3-6 Cycloalkyl, and C 5-8 Each bicycloalkyl group may independently have 1 to 3 substituents selected from substituent group 1); R 2 R represents a 6-membered heteroaryl containing phenyl, one or two nitrogen atoms as ring constituent atoms, or a 9 or 10-membered bicyclic heteroaryl containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms (wherein the phenyl, 6-membered heteroaryl, and 9 or 10-membered bicyclic heteroaryl each independently may have one to three substituents selected from substituent group 2); R 3 and R 4 Each independently represents hydrogen, halogen, or ethynyl, or R 3 and R 4 They bond to each other, and together with the carbon atoms to which they bond, form a 3 to 6-membered aliphatic heterocycle containing one or two nitrogen atoms as ring constituent atoms; and R 5 is hydrogen or C 1-6 This indicates alkyl. (Substituent group 1) Halogen, cyano, nitro, -NHC(=O)NH2, -NHC(=O)NHC(=O)NH2, -NHC(=O)-C 1-6 Alkyl, Carbamoyl, -C(=O)NH-C 1-6 Alkyl, -C(=O)NHOH, -C(=O)NHNH2, -C(=O)-C 1-6 Alkyl, carboxyl, -C(=O)OC 1-6 Alkyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -SC 1-6 Alkyl, -SC 3-6 Cycloalkyl, -S(=O)-C 1-6 Alkyl, -S(=O)-C 3-6 Cycloalkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)2-C 3-6 Cycloalkyl, C 1-6 Oxetanyl which may be alkyl-substituted, and 5-oxo-4H-1,2,4-oxadiazole-3-yl (in substituent group 1, the C 1-6 Alkyl and C 3-6 Cycloalkyls are, independently, halogen, hydroxyl, and -OC. 1-6 (May be further substituted with one or more groups selected from the group consisting of alkyl groups) (Substituent group 2) Halogen, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl (In substituent group 2, the C 1-6 Alkyl and C 3-6 Compounds represented by [the cycloalkyl group may be further substituted with one or more halogens independently] or pharmaceutically acceptable salts thereof, or solvates thereof.

55. n 1 and n 2 However, both are 1, n 3 and n 4 However, both are 2, -X- is -O- or -NH-, -Y- is -CF2- or -O-, R 1 However, phenyl, a 6-membered heteroaryl containing one or two nitrogen atoms as ring constituent atoms, C 3-6 Cycloalkyl, or C 5-8 Bicycloalkyl (wherein the phenyl, 6-membered heteroaryl, C 3-6 Cycloalkyl, and C 5-8 Each bicycloalkyl group may independently have one or two substituents selected from substituent group 1', and R 2 However, the substituent is phenyl (wherein the phenyl substituent may have one or two substituents selected from substituent group 2') or 3,4-methylenedioxyphenyl (substituent group 1') halogen, cyano, nitro, -NHC(=O)NH2, -NHC(=O)NHC(=O)NH2, -NHC(=O)-C 1-6 Alkyl, Carbamoyl, -C(=O)NH-C 1-6 Alkyl, -C(=O)NHOH, -C(=O)NHNH2, -C(=O)-C 1-6 Alkyl, carboxyl, -C(=O)OC 1-6 Alkyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -SC 1-6 Alkyl, -S(=O)-C 1-6 Alkyl, C 1-6 Oxetanyl which may be alkyl-substituted, and 5-oxo-4H-1,2,4-oxadiazole-3-yl (in substituent group 1', the C 1-6 Alkyl and C 3-6 Cycloalkyls are, independently, halogen, hydroxyl, and -OC. 1-6 (may be further substituted with one or more groups selected from the group consisting of alkyls), (substituent group 2') halogen, -OC 1-6 Alkyl and C 3-6 Cycloalkyl (in substituent group 2', the C 1-6 Alkyl and C 3-6 The compound according to claim 54, or a pharmaceutically acceptable salt thereof, or a solvate thereof, (each cycloalkyl group may be independently further substituted with one or more halogens).

56. Equations (VIII-22), (VIII-50), and (VIII-54): Any one compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

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