Antibody drug complex comprising heterocyclic compound having g12d mutant kras

Abstract

The present invention provides antibody drug complexes for use in the treatment of cancers expressing G12D mutant KRAS. In addition, a drug-linker complex for use in the antibody drug complex is provided. The present inventors produce an antibody drug complex capable of delivering a heterocyclic compound represented by formula (I) to cancer, such as cancer expressing EGFR, by binding the heterocyclic compound to an antibody, such as an anti-EGFR antibody. In addition, a drug-linker complex used in the antibody drug complex or a salt thereof has been found. The antibody drug complex inhibits G12D mutant KRAS by inducing the decomposition of the G12D mutant KRAS protein in cancer, such as EGFR expressing cancer, and exhibits an anti-tumor effect.

Description

TECHNICAL FIELD

[0001] The present application relates to a pharmaceutical composition, and particularly to an antibody-drug conjugate or a salt thereof comprising a heterocyclic compound having a KRAS protein decomposition-inducing action of G12D mutation (hereinafter, the compound is also referred to as a drug). In addition, the present application relates to a drug-linker conjugate or a salt thereof for the antibody-drug conjugate or the salt thereof. BACKGROUND

[0002] RAS protein is a low molecular guanosine triphosphate (GTP)-binding protein of about 21 kDa consisting of 188-189 amino acids, and there are four major proteins (KRAS (KRAS4A and KRAS4B), NRAS, HRAS) produced from three genes of KRAS gene, NRAS gene, and HRAS gene. RAS protein exists as GTP-binding type as an active type and as GDP-binding type as an inactive type. RAS protein is activated by exchanging guanosine diphosphate (GDP) for GTP by ligand stimulation of a cell membrane receptor such as EGFR or the like. Active type RAS binds to up to 20 effector proteins such as RAF, PI3K, RALGDS, and the like, and activates the downstream signal cascade. On the other hand, active type RAS is converted to the inactive type by converting GTP to GDP by endogenous GTPase activity. This GTPase activity is enhanced by GTPase-activating protein (GAP). From this, it is known that RAS assumes the function of an important "molecular switch" in the intracellular signal transduction pathway of EGFR or the like, and plays an important role in the processes of cell growth, proliferation, angiogenesis, and the like (Nature Rev. Cancer, 2011, 11, p. 761-774, Nature Rev. Drug Discov., 2014, 13, p. 828-851, Nature Rev. Drug Discov., 2016, 15, p. 771-785).

[0003] When an amino acid substitution occurs due to a mutation in the RAS gene, the function as a GTPase of RAS decreases, the response to GAP decreases to become a constant activated state, and signals are continuously delivered downstream. This excess signal can lead to carcinogenesis, hyperproliferation of cancer. For example, in more than 90% of patients with pancreatic ductal adenocarcinoma, a mutation in the KRAS gene can be confirmed, and this mutation is present from the early stage of pancreatic intraepithelial neoplasia (PanIN). In addition, mutations in the KRAS gene are also frequently confirmed in lung cancer, colorectal cancer. As a mutation in the KRAS gene, examples of point mutations at codon 12 of exon 2 of KRAS (KRAS G12C mutation, KRAS G12D mutation, etc.) are well known (Nat. Rev. Cancer, 2018, 18, p.767-777).

[0004] In recent years, as a technology for inducing the degradation of target proteins, bifunctional compounds collectively called PROTAC (PROteolysis-TArgeting Chimera), SNIPER (Specific and Nongenetic IAP-dependent Protein Eraser), and the like have been discovered, and are expected as one of new drug development models (Drug. Discov. Today Technol., 2019, 31, p15-27). These bifunctional compounds promote the formation of a complex of a target protein and an E3 ligase in cells, ubiquitinate the target protein, thereby inducing the degradation of the target protein using the ubiquitin-proteasome system. The ubiquitin-proteasome system is one of the protein degradation mechanisms in cells. A protein called E3 ligase recognizes a protein to be degraded and ubiquitinates it, thereby degrading it in the proteasome. There are more than 600 E3 ligases in living organisms, and currently, E3 ligases for bifunctional degradation inducers called PROTAC, SNIPER, and the like are limited, and as representatives, Von Hippel-Lindau (VHL), cereblon (CRBN), inhibitor of apoptosis protein (IAP), mouse double minute 2 homolog (MDM2), and the like can be exemplified.

[0005] These bifunctional compounds are compounds in which a ligand of a target protein and a ligand of an E3 ligase are connected with a linker, and bifunctional compounds that reduce the level of G12D mutant KRAS protein are reported in Patent Literatures 1 to 2. Patent Literature 3 reports bifunctional compounds that modulate G12D mutant KRAS protein. Patent Literature 4 reports compounds having G12D mutant KRAS decomposing action. Patent Literature 5 reports quinazoline compounds for inducing decomposition of G12D mutant KRAS protein. Patent Literature 6 reports compounds having G12D mutant KRAS decomposing action. In addition, Patent Literature 7 reports heteroaromatic ring compounds having G12D mutant KRAS decomposing action. In addition, Patent Literature 8, which was published after the priority date of the present application, reports heterocyclic compounds for inducing decomposition of G12D mutant KRAS protein, and Patent Literature 9, which was also published after the priority date of the present application, reports heterocyclic compounds that act on G12D mutant KRAS protein.

[0006] On the other hand, as a technique for selectively delivering a drug to cancer cells, an antibody drug conjugate (ADC) in which a drug molecule having a cytotoxic action is bound to an antibody that targets an antigen expressed on the surface of a cancer cell, an immune-stimulating antibody conjugate (ISAC) in which a drug molecule having an immune-activating action is bound to an antibody that targets an antigen expressed on the surface of a cancer cell, and the like are being studied, and this technique has also been used for approved pharmaceutical products (Cancer Science, 2016, Vol. 107, No. 7, p. 1039-1046; Clinical Cancer Research, 2005, Vol. 11, p. 843-852; Cancer Research, 2016, Vol. 76, No. 10, p. 3003-3013). Patent Literatures 10 to 13 describe ADCs containing bifunctional compounds having target protein decomposition-inducing action as a drug. However, as of the present, ADCs containing a drug having G12D mutant KRAS protein decomposition-inducing action are unknown.

[0007] Prior Art Documents

[0008] Patent Literature

[0009] Patent Literature 1: International Publication No. 2022 / 148421

[0010] Patent Literature 2: International Publication No. 2022 / 148422

[0011] Patent Literature 3: Chinese Patent Application Publication No. 115785199

[0012] Patent Literature 4: International Publication No. 2023 / 077441

[0013] Patent Literature 5: International Publication No. 2022 / 173032

[0014] Patent Literature 6: International Publication No. 2022 / 228576

[0015] Patent Literature 7: International Publication No. 2023 / 280026

[0016] Patent Literature 8: International Publication No. 2023 / 171781

[0017] Patent Literature 9: International Publication No. 2024 / 019103

[0018] Patent Literature 10: International Publication No. 2017 / 201449

[0019] Patent Literature 11: International Publication No. 2019 / 140003

[0020] Patent Literature 12: International Publication No. 2021 / 195598

[0021] Patent Literature 13: International Publication No. 2023 / 056069 SUMMARY

[0022] PROBLEMS TO BE SOLVED BY THE INVENTION

[0023] Provided is a pharmaceutical composition, particularly an antibody-drug conjugate or a salt thereof containing a heterocyclic compound having a G12D mutant KRAS protein decomposition-inducing action. In addition, provided is a drug-linker conjugate or a salt thereof for the antibody-drug conjugate or the salt thereof.

[0024] METHOD FOR SOLVING THE PROBLEM

[0025] The present inventors conducted intensive studies on a compound useful as an effective ingredient of a pharmaceutical composition, and as a result, found that an antibody-drug conjugate having a structure of Formula (I) has an excellent G12D mutant KRAS protein decomposition-inducing action, and further found that a drug-linker conjugate containing a compound having a G12D mutant KRAS protein decomposition-inducing action is useful for the synthesis of the antibody-drug conjugate, thereby completing the present invention.

[0026] That is, the present invention relates to the following [1] to

[45] .

[0027] [1] an antibody-drug conjugate of Formula (I) or a salt thereof,

[0028] (In the formula, Ab is an antibody or an antigen-binding fragment thereof, D is a heterocyclic compound having a KRAS protein decomposition-inducing action of G12D mutation, L A is a linker for binding Ab to D, n is a number of 1 to 20.

[0029] [2] The antibody drug conjugate or a salt thereof according to [1], wherein D is a heterocyclic compound represented by formula (II),

[0030] A is CR A or N, R A is H, cyano, or C 1-3 alkyl which can be substituted, Q is CR Q or N, R Q is H, halogen, C 3-6 cycloalkyl, vinyl, or C 1-3 alkyl which can be substituted, E is CH or N, R 1 is naphthyl which can be substituted by 1 or 2 groups selected from the group consisting of cyano, OH, halogen, and C 1-3 alkyl which can be substituted, or 1 group selected from the group consisting of the following formula (III), formula (IV), and formula (V),

[0031] R 1a , R 1b , and R 1c are each independently H, vinyl, halogen, or C 1-3 alkyl which can be substituted, R 2 is -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S-, or -N(R V1 )-, R V1 is H or C 1-3 alkyl which can be substituted, V 2 is 1 group selected from the group consisting of the following formula (VI) and formula (VII),

[0032] W is one group selected from the group consisting of formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV), formula (XV) and formula (XVI),

[0033] R 2a independently OH, OCH3, F or C 1-3 alkyl, which R 2a is bonded only to a carbon atom constituting a ring selected from the group consisting of an azetidine ring represented by formula (VI), a pyrrolidine ring represented by formula (VII), a piperidine ring represented by formula (VIII) and a piperazine ring represented by formula (IX), m is an integer of 0 to 2, R 3 is C 1-6 alkyl, heterocycloalkyl which can be substituted, or heteroaryl which can be substituted, X is a bond, -CH2-, -O-, -S- or -NR 4X -, R 4X is H or C 1-3 alkyl which can be substituted, Y 1 is -O-(C 1-3 alkylene) which can be substituted, Y2 -S-(C 1-3 alkylene) which can be substituted, Y2 -SO2-(C 1-3 alkylene) which can be substituted, Y2 -NR Y -(C 1-3 alkylene) which can be substituted, Y2 -(C 1-3 alkylene)-O Y2 -(C 1-3 alkylene)-S Y2 -(C 1-3 alkylene)-SO2 Y2 or -(C 1-3 alkylene)-NR Y Y2 Y2 represents a binding site to Y 2 , R Y is H or a C 1-3 alkyl group which can be substituted, Y 2 is a bond, a phenylene group which can be substituted, or a heteroarylene group which can be substituted, L P is a group which chemically binds Y 2 to EUB, EUB is a group having a binding ability to 1 E3 ubiquitin ligase selected from the group consisting of VHL, hydroxylated cerebroside, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR, L A is a linker for binding Ab to D, where L A binds to a nitrogen atom of any -NH- or an oxygen atom of -OH contained in D.

[0034] [3] The antibody drug conjugate or salt thereof according to [2], wherein V 2 is 1 group selected from the group consisting of the following formula (VIa) and formula (VIIa) LA represents a binding site to L A ,

[0035] W is 1 group selected from the group consisting of the following formula (VIIIa), formula (IXa), formula (Xa), formula (XIa), formula (XIIa), formula (XIIIa), formula (XIVa), formula (XVa), and formula (XVIa) LA represents a binding site to L A ,

[0036] L A is a linker for binding Ab to D, where L A binds to a nitrogen atom contained in V 2 or W LA binds to D via the binding site represented by

[0037] [4] The antibody drug conjugate or salt thereof according to [2], wherein A is N, Q is CR Q , R Qis cyclopropyl, E is CH, R 1 is the following formula (III-2),

[0038] R 2 is -V 1 -V 2 or W, V 1 is -N(CH3)-, V 2 is the following formula (VII-2),

[0039] W is the following formula (XIV),

[0040] R 3 is n-propyl or tetrahydropyranyl which can be substituted with -OCH3, X is -O-, Y 1 is -O-(methylene) Y2 Y2 represents a bonding site to Y 2 , Y 2 is phenylene, L P is a group that chemically binds Y 2 to EUB, EUB is a group having a binding ability to one E3 ubiquitin ligase selected from the group consisting of VHL and hydroxylated brain glycolipid.

[0041] [5] The antibody drug conjugate or salt thereof according to [4], wherein V 2 is the following formula (VII-2a) LA represents a bonding site to L A ,

[0042] W is the following formula (XIVa) LA represents a bonding site to L A ,

[0043] L A is a linker for binding Ab to D, and here, L A is V2 or the nitrogen atom contained in W LA the binding part shown is bound so as to bind to D.

[0044] [6] The antibody drug conjugate or a salt thereof according to any one of [1] or [2], wherein D is: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methyl-butyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methyl-butyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methyl-butyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methyl-butyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methyl-butyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{methyl[(3S)-pyrrolidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{methyl[(3S)-pyrrolidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{methyl[(3S)-pyrrolidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, 1-(6-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-1-methyl-1H-indazol-3-yl)-1,3-diazinan-2,4-dione, 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, or Phosphoric acid = dihydro- (2R) -2- ( { (4R) -1- [ (2S) -2- { 4- [4- ( { [ (7M) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- (2S) -2-methoxypropoxy) -4- (methyl [ (3S) -pyrrolidin-3-yl] amino) quinazolin-8-yl] oxy} methyl) phenyl] -1H-1, 2, 3-triazol-1-yl} -3-methylbutanoyl] -4-hydroxy-L-prolyl} amino) -2- [4- (1H-1, 2, 4-triazol-1-yl) phenyl] ethyl ester.

[0045] [7] The antibody drug conjugate or a salt thereof according to any one of [1] to [6], wherein L A is a linker represented by formula (XXVIII),

[0046] (in the formula, Str is an extension unit which binds with Ab and CLL, r is 0 or 1, CLL is a moiety which is cleavable in vivo, Sp is a spacer unit, t is 0 or 1, Ab represents a binding site to Ab.

[0047] [8] The antibody drug conjugate or a salt thereof according to [7], wherein Str is an extension unit represented by formula (ST-1), r is 1,

[0048] (in the formula, R st1 is a C 1-12 alkylene group, -(CH2CH2O) a1 -C 1-6 alkylene group, -C 1-6 alkylene group, -(OCH2CH2) a2 -, -a C 1-6 alkylene group, -NH-C(=O)-a C 1-6 alkylene group, -a C 1-6 alkylene group, -C(=O)-NH-a C 1-6 alkylene group, a C 1-6 alkylene group, -C(=O)-NH-(CH2CH2O) a3 -C 1-6 alkylene group, or a C 1-6 alkylene group, -NH-C(=O)-(CH2CH2O) a4 -C 1-6 alkylene group, a1, a2, a3, and a4 are each an integer of 1 to 10, Ab represents a binding site to Ab.

[0049] [9] The antibody drug conjugate or a salt thereof according to [8], wherein R st1 is a C5 alkylene group.

[0050]

[10] The antibody drug conjugate or a salt thereof according to [7], wherein CLL is a cleavable moiety in vivo represented by formula (CL-1).

[0051]

[0052] (in the formula, R AAindependently of one another H, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, hydroxymethyl, 1-hydroxyethyl, -CH2-C(=0)-OH, -(CH2)2-C(=0)-OH, -CH2-C(=0)-NH2, -(CH2)2-C(=0)-NH2, -(CH2)4-NH2, -(CH2)3-NH-C(=NH)-NH2, -(CH2)3-NH-C(=0)-NH2, -CH2-SH or -CH2-S-CH3, or one radical selected from the group consisting of the following formulae (RAA-1) and (RAA-2),

[0053] d is an integer from 1 to 6 STR represents a binding site to Str.

[0054] [10a] The antibody drug conjugate or a salt thereof according to

[10] , wherein R AA independently of one another H, methyl, isopropyl, benzyl, -(CH2)4-NH2, -(CH2)3-NH-C(=NH)-NH2 or -(CH2)3-NH-C(=0)-NH2, d is an integer from 2 to 4.

[0055] [10b] The antibody drug conjugate or a salt thereof according to

[10] , wherein R AA independently of one another methyl, isopropyl, benzyl, -(CH2)4-NH2, -(CH2)3-NH-C(=NH)-NH2 or -(CH2)3-NH-C(=0)-NH2, d is 2.

[0056] [10c] The antibody drug conjugate or a salt thereof according to

[10] , wherein R AA independently of one another methyl, isopropyl or -(CH2)3-NH-C(=0)-NH2, d is 2.

[0057]

[11] The antibody drug conjugate or a salt thereof according to

[10] , wherein R AA independently of one another methyl or isopropyl, d is 2.

[0058]

[12] The antibody drug conjugate or a salt thereof according to

[10] , wherein R AA independently of one another isopropyl or -(CH2)3-NH-C(=0)-NH2, d is 2.

[0059]

[13] The antibody drug conjugate or a salt thereof according to

[10] , wherein R AA independently of one another H or benzyl, d is 4.

[0060]

[14] The antibody drug conjugate or a salt thereof according to [7], wherein Sp is a spacer unit represented by formula (SP-1), t is 1,

[0061] (in the formula, R SP is H, C 1-6 alkyl, -O-C 1-6 alkyl, halogen or halogenated C 1-6 alkyl CLL represents a binding site to CLL).

[0062]

[15] The antibody drug conjugate or a salt thereof according to

[14] , wherein R SP is H.

[0063]

[16] The antibody drug conjugate or a salt thereof according to [7], wherein t is 0.

[0064]

[17] The antibody drug conjugate or a salt thereof according to [1], wherein formula (I) is represented by formula (AD-1a) or (AD-2a),

[0065] (in the formula, R is an antibody or an antigen binding fragment thereof, A is CR A or N, R A is H, cyano or C 1-3 alkyl which can be substituted, Q is CR Q or N, R Q is H, halogen, C 3-6 cycloalkyl, vinyl or C 1-3 alkyl which can be substituted, E is CH or N, R 1 is naphthyl which can be substituted by 1 or 2 groups selected from the group consisting of cyano, OH, halogen and C 1-3 alkyl which can be substituted, or 1 group selected from the group consisting of the following formula (III), formula (IV) and formula (V),

[0066] R 1a , R 1b and R 1c are each independently H, vinyl, halogen or C 1-3 alkyl which can be substituted, R3 C can be replaced 1-6 Alkyl, substituted heterocyclic alkyl, or substituted heteroaryl, X represents a bond, -CH2-, -O-, -S-, or -NR. 4X -, R 4X H or C that can be substituted 1-3 alkyl, Y 1 -O- (substitutable C) 1-3 Alkylene) Y2 -S- (substitutable C) 1-3 Alkylene) Y2 -SO2- (substitutable C 1-3 Alkylene) Y2 -NR Y -(C that can be replaced) 1-3 Alkylene) Y2 -(substitutable C) 1-3 (alkylene)-O Y2 -(substitutable C) 1-3 (alkylene)-S Y2 -(substitutable C) 1-3 (alkylene)-SO2 Y2 Or - (the C that can be replaced) 1-3 (alkylene)-NR Y Y2 Y2 Indicates Y 2 (the joint) R Y H or C that can be substituted 1-3 alkyl, Y 2 For bonds, substituted phenylene or substituted heteroaryl groups, L P To make Y 2 Groups that chemically bind with EUB EUB is a group that has the ability to bind to one E3 ubiquitin ligase selected from the group consisting of VHL, hydroxycerebroside, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR. R st1 C1-12 Alkylene R AA Each of the following can be independently H, methyl, isopropyl, benzyl, or -(CH2)3-NH-C(=O)-NH2, where d is an integer from 2 to 4. t is 0 or 1, n is a value from 1 to 20.

[0067]

[18] The antibody-drug complex or a salt thereof according to [1], wherein formula (I) is as shown in formula (AD-3a), (AD-4a), (AD-5a), (AD-6a), (AD-7a), (AD-8a), (AD-9a), (AD-10a), (AD-11a), (AD-12a), (AD-13a) or (AD-25a),

[0068] (where R is in the formula) st1 C 1-12 Alkylene, R AA Each of the following is independently H, methyl, isopropyl, benzyl, or -(CH2)3-NH-C(=O)-NH2, where d is an integer from 2 to 4, t is 0 or 1, and n is a value from 1 to 20. It should be noted that chemical structural formulas containing " The compound marked with "" indicates that the compound has a single axial chirality or central chirality. The same applies below.

[0069]

[19] The antibody-drug complex or a salt thereof according to [1], wherein formula (I) is as shown in formula (AD-14), (AD-15), (AD-16), (AD-17), (AD-18), (AD-19), (AD-20), (AD-21), (AD-22), (AD-23), (AD-24) or (AD-25),

[0070] (In the formula, n is a value from 1 to 20).

[0071]

[20] An antibody-drug complex or a salt thereof according to any one of [1] to

[19] , wherein Ab is cetuximab and n is a value of 2 to 5.

[0072]

[21] The antibody drug conjugate or a salt thereof according to any one of [1] to

[19] , wherein Ab is an antibody or an antigen-binding fragment that binds to 1 or 2 or more antigens selected from the group consisting of 5T4, ADAM9, ALPP, ALPPL2, AXL, B7H3, B7H4, BCMA, CA9, CCR2, CCR7, CD123, CD166, CD19, CD20, CD22, CD25, CD30, CD33, CD37, CD38, CD45, CD46, CD70, CD74, CD79b, CDH3, CDH6, CLDN1, CLDN4, CLDN6, CLDN18.2, cMET, EGFR, EphA3, FAP, FGFR3, Fibronectin, FOLRa, Globo H, GPRC5D, HER2, HER3, IGF1R, Integrin alphaV, KAAG1, LIV1, MSLN, MT1-MMP, MUC1, MUC4, NaPi2b, Nectin 4, PD-L1, PSMA, PTK7, ROR1, ROR2, SEZ6, Sialyl Tn, TF, TROP2, TSPAN8, and VEGF.

[0073]

[22] The antibody drug conjugate or a salt thereof according to any one of [1] to

[19] , wherein Ab is an antibody or an antigen-binding fragment that binds to 1 or 2 or more antigens selected from the group consisting of EGFR, HER2, cMET, and TROP2.

[0074]

[23] The antibody drug conjugate or a salt thereof according to any one of [1] to

[19] , wherein Ab is an anti-EGFR antibody or an antigen-binding fragment thereof.

[0075]

[24] The antibody drug conjugate or a salt thereof according to

[23] , wherein Ab is an anti-EGFR antibody or an antigen-binding fragment thereof that contains (1) or (2) a heavy chain variable region and a light chain variable region described below: (1) a heavy chain variable region containing a CDR1 consisting of the amino acid sequence of amino acid numbers 31 to 35 of SEQ ID NO: 1, a CDR2 consisting of the amino acid sequence of amino acid numbers 50 to 65 of SEQ ID NO: 1, and a CDR3 consisting of the amino acid sequence of amino acid numbers 98 to 108 of SEQ ID NO: 1, and a light chain variable region containing a CDR1 consisting of the amino acid sequence of amino acid numbers 24 to 34 of SEQ ID NO: 2, a CDR2 consisting of the amino acid sequence of amino acid numbers 50 to 56 of SEQ ID NO: 2, and a CDR3 consisting of the amino acid sequence of amino acid numbers 89 to 97 of SEQ ID NO: 2; or (2) a heavy chain variable region containing a CDR1 consisting of the amino acid sequence of amino acid numbers 31 to 35 of SEQ ID NO: 3, a CDR2 consisting of the amino acid sequence of amino acid numbers 50 to 65 of SEQ ID NO: 3, and a CDR3 consisting of the amino acid sequence of amino acid numbers 98 to 108 of SEQ ID NO: 3, and a light chain variable region containing a CDR1 consisting of the amino acid sequence of amino acid numbers 24 to 34 of SEQ ID NO: 4, a CDR2 consisting of the amino acid sequence of amino acid numbers 50 to 56 of SEQ ID NO: 4, and a CDR3 consisting of the amino acid sequence of amino acid numbers 89 to 97 of SEQ ID NO: 4.

[0076]

[25] The antibody drug conjugate or a salt thereof according to

[23] , wherein Ab is an anti-EGFR antibody or an antigen-binding fragment thereof containing a heavy chain variable region and a light chain variable region selected from the group consisting of (1) to (3) below: (1) a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 119 of SEQ ID NO: 1 and a light chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 107 of SEQ ID NO: 2; (2) a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 119 of SEQ ID NO: 3 and a light chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 107 of SEQ ID NO: 4; and (3) a heavy chain variable region and a light chain variable region having at least 90% or more identity to the heavy chain variable region and the light chain variable region described in (1) or (2) above.

[0077]

[26] The antibody drug conjugate or a salt thereof according to

[23] , wherein Ab is an anti-EGFR antibody of IgGl or IgG4 type.

[0078]

[27] The antibody drug conjugate or a salt thereof according to

[23] , wherein Ab is an anti-EGFR antibody consisting of the heavy chain of SEQ ID NO: 1 and the light chain of SEQ ID NO: 2.

[0079]

[28] The antibody drug conjugate or a salt thereof according to any one of

[21] to

[23] , wherein Ab is a post-translationally modified antibody, or an antibody in which any amino acid residue is substituted with cysteine or a non-natural amino acid.

[0080]

[29] A pharmaceutical composition containing the antibody drug conjugate or a salt thereof according to any one of [1] to

[28] , and a pharmaceutically acceptable excipient.

[0081]

[30] The pharmaceutical composition according to

[29] , which is used for the treatment of cancer.

[0082]

[31] The pharmaceutical composition according to

[30] , wherein the cancer is a hematological cancer or a solid cancer.

[0083]

[32] The pharmaceutical composition according to

[30] , wherein the cancer is a cancer expressing G12D mutant KRAS.

[0084]

[33] The antibody drug conjugate or a salt thereof according to any one of [1] to

[28] , wherein it is for use in the treatment of cancer.

[0085]

[34] A method for treating cancer, comprising the step of administering a therapeutically effective amount of the antibody drug conjugate or a salt thereof according to any one of [1] to

[28] to a subject.

[0086]

[35] Use of the antibody drug conjugate or a salt thereof according to any one of [1] to

[28] in the manufacture of a pharmaceutical composition for treating cancer.

[0087]

[36] A drug-linker complex represented by the formula (LD-1) or a salt thereof,

[0088] (in the formula, D is a heterocyclic compound having a G12D mutant KRAS protein decomposition-inducing action, R st1 is C 1-12 alkylene, CLL is a moiety structure cleavable in vivo, Sp is a spacer unit, which binds to CLL and D, and t is 0 or 1)

[37] The drug-linker complex according to

[36] , wherein D is a heterocyclic compound represented by the formula (II),

[0089] A is CR A or N, R A is H, cyano, or C 1-3 alkyl which can be substituted, Q is CR Q or N, R Q is H, halogen, C 3-6 cycloalkyl, vinyl, or C 1-3 alkyl which can be substituted, E is CH or N, R 1 is naphthyl which can be substituted by 1 or 2 groups selected from the group consisting of cyano, OH, halogen, and C 1-3 alkyl which can be substituted, or 1 group selected from the group consisting of the following formula (III), formula (IV), and formula (V),

[0090] R 1a , R 1b and R 1c are independently of each other H, vinyl, halogen or C 1-3 alkyl which can be substituted, R 2 is -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )-, R V1 is H or C 1-3 alkyl which can be substituted, V 2 is 1 radical selected from the group consisting of formula (VI) and formula (VII),

[0091] W is 1 radical selected from the group consisting of formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV), formula (XV) and formula (XVI),

[0092] R 2a are independently of each other OH, OCH3, F or C 1-3 alkyl which can be substituted, the R 2a are only bound to carbon atoms which are constituting atoms of a ring selected from the group consisting of an azetidine ring as shown in formula (VI), a pyrrolidine ring as shown in formula (VII), a piperidine ring as shown in formula (VIII) and a piperazine ring as shown in formula (IX), m is an integer from 0 to 2, R 3 is C 1-6 alkyl which can be substituted, heterocycloalkyl which can be substituted or heteroaryl which can be substituted, X is a bond, -CH2-, -O-, -S- or -NR 4X -, R 4X is H or C 1-3 alkyl which can be substituted, Y 1 is -O-(C 1-3 alkylene) which can be substituted, Y2 -S-(C 1-3 alkylene) which can be substituted Y2 , -SO2-(optionally substituted C 1-3 alkylene) Y2 , -NR Y -(optionally substituted C 1-3 alkylene) Y2 , -(optionally substituted C 1-3 alkylene)-O Y2 , -(optionally substituted C 1-3 alkylene)-S Y2 , -(optionally substituted C 1-3 alkylene)-SO2 Y2 or -(optionally substituted C 1-3 alkylene)-NR Y Y2 Y2 represents a bonding part to Y 2 , R Y is H or optionally substituted C 1-3 alkyl, Y 2 is a bond, optionally substituted phenylene or optionally substituted heteroarylene, L P is a group that chemically binds Y 2 to EUB, EUB is a group having a binding ability to 1 E3 ubiquitin ligase selected from the group consisting of VHL, hydroxylated cerebroside, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B and AhR, Sp is a spacer unit that binds to CLL and D, and here, Sp binds to a nitrogen atom of any -NH- or an oxygen atom of -OH contained in D.

[0093]

[38] The drug-linker complex or a salt thereof according to

[37] , wherein V 2 is 1 group selected from the group consisting of the following formula (VIb) and formula (VIIb) SP represents a bonding part to Sp,

[0094] W is one group selected from the group consisting of the following formula (VIIIb), formula (IXb), formula (Xb), formula (XIb), formula (XIIb), formula (XIIIb), formula (XIVb), formula (XVb), and formula (XVIb) SP represents a binding site to Sp),

[0095] Sp is a spacer unit, which binds to CLL and D, and here Sp binds to V 2 or the nitrogen atom included in W SP binds to D.

[0096]

[39] The drug-linker complex or a salt thereof according to

[37] , wherein A is N, Q is CR Q , R Q is cyclopropyl, E is CH, R 1 is the following formula (III-2),

[0097] R 2 is -V 1 -V 2 or W, V 1 is -N(CH3)-, V 2 is the following formula (VII-2),

[0098] W is the following formula (XIV),

[0099] R 3 is n-propyl or tetrahydropyranyl which can be substituted with -OCH3, X is -O-, Y 1 is -O-(methylene) Y2 Y2 represents a binding site to Y 2 ), Y 2 is phenylene, L P is a group which chemically binds Y 2 to EUB, EUB is a group having a binding ability to one E3 ubiquitin ligase selected from the group consisting of VHL and hydroxylated glycosides.

[0100]

[40] The drug-linker complex or a salt thereof according to

[39] , wherein, V 2 is the following formula (VII-2b) SP represents a binding site to Sp),

[0101] W is the following formula (XIVb) SP represents a binding site to Sp),

[0102] Sp is a spacer unit, which binds to CLL and D, and here, Sp binds to V 2 or the nitrogen atom included in W SP the binding site represented by the formula (VII-2b) binds to D.

[0103]

[41] The drug-linker complex or a salt thereof according to any one of

[36] or

[37] , wherein D is: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methyl-butyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methyl-butyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methyl-butyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2- [(2S)-2-methoxypropoxy]-4-{methyl[(3S)-pyrrolidin-3-yl]amino}quinazolin-8-yl]oxy}methyl) phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2- [(2S)-2-methoxypropoxy]-4-{methyl[(3S)-pyrrolidin-3-yl]amino}quinazolin-8-yl]oxy}methyl) phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5- yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6- fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl] benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1- yl)piperidine-2,6-dione, 1-(6-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6- fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl] benzoyl}-3-methylpiperazin-1-yl]methyl}-1-methyl-1H-indazol-3-yl)-1,3-diazinan-2,4-dione, 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6- fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl] benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1- yl)piperidine-2,6-dione, or Phosphoric acid = dihydro = (2R)-2-({(4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{methyl[(3S)-pyrrolidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-L-prolyl}amino)-2-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl ester.

[0104]

[42] The drug-linker complex or a salt thereof according to

[36] , wherein the formula (LD-1) is represented by formula (LD-2a) or (LD-3a),

[0105] (In the formula, A is CR A or N, R A is H, cyano or C 1-3 alkyl which can be substituted, Q is CR Q or N, R Q is H, halogen, C 3-6 cycloalkyl, vinyl or C 1-3 alkyl which can be substituted, E is CH or N, R 1 is naphthyl which can be substituted by 1 or 2 groups selected from the group consisting of cyano, OH, halogen and C 1-3 alkyl which can be substituted, or 1 group selected from the group consisting of the following formula (III), formula (IV) and formula (V),

[0106] R 1a , R 1b and R 1c are each independently H, vinyl, halogen or C 1-3 alkyl which can be substituted, R 3 is C 1-6 alkyl which can be substituted, heterocycloalkyl which can be substituted or heteroaryl which can be substituted, X is a bond, -CH2-, -O-, -S- or -NR 4X -, R 4X is H or C 1-3 alkyl which can be substituted, Y 1-O-(optionally substituted C 1-3 alkylene) Y2 -S-(optionally substituted C 1-3 alkylene) Y2 -SO2-(optionally substituted C 1-3 alkylene) Y2 -NR Y -(optionally substituted C 1-3 alkylene) Y2 -(optionally substituted C 1-3 alkylene)-O Y2 -(optionally substituted C 1-3 alkylene)-S Y2 -(optionally substituted C 1-3 alkylene)-SO2 Y2 or -(optionally substituted C 1-3 alkylene)-NR Y Y2 Y2 represents the binding site to Y 2 , R Y is H or optionally substituted C 1-3 alkyl, Y 2 is a bond, optionally substituted phenylene or optionally substituted heteroarylene, L P is a group that chemically binds Y 2 to EUB, EUB is a group having a binding ability to one E3 ubiquitin ligase selected from the group consisting of VHL and hydroxylated glycerolipid, R st1 is C 1-12 alkylene, R AA are independently of each other H, methyl, isopropyl, benzyl or -(CH2)3-NH-C(=O)-NH2, d is an integer from 2 to 4, and t is 0 or 1.

[0107]

[43] The drug-linker complex or a salt thereof according to

[36] , wherein the formula (LD-1) is represented by formula (LD-4a), (LD-5a), (LD-6a), (LD-7a), (LD-8a), (LD-9a), (LD-10a), (LD-11a), (LD-12a), (LD-13a), (LD-14a) or (LD-26a),

[0108] (in the formula, R st1 is C 1-12 alkylene, R AA independently of one another H, methyl, isopropyl, benzyl or -(CH2)3-NH-C(=O)-NH2, d is an integer of 2 to 4, and t is 0 or 1).

[0109]

[44] The drug-linker complex or a salt thereof according to

[36] , wherein the formula (LD-1) is represented by formula (LD-15), (LD-16), (LD-17), (LD-18), (LD-19), (LD-20), (LD-21), (LD-22), (LD-23), (LD-24), (LD-25) or (LD-26).

[0110]

[0111]

[45] Phosphoric acid-dihydro- (2R) -2- ( { (4R) -1- [ (2S) -2- { 4- [4- ( { [ (7M) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy] -4- { methyl [ (3S) -pyrrolidin-3-yl] amino} quinolin-8-yl] oxy} methyl) phenyl] -1H-1, 2, 3-triazol-1-yl} -3-methylbutanoyl] -4-hydroxy-L-prolyl} amino) -2- [4- (1H-1, 2, 4-triazol-1-yl) phenyl] ethyl ester or a salt thereof.

[0112] Note that, in the case where a symbol in a certain chemical formula in the present specification is used in other chemical formulae without being particularly described, the same symbol indicates the same meaning.

[0113] Effects of the Invention

[0114] The antibody-drug complex of formula (I) or a salt thereof has a G12D mutant KRAS protein degradation-inducing effect and can be used as a therapeutic agent for cancer, particularly cancer expressing G12D mutant KRAS. Furthermore, the drug-linker complex of the present invention comprises a compound having a G12D mutant KRAS protein degradation-inducing effect and can be used to synthesize the antibody-drug complex of the present invention or a salt thereof. Detailed Implementation

[0115] The present invention will now be described in detail.

[0116] In this specification, "substitutable" means unsubstituted or having 1 to 5 substituents. Alternatively, it means unsubstituted or having 1 to 3 substituents. It should be noted that when there are two or more substituents, these substituents can be the same or different from each other.

[0117] “C 1-12 "Alkyl" refers to a straight-chain or branched alkyl group with 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, dodecyl, etc. (Hereinafter, the number of carbon atoms will be described in the same way). As an example, it is ethyl or dodecyl.

[0118] Similarly, "C" 1-6 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl. Alternatively, it can be methyl, ethyl, n-propyl, isopropyl, or sec-butyl; or methyl, ethyl, n-propyl, isopropyl, or tert-butyl; or methyl, ethyl, n-propyl, isopropyl, or n-butyl; or methyl, ethyl, or n-propyl.

[0119] Similarly, "C" 1-3 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, or isopropyl. Examples include methyl or ethyl, n-propyl or isopropyl, methyl or isopropyl, methyl or n-propyl, ethyl or isopropyl, methyl, ethyl, isopropyl, and n-propyl.

[0120] Likewise, "C5 alkyl" means an alkyl group having 5 carbon atoms which is linear or branched, for example, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, and as one embodiment, n-pentyl.

[0121] "C 3-6 "Cycloalkyl" means a cycloalkyl group having 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. As one embodiment, cyclobutyl, cyclopentyl or cyclohexyl, as one embodiment, cyclobutyl or cyclopentyl, as one embodiment, cyclopentyl or cyclohexyl, as one embodiment, cyclopropyl or cyclobutyl, as one embodiment, cyclopropyl, as one embodiment, cyclobutyl, as one embodiment, cyclopentyl, as one embodiment, cyclohexyl.

[0122] "C 1-3 "Alkylene" means a divalent group in which a carbon atom of the above "C 1-3 alkyl" has another binding bond. For example, methylene, ethylene, trimethylene, methylmethylene, 1,1-dimethylmethylene, and the like. As one embodiment, C 1-3 alkylene which is linear or branched, as one embodiment, methylene, ethylene or trimethylene, as one embodiment, methylene or ethylene, as one embodiment, methylene, as one embodiment, ethylene.

[0123] Likewise, "C 1-6 alkylene" means a divalent group in which a carbon atom of the above "C 1-6 alkyl" has another binding bond. For example, methylene, ethylene, trimethylene, methylmethylene, 1,1-dimethylmethylene, and the like. As one embodiment, C 1-3 alkylene.

[0124] Likewise, "C 1-12 alkylene" means a divalent group in which a carbon atom of the above "C 1-12 alkyl" has another binding bond. For example, methylene, ethylene, trimethylene, methylmethylene, 1,1-dimethylmethylene, and the like. As one embodiment, C 1-12 alkylene which is linear or branched, as one embodiment, C 3-8 alkylene, as one embodiment, C5 alkylene, as one embodiment, pentamethylene.

[0125] Likewise, "C5 alkylene" refers to a divalent group in which the carbon atom of the above "C5 alkyl" has one more binding site. For example, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, and the like, and as one mode, pentamethylene.

[0126] "Heterocycloalkyl" refers to a 4- to 7-membered saturated heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, and can contain an unsaturated bond in part. In addition, the sulfur atom as a ring-constituting atom of the saturated heterocyclic group can be oxidized. As one mode of "heterocycloalkyl", "4- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms", as one mode, "4- to 6-membered heterocycloalkyl containing 1 to 2 oxygen atoms as ring-constituting atoms", as one mode, "4- to 6-membered heterocycloalkyl containing 1 oxygen atom as ring-constituting atom", as one mode, "4- to 6-membered heterocycloalkyl containing 1 to 2 nitrogen atoms as ring-constituting atoms", as one mode, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, oxazolidinyl, imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, as one mode, oxetanyl, tetrahydropyranyl, or tetrahydrofuranyl, as one mode, tetrahydropyranyl or tetrahydrofuranyl, as one mode, tetrahydropyranyl, as one mode, tetrahydrofuranyl, as one mode, azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, as one mode, piperidinyl or piperazinyl, as one mode, piperidinyl, as one mode, piperazinyl.

[0127] "Heterocycloalkylene" refers to a divalent group in which the nitrogen atom or carbon atom constituting the ring of the above "heterocycloalkyl" has one more binding site. As one mode of "heterocycloalkylene", "4- to 6-membered heterocycloalkylene containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms", as one mode, "4- to 6-membered heterocycloalkylene containing 1 to 2 oxygen atoms as ring-constituting atoms", as one mode, "4- to 6-membered heterocycloalkylene containing 1 oxygen atom as ring-constituting atom", as one mode, "4- to 6-membered heterocycloalkylene containing 1 to 2 nitrogen atoms as ring-constituting atoms", as one mode, oxetanediyl, tetrahydrofurandiyl, tetrahydropyrandiyl, azetidinodiyl, pyrrolidinodiyl, piperidinodiyl, oxazolidinediyl, imidazolidinediyl, piperazinediyl, morpholinodiyl, thiomorpholinodiyl, dioxothiomorpholinodiyl, as one mode, oxetanediyl, tetrahydropyranediyl or tetrahydrofurandiyl, as one mode, tetrahydropyranediyl or tetrahydrofurandiyl, as one mode, tetrahydropyranediyl, as one mode, tetrahydrofurandiyl, as one mode, azetidinediyl, pyrrolidinediyl, piperidindiyl or piperazinediyl, as one mode, piperidindiyl or piperazinediyl, as one mode, piperidindiyl, as one mode, piperazinediyl.

[0128] "Bridged heterocycloalkyl" means a 7- to 9-membered bridged heterocyclyl group containing 1 to 2 nitrogen atoms as ring-constituting atoms. As one mode, a saturated 7- to 9-membered bridged heterocyclyl group containing 1 to 2 nitrogen atoms as ring-constituting atoms, as one mode, a saturated 7- to 9-membered bridged heterocycloalkyl group containing 2 nitrogen atoms as ring-constituting atoms, as one mode, a saturated 7- to 9-membered bridged heterocycloalkyl group containing 2 nitrogen atoms as ring-constituting atoms and 1 of the 2 nitrogen atoms being bonded to 1 hydrogen atom. For example, diazabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl, diazabicyclo[3.1.1]heptanyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.3.1]nonyl. As one mode, diazabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]oct-6-enyl, diazabicyclo[3.2.1]oct-2-enyl, diazabicyclo[3.1.1]heptanyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]hept-5-enyl, as one mode, diazabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl, diazabicyclo[3.1.1]heptanyl or diazabicyclo[2.2.1]heptanyl, as one mode, diazabicyclo[2.2.1]heptanyl or diazabicyclo[3.2.1]octanyl, as one mode, diazabicyclo[2.2.1]heptanyl, as one mode, diazabicyclo[3.2.1]octanyl, as one mode, 2,5-diazabicyclo[2.2.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, as one mode, 2,5-diazabicyclo[2.2.1]heptanyl, as one mode, 3,8-diazabicyclo[3.2.1]octanyl.

[0129] "Bridged heterocyclic alkyl" refers to a divalent group in the aforementioned "bridged heterocyclic alkyl" in which the nitrogen or carbon atom constituting the ring has another bond. One example is a saturated 7- to 9-membered bridged heterocyclic alkyl containing two nitrogen atoms; another example is a saturated 7- to 9-membered bridged heterocyclic alkyl containing two nitrogen atoms, one of which is bonded to one hydrogen atom. Examples include diazabicyclo[2.2.2]octanediyl, diazabicyclo[3.2.1]octanediyl, diazabicyclo[3.1.1]heptanediyl, diazabicyclo[2.2.1]heptanediyl, and diazabicyclo[3.3.1]nonanediyl. As one embodiment, it is diazabicyclo[2.2.2]octanediyl, diazabicyclo[3.2.1]octanediyl, diazabicyclo[3.2.1]oct-6-endiyl, diazabicyclo[3.2.1]oct-2-endiyl, diazabicyclo[3.1.1]heptanediyl, diazabicyclo[2.2.1]heptanediyl, diazabicyclo[2.2.1]hept-5-endiyl; as another embodiment, it is diazabicyclo[2.2.2]octanediyl, diazabicyclo[3.2.1]octanediyl, diazabicyclo[3.1.1]heptanediyl or diazabicyclo[2.2.1]octanediyl. [2.2.1]Heptanediyl, as one form, is diazabicyclo[2.2.1]heptanediyl or diazabicyclo[3.2.1]octanediyl, as one form, is diazabicyclo[2.2.1]heptanediyl, as one form, is diazabicyclo[3.2.1]octanediyl, as one form, is 2,5-diazabicyclo[2.2.1]heptanediyl, 3,8-diazabicyclo[3.2.1]octanediyl, as one form, is 2,5-diazabicyclo[2.2.1]heptanediyl, as one form, is 3,8-diazabicyclo[3.2.1]octanediyl.

[0130] "Bridged piperazine group" refers to a piperazine group in which the carbon atoms on the ring have a bridging structure, which is composed of carbon atoms. Examples include diazabicyclo[2.2.1]heptyl, diazabicyclo[3.2.1]octyl, and diazabicyclo[3.1.1]heptyl. As one mode, it is diazabicyclo[2.2.1]heptyl. As one mode, it is diazabicyclo[3.2.1]octyl. As one mode, it is diazabicyclo[3.1.1]heptyl; as one mode, it is 2,5-diazabicyclo[2.2.1]heptyl and 3,8-diazabicyclo[3.2.1]octyl; as one mode, it is 2,5-diazabicyclo[2.2.1]heptyl; as one mode, it is 3,8-diazabicyclo[3.2.1]octyl.

[0131] "Bridged piperazinyl" refers to a divalent group in which the nitrogen atoms that form the ring of the above "piperazinyl" have another bond. For example, a divalent group of diazabicyclo[2.2.1]heptane, diazabicyclo[3.2.1]octane, diazabicyclo[3.1.1]heptane. As one mode, a divalent group of diazabicyclo[2.2.1]heptane. As one mode, a divalent group of diazabicyclo[3.2.1]octane. As one mode, a divalent group of diazabicyclo[3.1.1]heptane, as one mode, a divalent group of 2,5-diazabicyclo[2.2.1]heptane, 3,8-diazabicyclo[3.2.1]octane, as one mode, a divalent group of 2,5-diazabicyclo[2.2.1]heptane, as one mode, a divalent group of 3,8-diazabicyclo[3.2.1]octane.

[0132] "Spiro heterocycloalkyl" refers to a saturated 7- to 9-membered heterocyclic ring group having 1 to 2 nitrogen atoms as ring-constituting atoms and having a spiro atom. As one mode, a saturated 7- to 9-membered heterocyclic ring group having 2 nitrogen atoms as ring-constituting atoms and having a spiro atom. For example, a divalent group of diazaspiro[3.3]heptyl, diazaspiro[3.4]octyl, diazaspiro[3.5]nonyl, diazaspiro[4.4]nonyl. As one mode, a divalent group of 2,6-diazaspiro[3.4]octyl, as one mode, a divalent group of 2,6-diazaspiro[3.3]heptyl.

[0133] "Arylsulfonyl" means a radical of the formula -SO2-R wherein R is aryl as previously defined. For example, arylsulfonyl is phenylsulfonyl.

[0134] "Heterocycle" means an aromatic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms.

[0135] "5-membered heterocycle" means a 5-membered heterocycle containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms. As one embodiment of the "5-membered heterocycle", a pyrazole ring, an imidazole ring, a triazole ring, a tetrazole ring, azole ring, an isothiazole ring, azole ring, an isothiazole ring, azole ring, an isothiazole ring, azole ring, an isothiazole ring, azole ring, an isothiazole ring, azole ring, an isothiazole ring,

[0136] "6-membered heterocycle" means a 6-membered heterocycle containing 1 to 3 nitrogen atoms as ring-constituting atoms. As one embodiment of the "6-membered heterocycle", a 6-membered heterocycle containing 1 to 3 nitrogen atoms as ring-constituting atoms, as one embodiment, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring or a triazine ring.

[0137] "5- to 6-membered heterocycles" refers to either 5-membered or 6-membered heterocycles. As one type of "5- to 6-membered heterocycle," it is a 5-membered heterocycle; as another type, it is a 6-membered heterocycle.

[0138] "Heteroaryl" refers to a 5- to 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-forming atoms. One example is a 5-membered ring heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-forming atoms, or a 6-membered ring heteroaryl containing 1 to 3 nitrogen atoms as ring-forming atoms. Another example is a 5-membered ring heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-forming atoms, or a 6-membered ring heteroaryl containing 1 to 3 nitrogen atoms as ring-forming atoms. Another example includes pyrazolyl, imidazolyl, triazolyl, tetrazolyl, etc. azole group, iso azole group, thiazolyl group, isothiazol group, Diazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, in one mode being pyrazolyl, imidazoleyl, triazolyl, or tetrazolyl. azole group, iso azole group, thiazolyl group, isothiazol group, Diazolyl, thiadiazolyl, or in some form pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.

[0139] "Hypoaryl" refers to a divalent group in the aforementioned "heteroaryl" in which two different carbon atoms and / or nitrogen atoms constituting the ring are bonded together. One type of "hypoaryl" is a 5-membered ring heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms, or a 6-membered ring heteroaryl containing 1 to 3 nitrogen atoms as ring constituent atoms. Another type is a 5-membered ring heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms. A third type is a 6-membered ring heteroaryl containing 1 to 3 nitrogen atoms as ring constituent atoms. A fourth type is a pyrazolidinediyl, imidazolediyl, triazolediyl, tetraazolediyl, etc. azole dimethyl, isopropyl azolediyl, thiazolediyl, isothiazolediyl, Diazolediyl, thiadiazolediyl, pyridinediyl, pyrimidinediyl, pyrazindiyl, pyridazindiyl, or triazindiyl, in one manner, pyrazolediyl, imidazolediyl, triazolediyl, or tetrazoliumdiyl. azole dimethyl, isopropyl azolediyl, thiazolediyl, isothiazolediyl, Diazole dimethyl, thiadiazole dimethyl, or in one manner, pyridine dimethyl, pyrimidine dimethyl, pyrazine dimethyl, pyridazine dimethyl, or triazine dimethyl.

[0140] "4- to 8-membered saturated heterocycles" refer to 4- to 8-membered saturated heterocycles containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring atoms. These heterocycles may contain unsaturated bonds, may have bridges, and may form spirocyclic rings. Furthermore, the sulfur atoms in these heterocycles can be oxidized. Examples include oxoheterocyclic butanes, tetrahydrofuran, tetrahydropyran, azirrocyclic butanes, pyrrolidines, piperidines, and azirrocyclic heptanes. Alzolidine, imidazolidine, piperazine, morpholine, thiomorpholine, dioxothiomorpholine, azabicyclo[2.2.1]heptane, diazabicyclo[2.2.1]heptane, azaspiro[3.3]heptane, azaspiro[3.4]octane, oxazaspiro[3.3]heptane or diazaspiro[3.3]heptane, as an example, oxacyclobutane, tetrahydrofuran, tetrahydropyran, azabicyclobutane, pyrrolidine, Piperidine, piperazine, morpholine, thiomorpholine, dioxothiomorpholine, azaspiro[3.3]heptane or oxazaspiro[3.3]heptane, as an example, azacyclobutane, tetrahydropyran, morpholine or oxazaspiro[3.3]heptane, as an example, azacyclobutane or tetrahydropyran, as an example, morpholine or oxazaspiro[3.3]heptane, as an example, tetrahydropyran.

[0141] As "substitutable heterocyclic alkyl", "substitutable heterocyclic alkylene", and L P L 1A L 4A Includes "replaceable C" 1-6 One acceptable way to use substituents in "alkylene" is C10. 1-3 Alkyl, -O(C) 1-3 Alkyl groups, C=O, halogens, and OH groups are used as a way to form C=O. 1-3 Alkyl, -O(C) 1-3 Alkyl groups), halogens, as a form, are -O(C 1-3 Alkyl groups), halogens, as a way, are C 1-3 Alkyl, as a form, is OH, as a form, is F, as a form, is methyl, as a form, is ethyl.

[0142] As "replaceable C" 1-6 Alkyl group, substituted C 1-3 Alkyl group, substituted C 1-3 One acceptable way to use substituents in "alkylene" is C10. 1-3 Alkyl, -O(C) 1-3 Alkyl groups, C=O, halogens, and OH groups are used as a way to form C=O. 1-3 Alkyl, -O(C) 1-3 Alkyl groups), halogens, as a form, are -O(C1-3 Alkyl groups), halogens, as a way, are C 1-3 Alkyl, as a form, is OH, as a form, is F, as a form, is methyl, as a form, is ethyl.

[0143] As one way to accept substituents in "substitutable heteroaryl", "substitutable phenylene", and "substitutable heteroaryl", C 1-3 Alkyl, -O(C) 1-3 Alkyl groups, halogens, and OH groups are used as a way to form C. 1-3 Alkyl, -O(C) 1-3 Alkyl groups), halogens, as a way, are C 1-3 Alkyl, as a form, is methyl, as a form, is ethyl, as a form, is halogen, as a form, is F.

[0144] As "replaceable" One acceptable way to substituents in "azole" is C 1-3 Alkyl, as a form, is methyl or isopropyl, as a form, is methyl, as a form, isopropyl.

[0145] As "replaceable C" 1-12 "alkylene" and R st1 Includes "replaceable C" 1-6 One acceptable way to use substituents in "alkylene" is -NH2, -C 1-6 Alkylene -NH2, -NH-C(=O)-C 1-6 Alkyl group, -NH-C(=O)-C 1-3 Alkyl, as a form, is -C 1-6 Alkylene-NH2.

[0146] "Halogen" refers to F, Cl, Br, and I. As a form, it is F, Cl, or Br; as a form, it is F or Cl; as a form, it is F or Br; as a form, it is F; as a form, it is Cl; as a form, it is Br.

[0147] Halogenated C 1-6 "Alkyl" refers to a straight-chain or branched C14 group that has been substituted with one or more halogens. 1-6 Alkyl groups. Examples include trifluoromethyl, trifluoroethyl, trifluoropropyl, 2-fluoro-2-methylpropyl, difluoromethyl, difluoroethyl, fluoromethyl, or chloromethyl. One possible arrangement is difluoroethyl, trifluoromethyl, or difluoromethyl; furthermore, another possible arrangement is trifluoromethyl or difluoromethyl; and yet another possible arrangement is trifluoromethyl, while in other arrangements it is difluoromethyl.

[0148] “EUB” refers to a group having a binding ability to an E3 ubiquitin ligase. As one mode, a group having a binding ability to one E3 ubiquitin ligase selected from the group consisting of VHL (von Hippel-Lindau), cereblon, IAP (inhibitor of apoptosis protein), MDM2 (mouse double minute 2 homolog), DCAF11 (DDB1 and CUL4 associated factor 11), DCAF15 (DDB1 and CUL4 associated factor 15), DCAF16 (DDB1 and CUL4 associated factor 16), BIRC2 (Baculoviral IAP repeat containing 2), KEAP1 (Kelch-like ECH-associated protein 1), RNF4 (RING finge protein 4), RNF114 (RING finge protein 114), FEM1B (Protein fem-1 homolog B), and AhR (Aryl hydrocarbon receptor). As one mode, a group having a binding ability to one E3 ubiquitin ligase selected from the group consisting of VHL, cereblon, IAP, and MDM2. As one mode, a group having a binding ability to one E3 ubiquitin ligase selected from the group consisting of VHL and cereblon. As one mode, a group having a binding ability to VHL. As one mode, a group having a binding ability to cereblon. The person skilled in the art can understand, but is not limited to, by referring to the following literature.

[0149] [Documents]

[0150] Current Research in Chemical Biology., 2022, 2, 100020

[0151] Front. Chem., 2021, 9, 707317

[0152] J. Am. Chem. Soc., 2021, 143, 5141

[0153] Signal Transduct. Target. Ther., 2020, 5, 129

[0154] Nat. Chem. Biol., 2019, 15(7), 737

[0155] Communications Biology., 2020, 3, 140

[0156] Sci. Rep., 2020, 10(1), 15543

[0157] ACS Chem. Biol., 2019, 14, 2430

[0158] Cell Chem. Biol., 2021, 28(4), 559

[0159] J. Am. Chem. Soc., 2022, 144, 701

[0160] ACS Chem. Biol., 2019, 14, 2822

[0161] “G12D mutation” means a mutation in which the amino acid residue corresponding to the 12th position of the codon is changed from glycine to aspartic acid in a wild-type protein.

[0162] “G12D mutant KRAS” means KRAS having the above “G12D mutation”.

[0163] “Z N1 ” means 1 group selected from the group consisting of formulae (Z N1 -1) to (Z N1 -15) LGZ represents a bonding site to LG Z or L P , R Z1’ are each independently C 1-6 alkyl which can be substituted, halogen, cyano, -OH, -O-(C 1-6 alkyl which can be substituted), -S-(C 1-6 alkyl which can be substituted), -NH-(C 1-6 alkyl which can be substituted), or -N-(C 1-6 alkyl)2, n’ is an integer of 0 to 2, R Z2’ , R Z3’ , and R Z4’ are each independently H or C 1-6 alkyl which can be substituted, ring B1’ is a benzene ring or a 6-membered heterocyclic ring, and here, R Z1’ and LGZ and the carbon atom constituting the ring B1' forms a bond.

[0164]

[0165] "Z N2 " means one group selected from the group consisting of formulae (Z N2 -1) to (Z N2 -15) below. LGZ represents a bonding site to LG Z or L P , R Z1’ are each independently H or a substitutable C 1-6 alkyl group, halogen, cyano, -OH, -O- (a substitutable C 1-6 alkyl group), -S- (a substitutable C 1-6 alkyl group), -NH- (a substitutable C 1-6 alkyl group) or -N- (a substitutable C 1-6 alkyl group) 2, n' is an integer of 0 to 2, R Z2’ , R Z3’ and R 1-6 are each independently H or a substitutable C Z1’ alkyl group, and ring B1' is a benzene ring or a 6-membered heterocyclic ring. LGZ and the carbon atom constituting the ring B1' forms a bond.

[0166]

[0167] "Z C " means one group selected from the group consisting of formulae (Z C -16) to (Z C -27) below. LGZ represents a bonding site to LG Z or L P , R Z1’ are each independently H or a substitutable C 1-6 alkyl group, halogen, cyano, -OH, -O- (a substitutable C 1-6 alkyl group), -S- (a substitutable C 1-6 alkyl group), -NH- (a substitutable C 1-6 alkyl group) or -N- (a substitutable C 1-6 alkyl group) 2, n' is an integer of 0 to 2, R Z2’ , R Z4’ and R Z5’ are each independently H or a substitutable C 1-6 alkyl group, and M' is a bond, -O-, -S-, -N(RM’ ) - or C1-6alkyl which can be substituted 1-3 alkylene, R M’ is H or C1-6alkyl which can be substituted 1-3 alkyl, ring B1' is a benzene ring or a 6-membered heterocyclic ring, and ring B2' is a benzene ring or a 5- to 6-membered heterocyclic ring, where R Z1’ and LGZ forms a bond with a carbon atom constituting ring B1', M', R Z1’ and LGZ forms a bond with a carbon atom constituting ring B2').

[0168]

[0169] The "antigen" is used as a term indicating a molecule or a part of a molecule to which an antigen-binding protein such as an antibody, an antigen-binding fragment, etc. can specifically bind. The antigen can be a molecule such as a protein, a nucleic acid, etc. Sometimes, one antigen has one or more than one epitope capable of interacting with different antibodies, etc.

[0170] The antibody (or immunoglobulin) refers to a glycoprotein having a basic structure of 4 chain structure having left-right symmetrical Y-shaped structure composed of 2 heavy chains having a single sequence and 2 light chains having a single sequence. There are 5 classes of IgG, IgM, IgA, IgD, and IgE. The heavy chain is usually composed of a polypeptide chain containing about 440 amino acids, and has a characteristic structure in each class, and is called Igγ, Igμ, Igα, Igδ, Igε, respectively, corresponding to IgG, IgM, IgA, IgD, IgE. In addition, IgG has subclasses such as IgG1, IgG3, IgG3, IgG4, and the respective corresponding heavy chains are called Igγ1, Igγ2, Igγ3, Igγ4. The light chain is usually composed of a polypeptide chain containing about 220 amino acids, and there are known two types of λ type and κ type, and are called Igλ, Igκ, respectively. The above two types of light chains can be paired with any type of heavy chain.

[0171] Regarding the intrachain disulfide bond of an antibody molecule, there are four in the heavy chain (five in Igμ, Igε) and two in the light chain, and one loop is formed per 100 to 110 amino acid residues. Their stereostructures are similar between the loops and are called structural units or domains. The domain at the N-terminal end of the heavy chain and the light chain is called the variable region, and it is known that even antibodies produced from the same class (or subclass) of the same animal have diverse amino acid sequences and are involved in the binding specificity of the antibody to the antigen. The amino acid sequence of the domain on the C-terminal side downstream of the variable region is approximately constant among the classes or subclasses and is called the constant region. In the heavy chain, there are the heavy chain variable region (VH) and the heavy chain constant region (CH) from the N-terminal end to the C-terminal end. In the CH, further from the N-terminal side, there are three domains, the CH1 domain, the CH2 domain, and the CH3 domain. In the light chain, there are the light chain variable region (VL) and the light chain constant region (CL) from the N-terminal end to the C-terminal end.

[0172] The amino acid sequences of the three complementarity determining regions (CDRs) present in VH and VL vary greatly and contribute to the variability of the variable region. The CDRs are regions of about 5 to 10 amino acid residues present in the order of CDR1, CDR2, and CDR3 at the N-terminal end of the heavy chain and the light chain, respectively, and form the antigen binding site. On the other hand, the part of the variable region other than the CDRs is called the framework region (FR), which is composed of FR1 to FR4, and the variation in the amino acid sequence is less.

[0173] When an antibody is treated with papain, which is a proteolytic enzyme, three antibody fragments are obtained. The two fragments on the N-terminal side are called Fab (Fragment, antigen binding) regions, and the fragment on the C-terminal side is called the Fc (Fragment, crystallizable) region.

[0174] In the present specification, an "antibody" refers to a polypeptide that specifically binds to an antigen, and can be of any structure as long as it can specifically bind to an antigen. For example, an antibody includes not only polypeptides having a basic structure of four chains such as IgG but also various polypeptides of various shapes such as antigen-binding fragments, multispecific antibodies (e.g., bispecific antibodies), and the like described later.

[0175] An "antigen-binding fragment" refers to a molecule containing at least one polypeptide chain derived from an antibody and possessing antigen-binding activity. Representative antigen-binding fragments include single-chain variable region fragments (scFv), Fab fragments, Fab' fragments, and F(ab')2 fragments. scFv is a monovalent antigen-binding fragment composed of VH and VL linked by a linker. Fab fragments are monovalent antigen-binding fragments composed of a light chain and a VH and CH1 domain containing the heavy chain. Fab' fragments are monovalent antigen-binding fragments composed of a light chain, a VH and CH1 domain containing the heavy chain, and a portion of a hinge region, with cysteine ​​residues forming the SS bond between the heavy chains locally in the hinge region. F(ab')2 fragments are divalent molecules formed by Fab' fragments linked by disulfide bonds. Monovalent means containing one antigen-binding site, while divalent means containing two antigen-binding sites.

[0176] A polypeptide is a substance composed of multiple amino acids linked together by peptide bonds. The amino acids used in a polypeptide can be either natural or artificial. A polypeptide must contain at least two amino acid residues, preferably at least ten.

[0177] "Multispecific antibody" refers to an antibody that can specifically bind to two or more different antigens. Depending on the number of antigens bound, it may be called a bispecific antibody or a trispecific antibody. Multispecific antibodies include complexes of two or more antibodies and / or antigen-binding fragments that can bind to different antigens respectively. Unless otherwise specified in the context, the term "antibody" as used in this specification includes multispecific antibodies.

[0178] "Human antibody" refers to an antibody that has the amino acid sequence of human immunoglobulins. In this specification, "humanized antibody" refers to an antibody in which some, most, or all of the amino acid residues other than the CDR are replaced by amino acid residues derived from human immunoglobulin molecules. There are no particular limitations on the method of humanization; for example, humanized antibodies can be prepared with reference to U.S. Patent No. 5,225,539 and U.S. Patent No. 6,180,370.

[0179] Post-translational modification refers to the modification of antibodies after translation during intracellular expression. Examples of post-translational modifications include glycosylation to N- or O-linked forms, N-terminal or C-terminal processing, deamidation, isomerization of aspartic acid, and oxidation of methionine. Such post-translational modifications are known to occur in various antibodies (J. Pharma. Sci., 2008; Vol. 97: p. 2426-2447).

[0180] The amino acid residue numbering of the antibody used in the present specification can be defined according to these numbering systems by designating the Kabat numbering or the EU index (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed, 1991, NIH Publication No. 91-3242).

[0181] In the present specification, "Identity" means the value of Identity obtained using EMBOSS Needle (Necleic Acids Res., 2015; Vol. 43: pW580-W584) with default parameters. The above parameters are as follows.

[0182] Gap Open Penalty = 10

[0183] Gap Extend Penalty = 0.5

[0184] Matrix = EBLOSUM62

[0185] End Gap Penalty = false

[0186] In the present specification, an antibody or an antigen-binding fragment is sometimes expressed as "Ab" together.

[0187] "Antibody drug conjugate" means a complex in which an antibody and a drug are bound via a linker. The drug can be delivered to a cell or a tissue targeted by the antibody. As one mode of the antibody drug conjugate, the antibody drug conjugate is a complex in which an antibody and a drug are bound via a cleavable linker in a living organism. As one mode of the antibody drug conjugate, the antibody drug conjugate is a complex in which an antibody and a drug are bound via a non-cleavable linker.

[0188] "Linker" means a divalent chemical group that binds one functional compound to another functional compound. As one mode of the linker, it is a cleavable linker in a living organism, and as one mode, it is a non-cleavable linker.

[0189] "Cleavable linker in a living organism" means a linker having a partial structure that is cleavable in a living organism. "Partial structure cleavable in a living organism" means a partial structure that is cleavable in a living organism by the action of an enzyme or the like. As one mode, it is a partial structure that is cleavable by the action of a protease, and as one mode, it is a partial structure that is cleavable by the action of cathepsin B.

[0190] A "non-cleavable linker" refers to a linker which is not decomposed even by either of acidic conditions in vivo, particularly in lysosomes, or the action of a protease. For example, C=0, C(=0)NH-C 1-6 alkylene, C(=0)NH-C 1-6 alkylene, or polyethylene glycol.

[0191] "Subject" refers to a human or other animal in need of the prevention or treatment. In one mode, a human in need of treatment or prevention.

[0192] The following shows a mode of the antibody drug conjugate or salt thereof of the present application, and a drug (D), linker (L A ), and antibody or antigen-binding fragment (Ab) constituting the antibody drug conjugate or salt thereof. Even if the combination is not specifically described, one or two or more modes can be combined with other modes. That is, all modes can be freely combined.

[0193] 1. Drug (D)

[0194] The drug (D) constituting the antibody drug conjugate or salt thereof of the present application, and the drug-linker conjugate is a heterocyclic compound having a G12D mutant KRAS protein decomposition inducing action. A part or all of the linker (L A ) constituting the antibody drug conjugate or salt thereof of the present application is cleaved in a tumor cell, the drug (D) is liberated, whereby the effect appears. Note that in the case where -OH within the molecule of the drug (D) forms a phosphate ester, after being taken up by a tumor cell, sometimes the phosphate ester is cleaved by a phosphatase to generate a dephosphorylated body (Bioconjugate Chem., 2016; Vol. 27; p. 2081-2088). One mode of the drug (D) of the present application is shown below.

[0195] (1-1) A heterocyclic compound having a G12D mutant KRAS protein decomposition inducing action or a salt thereof.

[0196] (1-2) A heterocyclic compound having a structure represented by formula (II) or a salt thereof.

[0197]

[0198] (2-1) The heterocyclic compound according to (1-2) or a salt thereof, wherein A is CR A or N, R A is H, cyano, or C 1-3 alkyl which can be substituted.

[0199] (2-2) The heterocyclic compound according to (1-2) or a salt thereof, wherein A is CH or N.

[0200] (2-3) The heterocyclic compound or salt thereof according to (1-2), wherein A is CH.

[0201] (2-4) The heterocyclic compound or salt thereof according to (1-2), wherein A is N.

[0202] (3-1) The heterocyclic compound or salt thereof according to (1-2), wherein Q is CR Q or N, R Q is H, halogen, C 3-6 cycloalkyl, vinyl, or C 1-3 alkyl which can be substituted.

[0203] (3-2) The heterocyclic compound or salt thereof according to (1-2), wherein Q is CR Q , R Q is C 3-6 cycloalkyl.

[0204] (3-3) The heterocyclic compound or salt thereof according to (1-2), wherein Q is CR Q , R Q is cyclopropyl.

[0205] (4-1) The heterocyclic compound or salt thereof according to (1-2), wherein E is CH or N.

[0206] (4-2) The heterocyclic compound or salt thereof according to (1-2), wherein E is CH.

[0207] (5-1) The heterocyclic compound or salt thereof according to (1-2), wherein R 1 is naphthyl which can be substituted with 1 or 2 groups selected from the group consisting of cyano, OH, halogen, and C 1-3 alkyl which can be substituted, or 1 group selected from the group consisting of the following formula (III), formula (IV), and formula (V),

[0208] R 1a , R 1b , and R 1c are each independently H, vinyl, halogen, or C 1-3 alkyl which can be substituted.

[0209] (5-2) The heterocyclic compound or salt thereof according to (1-2), wherein R 1 is the following formula (III),

[0210] R 1a , and R 1c are each independently C1-3 Alkyl or halogen.

[0211] (5-3) The heterocyclic compound or its salt according to (1-2), wherein R 1 It is the following formula (III),

[0212] R 1a For halogens, R 1c C 1-3 alkyl.

[0213] (5-4) The heterocyclic compound or its salt according to (1-2), wherein R 1 It is given by the following formula (III-2).

[0214]

[0215] (6-1) The heterocyclic compound or its salt according to (1-2), wherein, R 2 -V 1 -V 2 Or W, V 1 For bonds, -CH2-, -O-, -S- or -N(R) V1 )-, R V1 H or C that can be substituted 1-3 alkyl, V 2 To select one group from the group consisting of formulas (VI) and (VII) below,

[0216] W is one group selected from the group consisting of formulas (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), and (XVI).

[0217] R 2a Each can be independently OH, OCH3, F, or a substituted C. 1-3 Alkyl, the R 2a It bonds only to the carbon atoms of the constituent atoms of the rings selected from the group consisting of the aza-butane ring shown in formula (VI), the pyrrolidine ring shown in formula (VII), the piperidine ring shown in formula (VIII), and the piperazine ring shown in formula (IX). m is an integer from 0 to 2.

[0218] (6-2) The heterocyclic compound or salt thereof according to (1-2), wherein, R 2 is -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S-, or -N(R V1 )-, R V1 is C 3-6 alkyl which can be substituted with 1 group selected from the group consisting of C 1-3 cycloalkyl, halogen, and -OH, V 2 is 1 group selected from the group consisting of the following formula (VI-2) or (VII-2),

[0219] W is 1 group selected from the group consisting of the following formula (VIII-2), formula (IX-2), formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV), formula (XV), and formula (XVI).

[0220]

[0221] (6-3) The heterocyclic compound or salt thereof according to (1-2), wherein, R 2 is -V 1 -V 2 or W, V 1 is a bond, -O-, or -N(R V1 )-, R V1 is C 1-3 alkyl, V 2 is the following formula (VII-2),

[0222] W is the following formula (XIV).

[0223]

[0224] (6-4) The heterocyclic compound or salt thereof according to (1-2), wherein, R 2 is -V 1 -V 2 or W, V 1 is -O- or -N(CH3)-, V2 is the following formula (VII-2),

[0225] W is the following formula (XIV).

[0226]

[0227] (6-5) The heterocyclic compound or a salt thereof according to (1-2), wherein, R 2 is -V 1 -V 2 or W, V 1 is -O-, V 2 is the following formula (VII-2),

[0228] W is the following formula (XIV).

[0229]

[0230] (6-6) The heterocyclic compound or a salt thereof according to (1-2), wherein, R 2 is -V 1 -V 2 or W, V 1 is -N(CH3)-, V 2 is the following formula (VII-2),

[0231] W is the following formula (XIV).

[0232]

[0233] (6-7) The heterocyclic compound or a salt thereof according to (1-2), wherein, R 2 is -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S-, or -N(R V1 )-, R V1 is C 3-6 alkyl which can be substituted with 1 group selected from the group consisting of C 1-3 cycloalkyl, halogen, and -OH, V 2(VI-2) or (VII-2) below,

[0234] W is 1 group selected from the group consisting of the following formula (IX-2), (XIII), and (XIV).

[0235]

[0236] (6-8) The heterocyclic compound or a salt thereof according to (1-2), wherein, R 2 is -V 1 -V 2 or W, V 1 is -O- or -N(R V1 )-, R V1 is C 1-3 alkyl, V 2 is the following formula (VI-2) or (VII-2),

[0237] W is 1 group selected from the group consisting of the following formula (IX-2), (XIII), and (XIV).

[0238]

[0239] (6-9) The heterocyclic compound or a salt thereof according to (1-2), wherein, R 2 is -V 1 -V 2 or W, V 1 is -O- or -N(CH3)-, V 2 is the following formula (VII-2),

[0240] W is the following formula (IX-2) or (XIV).

[0241]

[0242] (6-10) The heterocyclic compound or a salt thereof according to (1-2), wherein, R 2 is -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S-, or -N(RV1 R V1 is H or a C 1-3 alkyl group, V 2 is one group selected from the group consisting of the following formula (VI) and formula (VII),

[0243] W is one group selected from the following formula (VIII), formula (IX), or a 7- to 9-membered bridged heterocycloalkyl group containing 1 to 2 nitrogen atoms,

[0244] R 2a are each independently OH, OCH3, F, or a C 1-3 alkyl group, and R 2a binds only to a carbon atom constituting a ring selected from the group consisting of an azetidine ring represented by formula (VI), a pyrrolidine ring represented by formula (VII), a piperidine ring represented by formula (VIII), and a piperazine ring represented by formula (IX), m is an integer of 0 to 2.

[0245] (6-11) The heterocyclic compound or a salt thereof according to (1-2), wherein, R 2 is -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S-, or -N(R V1 )-, R V1 is H or a C 1-3 alkyl group, V 2 is one group selected from the group consisting of the following formula (VI) and formula (VII),

[0246] W is one group selected from the group consisting of the following formula (VIII), formula (IX), formula (X), formula (XI), formula (XII-2), formula (XIII), formula (XIV), formula (XV), and formula (XVI),

[0247] R 2a are each independently OH, OCH3, F, or a C 1-3 alkyl group, and R 2a ​only to a carbon atom that is a constituting atom of a ring selected from the group consisting of an azetidine ring represented by formula (VI), a pyrrolidine ring represented by formula (VII), a piperidine ring represented by formula (VIII), and a piperazine ring represented by formula (IX), m is an integer of 0 to 2.

[0248] (6-12) The heterocyclic compound or a salt thereof according to (1-2), wherein, R 2 is -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S-, or -N(R V1 )-, R V1 is C 3-6 alkyl which can be substituted with 1 group selected from the group consisting of C 1-3 cycloalkyl, halogen, and -OH. V 2 is 1 group selected from the group consisting of the following formulae (VI-2) or (VII-2),

[0249] W is 1 group selected from the group consisting of the following formulae (VIII-2), (IX-2), (X), (XI), (XII-2), (XIII), (XIV), (XV), and (XVI).

[0250]

[0251] (6-13) The heterocyclic compound or a salt thereof according to (1-2), wherein R 2 is a 7- to 9-membered bridged heterocycloalkyl group containing 1 to 2 nitrogen atoms.

[0252] (7-1) The heterocyclic compound or a salt thereof according to (1-2), wherein R 3 is C 1-6 alkyl which can be substituted, heterocycloalkyl which can be substituted, or heteroaryl which can be substituted.

[0253] (7-2) The heterocyclic compound or a salt thereof according to (1-2), wherein R 3 is C 1-6 alkyl which can be substituted with 1 group selected from the group consisting of -O-(C 1-6 alkyl), -S-(C 1-6 alkyl), -N-(C 1-6 alkyl)2, and heterocycloalkyl, or heterocycloalkyl which can be substituted.

[0254] (7-3) The heterocyclic compound or salt thereof according to (1-2), wherein R 3 is substituted with 1 group selected from the group consisting of -O(C 1-6 alkyl), oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl. 1-6 alkyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0255] (7-4) The heterocyclic compound or salt thereof according to (1-2), wherein R 3 is C 1-3 alkyl which can be substituted with tetrahydrofuranyl, tetrahydropyranyl, or -OCH3 or tetrahydrofuranyl.

[0256] (7-5) The heterocyclic compound or salt thereof according to (1-2), wherein R 3 is n-propyl which can be substituted with -OCH3 or tetrahydropyranyl.

[0257] (8-1) The heterocyclic compound or salt thereof according to (1-2), wherein X is a bond, -CH2-, -O-, -S-, or -NR 4X -, R 4X is H or C 1-3 alkyl which can be substituted.

[0258] (8-2) The heterocyclic compound or salt thereof according to (1-2), wherein X is -O- or -NR 4X -, R 4X is C 1-3 alkyl.

[0259] (8-3) The heterocyclic compound or salt thereof according to (1-2), wherein X is -O-.

[0260] (9-1) The heterocyclic compound or salt thereof according to (1-2), wherein Y 1 is -O-(C 1-3 alkylene which can be substituted) Y2 , -S-(C 1-3 alkylene which can be substituted) Y2 , -SO2-(C 1-3 alkylene which can be substituted) Y2 , -NR Y -(C 1-3 alkylene which can be substituted) Y2 , -(C 1-3 alkylene which can be substituted)-O Y2, -(substitutable C 1-3 alkylene)-S Y2 , -(substitutable C 1-3 alkylene)-SO2 Y2 or -(substitutable C 1-3 alkylene)-NR Y Y2 Y2 represents a bonding part to Y 2 , R Y is H or substitutable C 1-3 alkyl.

[0261] (9-2) The heterocyclic compound or a salt thereof according to (1-2), wherein Y 1 is -O-(C 1-3 alkylene) Y2 or -(C 1-3 alkylene)-O Y2 Y2 represents a bonding part to Y 2 .

[0262] (9-3) The heterocyclic compound or a salt thereof according to (1-2), wherein Y 1 is -O-(C 1-3 alkylene) Y2 Y2 represents a bonding part to Y 2 .

[0263] (9-4) The heterocyclic compound or a salt thereof according to (1-2), wherein Y 1 is -O-(methylene) Y2 Y2 represents a bonding part to Y 2 .

[0264] (10-1) The heterocyclic compound or a salt thereof according to (1-2), wherein Y 2 is a bond, substitutable phenylene or substitutable heteroarylene.

[0265] (10-2) The heterocyclic compound or a salt thereof according to (1-2), wherein Y 2 is phenylene or pyridinediyl.

[0266] (10-3) The heterocyclic compound or salt thereof according to (1-2), wherein Y 2 is a phenylene group which can be substituted with fluorine.

[0267] (10-4) The heterocyclic compound or salt thereof according to (1-2), wherein Y 2 is a phenylene group.

[0268] (10-5) The heterocyclic compound or salt thereof according to (1-2), wherein Y 2 is a substituted phenylene group or a pyridinediyl group.

[0269] (11-1) The heterocyclic compound or salt thereof according to (1-2), wherein L P is a group which chemically binds Y 2 and EUB.

[0270] (11-2) The heterocyclic compound or salt thereof according to (1-2), wherein, L P is -(L 1 -L 2 -L 3 -L 4 )-, L 1 , L 2 , L 3 , and L 4 are each independently a group selected from a bond, C=O, -O-, -S-, -SO2-, -NR L -, ethyne-1, 2-diyl, a substituted heterocycloalkylene group, a substituted heteroarylene group, a saturated 7- to 9-membered spiro-heterocycloalkylene group containing 1 to 2 nitrogen atoms, a saturated 7- to 9-membered bridged-heterocycloalkylene group containing 2 nitrogen atoms, and a substituted C 1-6 alkylene group, R L is H or C 1-6 alkyl.

[0271] (11-3) The heterocyclic compound or salt thereof according to (1-2), wherein, L P is -(L 1 -L 2 -L 3 -L 4 )-, L 1 is C=O, L 2 is a piperidinediyl group which can be substituted with C 1-3 alkyl, a piperazinediyl group which can be substituted with C 1-3 alkyl, a pyrrolidinediyl group which can be substituted with C1-3 alkyl-substituted pyrrolidine-diyl, bridged-piperazine-diyl or 2,6-diazaspiro[3.4]octane-diyl, L 3 is a bond, -N(R L3 )-, C 1-3 alkylene or piperazinediyl, L 4 is a bond, -N(R L4 )-, -O-, piperazinediyl or C 1-3 alkylene, R L3 is H or C 1-3 alkyl, R L4 is H or C 1-3 alkyl.

[0272] (11-4) The heterocyclic compound or salt thereof according to (1-2), wherein, L P is 1 group selected from the group consisting of the following formulae (L-1), (L-2), (L-3), (L-4), (L-5), (L-6) and (L-7), Herein, C=O and Y in the formulae (L-1), (L-2), (L-3), (L-4), (L-5), (L-6) and (L-7) form a bond, 2

[0273] L' is -O-, -(C 1-3 alkylene)-NH-, -N(CH3)(C 1-3 alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl, L" is a bond, C 1-3 alkylene or -(C 1-3 alkylene)-O-, R L2 is H or C 1-3 alkyl.

[0274] (11-5) The heterocyclic compound or salt thereof according to (1-2), wherein, L P is 1 group selected from the group consisting of the following formulae (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7), Herein, C=O and Y in the formulae (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7) form a bond, 2 ​​

[0275] L' is -0-, -(C 1-3 alkylene)-NH-, -N(CH3)(C 1-3 alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl, L" is a bond, C 1-3 alkylene or -(C 1-3 alkylene)-0-, R L2 is H or C 1-3 alkyl.

[0276] (11-6) The heterocyclic compound or salt thereof according to (1-2), wherein L P is the following formula (L-5A) or (L-7A), where C=0 and Y 2 form a bond in the formulae (L-5A) and (L-7A).

[0277]

[0278] (11-7) The heterocyclic compound or salt thereof according to (1-2), wherein L P is the formula (L-5A), where C=0 and Y 2 form a bond in the formula (L-5A).

[0279]

[0280] (11-8) The heterocyclic compound or salt thereof according to (1-2), wherein L P is -L V -J-, L V is -(L 5 -L 6 -L 7 -L 8 )-, L 5 , L 6 , L 7 , L 8 are each independently a group selected from the group consisting of a bond, -0-, -NR L5 -, a pyrrolidinediyl group which can be substituted, a piperidinediyl group which can be substituted, a piperazinediyl group which can be substituted, a C 1-3 alkylene group which can be substituted and C=0, R L5 is H or C 1-3 alkyl, J is NH or a 5-membered heteroalkylene group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen.

[0281] (12-1) The heterocyclic compound or a salt thereof according to (11-8), wherein L V is -(L 5 -L 6 -L 7 -L 8 )-, L 5 , L 6 , L 7 , L 8 are independently of each other a group selected from the group consisting of a bond, -O-, -NR L5 -, a pyrrolidine-diyl which can be substituted, a piperidine-diyl which can be substituted, a piperazine-diyl which can be substituted, a C 1-3 alkylene and C=O, R L5 is H or C 1-3 alkyl.

[0282] (12-2) The heterocyclic compound or a salt thereof according to (11-8), wherein L V is a bond, C 1-3 alkylene, C=O or a group selected from the group consisting of the following formula (L-10), formula (L-11), formula (L-12), formula (L-13), formula (L-14) and formula (L-15) (in the formulae Y2 represents a bonding part to Y 2 ,

[0283] R L5 is H or C 1-3 alkyl, R L6 , R L7 are independently of each other H, F, OH, OCH3 or C 1-3 alkyl which can be substituted, R L is CH or N, k is an integer of 1 to 2.

[0284] (12-3) The heterocyclic compound or a salt thereof according to (11-8), wherein L V is a bond.

[0285] (13-1) The heterocyclic compound or a salt thereof according to (11-8), wherein J is NH or a 5-membered heteroarylene group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen.

[0286] (13-2) The heterocyclic compound or its salt according to (11-8), wherein J is NH or a group selected from the group consisting of formulas (L-16), (L-17), (L-18) and (L-19) (where J is NH). LV Indicates with L V (the joint).

[0287]

[0288] (13-3) The heterocyclic compound or its salt according to (11-8), wherein J is the following formula (L-17) (where J is a heterocyclic compound or its salt according to (11-8) LV Indicates with L V (the joint).

[0289]

[0290] (14-1) The heterocyclic compound or its salt according to (11-8), wherein -Y 2 -L V -J is the following formula (L-20) (in Y) 1 When it is -O-CH2-, in the formula Y1 Y represents 2 -L V -J is the site where it binds to the carbon atom of -O-CH2-.

[0291]

[0292] (15-1) The heterocyclic compound or its salt according to (1-2), wherein EUB is a group having the ability to bind to one E3 ubiquitin ligase selected from the group consisting of VHL, hydroxycerebroside, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B and AhR.

[0293] (15-2) The heterocyclic compound or its salt according to (1-2), wherein EUB is a group having the ability to bind to one E3 ubiquitin ligase selected from the group consisting of VHL and hydroxycerebroside.

[0294] (15-2-1) A heterocyclic compound or a salt thereof, wherein EUB is a combination of the manner described in (15-5) and the manner described in (15-8).

[0295] (15-3) The heterocyclic compound or its salt according to (1-2), wherein EUB is a group having the ability to bind with VHL.

[0296] (15-4) The heterocyclic compound or salt thereof according to (1-2), wherein EUBis a group having a binding ability to hydroxycerebroside.

[0297] (15-5) The heterocyclic compound or salt thereof according to (1-2), wherein EUBis a group having a binding ability to hydroxycerebroside, and the group having a binding ability to hydroxycerebroside is a group of the following formula (E-1),

[0298] G is CR G or N, R G is H or C 1-6 alkyl, Z is a group selected from the group consisting of the following formulae (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), (Z-23), (Z-24), (Z-25), (Z-26), and (Z-27), Here, the rings B1and B2in the formulae (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), (Z-23), (Z-24), (Z-25), (Z-26), and (Z-27) and L P form a bond, wherein G is N, Z is a group selected from the group consisting of the formulae (Z-1), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), (Z-23), (Z-24), (Z-25), (Z-26), and (Z-27),

[0299] R Z1 independently of one another C 1-6 alkyl, halogen, cyano, -OH, -O-(C 1-6alkyl), -S- (optionally substituted C 1-6 alkyl), -NH- (optionally substituted C 1-6 alkyl) or -N- (optionally substituted C 1-6 alkyl)2, p is an integer of 0 to 2, R Z2 , R Z3 , R Z4 and R Z5 are independently of each other H or optionally substituted C 1-6 alkyl, M is a bond, -O-, -S-, -N(R M )- or optionally substituted C 1-3 alkylene, R M is H or optionally substituted C 1-3 alkyl, ring B1is a benzene ring or a 6-membered heterocyclic ring, here, R Z1 and L P form a bond with the carbon atom constituting ring B1, ring B2is a benzene ring or a 5- to 6-membered heterocyclic ring, here, M, R Z1 and L P form a bond with the carbon atom constituting ring B2.

[0300] (15-6) The heterocyclic compound or a salt thereof according to (1-2), wherein EUBis a group having a binding ability to cerebroside, and the group having a binding ability to cerebroside is a group of the following formula (E-1),

[0301] G is CH or N, Z is one member selected from the group consisting of the following formulae (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E), (Z-23F) and (Z-24A),

[0302] In this case, the benzene ring or 6-membered heterocyclic ring in the formula (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E), and (Z-23F) forms a bond with L P forms a bond, the benzene ring in (Z-24A) forms a bond with L P forms a bond, wherein G is N, Z is one group selected from the group consisting of (Z-1A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E), (Z-23F), and (Z-24A).

[0303] (15-7) The heterocyclic compound or a salt thereof according to (1-2), wherein EUBis a group having a binding ability to hydroxycerebroside, and the group having a binding ability to hydroxycerebroside is the following formula (E-1),

[0304] G is CH or N, Z is one group selected from the group consisting of the following formula (Z-1A) or (Z-16A),

[0305] In this case, the benzene ring in the formula (Z-1A) and (Z-16A) forms a bond with L P forms a bond.

[0306] (15-8) The heterocyclic compound or a salt thereof according to (1-2), wherein EUBis a group having a binding ability to VHL, and the group having a binding ability to VHL is the following formula (E-2),

[0307] R 5 is a C 1-6 alkyl group, a C 3-6 cycloalkyl group, or a 4- to 6-membered heterocycloalkyl group containing 1 heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen, R 6a , R 6b are each independently H or a C 1-6 alkyl group, or R 6a, R 6b may form, together with the carbon to which they are bonded, a C 3-6 cycloalkyl, or a substituted 4- to 6-membered heterocycloalkyl group containing 1 heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, R 7 is H, halogen, C 1-3 alkyl, -SO2CH3, C 3-6 cycloalkyl, a substituted 4- to 6-membered heterocycloalkyl group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, a substituted 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms, R P1 is OH or F, R P2a is H or F, R P2b is H, Ring group C is a substituted phenylene group or a substituted 6-membered heteroarylene group containing 1 to 3 nitrogen atoms.

[0308] (15-9) The heterocyclic compound or a salt thereof according to (1-2), wherein EUB is a group having a binding ability to VHL, and the group having a binding ability to VHL is a group of the following formula (E-2),

[0309] R 5 is isopropyl, R 6a is H, R 6b is hydroxymethyl or -CH2-OP(=O)(OH)2, R 7 is a group selected from the group consisting of the following formula (XVII-2), formula (XVIII-2), formula (XIX-2), formula (XIX-3), formula (XX), and formula (XXII-2),

[0310] R P1 is OH, R P2a is H, R P2b is H, Ring group C is a substituted phenylene group or a substituted 6-membered heteroarylene group containing 1 to 3 nitrogen atoms. R7 represents a bonding site to R 7 ,

[0311] W 1 、W 2 are each CH.

[0312] (15-10) The heterocyclic compound or salt thereof according to (15-8), wherein R P1 is OH, R P2a is H, R P2b is H.

[0313] (16-1) The heterocyclic compound or salt thereof according to (15-8), wherein R 5 is a C 1-6 alkyl group which can be substituted, a C 3-6 cycloalkyl group which can be substituted, or a 4- to 6-membered heterocycloalkyl group which can be substituted and contains 1 heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen.

[0314] (16-2) The heterocyclic compound or salt thereof according to (15-8), wherein R 5 is a methyl group, an ethyl group, an isopropyl group, a t-butyl group, or a C 3-6 cycloalkyl group.

[0315] (16-3) The heterocyclic compound or salt thereof according to (15-8), wherein R 5 is an ethyl group, an isopropyl group, a t-butyl group, or a C 3-6 cycloalkyl group.

[0316] (16-4) The heterocyclic compound or salt thereof according to (15-8), wherein R 5 is an isopropyl group or a C 3-6 cycloalkyl group.

[0317] (16-5) The heterocyclic compound or salt thereof according to (15-8), wherein R 5 is an isopropyl group.

[0318] (17-1) The heterocyclic compound or salt thereof according to (15-8), wherein R 6a , R 6b are each independently H or a C 1-6 alkyl group which can be substituted, or R 6a , R 6b may form, together with the carbon to which they are bonded, a C 3-6 cycloalkyl group which can be substituted, or a 4- to 6-membered heterocycloalkyl group which can be substituted and contains 1 heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen.

[0319] (17-2) The heterocyclic compound or salt thereof according to (15-8), wherein R 6a, R 6b independently H or C 1-3 alkyl, which C 1-3 alkyl can be substituted with a group selected from the group consisting of F, OH, OCH3, and N(CH3)2, or R 6a , R 6b may form, together with the carbon to which they are bound, a C 3-6 cycloalkyl group.

[0320] (17-3) The heterocyclic compound or a salt thereof according to (15-8), wherein R 6a , R 6b independently H or C 1-3 alkyl, which C 1-3 alkyl can be substituted with a group selected from the group consisting of F, OH, and N(CH3)2, or R 6a , R 6b may form, together with the carbon to which they are bound, a cyclopropyl group.

[0321] (17-4) The heterocyclic compound or a salt thereof according to (15-8), wherein R 6a is H, and R 6b is C 1-3 alkyl which can be substituted with OH.

[0322] (17-5) The heterocyclic compound or a salt thereof according to (15-8), wherein R 6a is H, and R 6b is hydroxymethyl.

[0323] (17-6) The heterocyclic compound or a salt thereof according to (15-8), wherein R 6a is H, and R 6b is OH or C 1-3 alkyl which can be substituted with OP(=O)(OH)2.

[0324] (17-7) The heterocyclic compound or a salt thereof according to (15-8), wherein R 6a is H, and R 6b is hydroxymethyl or -CH2-OP(=O)(OH)2.

[0325] (17-8) The heterocyclic compound or a salt thereof according to (15-8), wherein R 6a is H, and R 6b is -CH2-OP(=O)(OH)2.

[0326] (18-1) The heterocyclic compound or a salt thereof according to (15-8), wherein R 7 is H, halogen, C 1-3 alkyl, -SO2CH3, C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl which contains 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and which can be substituted, 5-membered heteroaryl which contains 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and which can be substituted, or 6-membered heteroaryl which contains 1 to 3 nitrogen atoms.

[0327] (18-2) The heterocyclic compound or a salt thereof according to (15-8), wherein R 7 H, halogen, C 1-3 alkyl, -SO2CH3, C 3-6 cycloalkyl, or a group selected from the group consisting of the following formula (XVII), formula (XVIII), formula (XIX), formula (XX), formula (XXI), formula (XXII), formula (XXIII), formula (XXIV), formula (XXV) and formula (XXVI),

[0328] R 7a , R 7b are each independently H or C 1-3 alkyl which can be substituted with OH.

[0329] (18-3) The heterocyclic compound or a salt thereof according to (15-8), wherein R 7 halogen, or a group selected from the group consisting of the following formula (XVII), formula (XVIII), formula (XIX), formula (XX), formula (XXI) and formula (XXII),

[0330] R 7a , R 7b are each independently H or C 1-3 alkyl which can be substituted with OH.

[0331] (18-4) The heterocyclic compound or a salt thereof according to (15-8), wherein R 7 the following formula (XVII), formula (XVIII), formula (XIX) or formula (XX),

[0332] R 7a C 1-3 alkyl which can be substituted with OH.

[0333] (18-5) The heterocyclic compound or a salt thereof according to (15-8), wherein R 7 the following formula (XVII) or formula (XIX),

[0334] R 7a is C 1-3 alkyl.

[0335] (18-6) The heterocyclic compound or a salt thereof according to (15-8), wherein R 7 is the following formula (XVII),

[0336] R 7a is C 1-3 alkyl.

[0337] (18-7) The heterocyclic compound or a salt thereof according to (15-8), wherein R 7 is H.

[0338] (18-8) The heterocyclic compound or a salt thereof according to (15-8), wherein R 7 is a group selected from the group consisting of the following formula (XVII-2), formula (XVIII-2), formula (XIX-2), formula (XIX-3), formula (XX), and formula (XXII-2).

[0339]

[0340] (19-1) The heterocyclic compound or a salt thereof according to (15-8), wherein ring group C is a phenylene group which can be substituted or a 6-membered heteroarylene group which contains 1 to 3 nitrogen atoms and which can be substituted.

[0341] (19-2) The heterocyclic compound or a salt thereof according to (15-8), wherein ring group C is the following formula (XXVII) (in the formula R7 represents a bonding site to R 7 ,

[0342] W 1 and W 2 are: (i) W 1 is CH, W 2 is C-SO2CH3; or (ii) W 1 , W 2 are each independently CH, CF, CCl, CCH3, or N, wherein, in the case of the above (i), R 7 is H.

[0343] (19-3) The heterocyclic compound or a salt thereof according to (15-8), wherein ring group C is the following formula (XXVII) (in the formula R7 represents a bonding part to R 7 ,

[0344] W 1 , W 2 are each independently CH or N.

[0345] (19-4) The heterocyclic compound or a salt thereof according to (15-8), wherein ring group C is the following formula (XXVII) (in the formula, R7 represents a bonding part to R 7 ,

[0346] W 1 , W 2 are each independently CH, CF, CCl, CCH3, or N.

[0347] (19-5) The heterocyclic compound or a salt thereof according to (15-8), wherein ring group C is the following formula (XXVII) (in the formula, R7 represents a bonding part to R 7 ,

[0348] W 1 , W 2 are each independently CH, CF, CCl, CCH3, or N.

[0349] (20) A heterocyclic compound or a salt thereof in a combination of two or more of the above (1-1) to (19-5) in a manner not contradictory to each other.

[0350] As one mode of the specific heterocyclic compound used as a drug constituting the antibody drug conjugate or a salt thereof of the present application, the following compound or a salt thereof can be exemplified.

[0351] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3- [3-yl]phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolylamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolylamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolylamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{methyl[(3S)-pyrrolidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{methyl[(3S)-pyrrolidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, 1-(6-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-1-methyl-1H-indazol-3-yl)-1,3-diazinan-2,4-dione, 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, or Phosphoric acid dihydro- (2R)-2-({(4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-methyl[(3S)-pyrrolidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-L-prolinyl}amino)-2-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl ester.

[0352] As a specific heterocyclic compound to be used as a medicine constituting the antibody drug conjugate or a salt thereof of the present application, the following compound or a salt thereof can be exemplified.

[0353] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3- [3-yl]phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolylamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolylamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolylamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, 1-(6-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-1-methyl-1H-indazol-3-yl)-1,3-diazinan-2,4-dione, or 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione.

[0354] As a specific heterocyclic compound to be used as a medicine constituting the antibody drug conjugate or a salt thereof of the present application, the following compounds or salts thereof can be mentioned.

[0355] (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazinan-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazinan-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro- pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3- methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl) phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, or (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

[0356] As a specific heterocyclic compound to be used as a medicine constituting the antibody drug conjugate or a salt thereof of the present application, the following compounds or salts thereof can be exemplified.

[0357] Phosphoric acid = dihydro = (2R)-2-({(4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{methyl[(3S)-pyrrolidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-L-prolyl}amino)-2-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl ester.

[0358] In addition, another example of a heterocyclic compound having a G12D mutant KRAS protein decomposition-inducing effect, which is used as a drug constituting the antibody drug conjugate or a salt thereof of the present application, is shown below.

[0359] A heterocyclic compound of the following formula (TP-1) or (TP-2) (refer to International Publication No. 2022 / 148421).

[0360]

[0361] A heterocyclic compound of the following formula (TP-3), (TP-4), (TP-5), (TP-6), or (TP-7) (refer to International Publication No. 2022 / 148422).

[0362]

[0363] Heterocyclic compounds represented by the general formula W-L-T

[0364] (in the formula, W is a G12D mutant KRAS protein binding ligand of the following formula (TP-8) or (TP-9),

[0365] X is N, C-H, C-F, C-Cl, C-CH3, C-C2H5, or C-C3H7, R 1 is a substituted or unsubstituted hydroxyl group, amino group, or mercapto group, R 2 and R 3 each independently is H, halogen, or halogenated methyl group (monohalogenated methyl group, dihalogenated methyl group, or trihalogenated methyl group), or R 2 and R3 together with the benzene ring to which they are bonded, form a substituted or unsubstituted fused benzene ring (including a naphthalene ring, but not limited thereto), which fused benzene ring can be substituted with 1 or more, for example, 2 or 3 groups selected from the group consisting of halogen, hydroxy, amino, halogenated methyl, C 1-2 alkyl, and C 2-4 alkynyl, T is a group having a binding ability to E3 ubiquitin ligase, L is a divalent linker for binding W to T. Refer to Chinese Patent Application Publication No. 115785199.

[0366] The heterocyclic compound of the following formula (TP-10), (TP-11), (TP-12), (TP-13), (TP-14), (TP-15), (TP-16), or (TP-17) (refer to Chinese Patent Application Publication No. 115785199.)

[0367] The heterocyclic compound of the following formula (TP-18)

[0368] (In the formula, Ar is an optionally substituted aryl group or an optionally substituted heteroaryl group, X is H or halogen, L is a linker, and E is a group having a binding ability to E3 ubiquitin ligase. Refer to International Publication No. 2023 / 077441.)

[0369] The heterocyclic compound of the following formula (TP-19), (TP-20), (TP-21), or (TP-22) (refer to International Publication No. 2023 / 077441).

[0370]

[0371] The heterocyclic compound of the following formula (TP-23)

[0372] (in the formula, R 2a is halogen, R 3a is a 7- to 8-membered bridged heterocycloalkyl group containing 2 Ns, R 5a is H, R 6 and R 7 are each independently H, halogen, C 1-12 alkyl, or C 2-6 alkynyl, X a is , M 1 is a 3- to 9-membered heterocycloalkyl group, Y 1 is absent, L a is , n1 is 1, 2, or 3, n4 is 0, 1, or 2, n5 is an integer of 1 to 5, n6 is 0, 1, or 2, Q a is a group having a binding ability to E3 ubiquitin ligase. Refer to International Publication No. 2022 / 228576.

[0373] The heterocyclic compound of the following formula (TP-24), (TP-25), (TP-26), or (TP-27) (refer to International Publication No. 2022 / 228576).

[0374]

[0375] The heterocyclic compound of the following formula (TP-28) or (TP-29)

[0376] (in the formula, R 1 is H or halogen, n is 0, 1, 2, 3, or 4, R 2 is 8-chloronaphthalen-1-yl, 3-hydroxynaphthalen-1-yl, 8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl, or 8-ethynyl-7-fluoronaphthalen-1-yl, L is , M is .

[0377] Refer to International Publication No. 2023 / 280026.

[0378] The following heterocyclic compounds of formula (TP-30) or (TP-31) (refer to International Publication No. 2023 / 280026).

[0379]

[0380] 2. Linker (L A )

[0381] In the present specification, the linker (L A ) of the antibody drug conjugate or the salt thereof constituting the present application is a bifunctional moiety that binds one or more drugs (D) to an antibody or an antigen-binding fragment (Ab) to form an antibody drug conjugate. As one mode of the linker (L A ), it is a linker having a moiety cleavable in vivo, and without particular limitation, it is a linker having a moiety cleavable by an enzyme such as cathepsin B. By cleaving this linker, the drug (D) is released in vivo. As one mode of the linker (L A ), it is bound to D at the nitrogen atom of any -NH- or the oxygen atom of -OH included in D to bind to D, and as one mode, it is bound to D at the binding portion represented by V 2 or W included in D to bind to D. LA

[0382] As one mode of the linker (L A ) in the present application, it is a linker represented by the following formula (XXVIII).

[0383]

[0384] (In the formula, Str is an extension unit that binds to Ab and CLL, r is 0 or 1, CLL is a moiety cleavable in vivo, Sp is a spacer unit that binds to CLL and D, t is 0 or 1, Ab represents a binding portion to Ab).

[0385] ​In the present specification, "a stretch unit (Str)" is present when it means a structural unit that binds Ab to CLL. The stretch unit forms a covalent bond with a functional group contained in Ab. As the functional group contained in Ab that forms a covalent bond with the stretch unit, there is no particular limitation, and examples include a mercapto group, an amino group, a hydroxyl group, and a carboxyl group, and as one mode, a mercapto group. By reducing an intramolecular disulfide bond contained in Ab, a mercapto group that can be used to form a covalent bond with Ab can also be generated. Note that when r is 0, the stretch unit is not present, and a portion of the structure that can be cleaved in vivo (CLL) is directly bound to Ab.

[0386] One mode of the stretch unit (Str) is shown below.

[0387] (21-1) A stretch unit of the formula (ST-1),

[0388] (In the formula, R st1 is a C 1-12 alkylene group, -(CH2CH2O) a1 -C 1-6 alkylene group, -C 1-6 alkylene group, -(OCH2CH2) a2 -, a C 1-6 alkylene group-NH-C(=O)-a C 1-6 alkylene group, a C 1-6 alkylene group-C(=O)-NH-a C 1-6 alkylene group, a C 1-6 alkylene group-C(=O)-NH-(CH2CH2O) a3 -C 1-6 alkylene group, or a C 1-6 alkylene group-NH-C(=O)-(CH2CH2O) a4 -C 1-6 alkylene group, a1, a2, a3, and a4 are each an integer of 1 to 10, Ab indicates a binding portion to Ab).

[0389] (21-2) The stretch unit according to (21-1), wherein R st1 is a C 1-12 alkylene group.

[0390] (21-3) The stretch unit according to (21-1), wherein R st1 is a C 3-8 alkylene group.

[0391] (21-4) The extension unit according to (21-1), wherein R st1 is a C5 alkylene group.

[0392] (21-5) The extension unit of formula (ST-2) or (ST-3),

[0393] (in the formula, R st1 is a C 1-12 alkylene group, -(CH2CH2O) a1 -C 1-6 alkylene group, -C 1-6 alkylene group, -(OCH2CH2) a2 -, 1-6 a C 1-6 alkylene group, a C 1-6 alkylene group, -C(=O)-NH- a C 1-6 alkylene group, a C 1-6 alkylene group, -C(=O)-NH-(CH2CH2O) a3 -C 1-6 alkylene group, or a C 1-6 alkylene group, -NH-C(=O)-(CH2CH2O) a4 -C 1-6 alkylene group, a1, a2, a3, and a4 are each an integer of 1 to 10, Ab represents a binding site to Ab).

[0394] (21-6) The extension unit according to (21-5), wherein R st1 is a C 1-12 alkylene group.

[0395] (21-7) The extension unit according to (21-5), wherein R st1 is a C 3-8 alkylene group.

[0396] (21-8) The extension unit according to (21-5), wherein R st1 is a C5 alkylene group.

[0397] The following shows a manner of the "part structure cleavable in vivo (CLL)" in the present application.

[0398] (22-1) A part structure cleavable in vivo of formula (CL-1),

[0399] (in the formula, R AA independently of one another H, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, hydroxymethyl, 1-hydroxyethyl, -CH2-C(=O)-OH, -(CH2)2-C(=O)-OH, -CH2-C(=O)-NH2, -(CH2)2-C(=O)-NH2, -(CH2)4-NH2, -(CH2)3-NH-C(=NH)-NH2, -(CH2)3-NH-C(=O)-NH2, -CH2-SH, or -CH2-S-CH3, or one group selected from the group consisting of the following formulae (RAA-1) and (RAA-2),

[0400] d is an integer of 1 to 6 STR represents a binding site to Str.

[0401] (22-2) The cleavable moiety in vivo according to (22-1), wherein R AA independently of one another H, methyl, isopropyl, benzyl, -(CH2)4-NH2, -(CH2)3-NH-C(=NH)-NH2, or -(CH2)3-NH-C(=O)-NH2, and d is an integer of 2 to 4.

[0402] (22-3) The cleavable moiety in vivo according to (22-1), wherein R AA independently of one another methyl, isopropyl, benzyl, -(CH2)4-NH2, -(CH2)3-NH-C(=NH)-NH2, or -(CH2)3-NH-C(=O)-NH2, and d is 2.

[0403] (22-4) The cleavable moiety in vivo according to (22-1), wherein R AA independently of one another methyl, isopropyl, or -(CH2)3-NH-C(=O)-NH2, and d is 2.

[0404] (22-5) The cleavable moiety in vivo according to (22-1), wherein R AA independently of one another methyl or isopropyl, and d is 2.

[0405] (22-6) The cleavable moiety in vivo according to (22-1), wherein R AA independently of one another isopropyl or -(CH2)3-NH-C(=O)-NH2, and d is 2.

[0406] (22-7) The cleavable moiety in vivo according to (22-1), wherein R AA independently H or benzyl, and d is 4.

[0407] In the present specification, when a "spacer unit (Sp)" is present, it refers to a structural unit that binds the CLL to the drug (D). When the spacer unit is present, as one mode, it forms a covalent bond with any of the groups of the drug (D), as one mode, it forms a covalent bond with the nitrogen atom of any -NH- or the oxygen atom of -OH of the drug (D), as one mode, it forms a covalent bond with the nitrogen atom of one secondary amino group included in Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), or Formula (XVI) of the drug (D), as one mode, it forms a covalent bond with the nitrogen atom of one secondary amino group included in the ring constituting atom in W of the drug (D). As one mode of the spacer unit, it is a self-cleavage type spacer unit. The CLL of the self-cleavage type spacer unit, when cleaved, does not undergo a further hydrolysis reaction but is itself decomposed, releasing the free drug (D). Note that when t is 0, the spacer unit is not present, and the cleavable moiety in vivo (CLL) is directly bound to the drug (D). 2 or the nitrogen atom of one secondary amino group included in the ring constituting atom in W. As one mode of the spacer unit, it is a self-cleavage type spacer unit. The CLL of the self-cleavage type spacer unit, when cleaved, does not undergo a further hydrolysis reaction but is itself decomposed, releasing the free drug (D). Note that when t is 0, the spacer unit is not present, and the cleavable moiety in vivo (CLL) is directly bound to the drug (D).

[0408] One mode of the spacer unit is shown below.

[0409] (23-1) A spacer unit of Formula (SP-1),

[0410] (In the formula, R SP is H, C 1-6 alkyl, -O-C 1-6 alkyl, halogen, or halogenated C 1-6 alkyl CLL represents a binding site to the CLL).

[0411] (23-2) The spacer unit according to (23-1), wherein R SP is H.

[0412] Although not bound by the following theory, it is believed that the self-cleavage type spacer unit used in the present application is decomposed and releases the drug (D) via the following mechanism after the bond of the CLL to the nitrogen atom is cleaved (Journal of Organic Chemistry, 2002, 67, p. 1866-1872).

[0413]

[0414] The following shows another example of the linker L constituting the antibody drug conjugate or a salt thereof of the present application. A One embodiment.

[0415] (24-1) The following linker of formula (LA-1) (in the formula Ab represents a binding portion to Ab).

[0416]

[0417] (24-2) The following linker of formula (LA-2) (in the formula Ab represents a binding portion to Ab).

[0418]

[0419] In addition, the following shows another example of the linker L constituting the antibody drug conjugate or a salt thereof of the present application. A

[0420] The following linker of formula (LA-3) (refer to International Publication No. 2015 / 095124. Formula Ab represents a binding portion to Ab).

[0421]

[0422] The following linker of formula (LA-4) (refer to International Publication No. 2015 / 095124. Formula Ab represents a binding portion to Ab).

[0423]

[0424] The following linker of formula (LA-5) (refer to International Publication No. 2015 / 095223. Formula Ab represents a binding portion to Ab).

[0425]

[0426] The following linker of formula (LA-6) (refer to International Publication No. 2015 / 095227. Formula Ab represents a binding portion to Ab).

[0427]

[0428] ​The following linker of formula (LA-7) (refer to International Publication No. 2014 / 057687. Formula Ab represents a binding site to Ab.

[0429]

[0430] The following linker of formula (LA-8) (refer to International Publication No. 2013 / 173337. Formula Ab represents a binding site to Ab.

[0431]

[0432] 3. A drug-linker complex (L A -D)

[0433] In the present specification, a "drug-linker complex" means a compound in which a linker (L A ) forms a covalent bond with a drug (D). The drug-linker complex of the present application or a salt thereof has a reactive site, and is capable of reacting with a functional group contained in an antibody or an antigen-binding fragment (Ab) to form a covalent bond, and is useful as an intermediate for synthesizing an antibody drug conjugate of the present application or a salt thereof. As the functional group contained in Ab which forms a covalent bond with the drug-linker complex of the present application or a salt thereof, there is no particular limitation, and examples include a thiol group, an amino group, a hydroxyl group, and a carboxyl group, and as one mode, a thiol group. By reducing an intramolecular disulfide bond contained in Ab, a thiol group which is capable of forming a covalent bond with Ab can also be generated.

[0434] For example, when the drug-linker complex of the present application or a salt thereof has a maleimide structure, by reacting with a thiol group contained in Ab, the following partial structure is formed, and an antibody drug conjugate of the present application or a salt thereof can be synthesized (in the formula, Ab'-SH represents Ab having a thiol group).

[0435]

[0436] The following shows a mode of the drug-linker complex of the present application or a salt thereof.

[0437] (25-1) A drug-linker complex of formula (LD-1) or a salt thereof,

[0438] (in the formula, D is a heterocyclic compound having a KRAS protein decomposition-inducing action of G12D mutation, R st1 is a C 1-12 alkylene group, CLL is a portion structure cleavable in vivo, Sp is a spacer unit, which binds to CLL and D, and t is 0 or 1).

[0439] (25-2) The drug-linker complex according to (25-1) or a salt thereof, wherein, D is a heterocyclic compound represented by formula (II),

[0440] A is CR A or N, R A is H, cyano or C 1-3 alkyl which can be substituted, Q is CR Q or N, R Q is H, halogen, C 3-6 cycloalkyl, vinyl or C 1-3 alkyl which can be substituted, E is CH or N, R 1 is naphthyl which can be substituted by 1 or 2 groups selected from the group consisting of cyano, OH, halogen and C 1-3 alkyl which can be substituted, or 1 group selected from the group consisting of the following formula (III), formula (IV) and formula (V),

[0441] R 1a , R 1b and R 1c are each independently H, vinyl, halogen or C 1-3 alkyl which can be substituted, R 2 is -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )-, R V1 is H or C 1-3 alkyl which can be substituted, V 2 is 1 group selected from the group consisting of the following formula (VI) and formula (VII),

[0442] W is one group selected from the group consisting of formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV), formula (XV) and formula (XVI),

[0443] R 2a independently OH, OCH3, F or C 1-3 alkyl, the R 2a only binds to a carbon atom which is a constituting atom of a ring selected from the group consisting of an azetidine ring represented by formula (VI), a pyrrolidine ring represented by formula (VII), a piperidine ring represented by formula (VIII) and a piperazine ring represented by formula (IX), m is an integer of 0 to 2, R 3 is C 1-6 alkyl, substituted heterocycloalkyl or substituted heteroaryl, X is a bond, -CH2-, -O-, -S- or -NR 4X -, R 4X is H or C 1-3 alkyl, Y 1 is -O-(C 1-3 alkylene)- Y2 , -S-(C 1-3 alkylene)- Y2 , -SO2-(C 1-3 alkylene)- Y2 , -NR Y -(C 1-3 alkylene)- Y2 , -(C 1-3 alkylene)-O Y2 , -(C 1-3 alkylene)-S Y2 , -(C 1-3 alkylene)-SO2 Y2 or -(C 1-3 alkylene)-NR Y Y2 Y2 represents Y 2a bonding portion to Sp), R Y is H or a C 1-3 alkyl group, Y 2 is a bond, a substituted phenylene group, or a substituted heteroarylene group, L P is a group that allows Y 2 to chemically bind to EUB, EUB is a group having a binding ability to one E3 ubiquitin ligase selected from the group consisting of VHL, hydroxylated cerebroside, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR, CLL is a moiety that is cleavable in vivo, Sp is a spacer unit that binds to CLL and D, and here, Sp binds to a nitrogen atom of any -NH- or an oxygen atom of -OH contained in D.

[0444] (25-3) The drug-linker complex according to (25-2), or a salt thereof, wherein V 2 is one group selected from the group consisting of the following formula (VIb) and formula (VIIb) SP represents a bonding portion to Sp),

[0445] W is one group selected from the group consisting of the following formula (VIIIb), formula (IXb), formula (Xb), formula (XIb), formula (XIIb), formula (XIIIb), formula (XIVb), formula (XVb), and formula (XVIb) SP represents a bonding portion to Sp),

[0446] Sp is a spacer unit that binds to CLL and D, and here, Sp binds to a nitrogen atom contained in V 2 or W SP is represented by the following formula (XVIIb) or formula (XVIIIb).

[0447] (25-4) The drug-linker complex according to (25-2), or a salt thereof, wherein, A is N, Q is CR Q , R Q is cyclopropyl, E is CH, R 1for the following formula (III-2),

[0448] R 2 for -V 1 -V 2 or W, V 1 for -N(CH3)-, V 2 for the following formula (VII-2),

[0449] W is the following formula (XIV),

[0450] R 3 for n-propyl or tetrahydropyranyl which can be substituted with -OCH3, X is -O-, Y 1 for -O-(methylene) Y2 Y2 indicates a bonding portion to Y 2 , Y 2 for phenylene, L P for a group which chemically binds Y 2 to EUB, EUB is a group having a binding ability to one E3 ubiquitin ligase selected from the group consisting of VHL and hydroxylated glycerol.

[0451] (25-5) The drug-linker complex according to (25-4) or a salt thereof, wherein, V 2 for the following formula (VII-2b) SP indicates a bonding portion to Sp,

[0452] W is the following formula (XIVb) SP indicates a bonding portion to Sp,

[0453] Sp is a spacer unit which binds to CLL and D, and here, Sp binds to the nitrogen atom 2 or W SP indicated in the bonding portion.

[0454] (25-6) The drug-linker complex according to (25-1), or a salt thereof, wherein D is: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro- pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3- methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl) phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro- pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3- methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3- oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro- pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3- methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5- yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro- pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3- methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5- yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxy- propoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3- methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{methyl[(3S)-pyrrolidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{methyl[(3S)-pyrrolidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, 1-(6-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-1-methyl-1H-indazol-3-yl)-1,3-diazinan-2,4-dione, 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, or Phosphoric acid = dihydro- (2R)-2-({(4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-methyl[(3S)-pyrrolidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-L-prolyl}amino)-2-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl ester.

[0455] (25-7) The drug-linker complex according to (25-1) or a salt thereof, wherein Formula (LD-1) is represented by Formula (LD-2a) or (LD-3a),

[0456] (In the formula, A is CR A or N, R A is H, cyano or C 1-3 alkyl which can be substituted, Q is CR Q or N, R Q is H, halogen, C 3-6 cycloalkyl, vinyl or C 1-3 alkyl which can be substituted, E is CH or N, R 1 is naphthyl which can be substituted by 1 or 2 radicals selected from the group consisting of cyano, OH, halogen and C 1-3 alkyl which can be substituted, or 1 radical selected from the group consisting of the following formulae (III), (IV) and (V),

[0457] R 1a , R 1b and R 1c are independently of one another H, vinyl, halogen or C 1-3 alkyl which can be substituted, R 3 is C 1-6 alkyl which can be substituted, heterocycloalkyl which can be substituted or heteroaryl which can be substituted, X is a bond, -CH2-, -O-, -S- or -NR 4X -, R 4X is H or C 1-3 alkyl which can be substituted, Y 1 is -O-(C 1-3 alkylene) which can be substituted, Y2 , -S-(C 1-3 alkylene) which can be substituted, Y2 , -SO2-(C 1-3 alkylene) which can be substituted, Y2 , -NR Y -(C 1-3 alkylene) which can be substituted, Y2 , -(C 1-3 alkylene)-O Y2 , -(C 1-3 alkylene)-S Y2 , -(C 1-3 alkylene)-SO2 Y2 or -(C 1-3 alkylene)-NRY Y2 Y2 represents a binding portion to Y 2 , R Y is H or C 1-3 alkyl which can be substituted, Y 2 is a bond, phenylene which can be substituted, or heteroarylene which can be substituted, L P is a group which chemically binds Y 2 to EUB, EUB is a group having a binding ability to an E3 ubiquitin ligase selected from the group consisting of VHL and hydroxylated glycerophospholipid, R st1 is C 1-12 alkylene, R AA are independently of each other H, methyl, isopropyl, benzyl or -(CH2)3-NH-C(=O)-NH2, d is an integer from 2 to 4, and t is 0 or 1.

[0458] (25-8) The drug-linker complex according to (25-1), wherein the formula (LD-1) is represented by formula (LD-4a), (LD-5a), (LD-6a), (LD-7a), (LD-8a), (LD-9a), (LD-10a), (LD-11a), (LD-12a), (LD-13a), (LD-14a) or (LD-26a). (25-9) The drug-linker complex according to (25-1), wherein the formula (LD-1) is represented by formula (LD-15), (LD-16), (LD-17), (LD-18), (LD-19), (LD-20), (LD-21), (LD-22), (LD-23), (LD-24), (LD-25) or (LD-26).

[0459]

[0460] (in the formula, R st1 is C 1-12 alkylene, R AA are independently of each other H, methyl, isopropyl, benzyl or -(CH2)3-NH-C(=O)-NH2, d is an integer from 2 to 4, and t is 0 or 1.

[0461] (25-8) The drug-linker complex according to (25-1), wherein the formula (LD-1) is represented by formula (LD-4a), (LD-5a), (LD-6a), (LD-7a), (LD-8a), (LD-9a), (LD-10a), (LD-11a), (LD-12a), (LD-13a), (LD-14a) or (LD-26a). (25-9) The drug-linker complex according to (25-1), wherein the formula (LD-1) is represented by formula (LD-15), (LD-16), (LD-17), (LD-18), (LD-19), (LD-20), (LD-21), (LD-22), (LD-23), (LD-24), (LD-25) or (LD-26).

[0462]

[0463] 4. Antibody or antigen-binding fragment (Ab)

[0464] The antibody or antigen-binding fragment used in the present application (also referred to as "Ab" in the present specification) binds to an antigen protein expressed on the cell surface or a modified body thereof (e.g., sugar chain modification, etc.). As one mode, the antibody or antigen-binding fragment used in the present application binds to a tumor-associated antigen or a cell surface receptor expressed on the surface of a cancer cell.

[0465] As one embodiment, the Ab used in the present application can be an antibody or an antigen-binding fragment that binds to 1 or 2 or more antigens selected from the group of 5T4, ADAM9, ALPP, ALPPL2, AXL, B7H3, B7H4, BCMA, CA9, CCR2, CCR7, CD123, CD166, CD19, CD20, CD22, CD25, CD30, CD33, CD37, CD38, CD45, CD46, CD70, CD74, CD79b, CDH3, CDH6, CLDN1, CLDN4, CLDN6, CLDN18.2, cMET, EGFR, EphA3, FAP, FGFR3, fibronectin, FOLRa, Globo H, GPRC5D, HER2, HER3, IGF1R, integrin alphaV, KAAG1, LIV1, MSLN, MT1-MMP, MUC1, MUC4, NaPi2b, nectin 4, PD-L1, PSMA, PTK7, ROR1, ROR2, SEZ6, sialyl Tn, TF, TROP2, TSPAN8, and VEGF. As one embodiment of the Ab used in the present application, it is an antibody or an antigen-binding fragment that binds to 1 or 2 or more antigens selected from the group of 5T4, ADAM9, ALPP, ALPPL2, AXL, B7H3, B7H4, BCMA, CA9, CCR2, CCR7, CD123, CD166, CD19, CD20, CD22, CD25, CD30, CD33, CD37, CD38, CD45, CD46, CD70, CD74, CD79b, CDH3, CDH6, CLDN1, CLDN6, EGFR, EphA3, FAP, FGFR3, fibronectin, FOLRa, Globo H, GPRC5D, IGF1R, integrin alphaV, KAAG1, LIV1, MSLN, MT1-MMP, MUC4, NaPi2b, nectin 4, PD-L1, PSMA, PTK7, ROR1, ROR2, SEZ6, sialyl Tn, TF, and VEGF, as one embodiment, it is an antibody or an antigen-binding fragment that binds to 1 or 2 or more antigens selected from the group of EGFR, HER2, cMET, and TROP2, as one embodiment, it is an antibody or an antigen-binding fragment that binds to EGFR.

[0466] As one mode, the Ab used in the present application is one or two or more antibodies or antigen-binding fragments thereof selected from the group of anti-5T4 antibody, anti-ADAM9 antibody, anti-ALPP antibody, anti-ALPPL2 antibody, anti-AXL antibody, anti-B7H3 antibody, anti-B7H4 antibody, anti-BCMA antibody, anti-CA9 antibody, anti-CCR2 antibody, anti-CCR7 antibody, anti-CD123 antibody, anti-CD166 antibody, anti-CD19 antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD25 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD37 antibody, anti-CD38 antibody, anti-CD45 antibody, anti-CD46 antibody, anti-CD70 antibody, anti-CD74 antibody, anti-CD79b antibody, anti-CDH3 antibody, anti-CDH6 antibody, anti-CLDN1 antibody, anti-CLDN4 antibody, anti-CLDN6 antibody, anti-CLDN18.2 antibody, anti-cMET antibody, anti-EGFR antibody, anti-EphA3 antibody, anti-FAP antibody, anti-FGFR3 antibody, anti-fibronectin antibody, anti-FOLRa antibody, anti-Globo H antibody, anti-GPRC5D antibody, anti-HER2 antibody, anti-HER3 antibody, anti-IGF1R antibody, anti-integrin alphaV antibody, anti-KAAG1 antibody, anti-LIV1 antibody, anti-MSLN antibody, anti-MT1-MMP antibody, anti-MUC1 antibody, anti-MUC4 antibody, anti-NaPi2b antibody, anti-nectin4 antibody, anti-PD-L1 antibody, anti-PSMA antibody, anti-PTK7 antibody, anti-ROR1 antibody, anti-ROR2 antibody, anti-SEZ6 antibody, anti-sialyl Tn antibody, anti-TF antibody, anti-TROP2 antibody, anti-TSPAN8 antibody, and anti-VEGF antibody.As one mode of the Ab used in the present application, 1 or 2 or more antibodies or antigen-binding fragments thereof selected from the group of anti-5T4 antibody, anti-ADAM9 antibody, anti-ALPP antibody, anti-ALPPL2 antibody, anti-AXL antibody, anti-B7H3 antibody, anti-B7H4 antibody, anti-BCMA antibody, anti-CA9 antibody, anti-CCR2 antibody, anti-CCR7 antibody, anti-CD123 antibody, anti-CD166 antibody, anti-CD19 antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD25 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD37 antibody, anti-CD38 antibody, anti-CD45 antibody, anti-CD46 antibody, anti-CD70 antibody, anti-CD74 antibody, anti-CD79b antibody, anti-CDH3 antibody, anti-CDH6 antibody, anti-CLDN1 antibody, anti-CLDN6 antibody, anti-EGFR antibody, anti-EphA3 antibody, anti-FAP antibody, anti-FGFR3 antibody, anti-fibronectin antibody, anti-FOLRa antibody, anti-Globo H antibody, anti-GPRC5D antibody, anti-IGF1R antibody, anti-integrin alphaV antibody, anti-KAAG1 antibody, anti-LIV1 antibody, anti-MSLN antibody, anti-MT1-MMP antibody, anti-MUC4 antibody, anti-NaPi2b antibody, anti-nectin4 antibody, anti-PD-L1 antibody, anti-PSMA antibody, anti-PTK7 antibody, anti-ROR1 antibody, anti-ROR2 antibody, anti-SEZ6 antibody, anti-sialyl Tn antibody, anti-TF antibody, and anti-VEGF antibody, as one mode, 1 or 2 or more antibodies or antigen-binding fragments thereof selected from the group of anti-EGFR antibody, anti-HER2 antibody, anti-cMET antibody, and anti-TROP2 antibody, as one mode, anti-EGFR antibody or antigen-binding fragment thereof.

[0467] The antibody or antigen-binding fragment thereof used in the present application can be obtained by a person skilled in the art by a publicly known method. For example, a polypeptide as an antigen can be immunized to an animal using a method generally practiced in the field, and an antibody produced in vivo can be collected and purified to obtain. The source of the antigen is not limited to human, and an antigen derived from an animal other than human such as mouse, rat, etc. can be immunized to an animal. In this case, by performing a cross test of the obtained antibody binding to a heterologous antigen with a human antigen, an antibody that can be used for a human disease can be screened. In addition, a hybridoma can be established by fusing an antibody-producing cell producing an antibody against an antigen with a myeloma cell according to a publicly known method (for example, Kohler and Milstein, Nature (1975) 256, p. 495-497; Kennet, R. ed., Monoclonal Antibodies, p. 365-367, Plenum Press, N.Y. (1980)), and a monoclonal antibody can be obtained. The antigen to be immunized can be obtained, for example, by introducing a gene encoding an arbitrary protein or polypeptide into a host cell using a vector or the like and expressing the gene, and purifying the expressed protein. In addition, an antibody can be obtained by a method of immunizing an animal with a cell expressing an arbitrary protein by gene manipulation or a cell strain endogenously expressing an antigen or the like.

[0468] Whether the antibody or antigen-binding fragment binds to the antigen can be confirmed using a publicly known binding activity measurement method. As a method of measuring the binding activity, a method such as an enzyme-linked immunosorbent assay (ELISA) method, a flow cytometry method, etc. can be exemplified.

[0469] The antibody or antibody-binding fragment used in the present application can be derived from any species such as human, rat, mouse, and rabbit. In the case where the antibody is derived from a species other than human, it is preferable to perform chimerization or humanization using a publicly known technique. The antibody or antibody-binding fragment used in the antibody drug conjugate of the present application can be a polyclonal antibody, or can be a monoclonal antibody.

[0470] As one mode, the Ab used in the present application is an antibody or antibody-binding fragment of IgG type. In IgG, subtypes of IgG1, IgG2, IgG3, IgG4 exist depending on the structure of the hinge region and the Fc region, and a person skilled in the art can appropriately select the antibody considering the effector function, DAR, etc. of the antibody. In one mode, the Ab used in the present application is of IgG1 or IgG4 type.

[0471] As an example, the Ab used in this invention is one or more antibodies or antigen-binding fragments thereof selected from the group consisting of anti-EGFR antibody, anti-HER2 antibody, anti-cMET antibody and anti-TROP2 antibody.

[0472] As an example, the Ab used in this invention is an anti-EGFR antibody, an anti-HER2 antibody, an anti-cMET antibody, or an anti-TROP2 antibody or an antigen-binding fragment thereof.

[0473] As an example, the Ab used in this invention is an anti-EGFR antibody or its antigen-binding fragment.

[0474] As an example, the Ab used in this invention is an anti-HER2 antibody or its antigen-binding fragment.

[0475] As an example, the Ab used in this invention is an anti-TROP2 antibody or its antigen-binding fragment.

[0476] As an example, the Ab used in this invention is an anti-EGFR antibody, anti-HER2 antibody, or anti-TROP2 antibody of type IgG1 or IgG4.

[0477] As an example, the Ab used in this invention is an anti-EGFR antibody of type IgG1 or IgG4.

[0478] As an example, the Ab used in this invention is an anti-EGFR antibody or its antigen-binding fragment containing the heavy chain variable region and light chain variable region as described in (1) or (2): (1) A heavy chain variable region comprising CDR1 consisting of amino acid sequences 31 to 35 of sequence number 1, CDR2 consisting of amino acid sequences 50 to 65 of sequence number 1, and CDR3 consisting of amino acid sequences 98 to 108 of sequence number 1, and The light chain variable region contains CDR1, consisting of amino acid sequences numbered 24 to 34 of sequence number 2; CDR2, consisting of amino acid sequences numbered 50 to 56 of sequence number 2; and CDR3, consisting of amino acid sequences numbered 89 to 97 of sequence number 2; or (2) The heavy chain variable region containing CDR1 composed of amino acid sequences 31 to 35 of sequence number 3, CDR2 composed of amino acid sequences 50 to 65 of sequence number 3, and CDR3 composed of amino acid sequences 98 to 108 of sequence number 3, and The light chain variable region contains CDR1, which consists of amino acid sequences numbered 24 to 34 of sequence number 4; CDR2, which consists of amino acid sequences numbered 50 to 56 of sequence number 4; and CDR3, which consists of amino acid sequences numbered 89 to 97 of sequence number 4.

[0479] In one embodiment, the Ab used in this invention is an anti-EGFR antibody or its antigen-binding fragment containing a heavy chain variable region and a light chain variable region selected from the group consisting of (1) to (3) below: (1) The heavy chain variable region consisting of amino acid sequences numbered 1 to 119 of sequence number 1 and the light chain variable region consisting of amino acid sequences numbered 1 to 107 of sequence number 2. (2) The heavy chain variable region consisting of amino acid sequences numbered 1 to 119 of sequence number 3 and the light chain variable region consisting of amino acid sequences numbered 1 to 107 of sequence number 4; and (3) Heavy chain variable regions and light chain variable regions that have at least 90% consistency with the heavy chain variable regions and light chain variable regions described in (1) or (2) above.

[0480] As an example, the Ab used in this invention is an anti-EGFR antibody composed of the heavy chain of sequence number 1 and the light chain of sequence number 2.

[0481] The antibody or antigen-binding fragment used in this invention can be subject to post-translational modifications such as glycosylation to N-linked or O-linked forms, processing at the N-terminus or C-terminus, deamidation, isomerization of aspartic acid, and oxidation of methionine.

[0482] In the antibodies or antibody-binding fragments used in this invention, any amino acid residue may be replaced with cysteine ​​or a non-natural amino acid. Replacement with cysteine ​​may be performed using methods described, for example, those specified in WO2008141044 and WO2016040856. Replacement with a non-natural amino acid may be performed using methods described, for example, those specified in WO2010081111 and WO2013185115.

[0483] The Fc region of the antibody used in this invention may contain mutations that reduce antibody-dependent cytotoxic activity (ADCC) and complement-dependent cytotoxic activity (CDC). L234A refers to the substitution of leucine to alanine at position 234 of the human Igγ1 constant region according to the EU index. L235A refers to the substitution of leucine to alanine at position 235 of the human Igγ1 constant region according to the EU index. The amino acid mutations L234A and L235A in the human Igγ1 constant region are referred to as "LALA mutations." These mutations are known to reduce antibody-dependent cytotoxic activity and complement-dependent cytotoxic activity (Mol. Immunol., 1992; Vol. 29: p. 633-639). P331G or P331S refers to the substitution of proline to glycine or serine at position 331 of the human Igγ1 constant region according to the EU index. This mutation is known to reduce the CDC of the antibody (J. Immunol., 2000, Vol / 164(8), p.4178-4184).

[0484] 5. Antibody-drug complex

[0485] The antibody-drug complex or its salt in this invention is the antibody-drug complex or its salt represented by the following formula (I).

[0486]

[0487] (in the formula, Ab represents an antibody or its antigen-binding fragment. D is a heterocyclic compound that induces the degradation of G12D mutant KRAS protein. L A For connecting Ab to D, n is a value from 1 to 20.

[0488] n represents the drug-to-antibody ratio (DAR) of the antibody-drug complex, i.e., the average number of compounds that bind to one antibody. One form of the antibody-drug complex or its salt according to formula (I) is an antibody-drug complex or its salt with n ranging from 1 to 20; another form is an antibody-drug complex or its salt with n ranging from 1 to 10; another form is an antibody-drug complex or its salt with n ranging from 2 to 8; and yet another form is an antibody-drug complex or its salt with n ranging from 2 to 5. As one form of the antibody drug complex or salt thereof of formula (I), it is an antibody drug complex or salt thereof with n being a value of 1 to 6; as another form, it is an antibody drug complex or salt thereof with n being a value of 1 to 5; as yet another form, it is an antibody drug complex or salt thereof with n being a value of 2 to 3; as yet another form, it is an antibody drug complex or salt thereof with n being a value of 3 to 4; as yet another form, it is an antibody drug complex or salt thereof with n being a value of 4 to 5; as yet another form, it is an antibody drug complex or salt thereof with n being a value of 2 to 4; as yet another form, it is an antibody drug complex or salt thereof with n being a value of 3 to 5.

[0489] The following illustrates the manner in which the antibody-drug complex or its salts are used in this invention.

[0490] (26-1) Antibody-drug complex of formula (I) or its salt,

[0491] (in the formula, Ab represents an antibody or its antigen-binding fragment. D is a heterocyclic compound that induces the degradation of G12D mutant KRAS protein. L A For connecting Ab to D, n is a value from 1 to 20.

[0492] (26-2) The antibody-drug complex or a salt thereof according to (26-1), wherein D is a heterocyclic compound represented by formula (II).

[0493] A is CR A Or N, R A It is H, cyano, or a substituted C. 1-3 alkyl, Q is CR Q Or N, R Q H, halogen, C 3-6 cycloalkyl, vinyl, or substituted C1-3 alkyl, E is CH or N. R 1 It can be selected from one or two cyano groups, OH groups, halogens, and substituted C groups. 1-3 The group consisting of alkyl groups substituted with naphthyl groups, or one group selected from the group consisting of formulas (III), (IV) and (V) below,

[0494] R 1a R 1b and R 1c Independent of each other, H, vinyl, halogen, or substituted C 1-3 alkyl, R 2 -V 1 -V 2 Or W, V 1 For bonds, -CH2-, -O-, -S- or -N(R) V1 )-, R V1 H or C that can be substituted 1-3 alkyl, V 2 To select one group from the group consisting of formulas (VI) and (VII) below,

[0495] W is one group selected from the group consisting of formulas (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), and (XVI).

[0496] R 2a Each can be independently OH, OCH3, F, or a substituted C. 1-3 Alkyl, the R 2a It bonds only to the carbon atoms of the constituent atoms of the rings selected from the group consisting of the aza-butane ring shown in formula (VI), the pyrrolidine ring shown in formula (VII), the piperidine ring shown in formula (VIII), and the piperazine ring shown in formula (IX). m is an integer between 0 and 2. R 3 C can be replaced 1-6 Alkyl, substituted heterocyclic alkyl, or substituted heteroaryl, X represents a bond, -CH2-, -O-, -S-, or -NR. 4X -, R4X H or C that can be substituted 1-3 alkyl, Y 1 -O- (substitutable C) 1-3 Alkylene) Y2 -S- (substitutable C) 1-3 Alkylene) Y2 -SO2- (substitutable C 1-3 Alkylene) Y2 -NR Y -(C that can be replaced) 1-3 Alkylene) Y2 -(substitutable C) 1-3 (alkylene)-O Y2 -(substitutable C) 1-3 (alkylene)-S Y2 -(substitutable C) 1-3 (alkylene)-SO2 Y2 Or - (the C that can be replaced) 1-3 (alkylene)-NR Y Y2 Y2 Indicates Y 2 (the joint) R Y H or C that can be substituted 1-3 alkyl, Y 2 For bonds, substituted phenylene or substituted heteroaryl groups, L P To make Y 2 Groups that chemically bind with EUB EUB is a group that has the ability to bind to one E3 ubiquitin ligase selected from the group consisting of VHL, hydroxycerebroside, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR. L A For the connector used to bind Ab to D, here, L A It can combine with any -NH- nitrogen atom or -OH oxygen atom contained in D.

[0497] (26-3) The antibody-drug complex or a salt thereof according to (26-2), wherein V2 One group selected from the group consisting of formulas (VIa) and (VIIa) below. LA Indicates with L A (the joint)

[0498] W is one group selected from the group consisting of formulas (VIIIa), (IXa), (Xa), (XIa), (XIIa), (XIIIa), (XIVa), (XVa), and (XVIa). LA Indicates with L A (the joint)

[0499] L A For the connector used to bind Ab to D, here, L A With V 2 or nitrogen atoms contained in W LA The joint shown is joined together and thus joined with D.

[0500] (26-4) The antibody-drug complex or a salt thereof according to (26-2), wherein, A is N, Q is CR Q R Q It is cyclopropyl. E stands for CH. R 1 It is the following formula (III-2),

[0501] R 2 -V 1 -V 2 Or W, V 1 It is -N(CH3)-, V 2 For example, the following formula (VII-2),

[0502] W is the following expression (XIV),

[0503] R 3 It can be a n-propyl or tetrahydropyranyl group that can be substituted with -OCH3. X is -O-. Y 1 -O-(methylene) Y2 Y2 Indicates Y 2 (the joint) Y 2 It is a phenylene. L P To make Y 2 Groups that chemically bind with EUB EUB is a group that has the ability to bind to one E3 ubiquitin ligase selected from the group consisting of VHL and hydroxycerebroside.

[0504] (26-5) The antibody-drug complex or a salt thereof according to (26-4), wherein, V 2 For example, the following formula (VII-2a) LA Indicates with L A (the joint)

[0505] W is defined by the following formula (XIVa) LA Indicates with L A (the joint)

[0506] L A For the connector used to bind Ab to D, here, L A With V 2 or nitrogen atoms contained in W LA The joint shown is joined together and thus joined with D.

[0507] (26-6) An antibody-drug complex or a salt thereof according to any one of (26-1) or (26-2), wherein D is: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolylamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3- [3-yl]phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolylamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolylamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolylamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- [Azol-5-yl]phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{methyl[(3S)-pyrrolidine-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolylamide, (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{methyl[(3S)-pyrrolidine-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolylamide, 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, 1-(6-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-1-methyl-1H-indazol-3-yl)-1,3-diazine-2,4-dione, 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, or Phosphoric acid = dihydrogen = (2R)-2-({(4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{methyl[(3S)-pyrrolidine-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutyryl]-4-hydroxy-L-prolyl}amino)-2-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl ester.

[0508] (26-7) An antibody-drug complex or a salt thereof according to any one of (26-1) to (26-6), wherein L A The connector is shown in equation (XXVIII).

[0509]

[0510] (in the formula, Str is an extension unit that combines with Ab and CLL, and r is 0 or 1. CLL is a segment of the structure that can be cut within a living organism. Sp is a spacing unit, combined with CLL and D, where t is 0 or 1. Ab (Indicates the junction with Ab).

[0511] (26-8) The antibody-drug complex or a salt thereof according to (26-7), wherein Str is the extension unit shown in formula (ST-1) and r is 1.

[0512]

[0513] (where R is in the formula) st1 C can be replaced 1-12 Alkylene, -(CH2CH2O) a1 -C 1-6 alkylene-, -C 1-6 Alkylene-(OCH2CH2) a2 -、- Replaceable C 1-6 Alkylene-NH-C(=O)-substitutable C 1-6 Alkylene-, -substitutable C 1-6 Alkylene-C(=O)-NH- substituted C 1-6 Alkylene-, substituted C 1-6 Alkylene -C(=O)-NH-(CH2CH2O) a3 -C 1-6 alkylene- or substituted C 1-6 Alkylene -NH-C(=O)-(CH2CH2O) a4 -C 1-6 alkylene- a1, a2, a3, and a4 are integers from 1 to 10. Ab (Indicates the junction with Ab).

[0514] (26-9) The antibody-drug complex or a salt thereof according to (26-8), wherein R st1 It is a C5 alkylene group.

[0515] (26-10) The antibody-drug complex or a salt thereof according to (26-7), wherein CLL is the in vivo cleavable portion of the structure of formula (CL-1).

[0516]

[0517] (where R is in the formula) AA The groups are independently selected from the group consisting of H, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, hydroxymethyl, 1-hydroxyethyl, -CH2-C(=O)-OH, -(CH2)2-C(=O)-OH, -CH2-C(=O)-NH2, -(CH2)2-C(=O)-NH2, -(CH2)4-NH2, -(CH2)3-NH-C(=NH)-NH2, -(CH2)3-NH-C(=O)-NH2, -CH2-SH or -CH2-S-CH3, or one group selected from the group consisting of the following formulas (RAA-1) and (RAA-2).

[0518] d is an integer from 1 to 6 STR (Indicates the junction with Str).

[0519] (26-11) The antibody-drug complex or a salt thereof according to (26-10), wherein R AA Each is independently either methyl or isopropyl, and d is 2.

[0520] (26-12) The antibody-drug complex or a salt thereof according to (26-10), wherein R AA They are independently isopropyl or -(CH2)3-NH-C(=O)-NH2, with d=2.

[0521] (26-13) The antibody-drug complex or a salt thereof according to (26-10), wherein R AA Each is independently either H or benzyl, and d is 4.

[0522] (26-14) The antibody-drug complex or its salt according to (26-7), wherein Sp is the spacer unit shown in formula (SP-1) and t is 1.

[0523]

[0524] (where R is in the formula) SP For H, C 1-6 Alkyl, -OC 1-6 Alkyl, halogen or halogenated C 1-6 alkyl CLL (Indicates the junction with CLL).

[0525] (26-15) The antibody-drug complex or a salt thereof according to (26-14), wherein R SP For H.

[0526] (26-16) The antibody-drug complex or its salt according to (26-7), wherein t is 0.

[0527] (26-17) The antibody-drug complex or a salt thereof according to (26-1), wherein formula (I) is as shown in formula (AD-1a) or (AD-2a).

[0528]

[0529] (in the formula, Ab represents an antibody or its antigen-binding fragment. A is CR A Or N, RA It is H, cyano, or a substituted C. 1-3 alkyl, Q is CR Q Or N, R Q H, halogen, C 3-6 cycloalkyl, vinyl, or substituted C 1-3 alkyl, E is CH or N. R 1 It can be selected from one or two cyano groups, OH groups, halogens, and substituted C groups. 1-3 The group consisting of alkyl groups substituted with naphthyl groups, or one group selected from the group consisting of formulas (III), (IV) and (V) below,

[0530] R 1a R 1b and R 1c Independent of each other, H, vinyl, halogen, or substituted C 1-3 alkyl, R 3 C can be replaced 1-6 Alkyl, substituted heterocyclic alkyl, or substituted heteroaryl, X represents a bond, -CH2-, -O-, -S-, or -NR. 4X -, R 4X H or C that can be substituted 1-3 alkyl, Y 1 -O- (substitutable C) 1-3 Alkylene) Y2 -S- (substitutable C) 1-3 Alkylene) Y2 -SO2- (substitutable C 1-3 Alkylene) Y2 -NR Y -(C that can be replaced) 1-3 Alkylene) Y2 -(substitutable C) 1-3 (alkylene)-O Y2 -(substitutable C) 1-3 (alkylene)-S Y2 -(substitutable C) 1-3 (alkylene)-SO2 Y2 Or - (the C that can be replaced) 1-3 (alkylene)-NR Y Y2 Y2 Indicates Y 2 (the joint) R Y H or C that can be substituted 1-3 alkyl, Y 2 For bonds, substituted phenylene or substituted heteroaryl groups, L P To make Y 2 Groups that chemically bind with EUB EUB is a group that has the ability to bind to one E3 ubiquitin ligase selected from the group consisting of VHL, hydroxycerebroside, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR. R st1 C 1-12 Alkylene R AA Each of the following can be independently H, methyl, isopropyl, benzyl, or -(CH2)3-NH-C(=O)-NH2, where d is an integer from 2 to 4. t is 0 or 1, n is a value from 1 to 20.

[0531] (26-18) The antibody-drug complex or a salt thereof according to (26-1), wherein formula (I) is as shown in formula (AD-3a), (AD-4a), (AD-5a), (AD-6a), (AD-7a), (AD-8a), (AD-9a), (AD-10a), (AD-11a), (AD-12a), (AD-13a) or (AD-25a).

[0532]

[0533] (where R is in the formula) st1 C 1-12 Alkylene, R AA Each of the following is independent of the others: H, methyl, isopropyl, benzyl, or -(CH2)3-NH-C(=O)-NH2, where d is an integer from 2 to 4, t is 0 or 1, and n is a value from 1 to 20.

[0534] (26-19) The antibody-drug complex or a salt thereof according to (26-1), wherein formula (I) is as shown in formula (AD-14), (AD-15), (AD-16), (AD-17), (AD-18), (AD-19), (AD-20), (AD-21), (AD-22), (AD-23), (AD-24) or (AD-25).

[0535]

[0536] (In the formula, n is a value from 1 to 20).

[0537] (26-20) An antibody-drug complex or a salt thereof according to any one of (26-1) to (26-19), wherein Ab is cetuximab and n is a value of 2 to 5.

[0538] The antibody-drug complex of formula (I) or its salts may contain tautomers and geometric isomers, depending on the type of substituents. In this specification, compounds of formula (I) are sometimes described only in one isomer form, but the invention also includes other isomers, as well as isolated products of the isomers or mixtures thereof.

[0539] Furthermore, antibody-drug complexes of formula (I) or their salts sometimes contain chiral carbon atoms and chiral axes, and diastereomers based thereon may exist. This invention also includes isolated products of diastereomers of antibody-drug complexes of formula (I) or their salts, or mixtures thereof.

[0540] Additionally, the antibody drug complex of formula (I) or its salt refers to a pharmaceutically acceptable salt of the antibody drug complex of formula (I) or its salt, which may sometimes form an acid addition salt or a salt with a base, depending on the type of substituent. Examples of such salts can be cited, for instance, those described in P. Heinrich Stahl's Handbook of Pharmaceutical Salts Properties, Selection, and Use, Wiley-VCH, 2008. Specifically, examples include: acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, xyleneformyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid; salts with inorganic metals such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with various amino acids and amino acid derivatives such as acetylleucine, lysine, and ornithine; and ammonium salts.

[0541] Furthermore, the present invention also includes various hydrates, solvates, and polymorphs of the antibody drug complex of formula (I) or its salts.

[0542] Furthermore, this invention includes all antibody-drug complexes of formula (I) or salts thereof labeled with one or more pharmaceutically acceptable radioactive or non-radioactive isotopes. Examples of preferred isotopes for isotopic labeling of the compounds of this invention include hydrogen (…). 2 H and 3 H, etc.), carbon ( 11 C 13 C and 14 C, etc.), nitrogen ( 13 N and 15 N, etc.), oxygen ( 15 O、 17 O and 18 O, etc.), fluorine ( 18 F, etc.), chlorine ( 36 Cl, etc.), iodine ( 123 I and 125 I, etc.), sulfur ( 35 Isotopes such as S.

[0543] The compounds of this invention, labeled with isotopes, can be used in studies such as tissue distribution research of drugs and / or substrates. For example, from the perspective of ease of labeling and simplicity of detection, tritium ( 3 H), carbon-14 ( 14 C) Radioactive isotopes such as those used for this purpose.

[0544] Replace with a heavier isotope, for example, replacing hydrogen with deuterium. 2 H) Sometimes, improved metabolic stability can be therapeutically advantageous (e.g., increased half-life in vivo, reduced dosage, and reduced drug interactions).

[0545] Emit isotopes to positrons ( 11 C 18 F, 15 O and 13 The substitution of N (e.g.) can be used in positron emission tomography (PET) tests to test substrate-acceptor occupancy.

[0546] The isotopically labeled compounds of the present invention can generally be manufactured by existing methods known to those skilled in the art, or by using suitable isotopically labeled reagents instead of unlabeled reagents, and by the same manufacturing method as in the examples or manufacturing examples.

[0547] (Manufacturing method)

[0548] The antibody-drug complex of formula (I) or its salt can be manufactured using various known synthetic methods based on the characteristics of its basic structure or the types of substituents. In this case, depending on the type of functional group, it is sometimes technically efficient to pre-replace the functional group with a suitable protecting group (a group that can be easily converted to the functional group) during the stage from the starting material to the intermediate. Examples of such protecting groups include those described in PGM Wuts and TW Greene, “Greene's Protective Groups in Organic Synthesis,” 5th edition, John Wiley & Sons Inc., 2014, which can be appropriately selected based on their reaction conditions. In such methods, after introducing the protecting group and reacting, the protecting group is removed as needed, thereby obtaining the desired compound.

[0549] The following describes the antibody-drug complex of formula (I) or its salt, and the drug (D) constituting the antibody-drug complex or its salt, and the drug-linker complex (L). A Representative manufacturing methods for antibodies or antigen-binding fragments (Abs) are described below. Each manufacturing method can also be performed with reference to the references appended to this description. It should be noted that the manufacturing methods of this invention are not limited to the examples shown below.

[0550] In this manual, the following abbreviations are sometimes used.

[0551] DMF: N,N-dimethylformamide, DMAc: N,N-dimethylacetamide, THF: tetrahydrofuran, MeCN: acetonitrile, MeOH: methanol, EtOH: ethanol, iPrOH: isopropanol, tBuOH: tert-butanol, DOX: 1,4-dioxane, DMSO: dimethyl sulfoxide, TEA: triethylamine, DIPEA: N,N-diisopropylethylamine, tBuOK: potassium tert-butoxide, PdCl2(dppf)·CH2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct, Pd / C: palladium on carbon, PyBOP: (benzotriazol-1-yloxy)tripyrrolidine Hexafluorophosphate, iPr2O: diisopropyl ether, HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-Oxide hexafluorophosphate, DABCO: 1,4-diazabicyclo[2.2.2]octane, TFA: trifluoroacetic acid, TfOH: trifluoromethanesulfonic acid, COMU: N-[({[(1Z)-1-cyano-2-ethoxy-2-oxoethylidene]amino}oxy)(morpholin-4-yl)methylene]-N-methylmethylamine hexafluorophosphate, NMM: N-methylmorpholine, CDI: 1,1'-carbonyldiimidazole, NMO: N-methylmorpholine N-oxide, NMP: N-methyl-2-pyrrolidone, LHMDS: lithium bis(trimethylsilyl)amide, NHMDS: sodium bis(trimethylsilyl)amide, DMEDA: N,N'-dimethylethylenediamine, Triton B: Benzyltrimethylammonium hydroxide, Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene, Ruphos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl.

[0552] I. Methods for manufacturing drug (D)

[0553] Drug (D) can be obtained, for example, by the methods described in International Publication No. 2022 / 173032, International Publication No. 2023 / 171781, and International Publication No. 2024 / 019103. The following shows a conventional synthetic method for drug (D).

[0554] (First method of pharmaceutical manufacturing)

[0555] This manufacturing method is a first method for manufacturing the drug (D) represented by formula (II) in the drug (D).

[0556]

[0557] (where PG) 1 -R 11 For in R 1 The NH or OH groups contained therein have PGs bonded as protecting groups. 1 PG groups 2 -R 21 For in R 2 The NH or OH groups contained therein have PGs bonded as protecting groups. 2 (The same applies below.)

[0558] The drug shown in formula (II) can be obtained by subjecting compound (1) to a deprotection reaction under acidic conditions. Examples of protecting groups that can be deprotected under acidic conditions include tert-butyloxycarbonyl, triphenylmethyl, tetrahydro-2H-pyran-2-yl, methoxymethyl, dimethylmethanediyl, tert-butylsulfinyl, etc.

[0559] In this reaction, the same or excess equivalent of the deprotecting agent as compound (1) is used, and the reaction is carried out in an inert solvent under cooling to reflux, typically with stirring for 0.1 hours to 5 days. Examples of deprotecting agents used herein are not particularly limited, but include acids such as hydrogen chloride (DOX solution), trifluoroacetic acid, methanesulfonic acid, phosphoric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and mixtures thereof. Examples of solvents used herein are not particularly limited, but include alcohols such as MeOH and EtOH; halogenated hydrocarbons such as dichloromethane, 1,2-dichloromethane, or chloroform; ethers such as diethyl ether, THF, DOX, and dimethoxyethane; DMF, DMSO, MeCN, TfOH, or water; and mixtures thereof.

[0560] Furthermore, by selecting a protecting group, deprotection can be achieved through catalytic hydrogenation or under alkaline conditions. Examples of protecting groups that can be deprotected by catalytic hydrogenation include benzyl, p-methoxybenzyl, and benzyloxycarbonyl. Alternatively, deprotection can be performed using a fluoride ion source such as tetra-n-butylammonium fluoride. Examples of protecting groups include tert-butyl(dimethyl)silyl and (trimethylsilyl)ethoxymethyl. Examples of protecting groups that can be deprotected under alkaline conditions include acetyl, trifluoroacetyl, and benzoyl. Additionally, as PG... 1 PG 2 Alternatively, protective groups that can be deprotected under different deprotection conditions can be selected separately, and deprotection can be carried out in stages.

[0561] For example, the following references may be consulted as references for this reaction.

[0562] PGMWuts and TWGreene, "Greene's Protective Groups in Organic Synthesis (5th Edition, 2014)".

[0563] It should be noted that when the compound (1) used as a raw material has axial chirality, the stereoisomer obtained by temporarily separating the compound (1) can also be used to carry out this reaction.

[0564] (Second method for manufacturing pharmaceuticals)

[0565] This manufacturing method is a second method for manufacturing the drug (D) represented by formula (II) in drug (D).

[0566]

[0567] The drug shown in formula (II) can be obtained by isolating compound (1) in its free form under acidic conditions followed by a deprotection reaction and then treating it under alkaline conditions, and then subjecting it to a salt-forming reaction. Examples of protecting groups that can be deprotected under acidic conditions include tert-butyloxycarbonyl, triphenylmethyl, tetrahydro-2H-pyran-2-yl, methoxymethyl, dimethylmethanediyl, tert-butylsulfinyl, etc.

[0568] In this reaction, the deprotecting agent, in the same or excess amount as compound (1), is stirred for 0.1 hours to 5 days under cooling to reflux in a solvent inert to the reaction, and isolated in free form after treatment with an alkaline aqueous solution. Then, the reaction is carried out in the same or excess amount of an acidic agent under cooling to reflux in a solvent inert to the reaction, stirred for 0.1 hours to 5 days. Examples of deprotecting agents used herein, without particular limitation, include acids such as hydrogen chloride (DOX solution), trifluoroacetic acid, methanesulfonic acid, phosphoric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and mixtures thereof. Examples of solvents used herein, without particular limitation, include alcohols such as MeOH and EtOH; halogenated hydrocarbons such as dichloromethane, 1,2-dichloromethane, or chloroform; ethers such as diethyl ether, THF, DOX, and dimethoxyethane; DMF, DMSO, MeCN, TfOH, or water; and mixtures thereof. Examples of acidic reagents used herein include hydrogen chloride (DOX solution), phosphoric acid, and p-toluenesulfonic acid. Examples of alkaline aqueous solutions used herein are not specifically limited, but include sodium bicarbonate aqueous solution.

[0569] Furthermore, by selecting a protecting group, deprotection can be carried out via catalytic hydrogenation or under alkaline conditions. Examples of protecting groups that can be deprotected via catalytic hydrogenation include benzyl, p-methoxybenzyl, and benzyloxycarbonyl. Alternatively, deprotection can be performed using a fluoride ion source such as tetra-n-butylammonium fluoride. Examples of protecting groups include tert-butyl(dimethyl)silyl and (trimethylsilyl)ethoxymethyl. Examples of protecting groups that can be deprotected under alkaline conditions include acetyl, trifluoroacetyl, and benzoyl. Furthermore, for PG1 and PG2, protecting groups capable of deprotection under different deprotection conditions can be selected separately, and deprotection can be carried out in stages.

[0570] For example, the following references may be consulted as references for this reaction.

[0571] PGMWuts and TWGreene, "Greene's Protective Groups in Organic Synthesis (5th Edition, 2014)".

[0572] It should be noted that when the compound (1) used as a raw material has axial chirality, the stereoisomer obtained by temporarily separating the compound (1) can also be used to carry out this reaction.

[0573] (Pharmaceutical raw material manufacturing method 1)

[0574] This manufacturing method is a method for manufacturing compound (1)-1 contained in compound (1), which is used as a raw material in the first manufacturing method and the second manufacturing method of a drug.

[0575]

[0576] (where L) 2A It means that it can be C 1-3 Alkyl-substituted piperidine dimethyl, which can be C 1-3 Alkyl-substituted piperazine dimethyl, which can be C 1-3 Alkyl-substituted pyrrolidinediyl, bridged piperazinediyl, or 2,6-diazaspiro[3,4]octanediyl, R LG Indicate C 1-12 Alkyl group. (The same applies below)

[0577] (First step)

[0578] This step is the process of obtaining compound (3) by subjecting compound (2) to hydrolysis conditions.

[0579] In this reaction, a hydrolytic reagent of the same or excess amount as compound (2) is used, and the reaction is carried out in a solvent inert to the reaction by stirring, typically for 1 hour to 5 days, under cooling to under reflux. Examples of hydrolytic reagents used herein are not particularly limited, but include aqueous solutions of sodium hydroxide, potassium hydroxide, lithium hydroxide, trimethyltin hydroxide, etc. Examples of solvents are not particularly limited, but include: alcohols such as methanol, ethanol, and n-propanol; ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, or chloroform; acetonitrile; water; and mixtures thereof.

[0580] (Second Step)

[0581] This step is the process of obtaining compound (1)-1 by subjecting compounds (3) and (4) to condensation reaction conditions.

[0582] In this reaction, compounds (3) and (4) are used in equal or excess amounts. A condensing agent and a base are added to the mixture, and the reaction is carried out in an inert solvent at room temperature, typically with stirring for 1 hour to 1 day. Examples of condensing agents used herein are not particularly limited, but include HATU, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride salt, dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, COMU, PyBOP, etc. Examples of bases are not particularly limited, but include organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine, etc.; and inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, etc. Examples of solvents, without particular limitation, include: halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, or chloroform; ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane; alcohols such as methanol, ethanol, and n-propanol; N,N-dimethylformamide; and mixtures thereof.

[0583] (Pharmaceutical raw material manufacturing method 2)

[0584] This manufacturing method is a first method for manufacturing compound (2)-1 contained in compound (2), which is a raw material for manufacturing pharmaceutical raw material method 1.

[0585]

[0586] (where PG) 3 LG represents the protecting group of OH. 1The leaving group is indicated by BLG, which represents a borate group or trifluoroborate group protected by a boric acid protecting group, such as a borate group or borate pinacol ester group (hereinafter sometimes referred to as borate group, etc.). Examples of leaving groups shown here include Cl, Br, methanesulfonyloxy, p-toluenesulfonyloxy, etc. (The same applies below.)

[0587] (First step)

[0588] This step is a method for producing compound (7) by in-situ substitution reaction of compound (5)-1 and compound (6)-1.

[0589] In this reaction, compounds (5)-1 and (6)-1 are used in equal or excess amounts, and the mixture is stirred for 0.1 hours to 5 days under cooling to reflux, preferably from 0°C to 120°C, in a solvent inert to the reaction or in the absence of a solvent. Examples of solvents used herein are not particularly limited, including: halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, dehydrated THF, DOX, and 1,2-dimethoxyethane; DMF, DMAc, DMSO, ethyl acetate, MeCN, and NMP; and mixtures thereof. The presence of organic bases such as TEA, DIPEA, NMM, DABCO, and tBuOK, and inorganic bases such as sodium hydride, potassium carbonate, sodium carbonate, and cesium carbonate can sometimes be advantageous in facilitating the reaction.

[0590] Alternatively, compound (7) can be prepared by catalytic hydrogenation of the compound obtained by the dōrümü-Heck reaction of compound (5)-1 and compound (6)-1.

[0591] [literature]

[0592] Chem. Rev., 2003, 103, p.2945-2964

[0593] (Second Step)

[0594] This step is a method for producing compound (9) by in-situ substitution reaction of compound (7) and compound (8).

[0595] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0596] Alternatively, compound (9) can be manufactured by coupling the hydrogen atoms of compound (8) to halogenated compounds with the root bank of compound (7).

[0597] [literature]

[0598] ACC. Chem. Res., 1982, 15, p.340-348

[0599] (Step 3)

[0600] This step involves reacting compound (9) with PG. 3 A method for producing compound (10)-1 by in-situ substitution reaction of -OH.

[0601] As used here, PG 3 Examples of -OH include benzyl alcohol, p-methoxybenzyl alcohol, and 1-phenylethanol.

[0602] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0603] (Fourth step)

[0604] This step involves compound (10) containing either compound (10)-1 obtained in the third step of this synthetic method or compound (10)-2 obtained in the third step of the pharmaceutical raw material manufacturing method 9, and compound (10) containing R. Q - A method for producing compound (11) by the Suzuki-Miyaura coupling reaction of boric acid derivatives such as boric acid groups. Examples of boric acid groups used herein are not particularly limited, and boric acid groups, borate ester groups, borate pinacol ester groups, triol borate ester salt groups, and trifluoroborate groups may be listed.

[0605] In this reaction, compound (10) and containing R are used in equal or excess equivalent amounts. QBoric acid derivatives such as borate groups are mixed and stirred in an inert solvent in the presence of a base and a palladium catalyst at room temperature to reflux, preferably 20°C to 140°C, typically for 0.1 hours to 5 days. Examples of solvents used herein are not particularly limited and include: halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; alcohols such as MeOH, EtOH, isopropanol, butanol, and pentanol; DMF, DMSO, MeCN, 1,3-dimethylimidazolidine-2-one, and water; and mixtures thereof. Inorganic bases such as potassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide, barium hydroxide, and cesium carbonate are also included. Examples of palladium catalysts include tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane adduct, (1E,4E)-1,5-diphenylpentan-1,4-dien-3-one / palladium (3:2), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, palladium(II) acetate, and methanesulfonyl[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II), etc. The presence of ligands such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine, 1,1'-bis(diphenylphosphino)ferrocene, butyldi-1-adamantylphosphine, and di(adamantane-1-yl)(butyl)phosphine can sometimes facilitate the reaction. Additionally, a pre-catalyst of (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) can be used as the palladium catalyst for this reaction. Furthermore, heating the mixture by microwave irradiation can sometimes facilitate the reaction.

[0606] [literature]

[0607] J. Am. Chem. Soc., 2005, 127, p.4685-4696

[0608] Org. Lett. 2011, 13, p.3948-3951

[0609] Org. Lett. 2012, 14, p.1278-1281

[0610] Compound (11) can be produced by the deiodination reaction of compound (10) using a Pd catalyst and a reducing agent (here, R Q(For hydrogen).

[0611] [literature]

[0612] J. Org. Chem., 1977, 42, p.3491-3494

[0613] Tetrahedron Letters 2013, 54, 5207-5210

[0614] (Step 5)

[0615] This step is a method for producing compound (13) by the Suzuki-Miyaura coupling reaction of compound (11) and compound (12).

[0616] The reaction conditions are the same as the fourth step of method 2 for manufacturing pharmaceutical raw materials.

[0617] It should be noted that compound (13) sometimes exhibits axial chirality and is sometimes obtained as a mixture of stereoisomers, which can be obtained by adjusting PG. 1 The individual stereoisomers are isolated by conventional resolution operations, such as using ODS column chromatography or silica gel column chromatography, on the compound (13) with the protecting group or the compound (14) obtained by deprotection reaction of the compound (13).

[0618] (Step Six)

[0619] This step is a method for producing compound (14) by deprotecting compound (13) using a catalytic hydrogenation reaction.

[0620] This reaction can be carried out by stirring compound (13) under a hydrogen atmosphere at atmospheric pressure to under pressure in a solvent that is inert to the reaction, such as MeOH, EtOH, or ethyl acetate, in the presence of a metal catalyst, under cooling to heating, preferably at room temperature, for 1 hour to 5 days. As a metal catalyst, palladium catalysts such as Pd / C and palladium black, platinum catalysts such as platinum plates and platinum oxide, and nickel catalysts such as reduced nickel and Raney nickel are used. Tetrahydro-2H-pyran-2-yl is used as the PG catalyst. 1 When protecting a group, a base is sometimes used to inhibit its deprotection. Examples of bases used here are not particularly limited, but include sodium bicarbonate, sodium carbonate, potassium carbonate, and cesium carbonate.

[0621] It should be noted that compound (14) sometimes exhibits axial chirality and is obtained as a mixture of stereoisomers, which can be obtained by adjusting PG. 1 The individual stereoisomers are isolated by conventional resolution operations, such as using ODS column chromatography or silica gel column chromatography, on the compound (14) with the protecting group or the compound (14) obtained by deprotection reaction.

[0622] For example, the following references may be consulted as references for this reaction.

[0623] Edited by the Chemical Society of Japan, "Lectures on Experimental Chemistry", 5th edition, Volume 13, Maruzen, 2004

[0624] (Seventh Step)

[0625] This step is a method for producing compound (2)-1 by reacting compound (14) with compound (15).

[0626] In this reaction, compounds (14) and (15) are used in equal or excess amounts, and the mixture thereof is reacted in the presence of a base in a solvent inert to the reaction under cooling to reflux, preferably from 0°C to 80°C, typically for 0.1 hours to 5 days. The solvent used herein is not particularly limited, but examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as MeOH and EtOH; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; DMF, DMSO, ethyl acetate, and MeCN; and mixtures thereof. Examples of bases are not particularly limited, but examples include: organic bases such as TEA, DIPEA, 1,8-diazabicyclo[5.4.0]-7-undecene, n-butyllithium, and tBuOK; and inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride. The reaction can sometimes be carried out in the presence of a phase-transfer catalyst such as tetra-n-butylammonium chloride.

[0627] For example, the following references may be consulted as references for this reaction.

[0628] Edited by the Chemical Society of Japan, "Lectures on Experimental Chemistry", 5th edition, Volume 14, Maruzen, 2005

[0629] It should be noted that compound (2)-1 sometimes exhibits axial chirality and is obtained as a mixture of stereoisomers, which can be obtained by adjusting PG. 1 The individual stereoisomers are isolated by conventional resolution operations, such as ODS column chromatography or silica gel column chromatography, of compound (2)-1, which is a protecting group or a compound obtained by deprotection reaction of compound (2)-1.

[0630] Furthermore, the compound (15) containing LG can be... 1 A significant portion of hydroxyl compounds undergo sulfonation in the presence of a base, thereby enabling the production of LG. 1Compounds that are sulfonyloxy groups. Examples of sulfonating agents used herein are not particularly limited, but may include, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride, and methanesulfonic anhydride. Examples of bases are not particularly limited, but may include, for example, TEA, DIPEA, pyridine, and tetramethylethylenediamine.

[0631] For example, the following references may be consulted as references for this reaction.

[0632] Synthesis 1999, 9, p.1633-1636

[0633] (Pharmaceutical raw material manufacturing method 3)

[0634] This manufacturing method is a second method for manufacturing compound (2)-1 contained in compound (2), which is a raw material in method 1 for manufacturing pharmaceutical raw materials.

[0635]

[0636] (In the formula, q represents 1 or 2. The same applies below.)

[0637] (First step)

[0638] This step involves reacting compound (7) with R. LG A method for producing compound (16) by in-situ substitution reaction of -SH. As used herein, R... LG Examples of -SH can be listed in C. 1-12 Alkyl mercaptans, such as ethanethiol and dodecyl mercaptan.

[0639] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0640] (Second Step)

[0641] This step involves reacting compound (16) with PG. 3 A method for producing compound (17)-1 by in-situ substitution reaction of -OH. As used herein, PG... 3 Examples of -OH include benzyl alcohol, p-methoxybenzyl alcohol, and 1-phenylethanol.

[0642] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0643] (Step 3)

[0644] This step involves compound (17) containing either compound (17)-1 obtained in the second step of this synthetic method or compound (17)-2 obtained in the fourth step of the pharmaceutical raw material manufacturing method 8, and compound (17) containing R. QA method for producing compound (18) by the Suzuki-Miyaura coupling reaction of boric acid derivatives such as boric acid groups.

[0645] The reaction conditions are the same as the fourth step of method 2 for manufacturing pharmaceutical raw materials.

[0646] Compound (18) can be prepared by deiodination of compound (17) using a Pd catalyst and a reducing agent (here, R Q (For hydrogen).

[0647] [literature]

[0648] J. Org. Chem., 1977, 42, p.3491-3494

[0649] Tetrahedron Letters 2013, 54, 5207-5210

[0650] (Fourth step)

[0651] This step is a method for producing compound (19) by the Suzuki-Miyaura coupling reaction of compound (18) and compound (12).

[0652] The reaction conditions are the same as the fourth step of method 2 for manufacturing pharmaceutical raw materials.

[0653] It should be noted that compound (19) is sometimes chiral and sometimes obtained as a mixture of stereoisomers. The individual stereoisomers of compound (19) can be isolated by conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography. Alternatively, the stereoisomers of compound (19) can also be isolated by deprotecting compound (19), isolating the stereoisomers, and then protecting them again with a protecting group.

[0654] Examples of protecting groups that can be used for further protection include tetrahydro-2H-pyran-2-yl.

[0655] (Step 5)

[0656] This step is a method for producing compound (20) by oxidation reaction of compound (19).

[0657] In this reaction, compound (19) is treated with an oxidant of equal or excess amount in a solvent inert to the reaction under cooling to heating, preferably -20°C to 80°C, typically for 0.1 hours to 3 days. Oxidation using m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium hypochlorite, or hydrogen peroxide is preferred in this reaction. Examples of solvents include: aromatic hydrocarbons such as benzene and toluene; ethers such as THF; halogenated hydrocarbons such as chloroform and dichloromethane; DMF, DMSO, ethyl acetate, MeCN; and mixtures thereof. Examples of other oxidants include cumene hydrogen peroxide, potassium persulfate (Oxone), activated manganese dioxide, chromic acid, potassium permanganate, sodium periodate, etc.

[0658] [literature]

[0659] Edited by the Chemical Society of Japan, "Lectures on Experimental Chemistry", 5th edition, Volume 17, Maruzen, 2004

[0660] (Step Six)

[0661] This step is a method for producing compound (13) by in-situ substitution reaction of compound (20) and compound (8).

[0662] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0663] It should be noted that when compound (13) is axially chiral, it is obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by conventional separation operations, such as separation using ODS column chromatography or silica gel column chromatography.

[0664] (Seventh Step)

[0665] This step is a method for producing compound (14) by deprotecting compound (13) using a catalytic hydrogenation reaction.

[0666] The reaction conditions are the same as those in step six of method 2 for manufacturing pharmaceutical raw materials.

[0667] It should be noted that compound (14) is sometimes chiral and sometimes obtained as a mixture of stereoisomers. The individual stereoisomers of compound (14) can be isolated by conventional separation operations, such as separation using ODS column chromatography or silica gel column chromatography.

[0668] (Step 8)

[0669] This step is a method for producing compound (2)-1 by reacting compound (14) with compound (15).

[0670] The reaction conditions are the same as those in step seven of method 2 for manufacturing pharmaceutical raw materials.

[0671] It should be noted that compound (2)-1 is sometimes axially chiral and sometimes obtained as a mixture of stereoisomers. The stereoisomers of compound (2)-1 can be isolated by conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography. Alternatively, the stereoisomers of compound (2)-1 can also be isolated by deprotecting compound (2)-1, isolating the stereoisomers, and then protecting it again with a protecting group.

[0672] Examples of protecting groups that can be used for further protection include tetrahydro-2H-pyran-2-yl.

[0673] (Drug raw material manufacturing method 4)

[0674] This manufacturing method is a third method for manufacturing compound (2)-1 contained in compound (2), which is a raw material in method 1 for manufacturing pharmaceutical raw materials.

[0675]

[0676] (First step)

[0677] This step is a method for producing compound (21) by deprotecting compound (20) using a catalytic hydrogenation reaction.

[0678] The reaction conditions are the same as those in step six of method 2 for manufacturing pharmaceutical raw materials.

[0679] It should be noted that compound (21) is sometimes chiral and sometimes obtained as a mixture of stereoisomers. The individual stereoisomers of compound (21) can be isolated by conventional separation operations, such as separation using ODS column chromatography or silica gel column chromatography.

[0680] (Second Step)

[0681] This step is a method for producing compound (22) by alkylation reaction of compound (21) and compound (15).

[0682] The reaction conditions are the same as those in step seven of method 2 for manufacturing pharmaceutical raw materials.

[0683] It should be noted that compound (22) is sometimes chiral and sometimes obtained as a mixture of stereoisomers. The individual stereoisomers of compound (22) can be isolated by conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography. Alternatively, the stereoisomers of compound (22) can also be isolated by deprotecting compound (22), isolating the stereoisomers, and then protecting them again with a protecting group.

[0684] Examples of protecting groups that can be used for further protection include tetrahydro-2H-pyran-2-yl.

[0685] (Step 3)

[0686] This step is a method for producing compound (2)-1 by in-situ substitution reaction of compound (22) and compound (8).

[0687] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0688] It should be noted that compound (2)-1 is sometimes chiral and is obtained as a mixture of stereoisomers. The individual stereoisomers can be isolated by conventional separation operations, such as separation using ODS column chromatography or silica gel column chromatography, on compound (2)-1 or the compound obtained by deprotection reaction of compound (2)-1.

[0689] The deprotection reaction conditions used here are the same as those described in manufacturing method 1.

[0690] (Pharmaceutical raw material manufacturing method 5)

[0691] This manufacturing method is a first method for manufacturing compound (2)-2 contained in compound (2), which is a raw material for manufacturing pharmaceutical raw material method 1.

[0692]

[0693] (where PG) 22 (This refers to tert-butyl. The same applies below.)

[0694] (First step)

[0695] This step is a method for producing compound (23) by hydrolyzing compound (5)-1.

[0696] In this reaction, compound (5)-1 and the hydrolysis reagent are used in equal or excess amounts, and the reaction is carried out in a solvent inert to the reaction by stirring under cooling to reflux for 0.1 hours to 5 days. Examples of solvents used herein are not particularly limited, but include: alcohols such as methanol and ethanol; acetone, DMF, THF, etc. In addition, a mixture of the above solvents and water is sometimes suitable for the reaction. Examples of hydrolysis reagents are not particularly limited, but include: aqueous solutions of sodium hydroxide, aqueous solutions of potassium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.

[0697] For example, the following references may be consulted as references for this reaction.

[0698] "Lectures on Experimental Chemistry (5th Edition)" edited by the Chemical Society of Japan, Volume 16 (2005) (Maruzen)

[0699] Angew. Chem. Int. Ed. 2005, 44, p.1378-1382.

[0700] (Second Step)

[0701] This step is a method for producing compound (24) by using tert-butyl to protect the hydroxyl group of compound (23).

[0702] In this reaction, compound (23) and the tert-butyl protecting agent are used in equal or excess amounts, and the reaction is carried out in an inert solvent by stirring, typically for 0.1 hours to 5 days, under cooling to reflux. Examples of solvents used herein are not particularly limited, but include ethers such as THF and DOX; halogenated hydrocarbons such as dichloromethane; and tBuOH and DMF. Examples of tert-butyl protecting agents are not particularly limited, but include isobutylene and 2-tert-butyl-1,3-diisopropylisourea.

[0703] Alternatively, compound (24) can be prepared by the dehydration condensation reaction of compound (23) with tBuOH.

[0704] For example, the following references may be consulted as references for this reaction.

[0705] PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis", 5th Edition, John Wiley & Sons Inc., 2014

[0706] Org. Lett., 2012, 14, 17, p.4678-4681

[0707] (Step 3)

[0708] This step involves reacting compound (24) with R. LG A method for producing compound (25) by in-situ substitution reaction of -SH.

[0709] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0710] (Fourth step)

[0711] This step involves reacting compound (25) with PG. 3A method for producing compound (26) by in-situ substitution reaction of -OH.

[0712] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0713] (Step 5)

[0714] This step involves compound (26) and containing R. Q A method for producing compounds (27) by the Suzuki-Miyaura coupling reaction of boric acid derivatives such as boric acid groups.

[0715] The reaction conditions are the same as the fourth step of method 2 for manufacturing pharmaceutical raw materials.

[0716] Compound (27) can be prepared by deiodination of compound (26) using a Pd catalyst and a reducing agent (here, R Q (For hydrogen).

[0717] [literature]

[0718] J. Org. Chem., 1977, 42, p.3491-3494

[0719] Tetrahedron Letters 2013, 54, 5207-5210

[0720] (Step Six)

[0721] This step is a method for producing compound (28) by the Suzuki-Miyaura coupling reaction of compound (27) and compound (12).

[0722] The reaction conditions are the same as the fourth step of method 2 for manufacturing pharmaceutical raw materials.

[0723] It should be noted that compound (28) is sometimes chiral and sometimes obtained as a mixture of stereoisomers. The individual stereoisomers of compound (28) can be isolated by conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography. Alternatively, the stereoisomers of compound (28) can also be isolated by deprotecting compound (28), isolating the stereoisomers, and then protecting them again with a protecting group.

[0724] Examples of protecting groups that can be used for further protection include tetrahydro-2H-pyran-2-yl.

[0725] (Seventh Step)

[0726] This step is a method for producing compound (29) by oxidation reaction of compound (28).

[0727] The reaction conditions are the same as those in step 5 of method 3 for manufacturing pharmaceutical raw materials.

[0728] For example, the following references may be consulted as references for this reaction.

[0729] PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis", 5th Edition, John Wiley & Sons Inc., 2014

[0730] (Step 8)

[0731] This step is a method for producing compound (30) by in-situ substitution reaction of compound (29) and compound (8).

[0732] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0733] (Step 9)

[0734] This step is a method for producing compound (31) by deprotecting compound (30) using a catalytic hydrogenation reaction.

[0735] The reaction conditions are the same as those in step six of method 2 for manufacturing pharmaceutical raw materials.

[0736] It should be noted that compound (31) is sometimes chiral and sometimes obtained as a mixture of stereoisomers. The individual stereoisomers of compound (31) can be isolated by conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography.

[0737] (Step 10)

[0738] This step is a method for producing compound (32) by alkylation reaction of compound (31) and compound (15).

[0739] The reaction conditions are the same as those in step seven of method 2 for manufacturing pharmaceutical raw materials.

[0740] It should be noted that compound (32) is sometimes chiral and sometimes obtained as a mixture of stereoisomers. The individual stereoisomers of compound (32) can be isolated by conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography. Alternatively, the stereoisomers of compound (32) can also be isolated by deprotecting compound (32), isolating the stereoisomers, and then protecting them again with a protecting group.

[0741] (Step 11)

[0742] This step is a method for producing compound (33) by subjecting compound (32) to a deprotection reaction.

[0743] The reaction conditions are the same as those described in the first method of manufacturing the drug.

[0744] Furthermore, after deprotection of compound (33), it can be protected again with a protecting group. Examples of protecting groups for reprotection include tetrahydro-2H-pyran-2-yl.

[0745] Alternatively, the series of operations described above, including deprotection and reprotection with a protecting group, can be performed as a single reaction.

[0746] (Step Twelfth)

[0747] This step is a method for producing compound (2)-2 by reacting compound (33) with compound (6)-1.

[0748] In this reaction, compounds (33) and (6)-1 are used in equal or excess amounts, and the mixture is stirred for 0.1 hours to 5 days in the presence of a condensing agent in a solvent inert to the reaction, under cooling to heating, preferably -20°C to 60°C. Examples of solvents are not particularly limited, including: aromatic hydrocarbons such as benzene and toluene; ethers such as THF and DOX; halogenated hydrocarbons such as chloroform and dichloromethane; alcohols such as methanol and ethanol; DMF, DMSO, ethyl acetate, MeCN; and mixtures thereof. Examples of condensing agents include PyBOP, HATU, and CDI. The presence of organic bases such as TEA, DIPEA, or NMM, or inorganic bases such as potassium carbonate, sodium carbonate, or cesium carbonate, can sometimes be advantageous in facilitating the reaction.

[0749] (Pharmaceutical raw material manufacturing method 6)

[0750] This manufacturing method is a method for manufacturing compound (13)-1 contained in compound (13), which is an intermediate in manufacturing method 2 of pharmaceutical raw materials.

[0751]

[0752] (First step)

[0753] This step is a method for producing compound (34) by subjecting compound (30) to a deprotection reaction.

[0754] The reaction conditions are the same as those described in the first method of manufacturing the drug.

[0755] Furthermore, after deprotection of compound (34), it can be protected again with a protecting group. Examples of protecting groups for reprotection include tetrahydro-2H-pyran-2-yl.

[0756] Alternatively, the series of operations described above, including deprotection and reprotection with a protecting group, can be performed as a single reaction.

[0757] (Second Step)

[0758] This step is a method for producing compound (13)-1 by reacting compound (34) with compound (6)-1.

[0759] The reaction conditions are the same as those in step 12 of method 5 for manufacturing pharmaceutical raw materials.

[0760] (Pharmaceutical raw material manufacturing method 7)

[0761] This manufacturing method is a method for manufacturing a compound (30) that is a raw material for manufacturing a pharmaceutical raw material in method 6.

[0762]

[0763] (First step)

[0764] This step is a method for producing compound (37) by in-situ substitution reaction of compound (24) and compound (8).

[0765] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0766] (Second Step)

[0767] This step involves reacting compound (37) with PG. 3 A method for producing compound (38) by in-situ substitution reaction of -OH.

[0768] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0769] (Step 3)

[0770] This step involves compound (38) and containing R. Q A method for producing compounds (39) by the Suzuki-Miyaura coupling reaction of boric acid derivatives such as boric acid groups.

[0771] The reaction conditions are the same as the fourth step of method 2 for manufacturing pharmaceutical raw materials.

[0772] Compound (39) can be produced by the dehalogenation reaction of compound (38) using a Pd catalyst and a reducing agent (here, R Q (For hydrogen).

[0773] [literature]

[0774] J. Org. Chem., 1977, 42, p.3491-3494

[0775] Tetrahedron Letters 2013, 54, 5207-5210

[0776] (Fourth step)

[0777] This step is a method for producing compound (30) by the Suzuki-Miyaura coupling reaction of compound (39) and compound (15).

[0778] The reaction conditions are the same as the fourth step of method 2 for manufacturing pharmaceutical raw materials.

[0779] It should be noted that compound (30) is sometimes chiral and sometimes obtained as a mixture of stereoisomers. The individual stereoisomers of compound (30) can be isolated by conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography. Alternatively, the stereoisomers of compound (30) can also be isolated by deprotecting compound (30), isolating the stereoisomers, and then protecting them again with a protecting group.

[0780] (Drug Raw Material Manufacturing Method 8)

[0781] This manufacturing method is a method for manufacturing compound (17)-2 contained in compound (17), which is an intermediate in manufacturing method 3 of pharmaceutical raw materials.

[0782]

[0783] (First step)

[0784] This step is a method for producing compound (5)-2 by chlorination reaction of compound (40).

[0785] In this reaction, compound (40) and a chlorinating agent are used in equal or excess amounts, and the mixture is stirred for 0.1 hours to 5 days in a solvent inert to the reaction or in the absence of a solvent, under cooling to reflux, preferably 60°C to reflux. Examples of solvents used herein are not particularly limited, but include: aromatic hydrocarbons such as toluene; ethers such as THF and DOX; halogenated hydrocarbons such as dichloromethane; and DMF and DMAc. Examples of chlorinating agents include phosphorus oxychloride and thionyl chloride. The presence of an organic base such as TEA, DIPEA, or NMM can sometimes be advantageous in facilitating the reaction.

[0786] (Second Step)

[0787] This step involves reacting compound (5)-2 with R... LG A method for producing compound (41) by in-situ substitution reaction of -SH.

[0788] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0789] (Step 3)

[0790] This step involves reacting compound (41) with PG. 3 A method for producing compound (42) by in-situ substitution reaction of -OH.

[0791] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0792] (Fourth step)

[0793] This step is a method for producing compound (17)-2 by in-situ substitution reaction of compound (42) with compound (6)-1.

[0794] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0795] (Pharmaceutical raw material manufacturing method 9)

[0796] This manufacturing method is a method for manufacturing compound (10)-2.

[0797]

[0798] (First step)

[0799] This step is a method for producing compound (43) by in-situ substitution reaction of compound (5)-2 with compound (8).

[0800] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0801] In addition, compound (43) can be produced by coupling the hydrogen atoms of compound (8) to halogenated compounds with the root-bank of compound (5)-2.

[0802] (Second Step)

[0803] This step involves reacting compound (43) with PG. 3 A method for producing compound (44) by in-situ substitution reaction of -OH.

[0804] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0805] (Step 3)

[0806] This step is a method for producing compound (10)-2 by in-situ substitution reaction of compound (44) with compound (6)-1.

[0807] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0808] (Pharmaceutical raw material manufacturing method 10)

[0809] This manufacturing method is a method for manufacturing compound (4)-1 contained in compound (4), which is an intermediate in manufacturing method 1 of pharmaceutical raw materials.

[0810]

[0811] (where L) 2B It means that it can be C 1-3 Alkyl-substituted piperazinediyl, bridged piperazinediyl, or 2,6-diazaspiro[3,4]octanediyl, PG E3 and PG L2 LG represents the protecting group of NH. Z The term "leaving group" indicates that BLG represents a borate group, pinacol borate ester group, or other borate group protected by a boric acid protecting group, or a trifluoroborate group (hereinafter sometimes referred to as borate group, etc.). It should be noted that the PG of compound (45)... E3 Compounds that are partially H can also be used to produce compound (4)-1 through the same reaction. Examples of leaving groups shown here include Cl, Br, methanesulfonyloxy, p-toluenesulfonyloxy, etc. (The same applies below)

[0812] (First step)

[0813] This step is the process of obtaining compound (47) by subjecting compound (45) and compound (46) to Suzuki-Miyaura coupling reaction conditions.

[0814] The reaction conditions are the same as the fourth step of method 2 for manufacturing pharmaceutical raw materials.

[0815] (Step 2-1A)

[0816] This step is the process of obtaining a 1,2-diol compound by subjecting compound (47) to oxidation reaction conditions.

[0817] In this reaction, the compound of compound (47), an oxidizing agent, and an excess equivalent of a re-oxidizing agent are used, and the reaction is carried out in a solvent inert to the reaction by stirring under ice-cooling conditions to room temperature, typically for 1 hour to 2 days. Examples of oxidizing agents used herein are not particularly limited, but include osmium tetroxide (VIII), PI osmium oxide (VIII), or PEM polymer microcapsule osmium oxide (VIII). Examples of re-oxidizing agents used herein are not particularly limited, but include NMO, trimethylamine oxide, tert-butanol peroxide (tBuOOH), K3Fe(CN)6, etc. Examples of solvents used herein are not particularly limited, but include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, tBuOH, acetone, acetonitrile, toluene, water, and mixtures thereof.

[0818] (Step 2-1B)

[0819] This step is the step of obtaining compound (48) by subjecting the compound obtained in the above (second step-1A) to oxidative pyrolysis reaction conditions.

[0820] In this reaction, the compound obtained in (step 2-1A) and an equal or excess equivalent of an oxidizing agent are used, and the reaction is typically carried out in an inert solvent by stirring under ice-cooling conditions to room temperature for 1 hour to 2 days. Examples of oxidizing agents used herein are not particularly limited, such as sodium periodate or periodic acid. Examples of solvents used herein are not particularly limited, such as ether solvents like tetrahydrofuran, diethyl ether, and 1,4-dioxane, acetonitrile, water, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

[0821] Alternatively, steps (second step-1A) and (second step-1B) described above can also be performed as a single-step reaction.

[0822] [literature]

[0823] J. Org. Chem. 1956, 21, 4, 478-479

[0824] (Step 2-2)

[0825] This step is a step of obtaining compound (48) by subjecting compound (47) to oxidation reaction conditions. This step is a method of obtaining compound (48) different from the methods of step 2-1A and step 2-1B.

[0826] In this reaction, compound (47) is stirred in an ozone atmosphere in a solvent inert to the reaction under ice cooling to room temperature, typically for 1 hour to 1 day, and then treated with a reducing agent. Examples of reducing agents used herein are not particularly limited, such as dimethyl sulfide, triphenylphosphine, and zinc. As for the solvent used herein, there are no particular limitations, such as methanol, ethanol, and other alcoholic solvents, dichloromethane, dichloroethane, chloroform, and other halogenated hydrocarbons, ethyl acetate, and mixtures thereof.

[0827] (Step 3)

[0828] This step is the process of obtaining compound (4)-1' by subjecting compounds (48) and (49) to reducing amination reaction conditions.

[0829] In this reaction, compounds (48) and (49) are used in equal or excess amounts, and the reaction is carried out typically for 1 hour to 5 days in a solvent inert to the reaction, under ice-cooled conditions to room temperature, with stirring in the presence of a reducing agent and acetic acid. Examples of reducing agents used herein are not particularly limited, such as NaBH(OAc)3, 2-methylpyridineborane, and NaBH3CN. Solvents used herein are not particularly limited, such as dichloromethane, dichloroethane, chloroform, tetrahydrofuran, diethyl ether, ether solvents such as 1,4-dioxane, alcohol solvents such as methanol and ethanol, or acetonitrile.

[0830] (Fourth step)

[0831] This step is the process of obtaining compound (4)-1 by subjecting (4)-1' to deprotection conditions.

[0832] The reaction conditions are the same as those in the first method of drug manufacturing.

[0833] (Pharmaceutical raw material manufacturing method 11)

[0834] This manufacturing method is for manufacturing PG containing compound (45)-1' and compound (45)-1' in compound (45) as raw materials in pharmaceutical raw material manufacturing method 10. E3 Methods for compound (45)-1, which is partly H.

[0835]

[0836] (where LG) E3 This indicates a leaving group. Examples of leaving groups shown here include Cl, Br, methanesulfonyloxy, p-toluenesulfonyloxy, etc. (The same applies below.)

[0837] (First step)

[0838] This step is the process of obtaining compound (45)-1' by subjecting compound (50) and compound (51) to alkylation reaction conditions.

[0839] In this reaction, compounds (50) and (51) are used in equal or excess amounts, and the reaction is carried out in the presence of a base in a solvent inert to the reaction, typically under ice cooling to reflux with stirring for 1 hour to 1 day. Examples of bases used herein are not particularly limited, but include sodium hydride, tBuOK, LHMDS, NHMDS, potassium carbonate, cesium carbonate, etc. Solvents used herein are not particularly limited, but include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, DMF, MeCN, etc.

[0840] Here, when the compound obtained by the above reaction has a protecting group, the obtained compound is attached to the reaction and subjected to deprotection reaction conditions, thereby obtaining compound (45)-1'.

[0841] The reaction conditions are the same as those in the first method of drug manufacturing.

[0842] (Second Step)

[0843] This step is the process of obtaining compound (45)-1 by subjecting (45)-1' to deprotection conditions.

[0844] The reaction conditions are the same as those in the first method of drug manufacturing.

[0845] (Pharmaceutical raw material manufacturing method 12)

[0846] This manufacturing method is for manufacturing PG containing compound (45)-2' and compound (45)-2' in compound (45) as raw materials in pharmaceutical raw material manufacturing method 10. E3 Methods for compounds (45)-2 that are partly H.

[0847]

[0848] (First step)

[0849] This step is the process of obtaining compound (45)-2' by subjecting compounds (52) and (53) to coupling reaction conditions using a copper catalyst.

[0850] In this reaction, compounds (52) and (53) are used in equal or excess amounts, along with a copper catalyst, ligands, and a base. The reaction is carried out in an inert solvent under stirring for 1 hour to 5 days at room temperature to under reflux. Examples of copper catalysts used herein are not particularly limited, but include copper iodide (I), ketone chloride (I), copper oxide (I), etc. Examples of ligands used herein are not particularly limited, but include DMEDA, trans-N,N'-dimethylcyclohexane-1,2'-diamine, etc. Examples of bases used herein are not particularly limited, but include organic bases such as diisopropylethylamine and triethylamine; inorganic bases such as potassium carbonate, cesium carbonate, sodium carbonate, and potassium phosphate, etc. Examples of solvents used herein are not particularly limited, but include ether solvents such as tetrahydrofuran and 1,4-dioxane; alcohol solvents such as methanol and ethanol; dimethyl sulfoxide, N,N-dimethylformamide, water, etc. In addition, heating the mixture by irradiating it with microwaves can sometimes be advantageous in making the reaction proceed smoothly.

[0851] (Second Step)

[0852] This step is the process of obtaining compound (45)-2 by subjecting (45)-2' to deprotection conditions.

[0853] The reaction conditions are the same as those in the first method of drug manufacturing.

[0854] (Pharmaceutical raw material manufacturing method 13)

[0855] This manufacturing method is a method for manufacturing compound (4)-2 contained in compound (4), which is an intermediate in manufacturing method 1 of pharmaceutical raw materials.

[0856]

[0857] (wherein, PG for compound (51) E3 Compounds that are partially H can also produce PG of compound (4)-2' through the same reaction. E3 Compounds that are partially composed of hydrogen (H). (The same applies below.)

[0858] (First step)

[0859] This step is the process of obtaining compound (55) by subjecting compound (54) and compound (50) to Suzuki-Miyaura coupling reaction conditions.

[0860] The reaction conditions are the same as the fourth step of method 2 for manufacturing pharmaceutical raw materials.

[0861] (Second Step)

[0862] This step is the process of obtaining compound (4)-2' by subjecting compound (55) and compound (51) to alkylation reaction conditions.

[0863] The reaction conditions are the same as the first step of the drug raw material manufacturing method 11.

[0864] (Step 3)

[0865] This step is the process of obtaining compound (4)-2 by subjecting (4)-2' to deprotection conditions.

[0866] The reaction conditions are the same as those in the first method of drug manufacturing.

[0867] (Pharmaceutical raw material manufacturing method 14)

[0868] This manufacturing method is a method for manufacturing compound (4)-3 contained in compound (4), which is an intermediate in manufacturing method 1 of pharmaceutical raw materials.

[0869]

[0870] (where LG) Z This indicates a leaving group. Examples of leaving groups shown here include Cl, Br, methanesulfonyloxy, p-toluenesulfonyloxy, etc. (The same applies below.)

[0871] (First step)

[0872] This step is the process of obtaining compound (57) by subjecting compounds (54) and (56) to Suzuki-Miyaura coupling reaction conditions.

[0873] The reaction conditions are the same as the fourth step of method 2 for manufacturing pharmaceutical raw materials.

[0874] (Second Step)

[0875] This step is the process of obtaining compound (4)-3' by subjecting compound (57) and compound (53) to coupling reaction conditions using a copper catalyst.

[0876] The reaction conditions are the same as the first step of the drug raw material manufacturing method 12.

[0877] (Step 3)

[0878] This step is the process of obtaining compound (4)-3 by subjecting (4)-3' to deprotection conditions.

[0879] The reaction conditions are the same as those in the first method of drug manufacturing.

[0880] (Pharmaceutical raw material manufacturing method 15)

[0881] This manufacturing method is a method for manufacturing compound (4)-1 contained in compound (4), which is an intermediate in manufacturing method 1 of pharmaceutical raw materials.

[0882]

[0883] (wherein, PG for compound (45) E3 Compounds that are partially H can also be used to produce compound (4)-1 through the same reaction. (The same applies below.)

[0884] (First step)

[0885] This step is the process of obtaining compound (4)-1' by subjecting compound (54) and compound (45) to Suzuki-Miyaura coupling reaction conditions.

[0886] The reaction conditions are the same as the fourth step of method 2 for manufacturing pharmaceutical raw materials.

[0887] (Second Step)

[0888] This step is the process of obtaining compound (4)-1 by subjecting (4)-1' to deprotection conditions.

[0889] The reaction conditions are the same as those in the first method of drug manufacturing.

[0890] (Pharmaceutical raw material manufacturing method 16)

[0891] This manufacturing method is a method for manufacturing compound (4)-5 contained in compound (4), which is an intermediate in manufacturing method 1 of pharmaceutical raw materials.

[0892]

[0893] (where LG) Z3 This indicates a leaving group. Examples of leaving groups shown here include Cl, Br, methanesulfonyloxy, p-toluenesulfonyloxy, etc. (The same applies below.)

[0894] (First step)

[0895] This step is the process of obtaining compound (60) by subjecting compounds (58) and (59) to cyclization reaction conditions.

[0896] In this reaction, compounds (58) and (59) are used in equal or excess amounts, and the reaction is carried out in the presence of a base in a solvent inert to the reaction, typically under ice cooling to reflux with stirring for 1 hour to 5 days. Examples of bases used herein are not particularly limited, but include organic bases such as triethylamine and N,N'-diisopropylethylamine, or inorganic bases such as potassium carbonate and cesium carbonate. Examples of solvents used herein are not particularly limited, but include ether solvents such as tetrahydrofuran and 1,4-dioxane; and N,N-dimethylformamide.

[0897] (Second Step)

[0898] This step is the process of obtaining compound (61) by subjecting compound (60) and compound (54) to Suzuki-Miyaura coupling reaction conditions.

[0899] The reaction conditions are the same as the fourth step of method 2 for manufacturing pharmaceutical raw materials.

[0900] (Step 3)

[0901] This step is the process of obtaining compound (4)-5' by subjecting compound (61) to cyclization reaction conditions.

[0902] The reaction conditions are the same as those in the third step of method 17 for manufacturing pharmaceutical raw materials.

[0903] (Fourth step)

[0904] This step is the process of obtaining compound (4)-5 by subjecting compound (4)-5' to deprotection conditions.

[0905] The reaction conditions are the same as those in the first method of drug manufacturing.

[0906] (Pharmaceutical raw material manufacturing method 17)

[0907] This manufacturing method is a method for manufacturing compound (4)-6. By using compound (4)-6 instead of compound (4) described in pharmaceutical raw material manufacturing method 1, a portion of the compounds contained in the compound of formula (1) can be synthesized.

[0908]

[0909] (where L) 17 -(-L 2 -L 3 -L 4 )-, L 2 For can be C 1-3 Alkyl-substituted piperidine dimethyl, which can be C 1-3 Alkyl-substituted piperazine dimethyl, which can be C 1-3Alkyl-substituted pyrrolidinediyl, 3,8-diazabicyclo[3.2.1]octanediyl or 2,6-diazaspiro[3.4]octanediyl, L 3 For key, -N(R) L3 )-、C 1-3 alkylene or piperazine dimethyl, L 4 For key, -N(R) L4 -, -O-, piperazine dimethyl or C 1-3 Alkylene, R L3 For H or C 1-3 Alkyl, R L4 For H or C 1-3 Alkyl, PG L R represents a protecting group indicating NH or OH. LG Indicate C 1-12 Alkyl group. (The same applies below)

[0910] (First step)

[0911] This step is the process of obtaining compound (64) by Michael addition reaction of compound (62) and compound (63).

[0912] In this reaction, compounds (62) and (63) are used in equivalence or an excess of one of them, and the reaction is carried out by stirring for 1 to 5 days at room temperature to under reflux in the presence of a base and an excess of an acid reagent. Examples of bases used herein are not particularly limited, such as organic bases like 1,8-diazabicyclo[5.4.0]undec-7-ene and N,N'-diisopropylethylamine. Examples of acid reagents used herein are not particularly limited, such as lactic acid, trifluoroacetic acid, or acetic acid.

[0913] (Second Step)

[0914] This step is the process of obtaining compound (65) by subjecting compound (64) to ureation reaction conditions.

[0915] The reaction is carried out by stirring for 1 to 5 days at room temperature to under reflux in the presence of compound (64), a ureating agent, and an acid, in a solvent inert to the reaction, or in the absence of a solvent. Examples of ureating agents used herein are not particularly limited, such as sodium cyanate or potassium cyanate. Examples of acids used herein are not particularly limited, such as acetic acid, hydrochloric acid, or trifluoroacetic acid. Examples of solvents used herein are not particularly limited, such as dichloromethane, dichloroethane, chloroform, and other halogenated hydrocarbons, tetrahydrofuran, ether solvents such as 1,4-dioxane, acetic acid, toluene, water, and mixtures thereof.

[0916] (Step 3)

[0917] This step is the process of obtaining compound (4)-6' by subjecting compound (65) to cyclization reaction conditions.

[0918] The reaction is carried out by stirring compound (65) in the presence of a base in a solvent inert to the reaction, typically under ice cooling to reflux for 1 hour to 5 days. Examples of bases used herein are not particularly limited, but include Triton B, potassium trimethylsilyl acrylate, sodium ethoxide, etc. Examples of solvents used herein are not particularly limited, but include ether solvents such as tetrahydrofuran and 1,4-dioxane; N,N-dimethylformamide; acetonitrile, etc.

[0919] (Fourth step)

[0920] This step is the process of obtaining compound (4)-6 by subjecting compound (4)-6' to deprotection conditions.

[0921] The reaction conditions are the same as those in the first method of drug manufacturing.

[0922] (Pharmaceutical raw material manufacturing method 18)

[0923] This manufacturing method is a method for manufacturing compound (67). By using compound (67) instead of compound (4) described in pharmaceutical raw material manufacturing method 1, a portion of the compounds contained in the compound of formula (1) can be synthesized.

[0924]

[0925] (where L) 1 For can be C 1-3 Alkyl-substituted piperidine dimethyl, which can be C 1-3 Alkyl-substituted piperazine dimethyl, which can be C 1-3 Alkyl-substituted pyrrolidinediyl, 3,8-diazabicyclo[3.2.1]octanediyl or 2,6-diazaspiro[3.4]octanediyl, L 2 For key, -N(R) L3 )-、C 1-3 alkylene or piperazine dimethyl, L 3 For key, -N(R) L4 -, -O-, piperazine dimethyl or C 1-3 Alkylene, R L3 For H or C 1-3 Alkyl, R L4 For H or C 1-3 Alkyl, X L PG represents an oxygen atom or a nitrogen atom. L1 PG represents a protecting group for NH or OH. E3 This indicates the protecting group of NH or H. (The same applies below.)

[0926] (First step)

[0927] This step is the process of obtaining compound (67') by subjecting compound (66) and compound (65) to in-situ reaction conditions.

[0928] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0929] Alternatively, compound (67') can be prepared by providing coupling reaction conditions using a copper catalyst.

[0930] The reaction conditions are the same as the first step of the drug raw material manufacturing method 12.

[0931] Alternatively, compound (67') can be prepared by providing reaction conditions for carbon-nitrogen bond formation.

[0932] In this reaction, compounds (66) and (65) are used in equal or excess amounts, by adding a metal catalyst, ligand, and base to the mixture and stirring at 80°C under reflux for typically 1 hour to 5 days in a solvent inert to the reaction.

[0933] Examples of metal reagent catalysts used herein are not particularly limited, but include palladium(II) acetate, tris(dibenzylacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, etc. Examples of ligands are not particularly limited, but include Xantphos, Ruphos, Xphos, BINAP, etc. Examples of bases are not particularly limited, but include inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, and sodium tert-butoxide; and organic bases such as triethylamine and N,N-diisopropylethylamine, etc. Examples of solvents are not particularly limited, but include 1,4-dioxane, toluene, N,N-dimethylformamide, and mixtures thereof, etc. Furthermore, this reaction can be carried out under microwave irradiation.

[0934] Alternatively, compound (67') can be prepared by providing alkylation reaction conditions.

[0935] The reaction conditions are the same as the first step of the raw material manufacturing method 2.

[0936] (Second Step)

[0937] This step is the process of obtaining compound (67) by subjecting compound (67') to deprotection conditions.

[0938] The reaction conditions are the same as those in the first method of drug manufacturing.

[0939] (Pharmaceutical raw material manufacturing method 19)

[0940] This manufacturing method is a method for manufacturing compound (1)-2 contained in compound (1), which is a raw material for the first manufacturing method of a pharmaceutical product.

[0941]

[0942] (where L) 1A and L 4A The selection is made from substituted heterocyclic alkylene groups, substituted heteroaryl groups, saturated 7- to 9-membered spirocyclic alkylene groups containing 1 to 2 nitrogen atoms, saturated 7- to 9-membered bridged heterocyclic alkylene groups containing 2 nitrogen atoms, and substituted C-membered alkylene groups. 1-6 One of the groups in the group consisting of alkylene groups, L 3A It means that it can be C 1-3 Alkyl-substituted piperidine dimethyl, which can be C 1-3 Alkyl-substituted piperazine dimethyl, which can be C 1-3 Alkyl-substituted pyrrolidine dieryl, piperazine dieryl, or 2,6-diazaspiro[3,4]octane dieryl. (The same applies below)

[0943] (First step)

[0944] This step is a method for producing compound (69) by alkylation reaction of compound (14) and compound (68).

[0945] The reaction conditions are the same as those in step seven of method 2 for manufacturing pharmaceutical raw materials.

[0946] (Second Step)

[0947] This step is the process of obtaining compound (70) by subjecting compound (69) to hydrolysis conditions.

[0948] The reaction conditions are the same as the first step of method 1 for manufacturing pharmaceutical raw materials.

[0949] (Step 3)

[0950] This step is the process of obtaining compound (1)-2 by subjecting compounds (70) and (71) to condensation reaction conditions.

[0951] The reaction conditions are the same as the second step of method 1 for manufacturing pharmaceutical raw materials.

[0952] (Pharmaceutical raw material manufacturing method 20)

[0953] This manufacturing method is a method for manufacturing compound (74). By using compound (74) instead of compound (4) described in pharmaceutical raw material manufacturing method 1, a portion of the compounds contained in the compound of formula (1) can be synthesized.

[0954]

[0955] (wherein, PG for compound (51) E3 Compounds that are partially H can also be synthesized through the same reaction (74)

[0956] (First step)

[0957] This step is the process of obtaining compound (73) by subjecting compound (72) and compound (51) to nucleophilic substitution reaction conditions.

[0958] The reaction conditions are the same as the first step of the drug raw material manufacturing method 11.

[0959] (Second Step)

[0960] This step is the process of obtaining compound (74) by subjecting compound (73) to deprotection conditions.

[0961] The reaction conditions are the same as those in the first method of drug manufacturing.

[0962] (Pharmaceutical raw material manufacturing method 21)

[0963] This manufacturing method is a method for manufacturing compound (2)-3 contained in (2) as a raw material in method 1 for manufacturing pharmaceutical raw materials.

[0964] (First step)

[0965] This step is a method for producing compound (77) by reacting compound (75) and compound (76).

[0966] In this reaction, compound (75) is converted to the corresponding acrylate using an orthoester such as trimethyl orthoformate under acidic conditions. Then, an equivalent or excess of compound (76) is added, and the mixture is stirred for 0.1 hours to 5 days in a solvent inert to the reaction under reflux, preferably at 60°C or higher. Examples of solvents used herein are not particularly limited, but include: aromatic hydrocarbons such as toluene; ethers such as THF and DOX; and DMF and DMAc.

[0967] (Second Step)

[0968] This step is a method for producing compound (78) from compound (77).

[0969] In this reaction, compound (77) is stirred in a solvent inert to the reaction under reflux, preferably at 150°C or higher, typically for 0.1 hours to 5 days. Examples of solvents used herein are not particularly limited, but include NMP, etc.

[0970] (Step 3)

[0971] This step is a method for producing compound (79) from compound (78).

[0972] In this reaction, compound (78) and the brominating agent are used in equal or excess amounts, and the mixture is stirred for 0.1 hours to 5 days in a solvent inert to the reaction or in the absence of a solvent, under cooling to reflux, preferably at room temperature. Examples of solvents used herein are not particularly limited, but include: aromatic hydrocarbons such as toluene; ethers such as THF and DOX; halogenated hydrocarbons such as dichloromethane; DMF, etc. Examples of brominating agents include N-bromosuccinimide, N-bromosaccharin, 1,3-dibromo-5,5-dimethylhydantoin, dibromoisocyanuric acid, etc.

[0973] (Fourth step)

[0974] This step is a method for producing compound (80) from compound (79).

[0975] The reaction conditions are the same as the first step of method 8 for manufacturing pharmaceutical raw materials.

[0976] (Step 5)

[0977] This step is a method for producing compound (81) by in-situ substitution reaction of compound (80) with compound (6)-1.

[0978] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0979] (Step Six)

[0980] This step is a method for producing compound (82) by in-situ substitution reaction of compound (81) with compound (8)-1.

[0981] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0982] (Seventh Step)

[0983] This step involves reacting compound (82) with PG. 3 A method for producing compound (82) by in-situ substitution reaction of -OH.

[0984] As used here, PG 3 Examples of -OH include benzyl alcohol, p-methoxybenzyl alcohol, and 1-phenylethanol.

[0985] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[0986] (Step 8)

[0987] This step is a method for producing compound (84) by the Suzuki-Miyaura coupling reaction of compound (83) with compound (12) of boric acid derivative.

[0988] The reaction conditions are the same as the fourth step of method 2 for manufacturing pharmaceutical raw materials.

[0989] It should be noted that when compound (84) is axially chiral, it is obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by conventional separation operations, such as separation using ODS column chromatography or silica gel column chromatography.

[0990] Additionally, in order to enable the use of the subsequently imported protection base PG 2 Deprotection occurs under different conditions, sometimes after compound (84) is subjected to a deprotection reaction, PG is used. 1 It transforms into other protective groups.

[0991] The deprotection reaction conditions used here are the same as those described in Method 1 for the manufacture of pharmaceutical raw materials.

[0992] As the PG that was subsequently converted 1 Examples of protecting groups include tetrahydro-2H-pyran-2-yl, etc.

[0993] For example, the following references may be consulted as references for this reaction.

[0994] PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis", 5th Edition, John Wiley & Sons Inc., 2014

[0995] (Step 9)

[0996] This step is a method for producing compound (85) by deprotecting compound (84) using a catalytic hydrogenation reaction.

[0997] The reaction conditions are the same as those in step six of method 2 for manufacturing pharmaceutical raw materials.

[0998] (Step 10)

[0999] This step is a method for producing compound (2)-3 by reacting compound (85) with compound (15).

[1000] The reaction conditions are the same as those in step seven of method 2 for manufacturing pharmaceutical raw materials.

[1001] (Pharmaceutical raw material manufacturing method 22)

[1002] This manufacturing method is a method for manufacturing compound (4)-7 contained in compound (4), which is an intermediate in manufacturing method 1 of pharmaceutical raw materials.

[1003] (First step)

[1004] This step is a method for producing compound (87) from compound (86).

[1005] The reaction conditions are the same as the first step of the drug raw material manufacturing method 17.

[1006] (Second Step)

[1007] This step is a method for producing compound (88) from compound (87).

[1008] The reaction is typically carried out in the presence of compound (87), triphosgene, and a base in a solvent inert to the reaction, with the addition of an ammonia reagent at room temperature and stirring for 1 to 5 days. Examples of the ammonia reagent used herein are not particularly limited; ammonia in methanol solution, etc., are also acceptable. Examples of the base used herein are not particularly limited; organic bases such as pyridine, triethylamine, or N,N-diisopropylethylamine, etc., are also acceptable. Examples of the solvent used herein are not particularly limited; halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, etc., are also acceptable.

[1009] (Step 3)

[1010] This step is a method for producing compound (89) from compound (88).

[1011] The reaction conditions are the same as those in the third step of method 17 for manufacturing pharmaceutical raw materials.

[1012] (Fourth step)

[1013] This step is the process of obtaining compound (90) by subjecting compound (89) and compound (54) to Suzuki-Miyaura coupling reaction conditions.

[1014] The reaction conditions are the same as the fourth step of method 2 for manufacturing pharmaceutical raw materials.

[1015] (Step 5)

[1016] This step is the process of obtaining compound (4)-7 by subjecting compound (90) to deprotection conditions.

[1017] The reaction conditions are the same as those in the first method of drug manufacturing.

[1018] (Pharmaceutical raw material manufacturing method 23)

[1019] This manufacturing method is a method for manufacturing compound (45)-3 contained in compound (45), which is a raw material for manufacturing pharmaceutical raw material 10.

[1020]

[1021] This step is the process of obtaining compound (45)-3 by subjecting compounds (92) and (53) to coupling reaction conditions using a copper catalyst.

[1022] The reaction conditions are the same as the first step of the drug raw material manufacturing method 12.

[1023] (Pharmaceutical raw material manufacturing method 24)

[1024] This manufacturing method is the first method for manufacturing compound (1)-3 contained in raw material compound (1).

[1025] (First step)

[1026] This step is a method for producing compound (1)-3 by cyclization addition reaction of compound (93) and compound (94).

[1027] In this reaction, compounds (93) and (94) are used in equal or excess amounts, and the mixture thereof is stirred for 0.1 hours to 5 days, preferably in the presence of a copper salt, more preferably in the presence of a copper salt and a reducing agent, in a solvent inert to the reaction or in the absence of a solvent, under cooling to reflux, preferably at 0°C to 100°C. Examples of solvents used herein are not particularly limited, but include: halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; DMF, DMSO, ethyl acetate, MeCN, tBuOH, water, and mixtures thereof. Examples of copper salts include CuI, CuSO4, and copper trifluoromethanesulfonate (I) (CuOTf). Examples of reducing agents include sodium ascorbate. The presence of substances such as TEA, DIPEA, N-methylmorpholine (NMM), 2,6-dimethylpyridine, and tris[(1-phenylmethyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) can sometimes be advantageous in facilitating the reaction.

[1028] 〔literature〕

[1029] Angew. Chem. Int. Ed. 2002, 41, p.2596-2599.

[1030] It should be noted that the PG of compound (93) can also be used.1 The reaction is carried out using the compound obtained from the deprotection reaction.

[1031] (Pharmaceutical raw material manufacturing method 25)

[1032] (In the formula, R represents C) 1-3 Alkyl group. (The same applies below)

[1033] This manufacturing method is a second method for manufacturing compound (1)-3 contained in raw material compound (1).

[1034] (First step)

[1035] This step is a method for producing compound (96) by cyclization addition reaction of compound (93) and compound (95).

[1036] The reaction conditions are the same as the first step of the drug raw material manufacturing method 24.

[1037] (Second Step)

[1038] This step is a method for producing compound (97) by hydrolyzing compound (96).

[1039] This reaction is carried out by stirring compound (96) under cooling to reflux, typically for 0.1 hours to 5 days. Examples of solvents used herein are not particularly limited, but include alcohols, acetone, DMF, THF, etc. Additionally, a mixture of the above solvents and water is sometimes suitable for the reaction. Examples of hydrolysis reagents are not particularly limited, but include aqueous solutions of sodium hydroxide, aqueous solutions of potassium hydroxide, trimethyltin hydroxide, etc.

[1040] For example, the following references may be consulted as references for this reaction.

[1041] "Lectures on Experimental Chemistry (5th Edition)" edited by the Chemical Society of Japan, Volume 16 (2005) (Maruzen)

[1042] Angew. Chem. Int. Ed. 2005, 44, p.1378-1382.

[1043] (Step 3)

[1044] This step is a method for producing compound (1)-3 by amidation reaction of compound (97) and compound (98).

[1045] In this reaction, compounds (97) and (98) are used in equal or excess amounts, and the mixture is stirred for 0.1 hours to 5 days in the presence of a condensing agent, in a solvent inert to the reaction, under cooling to heating, preferably -20°C to 60°C. Examples of solvents, without particular limitation, include: aromatic hydrocarbons such as toluene; ethers such as THF and DOX; halogenated hydrocarbons such as dichloromethane; alcohols, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of condensing agents include hexafluorophosphate (benzotriazol-1-yloxy)tripyrrolidine. (PyBOP), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea Hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride, N,N'-dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI), diphenyl azidophosphate (DPPA), etc. The use of additives (e.g., 1-hydroxybenzotriazole) is sometimes preferred for the reaction. The presence of organic bases such as TEA, DIPEA, or NMM, or inorganic bases such as potassium carbonate, sodium carbonate, or potassium hydroxide, is sometimes advantageous in facilitating the reaction.

[1046] Alternatively, an acylation reaction can be carried out after converting compound (97) into a reactive derivative. Examples of reactive derivatives of carboxylic acids include acyl halides obtained by reacting with halogenating agents such as phosphorus oxychloride and thionyl chloride, mixed acid anhydrides obtained by reacting with isobutyl chloroformate, and active esters obtained by condensation with 1-hydroxybenzotriazole. The reaction of these reactive derivatives with compound (98) can be carried out in solvents that are inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, and ethers, under cooling to heating, preferably at -20°C to 120°C.

[1047] [literature]

[1048] S.R. Sandler and W. Karo, "Organic Functional Group Preparations", 2nd edition, Volume 1, Academic Press Inc., 1991.

[1049] "Lectures on Experimental Chemistry (5th Edition)" edited by the Chemical Society of Japan, Volume 16 (2005) (Maruzen)

[1050] (Pharmaceutical raw material manufacturing method 26)

[1051] This manufacturing method is the first method for manufacturing the raw material compound (93).

[1052] This manufacturing method is a method of producing compound (93) by reacting compound (14) with compound (100).

[1053] This reaction is carried out by using equal or one in excess of compounds (14) and (100), and by reacting a mixture of these in the presence of a base, in a solvent inert to the reaction, under cooling to reflux, preferably at 0°C to 80°C, typically for 0.1 hours to 5 days. The solvent used herein is not particularly limited, but examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as MeOH and EtOH; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; haloalkanes such as dichloromethane, 1,2-dichloroethane, and chloroform; DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of bases are not particularly limited, but examples include: organic bases such as TEA, DIPEA, 1,8-diazabicyclo[5.4.0]-7-undecene, n-butyllithium, and tBuOK; and inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride. The reaction can sometimes be carried out in the presence of a phase-transfer catalyst such as tetra-n-butylammonium chloride.

[1054] For example, the following references may be consulted as references for this reaction.

[1055] Edited by the Chemical Society of Japan, "Lectures on Experimental Chemistry", 5th edition, Volume 14, Maruzen, 2005

[1056] It should be noted that compound (93) sometimes exhibits axial chirality and is obtained as a mixture of stereoisomers, which can be obtained by adjusting PG. 2 The individual stereoisomers are isolated by conventional resolution operations, such as using ODS column chromatography or silica gel column chromatography, on the compound (93) with the protecting group or the compound (93) obtained by deprotection reaction.

[1057] The deprotection reaction conditions used here are the same as those described in the first method of manufacturing the drug.

[1058] Additionally, compound (100) can be made by combining with LG 1 A significant portion of LG is manufactured by halogenating hydroxyl compounds. 1 The compound is a halogenated compound. Examples of halogenating agents used herein are not particularly limited, but may include thionyl chloride, phosphorus oxychloride, hydrobromic acid, phosphorus tribromide, etc.

[1059] For reference in this reaction, see, for example, the following literature.

[1060] Edited by the Chemical Society of Japan, "Lectures on Experimental Chemistry", 5th edition, Volume 13, Maruzen, 2004

[1061] Furthermore, the compound (100) can be combined with LG 1 A significant portion of hydroxyl compounds undergo sulfonation in the presence of a base, thereby enabling the production of LG. 1 Compounds that are sulfonyloxy groups. Examples of sulfonating agents used herein are not particularly limited, but may include, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride, and methanesulfonic anhydride. Examples of bases are not particularly limited, but may include, for example, TEA, DIPEA, pyridine, and tetramethylethylenediamine.

[1062] For reference in this reaction, see, for example, the following literature.

[1063] Synthesis 1999, 9, p.1633-1636

[1064] (Pharmaceutical raw material manufacturing method 27)

[1065] This manufacturing method is a second method for manufacturing the raw material compound (93).

[1066] (First step)

[1067] This step is a method for producing compound (101) by reacting compound (21) with compound (100).

[1068] The reaction conditions are the same as those in method 26 for manufacturing the drug raw materials.

[1069] (Second Step)

[1070] This step is a method for producing compound (93) by in-situ substitution reaction of compound (101) and compound (8).

[1071] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[1072] It should be noted that compound (93) sometimes exhibits axial chirality and is obtained as a mixture of stereoisomers, which can be obtained by adjusting PG. 2 The individual stereoisomers are isolated by conventional resolution operations, such as using ODS column chromatography or silica gel column chromatography, on the compound (93) with the protecting group or the compound (93) obtained by deprotection reaction.

[1073] The deprotection reaction conditions used here are the same as those described in the first method of manufacturing the drug.

[1074] (Pharmaceutical raw material manufacturing method 28)

[1075] (where PG) 4 PG 5 (Indicates protective base)

[1076] This manufacturing method is a method for manufacturing raw material compound (94).

[1077] (First step)

[1078] This step is a method for producing compound (103) by amidation reaction of compound (98) and compound (102).

[1079] The reaction conditions are the same as those in the third step of the drug raw material manufacturing method 25.

[1080] (Second Step)

[1081] This step is a method for producing compound (104) by subjecting compound (103) to a deprotection reaction.

[1082] The reaction conditions are the same as those described in the first method of manufacturing the drug.

[1083] (Step 3)

[1084] This step is a method for producing compound (31) by amidation reaction of compound (104) and compound (105).

[1085] The reaction conditions are the same as those in the third step of the drug raw material manufacturing method 25.

[1086] (Fourth step)

[1087] This step is a method for producing compound (107) by subjecting compound (106) to a deprotection reaction.

[1088] The reaction conditions are the same as those described in the first method of manufacturing the drug.

[1089] (Step 5)

[1090] This step is a method for producing compound (94) by reacting compound (107) with a diazo transfer reagent.

[1091] In this reaction, compound (107) is typically treated with an equal or excess diazo transfer reagent for 0.1 hours to 3 days in a solvent inert to the reaction, under cooling to heating, preferably from 0°C to 50°C. Examples of diazo transfer reagents are not particularly limited, but include, for example, trifluoromethanesulfonyl azide, imidazole-1-sulfonyl azide or its salts, and 2-azido-1,3-dimethylimidazole. Hexafluorophosphate (ADMP), etc. Reactions are sometimes advantageous in the presence of organic bases such as TEA, 4-dimethylaminopyridine (DMAP), and 2,6-dimethylpyridine, and catalytic amounts of copper salts such as CuSO4. Examples of solvents include THF, halogenated hydrocarbons such as dichloromethane, MeCN, alcohols, water, and mixtures thereof.

[1092] [literature]

[1093] J. Org. Chem. 2012, 77, p.1760-1764

[1094] Nature 2019, 574, pp. 86-89

[1095] Org. Biomol. Chem. 2014, 12, p.4397-4406

[1096] (Pharmaceutical raw material manufacturing method 29)

[1097] (where PG) 11 R represents tert-butyl. 3A Indicates -O- or -N(R) P )-)

[1098] This manufacturing method is a method for manufacturing raw material compound (120).

[1099] (First step)

[1100] This step is a method for producing compound (108) by hydrolyzing compound (5)-1.

[1101] This reaction is carried out by stirring compound (5)-1 under cooling to reflux for 0.1 hours to 5 days. Examples of solvents used herein are not particularly limited, but include alcohols, acetone, DMF, THF, etc. Additionally, a mixture of the above solvents and water is sometimes suitable for the reaction. Examples of hydrolysis reagents are not particularly limited, but include aqueous solutions of sodium hydroxide, aqueous solutions of potassium hydroxide, etc.

[1102] For reference in this reaction, see, for example, the following literature.

[1103] "Lectures on Experimental Chemistry (5th Edition)" edited by the Chemical Society of Japan, Volume 16 (2005) (Maruzen)

[1104] Angew. Chem. Int. Ed. 2005, 44, p.1378-1382.

[1105] (Second Step)

[1106] This step involves utilizing tert-butyl (PG) 11 A method for producing compound (109) by protecting the hydroxyl groups of compound (108).

[1107] This reaction is carried out by stirring compound (108) under cooling to reflux, typically for 0.1 hours to 5 days. Examples of solvents used herein are not particularly limited, including ethers such as THF and DOX; halogenated hydrocarbons such as dichloromethane; and tBuOH and DMF. Examples of tert-butyl protecting agents are not particularly limited, including isobutylene and 2-tert-butyl-1,3-diisopropylisourea.

[1108] Alternatively, compound (109) can be produced by the dehydration condensation reaction of compound (108) with tBuOH.

[1109] For reference in this reaction, see, for example, the following literature.

[1110] PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis", 5th Edition, John Wiley & Sons Inc., 2014

[1111] Org. Lett., 2012, 14, 17, p.4678-4681

[1112] (Step 3)

[1113] This step involves reacting compound (109) with R. LG A method for producing compound (110) by in-situ substitution reaction of -SH.

[1114] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[1115] (Fourth step)

[1116] This step involves reacting compound (110) with PG. 3 A method for producing compound (111) by in-situ substitution reaction of -OH.

[1117] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[1118] (Step 5)

[1119] This step involves reacting compound (111) with R... QA method for producing compound (112) by the Suzuki-Miyaura coupling reaction of boric acid derivatives such as boric acid groups.

[1120] The reaction conditions are the same as the fourth step of method 2 for manufacturing pharmaceutical raw materials.

[1121] Compound (112) can be prepared by the dehalogenation reaction of compound (111) using a Pd catalyst and a reducing agent (here, R Q (For hydrogen).

[1122] 〔literature〕

[1123] J. Org. Chem., 1977, 42, p.3491-3494

[1124] Tetrahedron Letters 2013, 54, 5207-5210

[1125] (Step Six)

[1126] This step is a method for producing compound (113) by the Suzuki-Miyaura coupling reaction of compound (112) and compound (12).

[1127] The reaction conditions are the same as the fourth step of method 2 for manufacturing pharmaceutical raw materials.

[1128] (Seventh Step)

[1129] This step is a method for producing compound (114) by oxidation reaction of compound (113).

[1130] The reaction conditions are the same as those in step 5 of method 3 for manufacturing pharmaceutical raw materials.

[1131] It should be noted that compound (114) is sometimes chiral and sometimes obtained as a mixture of stereoisomers, and the individual stereoisomers can be isolated by conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography.

[1132] Additionally, in order to enable the use of the subsequently imported protection base PG 1 Deprotection occurs under different conditions, sometimes after compound (114) is subjected to a deprotection reaction, PG is added. 2 It transforms into other protective groups.

[1133] The deprotection reaction conditions used here are the same as those described in the first method of manufacturing the drug.

[1134] As the PG that was subsequently transformed 2 Examples of protecting groups include tetrahydro-2H-pyran-2-yl, etc.

[1135] For reference in this reaction, see, for example, the following literature.

[1136] PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis", 5th Edition, John Wiley & Sons Inc., 2014

[1137] (Step 8)

[1138] This step is a method for producing compound (115) by deprotecting compound (114) using a catalytic hydrogenation reaction.

[1139] The reaction conditions are the same as those in step six of method 2 for manufacturing pharmaceutical raw materials.

[1140] (Step 9)

[1141] This step is a method for producing compound (116) by reacting compound (115) with compound (100).

[1142] The reaction conditions are the same as the first step of the drug raw material manufacturing method 26.

[1143] (Step 10)

[1144] This step is a method for producing compound (117) by in-situ substitution reaction of compound (116) and compound (8).

[1145] The reaction conditions are the same as the first step of method 2 for manufacturing pharmaceutical raw materials.

[1146] (Step 11)

[1147] This step is a method for producing compound (118) by subjecting compound (117) to a deprotection reaction.

[1148] The reaction conditions are the same as those described in the first method of manufacturing the drug.

[1149] (Step Twelfth)

[1150] This step is a method for producing compound (120) by reacting compound (118) with compound (119).

[1151] In this reaction, compounds (118) and (119) are used in equal or excess amounts, and the mixture is stirred for 0.1 hours to 5 days in the presence of a condensing agent, in a solvent inert to the reaction, under cooling to heating, preferably -20°C to 60°C. Examples of solvents are not particularly limited, including: aromatic hydrocarbons such as toluene; ethers such as THF and DOX; halogenated hydrocarbons such as dichloromethane; alcohols, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of condensing agents include PyBOP, HATU, CDI, etc. The presence of organic bases such as TEA, DIPEA, or NMM, or inorganic bases such as potassium carbonate, sodium carbonate, or cesium carbonate, is sometimes advantageous in facilitating the reaction.

[1152] II. Drug-linker complex (L A Manufacturing method of -D)

[1153] (First method for manufacturing drug-linker complex)

[1154] The drug-linker complex of formula (LD-27) used in the synthesis of the antibody-drug complex of the present invention can be obtained by reacting compound (122) with compound (121) in the presence of a base and then reacting it with a drug.

[1155]

[1156] (where R is in the formula) st1 C 1-12 Alkylene, R AA Each of these can be independently represented by H, methyl, isopropyl, benzyl, -(CH2)4-NH2, -(CH2)3-NH-C(=NH)-NH2, or -(CH2)3-NH-C(=O)-NH2, where d is an integer from 2 to 4. Additionally, DH indicates a drug, where H represents the hydrogen atom of -NH- or -OH contained in the drug. (The same applies below.)

[1157] For reference in this reaction, see, for example, the following literature.

[1158] International Publication No. 2004 / 010957

[1159] (Second method for manufacturing drug-linker complex)

[1160] The drug-linker complex of formula (LD-28) used in the synthesis of the antibody-drug complex of the present invention can be obtained by reacting compound (123) with a drug in the presence of a condensing agent.

[1161]

[1162] (where R is in the formula) st1 C 1-12 Alkylene, R AA Each of the following is independently H, methyl, isopropyl, benzyl, -(CH2)4-NH2, -(CH2)3-NH-C(=NH)-NH2 or -(CH2)3-NH-C(=O)-NH2, and d is an integer from 2 to 4.

[1163] For reference in this reaction, see, for example, the following literature.

[1164] International Publication No. 2023 / 037268

[1165] III. Synthesis of Antibody-Drug Complexes

[1166] The antibody-drug complex of formula (AD-26) in the present invention can be obtained by reacting an antibody or antigen-binding fragment (Ab) with a drug-linker complex (LD-29).

[1167]

[1168] (where R is in the formula) st1 C 1-12 Alkylene, R AA Each of the following is independent of the others: H, methyl, isopropyl, benzyl, -(CH2)4-NH2, -(CH2)3-NH-C(=NH)-NH2 or -(CH2)3-NH-C(=O)-NH2, where d is an integer from 2 to 4, t is 0 or 1, and n is a value from 2 to 8.

[1169] For reference in this reaction, see, for example, the following literature.

[1170] International Publication No. 2004 / 010957

[1171] The antibody-drug complex of formula (I) or its salts are isolated and purified in the form of free compounds, their salts, hydrates, solvates, polymorphs, or amorphous solids. Salts of the antibody-drug complex of formula (I) can also be prepared by salt-forming reactions using conventional methods.

[1172] Separation and purification can be carried out using common chemical operations such as extraction, fractional crystallization, and various fractionation chromatography.

[1173] Various isomers can be produced by selecting appropriate starting material compounds, or they can be separated by utilizing the differences in physicochemical properties between the isomers. For example, optical isomers can be obtained by conventional optical resolution methods for racemates (e.g., stepwise crystallization guided by diastereomeric salts of optically active bases or acids, chromatography using chiral columns, etc.), or they can be produced from appropriate optically active starting material compounds.

[1174] In addition, the antibody drug complex of formula (I) or its salt or intermediate sometimes has axial chirality and is obtained as a mixture of stereoisomers, which can be isolated by conventional separation operations, such as separation using octadecylsilane (ODS) column chromatography or silica gel column chromatography.

[1175] The pharmacological activity of the antibody-drug complex of formula (I) or its salt can be confirmed by the methods described in the test examples.

[1176] 6. Pharmaceutical Composition

[1177] The present invention also provides pharmaceutical compositions containing the antibody-drug complex of the present invention or a salt thereof (also referred to as "pharmaceutical compositions of the present invention").

[1178] The pharmaceutical compositions of the present invention containing one or more of the antibody-drug complex of formula (I) or its salts as active ingredients can be prepared by conventional methods using excipients, pharmaceutical excipients or pharmaceutical carriers commonly used in the art.

[1179] The dosage form of the pharmaceutical composition of the present invention can be, for example, an injection, an infusion, a suppository, an eye drop, an eye ointment, a transdermal liquid, an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, an inhaler, etc., and can be administered non-orally via intra-articular, intravenous, intramuscular, subcutaneous, intraperitoneal, or intratumoral administration. It can be any form. Injections and infusions can be administered via suitable methods such as intravenous administration, subcutaneous administration, intraperitoneal administration, or intratumoral administration.

[1180] Injectable preparations intended for non-oral administration contain sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Aqueous solvents include, for example, distilled water for injection or physiological saline. Non-aqueous solvents include, for example, alcohols such as EtOH. Such compositions may also contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizers. They are sterilized, for example, by filtration through a bacterial trap, by the addition of a bactericide, or by irradiation. Alternatively, they can be formulated as sterile solid compositions and dissolved or suspended in sterile water or sterile solvents for injection before use.

[1181] Although the dosage form, administration site, type of excipient or additive may vary, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, or in one manner, 0.01 to 50% by weight, of one or more compounds of formula (I) or salts thereof as active ingredients.

[1182] The antibody-drug complex of formula (I) or a salt thereof may be used in combination with various therapeutic or preventative agents for diseases for which the antibody-drug complex of formula (I) or a salt thereof is considered effective. This combination may be administered simultaneously, or separately, continuously, or at desired intervals. Simultaneously administered formulations may be combination agents or separately formulated.

[1183] 7. Pharmaceutical uses of the pharmaceutical compositions of the present invention, etc.

[1184] The antibody-drug complex or its salt, and the pharmaceutical compositions of the present invention (hereinafter collectively referred to as "pharmaceutical compositions of the present invention, etc.") can be used for the treatment of cancer. Furthermore, the present invention includes a method for treating cancer, comprising the step of administering a therapeutically effective amount of the pharmaceutical compositions of the present invention, etc., to a subject. Additionally, the present invention includes the use of the antibody-drug complex or its salt in the manufacture of pharmaceutical compositions for cancer treatment.

[1185] The cancers that can be treated using the pharmaceutical compositions of the present invention can be any type of hematologic cancer or solid cancer. There is no particular limitation on the target cancer, but examples include: gastric cancer, lung cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin's lymphoma, non-Hodgkin's lymphoma, B-cell lymphoma, multiple myeloma, T-cell lymphoma, and other hematologic cancers; myelodysplastic syndrome, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, large cell carcinoma, non-small cell lung cancer, small cell lung cancer, mesothelioma, skin cancer, cutaneous T-cell lymphoma, breast cancer, prostate cancer, bladder cancer, vaginal cancer, cervical cancer, and head cancer. Solid cancers including cervical cancer, uterine cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, pancreatic cancer, colon cancer, colorectal cancer, rectal cancer, small bowel cancer, stomach cancer, esophageal cancer, testicular cancer, ovarian cancer, and brain tumors; as well as cancers of bone tissue, cartilage tissue, adipose tissue, muscle tissue, vascular tissue, and hematopoietic tissue; sarcomas such as chondrosarcoma, Ewing sarcoma, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma, and soft tissue sarcoma; and blastomas such as glioblastoma, glioblastoma multiforme, hepatoblastoma, medulloblastoma, nephroblastoma, neuroblastoma, pancreatoblastoma, pleural pulmonary blastoma, and retinoblastoma.

[1186] In one approach, the cancer that is targeted for treatment using the pharmaceutical composition of the present invention is a cancer that expresses G12D-mutant KRAS in its cells.

[1187] Specific embodiments are provided herein for further understanding of the invention, but these are illustrative and not intended to limit the invention.

[1188] Example

[1189] The following examples describe the antibody-drug complex of formula (I) or its salt, and the drug (D) constituting the antibody-drug complex or its salt, and the drug-linker complex (L). A The manufacturing methods of the antibody-drug complex (-D) and antibody or antigen-binding fragment (Ab) will be described in further detail. Furthermore, the antibody-drug complex or its salt described in the following examples are specific antibody-drug complexes or their salts included in Formula (I). However, the manufacturing methods of the antibody-drug complex or its salt of Formula (I) are not limited to the manufacturing methods of the specific examples shown below. The antibody-drug complex or its salt of Formula (I) can also be manufactured by a combination of these manufacturing methods or by methods obvious to those skilled in the art.

[1190] It should be noted that in this specification, the naming of compounds sometimes uses naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.).

[1191] In addition, for convenience, the concentration in mol / L is expressed as M. For example, 1M sodium hydroxide aqueous solution means a 1 mol / L sodium hydroxide aqueous solution.

[1192] Example 1 Synthesis of drug (D)

[1193] Drugs D1 to D6 were synthesized by the methods described in Examples 8, 20, 23, 48, 70 and 72 of International Publication No. 2022 / 173032.

[1194] The synthetic methods for drugs D7 to D12 are shown below. It should be noted that the number assigned to each intermediate indicates which step in the synthetic route of each drug it was synthesized in. For example, the intermediate synthesized in the first step of the synthesis of drug D7 is designated as D7-1.

[1195] Synthesis of drug D7

[1196] (First step)

[1197] 40 g of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline was suspended in 400 mL of THF. A 1 M, 190 mL aqueous solution of sodium hydroxide was added dropwise under ice-cooling to bring the internal temperature below 10°C, and the mixture was stirred for 2 hours under these conditions. The reaction mixture was then transferred in a single batch to an Erlenmeyer flask containing 1 M, 190 mL of hydrochloric acid and approximately 900 g of ice water, and stirred at room temperature for about 30 minutes (until the ice melted). The insoluble residue was filtered while washing with water and dried under reduced pressure to obtain 7-bromo-2-chloro-8-fluoro-6-iodoquinazoline-4-ol (D7-1, 33.56 g) as a solid.

[1198] (Second Step)

[1199] Under a nitrogen stream, 2-tert-butyl-1,3-diisopropylisourea (73.4 g) was added dropwise over 15 minutes to a mixture of 7-bromo-2-chloro-8-fluoro-6-iodoquinazoline-4-ol (D7-1, 24.6 g) and THF (260 mL) heated to 60 °C. The mixture was stirred at this temperature for 2.5 hours. After natural cooling to room temperature, the colorless solid was separated by filtration while washing with THF (approximately 500 mL). The solid obtained by concentrating the filtrate was resuspended by adding MeOH (210 mL) and stirring at room temperature for 1 hour. The solid was then filtered off using MeOH (100 mL) to obtain 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (D7-2, 23.2 g) in solid form.

[1200] (Step 3)

[1201] At room temperature, ethanethiol (3.6 mL) and DABCO (7.7 g) were added to a suspension of 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (D7-2, 21 g) in CH2Cl2 (200 mL), and stirred overnight at room temperature under an argon atmosphere. The reaction was stopped by adding water under ice cooling. CHCl3 was added to separate the organic layer from the aqueous layer, and the aqueous layer was extracted three times with CHCl3. The collected organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7-bromo-4-tert-butoxy-2-(ethylthio)-8-fluoro-6-iodoquinazoline (D7-3, 23.4 g) as a solid.

[1202] (Fourth step)

[1203] tBuOK (10 g) was added to a THF (400 mL) solution of 7-bromo-4-tert-butoxy-2-(ethylthio)-6-fluoro-6-iodoquinazoline (D7-3, 32 g) and (1S)-1-phenylethane-1-ol (11 mL), and the mixture was stirred for 1 hour under an argon atmosphere and under ice-cooled conditions. The reaction was stopped by adding a saturated aqueous solution of ammonium chloride under ice-cooled conditions. Water and ethyl acetate were added to separate the organic layer from the aqueous layer. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 7-bromo-4-tert-butoxy-2-(ethylthio)-6-iodo-8-[(1S)-1-phenylethoxy]quinazoline (D7-4, 36.6 g) as an oil.

[1204] (Step 5)

[1205] At room temperature, 7-bromo-4-tert-butoxy-2-(ethylthio)-6-iodo-8-[(1S)-1-phenylethoxy]quinazoline (D7-4, 36.6 g), cyclopropylboronic acid (7.5 g), PdCl2(dppf)·CH2Cl2 (7.6 g), tripotassium phosphate (53 g), MeCN (440 mL), and water (80 mL) were mixed and stirred at 90 °C for 4 hours under an argon atmosphere. After the reaction mixture was allowed to return to room temperature, it was diluted with ethyl acetate and water. The organic layer was separated from the aqueous layer, washed with a saturated sodium chloride aqueous solution, and dried with anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 7-bromo-4-tert-butoxy-6-cyclopropyl-2-(ethylthio)-8-[(1S)-1-phenylethoxy]quinazoline (D7-5, 22.9 g) as an oil.

[1206] (Step Six)

[1207] Add 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2-(triphenylmethyl)-2H-indazole (19.3 g), palladium(II) acetate (0.67 g), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (2.67 g), anhydrous barium hydroxide (14.6 g), and DOX (500 mL) / water (100 mL) to 7-bromo-4-tert-butoxy-6-cyclopropyl-2-(ethylthio)-8-[(1S)-1-phenylethoxy]quinazolin (D7-5, 14.21 g) and argon purging several times. Then heat and stir overnight at 50 °C under argon atmosphere. The naturally cooled reaction suspension was washed with ethyl acetate while being filtered through diatomaceous earth (registered trademark) to remove gray insoluble matter. The filtrate was concentrated to about 1 / 4 under reduced pressure, water was added, and the mixture was extracted twice with ethyl acetate. The collected organic layer was washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (hexane / ethyl acetate) to give 4-tert-butoxy-6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (D7-6, from a axially chiral mixture of approximately 3.3:1 diastereomers, 16.44 g).

[1208] (Seventh Step)

[1209] Under a nitrogen atmosphere, 4-tert-butoxy-6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (D7-6, from a 3.3:1 diastereomer mixture of axially chiral derivatives, 33.71 g) was dissolved in CH2Cl2 (500 mL). Under ice-cooling, m-chloroperbenzoic acid (approximately 30% water, 22.4 g) was added (internal temperature: 5-10 °C), and the mixture was stirred at room temperature for 2 hours. Under ice-cooling, an aqueous solution (300 mL) of sodium thiosulfate pentahydrate (11 g) and a saturated aqueous solution of sodium bicarbonate (300 mL) were added to the reaction mixture. After stirring at room temperature for 30 minutes, the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous solutions of sodium bicarbonate and sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (from a mixture of axially chiral diastereomers). iPrOH (1000 mL) was added to the resulting residue, and the mixture was stirred overnight at room temperature. The resulting solid was filtered, washed with iPrOH, and dried under reduced pressure to give 4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (from an approximately 1:1 diastereomer mixture of axially chiral derivatives, 11.52 g). The filtrate was concentrated under reduced pressure to give (7M)-4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (D7-7, a single diastereomer, 23.29 g) as the target.

[1210] (Step 8)

[1211] Under a nitrogen atmosphere, 230 mg of 4-methylbenzene-1-sulfonic acid monohydrate was added to a 50 mL THF solution of (7 M)-4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (D7-7, 2.00 g) at room temperature, and the mixture was stirred at 50 °C for 1 hour. After the reaction solution was allowed to cool naturally to room temperature, 350 μL of TEA was added, and the solution was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give (7M)-4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-[(1S)-1-phenylethoxy]quinazoline (D7-8, 740 mg) as a bubble solid.

[1212] (Step 9)

[1213] Under a nitrogen atmosphere, at room temperature, 900 μL of 3,4-dihydro-2H-pyran and 35 mg of 4-methylbenzene-1-sulfonic acid monohydrate were added to a 10 mL THF solution of (7 M)-4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-[(1S)-1-phenylethoxy]quinazoline (D7-8, 735 mg). The mixture was stirred overnight at room temperature, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give (7M)-4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-1-(tetrahydropyran-2-yl)-1H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (D7-9, 735 mg) as a bubble solid.

[1214] (Step 10)

[1215] Under an argon atmosphere, sodium bicarbonate (450 mg) and 10% Pd / C (approximately 50% water, 250 mg) were added to a MeOH (15 mL) / THF (15 mL) solution of (7 M)-4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-1-(tetrahydropyran-2-yl)-1H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (D7-9, 730 mg) at room temperature. The mixture was stirred overnight at room temperature and pressure under a hydrogen atmosphere. After purging with argon, the reaction solution was filtered through diatomaceous earth (registered trademark) and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give (7M)-4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-1-(tetrahydropyran-2-yl)-1H-indazol-4-yl]quinazolin-8-ol (D7-10, 630 mg) as a bubble solid.

[1216] (Step 11)

[1217] Under a nitrogen atmosphere, (7M)-4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-1-(tetrahydropyran-2-yl)-1H-indazol-4-yl]quinazolin-8-ol (D7-10, 1.4 g) and cesium carbonate (2.4 g) were suspended in DMF (17 mL), and 1-(chloromethyl)-4-ethynylbenzene (500 mg) was added at room temperature. The mixture was stirred at 60 °C for 1.5 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (7M)-4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-(tetrahydropyran-2-yl)-1H-indazol-4-yl]quinazoline (D7-11, 1.47 g) as a bubble solid.

[1218] (Step Twelfth)

[1219] Under a nitrogen atmosphere and while cooling in an ice / MeOH bath (-20℃ to -15℃), tBuOK (275 mg) was added to a THF (11 mL) solution of (7M)-4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-(tetrahydropyran-2-yl)-1H-indazol-4-yl]quinazoline (D7-11, 1.47 g) and (2S)-2-methoxypropane-1-ol (0.25 mL), and the mixture was stirred for 30 minutes at the same temperature. At the same temperature, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain (7M)-4-tert-butoxy-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-(tetrahydropyran-2-yl)-1H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin (D7-12, 1.43 g) as a bubbly solid.

[1220] (Step Thirteen)

[1221] Under a nitrogen atmosphere, at room temperature, 120 mg of 4-methylbenzene-1-sulfonic acid monohydrate was added to a 15 mL THF solution of (7M)-4-tert-butoxy-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-(tetrahydropyran-2-yl)-1H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin (D7-12, 1.43 g), and the mixture was stirred at 50 °C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-(tetrahydropyran-2-yl)-1H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-4-ol (D7-13, 1.05 g) as a bubble solid.

[1222] (Step Fourteen)

[1223] Under a nitrogen atmosphere, cesium carbonate (2.68 g) and PyBOP (1.20 g) were added sequentially to a THF (15 mL) solution of (7 M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-(tetrahydropyran-2-yl)-1H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-4-ol (D7-13, 1.05 g) (D7-13 ... The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain (3S)-3-[{(7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-(tetrahydropyran-2-yl)-1H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}(methyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (D7-14, 1.62 g) as an oil.

[1224] (Step 15)

[1225] Under an argon atmosphere, at room temperature, (4R)-1-[(2S)-2-azido-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolylamide (75 mg) and (3S)-3-[{(7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-(tetrahydropyran-2-yl)-1H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}(methyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (D7-14, Anhydrous copper(II) sulfate (10 mg) and sodium ascorbate (30 mg) were added to a solution of 2.0 mL of tBuOH / THF / water (1:1:1 mixture), and the mixture was stirred at room temperature for 1 hour. Disodium ethylenediaminetetraacetate (175 mg) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 1 hour. Water and CHCl3 / MeOH (9 / 1) were added to the reaction mixture. The aqueous layer was separated from the organic layer, and the aqueous layer was extracted with CHCl3 / MeOH (9 / 1). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) to obtain (3S)-3-[{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(tetrahydropyran-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)- 2-Hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutane-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}(methyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (D7-15, 197 mg).

[1226] (Step Sixteen)

[1227] Under a nitrogen atmosphere and under ice cooling, tert-butyl pyrrolidine-1-carboxylate (D7-15) was produced. 0.5 mL of trifluoroacetic acid was added to a 2 mL solution of CH₂Cl₂ (197 mg) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and MeCN, saturated sodium bicarbonate aqueous solution, and water were added to the residue, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was purified by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution), and the fraction containing the target analyte was concentrated. The residue was dissolved in CHCl₃ / iPrOH (9 / 1), saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted twice with CHCl₃ / MeOH (5 / 1). The combined organic layers were dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{methyl[(3S)-pyrrolidine-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolylamide (D7, 65 mg).

[1228] Synthesis of drug D8

[1229] (First step)

[1230] At room temperature, (4R...

Claims

1. An antibody drug conjugate of the formula (I) or a salt thereof, in the formula, Ab is an antibody or an antigen binding fragment thereof, D is a heterocyclic compound having a KRAS protein decomposition inducing action of G12D mutation, L A a linker for binding Ab to D, n is a number of 1 to 20.

2. The compound according to claim 1, or a salt thereof, wherein, D is a heterocyclic compound represented by the formula (II), A is CR A or N, R A H, cyano or C 1-3 alkyl, Q is CR Q or N, R Q H, halogen, C 3-6 cycloalkyl, vinyl or C 1-3 alkyl, E is CH or N, R 1 is naphthyl which can be substituted by 1 or 2 radicals selected from the group consisting of cyano, OH, halogen and a radical which can be substituted alkyl, or a radical selected from the group consisting of formula (III), formula (IV) and formula (V), 1-3 alkyl, or a radical selected from the group consisting of formula (III), formula (IV) and formula (V), R 1a , R 1b and R 1c are independently of one another H, vinyl, halogen or a C 1-3 alkyl group which can be substituted, R 2 is -V 1 -V 2 or W, V 1 is a bond, -CH2-, -0-, -S-, or -N(R V1 )-, R V1 H or C 1-3 alkyl, V 2 is selected from the group consisting of formula (VI) and formula (VII), W is one group selected from the group consisting of the following formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV), formula (XV), and formula (XVI), R 2a independently of one another OH, OCH3, F or a C 1-3 alkyl group, which R 2a only binds to a carbon atom which is a constituting atom of a ring selected from the group consisting of an azetidine ring of formula (VI), a pyrrolidine ring of formula (VII), a piperidine ring of formula (VIII) and a piperazine ring of formula (IX), m is an integer of 0 to 2, R 3 C can be replaced 1-6 Alkyl, substituted heterocyclic alkyl, or substituted heteroaryl, X is a bond, -CH2-, -0-, -S-, or -NR 4X - R 4X H or C 1-3 alkyl, Y 1 -O-(optionally substituted C 1-3 alkylene) Y2 -S-(optionally substituted C 1-3 alkylene) Y2 -SO2-(optionally substituted C 1-3 alkylene) Y2 -NR Y -(optionally substituted C 1-3 alkylene) Y2 -(optionally substituted C 1-3 alkylene)-O Y2 -(optionally substituted C 1-3 alkylene)-S Y2 -(optionally substituted C 1-3 alkylene)-SO2 Y2 or -(optionally substituted C 1-3 alkylene)-NR Y Y2 Y2 represents the bonding part to Y 2 , R Y H or C 1-3 alkyl, Y 2 is a bond, optionally substituted phenylene, or optionally substituted heteroarylene, L P For Y 2 Group chemically combined with EUB, EUB is a group having a binding ability to one E3 ubiquitin ligase selected from the group consisting of VHL, hydroxylated cerebrosides, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR, L A is a linker for binding Ab to D, where L A binds to any -NH- nitrogen atom or -OH oxygen atom contained in D.

3. The antibody drug conjugate or a salt thereof according to claim 2, wherein, V 2 (VIa) and formula (VIIa) LA represents a binding site to L A , W is selected from one group consisting of formula (VIIIa), formula (IXa), formula (Xa), formula (XIa), formula (XIIa), formula (XIIIa), formula (XIVa), formula (XVa) and formula (XVIa) LA represents the binding part to L A , L A L is a linker for binding Ab to D, where L A with the nitrogen atom contained in V 2 or W LA is bound to D via the binding moiety shown.

4. The antibody drug conjugate according to claim 2 or a salt thereof, wherein A is N, Q is CR Q , R Q is cyclopropyl, E is CH, R 1 is of the following formula (III-2), R 2 -V 1 -V 2 or W, V 1 is -N(CH3)-, V 2 is of the following formula (VII-2), W is the following formula (XIV), R 3 is n-propyl which can be substituted by -OCH3 or tetrahydropyranyl, X is -O-, Y 1 -O-(methylene) Y2 Y2 represents a bonding part with Y 2 , Y 2 is phenylene, L P For Y 2 Group chemically combined with EUB, EUB is a group having a binding ability to one E3 ubiquitin ligase selected from the group consisting of VHL and hydroxylated cerebrosides.

5. The antibody drug conjugate according to claim 4 or a salt thereof, wherein V 2 (VII-2a) for the following formula LA represents the binding site to L A , W is of the following formula (XIVa) LA represents the binding site to L A of the following formula (XIVa) L A L is a linker for binding Ab to D, where L A with the nitrogen atom contained in V 2 or W LA is bound to D via the binding moiety shown.

6. The antibody drug conjugate or a salt thereof according to any one of claims 1 or 2, wherein, D is: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3- [3-yl]phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- [Azol-5-yl]phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{methyl[(3S)-pyrrolidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{methyl[(3S)-pyrrolidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, 1-(6-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-1-methyl-1H-indazol-3-yl)-1,3-diazinan-2,4-dione, or 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, or Phosphoric acid dihydro- (2R)-2-({(4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-methyl[(3S)-pyrrolidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-L-prolyl}amino)-2-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl ester.

7. The antibody drug conjugate or a salt thereof according to any one of claims 1 to 6, wherein, L A is a linker of formula (XXVIII), wherein Str is an extension unit which binds to Ab and CLL, and r is 0 or 1, CLL is a moiety which is cleavable in vivo, Sp is a spacer unit which binds to CLL and D, and t is 0 or 1, Ab represents the binding site for Ab.

8. The antibody drug conjugate or a salt thereof according to claim 7, wherein, Str is an extension unit represented by formula (ST-1), and r is 1, wherein R st1 is a C 1-12 alkylene, -(CH2CH2O) a1 -C 1-6 alkylene, -C 1-6 alkylene, -(OCH2CH2) a2 -, a C 1-6 alkylene, -NH-C(=O)- a C 1-6 alkylene, - a C 1-6 alkylene, -C(=O)-NH- a C 1-6 alkylene, a C 1-6 alkylene, -C(=O)-NH-(CH2CH2O) a3 -C 1-6 alkylene, or a C 1-6 alkylene, -NH-C(=O)-(CH2CH2O) a4 -C 1-6 alkylene, a1, a2, a3, and a4 are each an integer of 1 to 10, Ab represents the binding site for Ab.

9. The antibody drug conjugate or a salt thereof according to claim 8, wherein, R st1 is C5alkylene.

10. The antibody drug conjugate or a salt thereof according to claim 7, wherein, CLL is a moiety which is cleavable in vivo represented by formula (CL-1), wherein R AA independently of one another H, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, hydroxymethyl, 1-hydroxyethyl, -CH2-C(=0)-OH, -(CH2)2-C(=0)-OH, -CH2-C(=0)-NH2, -(CH2)2-C(=0)-NH2, -(CH2)4-NH2, -(CH2)3-NH-C(=NH)-NH2, -(CH2)3-NH-C(=0)-NH2, -CH2-SH or -CH2-S-CH3, or one radical selected from the group consisting of the following formulae (RAA-1) and (RAA-2) d is an integer from 1 to 6 STR represents the binding site to Str.

11. The antibody drug conjugate or a salt thereof according to claim 10, wherein, R AA independently of one another, are methyl or isopropyl, and d is 2.

12. The antibody drug conjugate or a salt thereof according to claim 10, wherein, R AA independently of one another is isopropyl or -(CH2)3-NH-C(=0)-NH2, d is 2.

13. The antibody drug conjugate or a salt thereof according to claim 10, wherein, R AA independently H or benzyl, and d is 4.

14. The antibody drug conjugate or a salt thereof according to claim 7, wherein, Sp is a spacer unit represented by formula (SP-1), and t is 1, wherein R SP is H, C 1-6 alkyl, -O-C 1-6 alkyl, halogen or halogenated C 1-6 alkyl CLL represents the binding site to CLL.

15. The antibody drug conjugate or a salt thereof according to claim 14, wherein, R SP is H.

16. The antibody drug conjugate or a salt thereof according to claim 7, wherein, t is 0.

17. The antibody drug conjugate according to claim 1, or a salt thereof, wherein, Formula (I) is represented by formula (AD-1a) or (AD-2a), wherein Ab is an antibody or an antigen-binding fragment thereof, A is CR A or N, R A is H, cyano or a C 1-3 alkyl group which can be substituted, Q is CR Q or N, R Q H, halogen, C 3-6 cycloalkyl, vinyl or C 1-3 alkyl, E is CH or N, R 1 is naphthyl which can be substituted by 1 or 2 radicals selected from the group consisting of cyano, OH, halogen and a substituted or unsubstituted C 1-3 alkyl group, or a radical selected from the group consisting of formula (III), formula (IV) and formula (V) R 1a , R 1b and R 1c are independently of one another H, vinyl, halogen or a C 1-3 alkyl group which can be substituted, R 3 C can be replaced 1-6 Alkyl, substituted heterocyclic alkyl, or substituted heteroaryl, X is a bond, -CH2-, -0-, -S-, or -NR 4X - R 4X H or C 1-3 alkyl, Y 1 -O-(optionally substituted C 1-3 alkylene) Y2 -S-(optionally substituted C 1-3 alkylene) Y2 -SO2-(optionally substituted C 1-3 alkylene) Y2 -NR Y -(optionally substituted C 1-3 alkylene) Y2 -(optionally substituted C 1-3 alkylene)-O Y2 -(optionally substituted C 1-3 alkylene)-S Y2 -(optionally substituted C 1-3 alkylene)-SO2 Y2 or -(optionally substituted C 1-3 alkylene)-NR Y Y2 Y2 represents the bonding part to Y 2 , R Y H or C 1-3 alkyl, Y 2 is a bond, optionally substituted phenylene, or optionally substituted heteroarylene, L P For Y 2 Group chemically combined with EUB, EUB is a group having a binding ability to one selected from the group consisting of VHL, sulfatase, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR, R st1 is C 1-12 alkylene, R AA independently of one another H, methyl, isopropyl, benzyl or -(CH2)3-NH-C(=0)-NH2, d is an integer from 2 to 4, t is 0 or 1, n is a number of 1 to 20.

18. The antibody drug conjugate or a salt thereof according to claim 1, wherein, Formula (I) is represented by formula (AD-3a), (AD-4a), (AD-5a), (AD-6a), (AD-7a), (AD-8a), (AD-9a), (AD-10a), (AD-11a), (AD-12a), (AD-13a), or (AD-25a), In the formula, R st1 C 1-12 Alkylene, R AA Each of the following is independently H, methyl, isopropyl, benzyl, or -(CH2)3-NH-C(=O)-NH2, d is an integer from 2 to 4, t is 0 or 1, and n is a value from 1 to 20. It should be noted that chemical structural formulas containing " The compound indicated by the symbol "" indicates that the compound has a single axial chirality or central chirality, and the same applies below.

19. The antibody drug conjugate according to claim 1, or a salt thereof, wherein, Formula (I) is represented by formula (AD-14), (AD-15), (AD-16), (AD-17), (AD-18), (AD-19), (AD-20), (AD-21), (AD-22), (AD-23), (AD-24), or (AD-25), in the formula, n is a number from 1 to 20.

20. The antibody drug conjugate according to any one of claims 1 to 19, or a salt thereof, wherein, Ab is cetuximab, and n is a number from 2 to 5.

21. The antibody drug conjugate according to any one of claims 1 to 19, or a salt thereof, wherein, Ab is an antibody or an antigen-binding fragment that binds to 1 or 2 or more antigens selected from the group consisting of 5T4, ADAM9, ALPP, ALPPL2, AXL, B7H3, B7H4, BCMA, CA9, CCR2, CCR7, CD123, CD166, CD19, CD20, CD22, CD25, CD30, CD33, CD37, CD38, CD45, CD46, CD70, CD74, CD79b, CDH3, CDH6, CLDN1, CLDN4, CLDN6, CLDN18.2, cMET, EGFR, EphA3, FAP, FGFR3, fibronectin, FOLRa, Globo H, GPRC5D, HER2, HER3, IGF1R, integrin alphaV, KAAG1, LIV1, MSLN, MT1-MMP, MUC1, MUC4, NaPi2b, nectin 4, PD-L1, PSMA, PTK7, ROR1, ROR2, SEZ6, sialyl Tn, TF, TROP2, TSPAN8, and VEGF.

22. The antibody drug conjugate according to any one of claims 1 to 19, or a salt thereof, wherein, Ab is an antibody or an antigen-binding fragment that binds to 1 or 2 or more antigens selected from the group consisting of EGFR, HER2, cMET, and TROP2.

23. The antibody drug conjugate according to any one of claims 1 to 19, or a salt thereof, wherein, Ab is an anti-EGFR antibody or an antigen-binding fragment thereof.

24. The antibody drug conjugate according to claim 23, or a salt thereof, wherein, Ab is an anti-EGFR antibody or an antigen-binding fragment thereof that contains a heavy chain variable region and a light chain variable region described in (1) or (2) below: (1) a heavy chain variable region containing a CDR1 consisting of the amino acid sequence of amino acid numbers 31 to 35 of SEQ ID NO: 1, a CDR2 consisting of the amino acid sequence of amino acid numbers 50 to 65 of SEQ ID NO: 1, and a CDR3 consisting of the amino acid sequence of amino acid numbers 98 to 108 of SEQ ID NO: 1, and a light chain variable region containing a CDR1 consisting of the amino acid sequence of amino acid numbers 24 to 34 of SEQ ID NO: 2, a CDR2 consisting of the amino acid sequence of amino acid numbers 50 to 56 of SEQ ID NO: 2, and a CDR3 consisting of the amino acid sequence of amino acid numbers 89 to 97 of SEQ ID NO: 2; or (2) a heavy chain variable region containing a CDR1 consisting of an amino acid sequence of amino acid numbers 31 to 35 of SEQ ID NO: 3, a CDR2 consisting of an amino acid sequence of amino acid numbers 50 to 65 of SEQ ID NO: 3, and a CDR3 consisting of an amino acid sequence of amino acid numbers 98 to 108 of SEQ ID NO: 3, and a light chain variable region containing a CDR1 consisting of an amino acid sequence of amino acid numbers 24 to 34 of SEQ ID NO: 4, a CDR2 consisting of an amino acid sequence of amino acid numbers 50 to 56 of SEQ ID NO: 4, and a CDR3 consisting of an amino acid sequence of amino acid numbers 89 to 97 of SEQ ID NO:

4.

25. The antibody drug conjugate according to claim 23, wherein, Ab is an anti-EGFR antibody or an antigen-binding fragment thereof containing a heavy chain variable region and a light chain variable region selected from the group consisting of (1) to (3) below: (1) a heavy chain variable region consisting of an amino acid sequence of amino acid numbers 1 to 119 of SEQ ID NO: 1 and a light chain variable region consisting of an amino acid sequence of amino acid numbers 1 to 107 of SEQ ID NO: 2; (2) a heavy chain variable region consisting of an amino acid sequence of amino acid numbers 1 to 119 of SEQ ID NO: 3 and a light chain variable region consisting of an amino acid sequence of amino acid numbers 1 to 107 of SEQ ID NO: 4; and (3) a heavy chain variable region and a light chain variable region having an identity of at least 90% or more to the heavy chain variable region and the light chain variable region described in the above (1) or (2).

26. The antibody drug conjugate according to claim 23, wherein, Ab is an anti-EGFR antibody of IgGl or IgG4 type.

27. The antibody drug conjugate according to claim 23, wherein, A is -C(O)-, B is -C(O)-, and R6 is -CH2-0-CH2-. Ab is an anti-EGFR antibody consisting of a heavy chain of SEQ ID NO: 1 and a light chain of SEQ ID NO:

2.

28. The antibody drug conjugate or a salt thereof according to any one of claims 21 to 23, wherein, Ab is a post-translationally modified antibody, or an antibody in which any amino acid residue is substituted with cysteine or a non-natural amino acid.

29. A pharmaceutical composition containing the antibody drug conjugate or a salt thereof according to any one of claims 1 to 28, and a pharmaceutically acceptable excipient.

30. The pharmaceutical composition according to claim 29, which is used for the treatment of cancer.

31. The pharmaceutical composition of claim 30, wherein, The cancer is a hematological cancer or a solid cancer.

32. The pharmaceutical composition of claim 30, wherein, The cancer is a cancer expressing G12D mutant KRAS.

33. The antibody drug conjugate or a salt thereof according to any one of claims 1 to 28, for use in the treatment of cancer.

34. A method for treating cancer, comprising the step of administering a therapeutically effective amount of the antibody drug conjugate or a salt thereof according to any one of claims 1 to 28 to a subject.

35. Use of the antibody drug conjugate or a salt thereof according to any one of claims 1 to 28 for the manufacture of a pharmaceutical composition for the treatment of cancer.

36. A drug-linker complex represented by formula (LD-1) or a salt thereof, in the formula, D is a heterocyclic compound having a G12D mutant KRAS protein decomposition-inducing action, R st1 is C 1-12 alkylene, CLL is a moiety structure cleavable in vivo, Sp is a spacer unit, and t is 0 or 1.

37. The drug-linker complex of claim 36, or a salt thereof, wherein, D is a heterocyclic compound represented by formula (II), A is CR A or N, R A H, cyano or C 1-3 alkyl, Q is CR Q or N, R Q H, halogen, C 3-6 cycloalkyl, vinyl or C 1-3 alkyl, E is CH or N, R 1 is naphthyl which can be substituted by 1 or 2 radicals selected from the group consisting of cyano, OH, halogen and a radical which can be substituted alkyl, or a radical selected from the group consisting of formula (III), formula (IV) and formula (V), 1-3 alkyl, or a radical selected from the group consisting of formula (III), formula (IV) and formula (V), R 1a , R 1b and R 1c are independently of one another H, vinyl, halogen or a C 1-3 alkyl group which can be substituted, R 2 -V 1 -V 2 or W, V 1 is a bond, -CH2-, -0-, -S-, or -N(R V1 )-, R V1 H or C 1-3 alkyl, V 2 is selected from the group consisting of formula (VI) and formula (VII), W is one group selected from the group consisting of formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV), formula (XV), and formula (XVI), R 2a independently of one another OH, OCH3, F or C 1-3 alkyl, which R 2a only to a carbon atom which constitutes a ring with a ring selected from the group consisting of an azetidine ring of formula (VI), a pyrrolidine ring of formula (VII), a piperidine ring of formula (VIII) and a piperazine ring of formula (IX), m is an integer of 0 to 2, R 3 C can be replaced 1-6 Alkyl, substituted heterocyclic alkyl, or substituted heteroaryl, X is a bond, -CH2-, -0-, -S-, or -NR 4X - R 4X H or C 1-3 alkyl, Y 1 -O-(optionally substituted C 1-3 alkylene) Y2 -S-(optionally substituted C 1-3 alkylene) Y2 -SO2-(optionally substituted C 1-3 alkylene) Y2 -NR Y -(optionally substituted C 1-3 alkylene) Y2 -(optionally substituted C 1-3 alkylene)-O Y2 -(optionally substituted C 1-3 alkylene)-S Y2 -(optionally substituted C 1-3 alkylene)-SO2 Y2 or -(optionally substituted C 1-3 alkylene)-NR Y Y2 Y2 represents the bonding part to Y 2 , R Y H or C 1-3 alkyl, Y 2 is a bond, optionally substituted phenylene, or optionally substituted heteroarylene, L P For Y 2 Group chemically combined with EUB, EUBis a group having a binding ability to one of E3 ubiquitin ligases selected from the group consisting of VHL, hydroxylated cerebroside, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR, Sp is a spacer unit, and is bound to CLL and D, and here, Sp is bound to the nitrogen atom of any -NH- or the oxygen atom of -OH contained in D.

38. The drug-linker complex or a salt thereof according to claim 37, wherein, V 2 (VIb) and formula (VIIb) SP represents a bonding part to Sp, W is selected from one group consisting of formula (VIIIb), formula (IXb), formula (Xb), formula (XIb), formula (XIIb), formula (XIIIb), formula (XIVb), formula (XVb) and formula (XVIb) SP represents the bonding part with Sp, Sp is a spacer unit, which binds to CLL and D, here Sp binds to V 2 or the nitrogen atom contained in W SP the binding moiety shown binds to D.

39. The drug-linker complex or a salt thereof according to claim 37, wherein A is N, Q is CR Q , R Q is cyclopropyl, E is CH, R 1 is of the following formula (III-2), R 2 -V 1 -V 2 or W, V 1 -N(CH3)-, V 2 is of the following formula (VII-2), W is the following formula (XIV), R 3 is n-propyl which can be substituted by -OCH3 or tetrahydropyranyl, X is -O-, Y 1 -O-(methylene) Y2 Y2 represents a bonding part with Y 2 , Y 2 is phenylene, L P For Y 2 a group which chemically combines with EUB EUBis a group having a binding ability to one of E3 ubiquitin ligases selected from the group consisting of VHL and hydroxylated cerebroside.

40. The drug-linker complex or a salt thereof according to claim 39, wherein V 2 is the following formula (VII-2b) SP represents a bonding part with Sp, W is of the following formula (XIVb) SP represents the bonding site to Sp, Sp is a spacer unit, which binds to CLL and D, here Sp binds to V 2 or the nitrogen atom contained in W SP the binding moiety shown binds to D.

41. The drug-linker complex of any one of claims 36 or 37, or a salt thereof, wherein, D is: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydropyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3- [3-yl]phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- [Azol-5-yl]phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{methyl[(3S)-pyrrolidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{methyl[(3S)-pyrrolidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, 1-(6-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(tetrahydro-pyran-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-1-methyl-1H-indazol-3-yl)-1,3-diazinan-2,4-dione, 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy) methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, or Phosphoric acid = dihydro- (2R)-2-({(4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-methyl[(3S)-pyrrolidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-L-prolyl}amino)-2-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl ester.

42. The drug-linker complex or salt thereof according to claim 36, wherein, Formula (LD-1) is represented by Formula (LD-2a) or (LD-3a), in which A is CR A or N, R A is H, cyano or a C 1-3 alkyl group, Q is CR Q or N, R Q H, halogen, C 3-6 cycloalkyl, vinyl or C 1-3 alkyl, E is CH or N, R 1 naphthyl group which can be substituted by 1 or 2 radicals selected from the group consisting of cyano, OH, halogen and a substituted or unsubstituted C 1-3 alkyl group, or a radical selected from the group consisting of the following formulae (III), (IV) and (V) R 1a , R 1b and R 1c are independently of one another H, vinyl, halogen or a C 1-3 alkyl group which can be substituted, R 3 C can be replaced 1-6 Alkyl, substituted heterocyclic alkyl, or substituted heteroaryl, X is a bond, -CH2-, -0-, -S-, or -NR 4X - R 4X H or C 1-3 alkyl, Y 1 -O-(optionally substituted C 1-3 alkylene) Y2 -S-(optionally substituted C 1-3 alkylene) Y2 -SO2-(optionally substituted C 1-3 alkylene) Y2 -NR Y -(optionally substituted C 1-3 alkylene) Y2 -(optionally substituted C 1-3 alkylene)-O Y2 -(optionally substituted C 1-3 alkylene)-S Y2 -(optionally substituted C 1-3 alkylene)-SO2 Y2 or -(optionally substituted C 1-3 alkylene)-NR Y Y2 Y2 the bonding part to Y 2 , R Y H or C 1-3 alkyl, Y 2 is a bond, optionally substituted phenylene, or optionally substituted heteroarylene, L P to Y 2 a group that chemically combines with EUB EUB is a group having a binding ability to one E3 ubiquitin ligase selected from the group consisting of VHL and hydroxylated cerebrosides, R st1 is C 1-12 alkylene, R AA independently of one another H, methyl, isopropyl, benzyl or -(CH2)3-NH-C(=0)-NH2, d is an integer from 2 to 4, t is 0 or 1.

43. The drug-linker complex of claim 36, or a salt thereof, wherein, Formula (LD-1) is represented by Formula (LD-4a), (LD-5a), (LD-6a), (LD-7a), (LD-8a), (LD-9a), (LD-10a), (LD-11a), (LD-12a), (LD-13a), (LD-14a), or (LD-26a), wherein R st1 is C 1-12 alkylene, R AA independently of one another H, methyl, isopropyl, benzyl or -(CH2)3-NH-C(=O)-NH2, d is an integer from 2 to 4 and t is 0 or 1.

44. The drug-linker complex of claim 36, or a salt thereof, wherein, Formula (LD-1) is represented by Formula (LD-15), (LD-16), (LD-17), (LD-18), (LD-19), (LD-20), (LD-21), (LD-22), (LD-23), (LD-24), (LD-25), or (LD-26), Formula (LD-1) is represented by Formula (LD-15), (LD-16), (LD-17), (LD-18), (LD-19), (LD-20), (LD-21), (LD-22), (LD-23), (LD-24), (LD-25), or (LD-26), 。

Images