Antibody-drug conjugate containing heterocyclic compound having activity of inducing decomposition of KRAS mutant proteins

Abstract

Provided is an antibody-drug conjugate for use in the treatment of cancer in which one or more KRAS mutants, particularly a KRAS G12V mutant, a KRAS G12D mutant, and a KRAS G12C mutant, are expressed. Also provided are a drug and a drug-linker conjugate for use in the antibody-drug conjugate.　The present inventors have produced an antibody-drug conjugate with which a heterocyclic compound represented by formula (II) and having an activity of inducing the decomposition of KRAS mutant proteins can be delivered to cancer in which EGFRs are expressed, the production being achieved by linking the compound to an anti-EGFR antibody. The present inventors have also discovered a drug-linker conjugate for use in the antibody-drug conjugate or a salt thereof. In cancer in which EGFRs are expressed, the antibody-drug conjugate induces the decomposition of one or more KRAS mutants, particularly a KRAS G12V mutant protein, a KRAS G12D mutant protein, and a KRAS G12C mutant protein, thereby inhibiting the KRAS mutants and exhibiting an anti-tumor effect.

Description

Full specificationDESCRIPTION TITLE OF INVENTION: ANTIBODY-DRUG CONJUGATE CONTAINING HETEROCYCLIC COMPOUND HAVING MUTANT KRAS PROTEIN DEGRADATION-INDUCING EFFECT TECHNICAL FIELD

[0001] The present invention relates to a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, particularly, G12V mutant, G12D mutant, and G12C mutant KRAS protein degradation-inducing effect (hereinafter, the compound is also referred to as a drug), an antibody-drug conjugate or a salt thereof containing the heterocyclic compound, and a pharmaceutical composition containing the antibody-drug conjugate or the salt thereof. The present invention also relates to a drug-linker conjugate or a salt thereof for use in the antibody-drug conjugate or the salt thereof. BACKGROUND ART

[0002] RAS protein is an approximately 21 kDa low-molecular guanosine triphosphate (GTP) binding protein composed of 188 or 189 amino acids, and includes four types of major proteins (KRAS (KRAS4A and KRAS4B), NRAS, and HRAS) resulting from three genes, KRAS gene, NRAS gene, and HRAS gene. The RAS protein has a GTP-bound form which is an active form, and a GDP-bound form which is an inactive form. The RAS protein is activated by the exchange between guanosine diphosphate (GDP) and GTP through the ligand stimulation of a cell membrane receptor such as EGFR, for example. The active RAS binds to various effector proteins as many as 11 types such as RAF, PI3K, and RALGDS, and activates downstream signal cascades. The active RAS becomes inactive by the conversion of GTP to GDP ascribable to endogenous GTP hydrolysis (GTPase) activity. This GTPase activity is enhanced by GTPase activating protein (GAP). Thus, RAS is responsible for an important function of "molecular switch" for the intracellular signaling pathway of EGFR or the like, and plays an important role in processes such as cell growth, proliferation, and angiogenesis (Nature Rev. Cancer, 2011, 11, p. 761-774; Nature Rev. Drug Discov., 2014, 13, p. 828-851; and Nature Rev. Drug Discov., 2016, 15, p. 771-785).

[0003] When amino acid substitution occurs due to a mutation in RAS gene, RAS becomes constantly active by a reduced function as GTPase or reduced response to GAP and thus continues to send signals to downstream. This excessive signal brings about oncogenesis or increased tumor growth. For example, a mutation in KRAS gene is found in approximately 85% patients with pancreatic ductal adenocarcinoma, and the mutation exists from an initial stage of pancreatic intraepithelial neoplasia (PanIN). Also, a mutation in KRAS gene is highly frequently found in lung cancer and colorectal cancer. Point mutations in codon 12 positioned in KRAS exon 2 (KRAS G12C mutation, KRAS G12D mutation, etc.) are commonly known as examples of the mutation in KRAS gene (Nat Rev Cancer. 2010. 10 (10). 683-695; Semin Oncol. 2021. 48 (1). 10-18; and Nat Rev Cancer. 2018. 18. 767-777).

[0004] In recent years, bifunctional compounds collectively called PROTAC (proteolysis-targeting chimera), SNIPER (specific and nongenetic IAP-dependent protein eraser), or the like have been found as techniques of inducing the degradation of targeted proteins, and expected as one of the novel drug discovery modalities (Drug. Discov. Today Technol., 2019, 31, p. 15-27). These bifunctional compounds promote the intracellular complex formation between a target protein and E3 ligase and ubiquitinate the target protein, thereby inducing the degradation of the target protein by the ubiquitin-proteasome system. The ubiquitin-proteasome system is one of the intracellular protein degradation mechanisms. A protein called E3 ligase recognizes and ubiquitinates the protein to be degraded so that its degradation in proteasome proceeds. More than 600 types of E3 ligases reside in vivo. Nonetheless, a limited number of E3 ligases have been used so far as bifunctional degradation inducers called PROTAC, SNIPER, or the like. Representative examples thereof include Von Hippel-Lindau (VHL), cereblon (CRBN), inhibitor of apoptosis protein (IAP), and mouse double minute 2 homolog (MDM2).

[0005] These bifunctional compounds are compounds in which a ligand of a target protein and a ligand of E3 ligase are linked via a linker. PTL 1 to PTL 7 each describe a bifunctional compound that degrades mutant KRAS protein. PTL 8 to PTL 10 each describe a compound in which a substituent at position 8 of quinoline or quinazoline is linked to a ligand of E3 ligase, as a bifunctional compound that degrades KRAS having a G12D mutation. PTL 11 to PTL 16 published after the priority date of the present application each describe a bifunctional compound that degrades mutant KRAS protein.

[0006] Meanwhile, for example, antibody-drug conjugates (ADC) in which a drug molecule having cytotoxicity is connected to an antibody targeting an antigen expressed on cancer cell surface, or immune-stimulating antibody conjugates (ISAC) in which a drug molecule having an immunostimulatory effect is connected thereto are under study as techniques of selectively delivering drugs to cancer cells, and medicaments obtained through the use of this technique have been approved (Cancer Science, 2016, Vol. 107, No. 7, p. 1039-1046; Clinical Cancer Research, 2005, Vol. 11, p. 843-852; and Cancer Research, 2016, Vol. 76, No. 10, p. 3003-3013). PTL 17 to PTL 21 each describe ADC having a bifunctional compound having an effect of inducing the degradation of a target protein as a drug. NPL 1 describes antibody-based PROTAC (AbTAC) that has an anti-EGFR antibody and degrades EGFR. However, ADC containing a drug having a mutant KRAS protein degradation-inducing effect, particularly, a G12V mutant, G12D mutant, and G12C mutant KRAS protein degradation-inducing effect has not been known so far. CITATION LISTPATENT LITERATURE

[0007] PTL 1: International Publication No. WO 2023 / 099620PTL 2: International Publication No. WO 2023 / 141570PTL 3: International Publication No. WO 2022 / 271823PTL 4: International Publication No. WO 2023 / 130012PTL 5: International Publication No. WO 2022 / 087335PTL 6: International Publication No. WO 2022 / 266249PTL 7: International Publication No. WO 2023 / 185864PTL 8: International Publication No. WO 2022 / 173032PTL 9: International Publication No. WO 2023 / 171781PTL 10: International Publication No. WO 2024 / 019103PTL 11: International Publication No. WO 2024 / 118966PTL 12: International Publication No. WO 2024 / 119278PTL 13: International Publication No. WO 2024 / 120424PTL 14: International Publication No. WO 2024 / 083256PTL 15: International Publication No. WO 2024 / 029613PTL 16: International Publication No. WO 2024 / 034593PTL 17: International Publication No. WO 2021 / 195598PTL 18: International Publication No. WO 2023 / 056069PTL 19: International Publication No. WO 2020 / 086858PTL 20: International Publication No. WO 2022 / 020288PTL 21: International Publication No. WO 2022 / 220625NON PATENT LITERATURE

[0008] NPL 1: Int. J. Biol. Macromol., 252, 126413 (2023) SUMMARY OF INVENTIONTECHNICAL PROBLEM

[0009] Provided are a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, particularly, G12V mutant, G12D mutant, and G12C mutant KRAS protein degradation-inducing effect, an antibody-drug conjugate or a salt thereof containing the heterocyclic compound, and a pharmaceutical composition containing the antibody-drug conjugate or the salt thereof. Also provided is a drug-linker conjugate or a salt thereof for use in the antibody-drug conjugate or the salt thereof. SOLUTION TO PROBLEM

[0010] The present inventors have conducted diligent studies on compounds useful as active ingredients for pharmaceutical compositions and consequently completed the present invention by finding that an antibody-drug conjugate having a structure of formula (I) has an excellent mutant KRAS protein degradation-inducing effect, particularly, G12V mutant, G12D mutant, and G12C mutant KRAS protein degradation-inducing effect, and further finding that a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, particularly, G12V mutant, G12D mutant, and G12C mutant KRAS protein degradation-inducing effect, and a drug-linker conjugate containing the heterocyclic compound are useful in the synthesis of the antibody-drug conjugate.

[0011] Specifically, the present invention relates to the following [0] to [45-2].

[0012] [0] An antibody-drug conjugate represented by formula (I') or a salt thereof:[Chemical Formula 1]whereinAb is an antibody or an antigen binding fragment thereof,D' is a heterocyclic compound having a RAS protein degradation-inducing effect,LA is a linker for connecting Ab and D, andm is a number of 1 to 20.

[0013] [1] An antibody-drug conjugate represented by formula (I) or a salt thereof:[Chemical Formula 2]whereinAb is an antibody or an antigen binding fragment thereof,D is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect,LA is a linker for connecting Ab and D, andm is a number of 1 to 20.

[0014] [2] The antibody-drug conjugate or the salt thereof according to [1], whereinD is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (II):[Chemical Formula 3]whereinA is CRA or N,RA is H or C1-3 alkyl,X1 is -CH2- or -O-,R1 is naphthyl optionally substituted by OH, or a group represented by the following formula (III):[Chemical Formula 4]R1a is H, methyl, F, or Cl,R1b is F, Cl, methyl, or ethyl,R2 is H, halogen, cyclopropyl, vinyl, or C1-3 alkyl optionally substituted by a group selected from the group consisting of OH and OCH3,R3 is a group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII):[Chemical Formula 5]R3a is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 5- or 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,R3b is H or C1-3 alkyl,each of R3c and R3d is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,on the proviso that when R3c is -(CH2)pCHR3f-NRN1RN2, X2 in formula (V) is -O-, -NH-, or -N(C2-3 alkyl)-,R3e is -O-C2-3 alkylene-NRN1RN2,R3f is H, F, or C1-3 alkyl,R3g is H or C1-3 alkyl,R3h is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms,R3i are the same or different from each other and each is a group selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, -NH-optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)2, halogen, -CN, and oxo, ortwo R3i present on the same carbon atom optionally form, together with the adjacent carbon atom, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a spiro ring as the group of formula (XIII), wherein the spiro ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two adjacent carbon atoms optionally form, together with the two carbon atoms, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a condensed ring as the group of formula (XIII), wherein the condensed ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two non-adjacent carbon atoms, optionally form, together with the two carbon atoms, a bridged structure of 1 or 2 carbon atoms, wherein the group of formula (XIII) which is a ring having the bridged structure is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl, orRN1 and RN2 optionally form, together with the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, orR3f and RN1 optionally form, together with the carbon atom and the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,X2 is -O-, -NH-, or -N(C1-3 alkyl)-,X3 is O or S,X4 is -CH2-, -CH2-CH2-, or -O-CH2-,n is 1 or 2,p is 1 or 2,q is an integer of 1 to 8,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, R4a, cyclopropyl, N(R4a)2, pyrrolidinyl optionally substituted by R4a, and tetrahydrofuranyl optionally substituted by R4a; piperidinyl optionally substituted by R4b; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl optionally substituted by F,R4b is C1-3 alkyl substituted by 1 to 3 F,Y is phenylene optionally substituted by F or Cl, or pyridinediyl,LP is a group that chemically bonds Y to EUB,EUB is a group having the ability to bind to E3 ubiquitin ligase, andLA is a linker for connecting Ab and D and is bonded to an arbitrary nitrogen atom or oxygen atom of -OH contained in D, wherein when the nitrogen atom is tertiary amine, the nitrogen atom is bonded to LA to form quaternary ammonium.

[0015] [3] The antibody-drug conjugate or the salt thereof according to [2], wherein LA is a linker for connecting Ab and D and is bonded to a nitrogen atom of amine or an oxygen atom of -OH contained in the group R3, R4, or EUB of D to form N-LA or O-LA, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to LA to form quaternary ammonium.

[0016] [4] The antibody-drug conjugate or the salt thereof according to [3], whereinA is CRA or N,RA is H,X1 is -O-,R1 is a group represented by the following formula (III-a):[Chemical Formula 6]R2 is cyclopropyl,R3 is a group selected from the group consisting of the following formula (IV), formula (V), and formula (XI):[Chemical Formula 7]R3a is -(CH2)pCHR3f-NRN1RN2,R3b is H,R3c is C3-6 cycloalkyl optionally substituted by -NRN1RN2,R3f is H,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl,X2 is -O- or -NH-,X3 is O,n is 1,p is 1,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of OCH3, N(R4a)2, and pyrrolidinyl optionally substituted by R4a; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl, andY is phenylene.

[0017] [5] The antibody-drug conjugate or the salt thereof according to [4], whereinA is N,R3 is a group represented by the following formula (XI):[Chemical Formula 8]R4 is C1-6 alkyl substituted by N(R4a)2, andR4a is C1-3 alkyl.

[0018] [6] The antibody-drug conjugate or the salt thereof according to [3], wherein EUB is a group having the ability to bind to VHL.[6-2] The antibody-drug conjugate or the salt thereof according to [3], wherein EUB is a group having the ability to bind to CRBN.[6-3] The antibody-drug conjugate or the salt thereof according to [3], wherein EUB is a group having the ability to bind to VHL or CRBN.

[0019] [7] The antibody-drug conjugate or the salt thereof according to any of [3] to [5], whereinEUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 9]R5 is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, C3-6 cycloalkylmethyl, or C3-6 cycloalkyl,R6a and R6b are the same or different from each other and each is H or C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, and N(CH3)2, orR6a and R6b optionally form, together with the carbon bonded thereto, optionally substituted C3-6 cycloalkane, or an optionally substituted 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,R7 is an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or 6-membered heteroaryl containing 1 to 3 nitrogen atoms,W is optionally substituted phenylene or optionally substituted 6-membered heteroarenediyl containing 1 to 3 nitrogen atoms as ring-constituting atom,LP is -(L1-L2-L3-L4)-,L1, L2, L3, and L4 are the same or different from each other and each is a group selected from the group consisting of a bond, -O-, -NRL1-, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3 alkylene, and C=O,RL1 is H or C1-3 alkyl, andZ is NH or 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom.[8] The antibody-drug conjugate or the salt thereof according to [7], whereinEUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 10]R5 is isopropyl or tert-butyl,R6a and R6b are different from each other and each is H, or C1-6 alkyl optionally substituted by OH,R7 is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen,W is phenylene,LP is a bond, andZ is 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom.

[0020] [9] The antibody-drug conjugate or the salt thereof according to [8], whereinR7 is a group selected from the group consisting of the following formula (XIX-a), formula (XX-a), and formula (XVI):[Chemical Formula 11]W is a group represented by the following formula (XVII-a):[Chemical Formula 12]andZ is a group represented by the following formula (XVIII):[Chemical Formula 13]

[0021]

[10] The antibody-drug conjugate or the salt thereof according to [9], wherein R7 is a group represented by the following formula (XVI):[Chemical Formula 14]

[0022]

[11] The antibody-drug conjugate or the salt thereof according to [3], wherein LA is a linker represented by formula (XV):[Chemical Formula 15]whereinStr is a stretcher unit and is connected to Ab and CLL,CLL is a partial structure cleavable in vivo,Sp is a spacer unit and is connected to CLL and D, t is 0 or 1, and*Ab represents a site of connection to Ab.

[0023]

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

[11] , whereini) Str is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 16]Rst1 is optionally substituted C1-12 alkylene, -optionally substituted C1-6 alkylene-C(=O)-NH-C1-6 alkylene-(OCH2CH2)a-, or -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-, a is an integer of 1 to 10,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20, CLL is a partial structure cleavable in vivo represented by formula (CL-1), *STR represents a site of connection to Str,[Chemical Formula 17]RAA are each independently one group selected from the group consisting of H, methyl, isopropyl, benzyl, and -(CH2)3-NH-C(=O)-NH2,d is an integer of 2 to 4,Sp is a spacer unit represented by formula (SP-1), formula (SP-2), or formula (SP-3), t is 1, *CLL represents a site of connection to CLL,[Chemical Formula 18]andRSP is H,orii) Str is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 19]Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivorepresented by formula (CL-2), *STR represents a site of connection to Str,[Chemical Formula 20]andt is 0.

[0024]

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

[12] , whereinStr is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 21]Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-2), *STR represents a site of connection to Str,[Chemical Formula 22]andt is 0.

[0025]

[14] The antibody-drug conjugate or the salt thereof according to [3], whereinA is CRA or N,RA is H,X1 is -O-,R1 is a group represented by the following formula (III-a):[Chemical Formula 23]R2 is cyclopropyl,R3 is a group selected from the group consisting of the following formula (IV), formula (V), and formula (XI):[Chemical Formula 24]R3a is -(CH2)pCHR3f-NRN1RN2,R3b is H,R3c is C3-6 cycloalkyl optionally substituted by -NRN1RN2,R3f is H,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl,X2 is -O- or -NH-,X3 is O,n is 1,p is 1,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of OCH3, N(R4a)2, and pyrrolidinyl optionally substituted by R4a; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl,Y is phenylene,EUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 25]R5 is isopropyl or tert-butyl,R6a and R6b are different from each other and each is H, or C1-6 alkyl optionally substituted by OH,R7 is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen,W is phenylene,LP is a bond,Z is 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,LA is a linker represented by formula (XV) (wherein *Ab represents a site of connection to Ab):[Chemical Formula 26]Str is a stretcher unit and is connected to Ab and CLL,CLL is a partial structure cleavable in vivo,Sp is a spacer unit and is connected to CLL and D, t is 0 or 1, whereini) Str is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 27]Rst1 is optionally substituted C1-12 alkylene, -optionally substituted C1-6 alkylene-C(=O)-NH-C1-6 alkylene-(OCH2CH2)a-, or -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-, a is an integer of 1 to 10,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-1), *STR represents a site of connection to Str,[Chemical Formula 28]RAA are each independently one group selected from the group consisting of H, methyl, isopropyl, benzyl, and -(CH2)3-NH-C(=O)-NH2,d is an integer of 2 to 4,Sp is a spacer unit represented by formula (SP-1), formula (SP-2), or formula (SP-3), t is 1, *CLL represents a site of connection to CLL,[Chemical Formula 29]andRSP is H,or ii) Str is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 30]Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-2), *STR represents a site of connection to Str,[Chemical Formula 31]t is 0,LA is bonded to a nitrogen atom of amine contained in the group R3 or R4 of D, or an oxygen atom of -OH contained in EUB to form N-LA or O-LA, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded LA to form quaternary ammonium,and m is a number of 2 to 10.

[0026]

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

[14] , whereinA is N,R3 is a group represented by the following formula (XI):[Chemical Formula 32]R4 is C1-6 alkyl substituted by N(R4a)2,R4a is C1-3 alkyl,R7 is a group represented by the following formula (XVI):[Chemical Formula 33]W is a group represented by the following formula (XVII-a):[Chemical Formula 34]Z is a group represented by the following formula (XVIII):[Chemical Formula 35]Str is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 36]Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-2), *STR represents a site of connection to Str,[Chemical Formula 37]t is 0, andLA is bonded to a nitrogen atom of N(R4a)2 contained in R4 to form -N+(R4a)2-LA.

[0027] [15-2] The antibody-drug conjugate or the salt thereof according to [3], whereinA is N,X1 is -O-,R1 is a group represented by the following formula (III-a):[Chemical Formula 38]R2 is cyclopropyl,R3 is a group represented by the following formula (XI):[Chemical Formula 39]R4 is C1-6 alkyl substituted by N(R4a)2,R4a is C1-3 alkyl,Y is phenylene,LP is a bond,EUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 40]R5 is isopropyl or tert-butyl,R6a and R6b are different from each other and each is H, or C1-6 alkyl optionally substituted by OH,R7 is a group represented by the following formula (XVI):[Chemical Formula 41]W is a group represented by the following formula (XVII-a):[Chemical Formula 42]andZ is a group represented by the following formula (XVIII):[Chemical Formula 43]

[0028] [15-3] The antibody-drug conjugate or the salt thereof according to [3], whereinA is CRA or N,RA is H,X1 is -O-,R1 is a group represented by the following formula (III-a):[Chemical Formula 44]R2 is cyclopropyl,R3 is a group selected from the group consisting of the following formula (IV-a) and formula (V-a):[Chemical Formula 45]R3a is -(CH2)pCHR3f-NRN1RN2,R3b is H,R3c is C3-6 cycloalkyl optionally substituted by -NRN1RN2,R3f is H,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl,X2 is -O- or -NH-,X3 is O,p is 1,R4 is C1-6 alkyl optionally substituted by OCH3,Y is phenylene,LP is a bond,EUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 46]R5 is isopropyl,R6a is H, R6b is hydroxymethyl,R7 is a group selected from the group consisting of the following formula (XIX-a) and formula (XVI):[Chemical Formula 47]W is a group represented by formula (XVII-a):[Chemical Formula 48]andZ is a group represented by the following formula (XVIII-a):[Chemical Formula 49]wherein * represents a site of connection to LP.

[0029] [15-4] The antibody-drug conjugate or the salt thereof according to [3], whereinLA is a linker represented by formula (XV) (wherein *Ab represents a site of connection to Ab):[Chemical Formula 50]Str is a stretcher unit and is connected to Ab and CLL, r is 0,CLL is a partial structure cleavable in vivorepresented by formula (CL-3):[Chemical Formula 51](wherein*STR represents a site of connection to Str),Sp is a spacer unit represented by formula (SP-4):[Chemical Formula 52](wherein*CLL represents a site of connection to CLL) and is connected to CLL and D, t is 1, andLA is bonded to an oxygen atom of -OH contained in EUB to form O-LA.

[0030]

[16] The antibody-drug conjugate or the salt thereof according to [3], wherein the antibody-drug conjugate is represented by the following formula (AD-1), (AD-2), or (AD-3):[Chemical Formula 53-1][Chemical Formula 53-2][Chemical Formula 53-3]wherein b is an integer of 2 to 20, and m is a number of 2 to 10.

[0031]

[17] The antibody-drug conjugate or the salt thereof according to

[16] , wherein b is 12, and m is a number of 3 to 9.

[0032]

[18] The antibody-drug conjugate or the salt thereof according to any of [1] to

[17] , wherein Ab is an antibody or an antigen binding fragment that binds to an antigen 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, CEACAM5, CEACAM6, CLDN1, CLDN4, CLDN6, CLDN18.2, cMET, EGFR, EphA3, FAP, FGFR3, Fibronectin, FOLRa, Globo H, GPRC5D, HER2, HER3, IGF1R, Integrin αV, KAAG1, LIV1, MSLN, MT1-MMP, MUC1, MUC4, NaPi2b, Nectin-4, PD-L1, PSMA, PTK7, ROR1, ROR2, SEZ6, SialylTn, TF, TROP2, TSPAN8, and VEGF.

[19] The antibody-drug conjugate or the salt thereof according to any of [1] to

[17] , wherein Ab is an antibody or an antigen binding fragment that binds to an antigen selected from the group consisting of EGFR, HER2, Nectin-4, and TROP2.

[20] The antibody-drug conjugate or the salt thereof according to any of [1] to

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

[21] The antibody-drug conjugate or the salt thereof according to

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

[22] The antibody-drug conjugate or the salt thereof according to

[21] , wherein Ab is an anti-EGFR antibody including a heavy chain variable region and a light chain variable region selected from the group consisting of the following (1) to (3) or an antigen binding fragment thereof:(1) a heavy chain variable region consisting of an amino acid sequence from amino acid positions 1 to 119 of SEQ ID NO: 1 and a light chain variable region consisting of an amino acid sequence from amino acid positions 1 to 107 of SEQ ID NO: 2;(2) a heavy chain variable region consisting of an amino acid sequence from amino acid positions 1 to 119 of SEQ ID NO: 3 and a light chain variable region consisting of an amino acid sequence from amino acid positions 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 higher identity to the heavy chain variable region and the light chain variable region described in (1) or (2) above.

[23] The antibody-drug conjugate or the salt thereof according to

[22] , wherein Ab is an IgG1 or IgG4 type anti-EGFR antibody.

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

[23] , wherein Ab is cetuximab.

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

[23] , wherein 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.

[26] The antibody-drug conjugate or the salt thereof according to any of

[18] to

[25] , wherein Ab is a post-translationally modified antibody or an antigen binding fragment, or an antibody or an antigen binding fragment with an arbitrary amino acid residue substituted by cysteine or a non-natural amino acid.

[27] An antibody-drug conjugate represented by formula (I) or a salt thereof:[Chemical Formula 54]whereinAb is an anti-EGFR antibody including a heavy chain variable region and a light chain variable region described in the following (1) or (2) or an antigen binding fragment thereof:(1) a heavy chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 31 to 35 of SEQ ID NO: 1, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 65 of SEQ ID NO: 1, and CDR3 consisting of an amino acid sequence from amino acid positions 98 to 108 of SEQ ID NO: 1, anda light chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 24 to 34 of SEQ ID NO: 2, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 56 of SEQ ID NO: 2, and CDR3 consisting of an amino acid sequence from amino acid positions 89 to 97 of SEQ ID NO: 2; or(2) a heavy chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 31 to 35 of SEQ ID NO: 3, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 65 of SEQ ID NO: 3, and CDR3 consisting of an amino acid sequence from amino acid positions 98 to 108 of SEQ ID NO: 3, anda light chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 24 to 34 of SEQ ID NO: 4, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 56 of SEQ ID NO: 4, and CDR3 consisting of an amino acid sequence from amino acid positions 89 to 97 of SEQ ID NO: 4,LA is a linker represented by formula (LA-3) (wherein *Ab represents a site of connection to Ab):[Chemical Formula 55]b is 12,D is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (PL-1') (wherein*LA represents a site of connection to LA):[Chemical Formula 56]andm is a number of 3 to 9.

[0033] [27-2] The antibody-drug conjugate or the salt thereof according to [1], whereinAb is an anti-EGFR antibody including a heavy chain variable region and a light chain variable region described in the following (1) or (2) or an antigen binding fragment thereof:(1) a heavy chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 31 to 35 of SEQ ID NO: 1, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 65 of SEQ ID NO: 1, and CDR3 consisting of an amino acid sequence from amino acid positions 98 to 108 of SEQ ID NO: 1, anda light chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 24 to 34 of SEQ ID NO: 2, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 56 of SEQ ID NO: 2, and CDR3 consisting of an amino acid sequence from amino acid positions 89 to 97 of SEQ ID NO: 2; or(2) a heavy chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 31 to 35 of SEQ ID NO: 3, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 65 of SEQ ID NO: 3, and CDR3 consisting of an amino acid sequence from amino acid positions 98 to 108 of SEQ ID NO: 3, anda light chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 24 to 34 of SEQ ID NO: 4, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 56 of SEQ ID NO: 4, and CDR3 consisting of an amino acid sequence from amino acid positions 89 to 97 of SEQ ID NO: 4,LA is a linker represented by formula (XV) (wherein *Ab represents a site of connection to Ab):[Chemical Formula 57]Str is a stretcher unit and is connected to Ab and CLL,CLL is a partial structure cleavable in vivo,Sp is a spacer unit and is connected to CLL and D, t is 0 or 1,D is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (TP-1), (TP-2), or (TP-3):[Chemical Formula 58]A is CRA or N,RA is H or C1-3 alkyl,X1 is -CH2- or -O-,R1 is naphthyl optionally substituted by OH, or a group represented by the following formula (III):[Chemical Formula 59]R1a is H, methyl, F, or Cl,R1b is F, Cl, methyl, or ethyl,R2 is H, halogen, cyclopropyl, vinyl, or C1-3 alkyl optionally substituted by a group selected from the group consisting of OH and OCH3,R3 is a group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII):[Chemical Formula 60]R3a is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 5- or 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,R3b is H or C1-3 alkyl,each of R3c and R3d is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,on the proviso that when R3c is -(CH2)pCHR3f-NRN1RN2, X2 in formula (V) is -O-, -NH-, or -N(C2-3 alkyl)-,R3e is -O-C2-3 alkylene-NRN1RN2,R3f is H, F, or C1-3 alkyl,R3g is H or C1-3 alkyl,R3h is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms,R3i are the same or different from each other and each is a group selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, -NH-optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)2, halogen, -CN, and oxo, ortwo R3i present on the same carbon atom optionally form, together with the adjacent carbon atom, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a spiro ring as the group of formula (XIII), wherein the spiro ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two adjacent carbon atoms optionally form, together with the two carbon atoms, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a condensed ring as the group of formula (XIII), wherein the condensed ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two non-adjacent carbon atoms optionally form, together with the two carbon atoms, a bridged structure of 1 or 2 carbon atoms, wherein the group of formula (XIII) which is a ring having the bridged structure is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl, orRN1 and RN2 optionally form, together with the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, orR3f and RN1 optionally form, together with the carbon atom and the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,X2 is -O-, -NH-, or -N(C1-3 alkyl)-,X3 is O or S,X4 is -CH2-, -CH2-CH2-, or -O-CH2-,n is 1 or 2,p is 1 or 2,q is an integer of 1 to 8,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, R4a, cyclopropyl, N(R4a)2, pyrrolidinyl optionally substituted by R4a, and tetrahydrofuranyl optionally substituted by R4a; piperidinyl optionally substituted by R4b; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl optionally substituted by F,R4b is C1-3 alkyl substituted by 1 to 3 F,Y is phenylene optionally substituted by F or Cl, or pyridinediyl,LP is a group that chemically bonds Y to EUB,EUB is a group having the ability to bind to E3 ubiquitin ligase, andR8 is H or halogen.[27-3] The antibody-drug conjugate or the salt thereof according to [27-2], wherein D is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (TP-1).[27-4] The antibody-drug conjugate or the salt thereof according to [27-2], wherein D is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (TP-2).[27-5] The antibody-drug conjugate or the salt thereof according to [27-2], wherein D is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (TP-3).

[0034]

[28] A pharmaceutical composition including an antibody-drug conjugate or a salt thereof according to any of [1] to

[27] and a pharmaceutically acceptable excipient.

[29] The pharmaceutical composition according to

[28] for use in the treatment of a cancer.

[30] The pharmaceutical composition according to

[29] , wherein the cancer is blood cancer or solid cancer.

[31] The pharmaceutical composition according to

[29] , wherein the cancer is colorectal cancer, pancreatic cancer, or lung cancer.

[32] The pharmaceutical composition according to

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

[33] The pharmaceutical composition according to

[32] , wherein the mutant KRAS is G12V mutant, G12D mutant, or G12C mutant KRAS.

[0035]

[34] The antibody-drug conjugate or the salt thereof according to any of [1] to

[27] for use in the treatment of a cancer.

[35] A method for treating a cancer, including the step of administering a therapeutically effective amount of an antibody-drug conjugate or a salt thereof according to any of [1] to

[27] to a subject.

[36] Use of an antibody-drug conjugate or a salt thereof according to any of [1] to

[27] in the production of a pharmaceutical composition for the treatment of a cancer.

[0036]

[37] A drug-linker conjugate represented by formula (LD-1) or a salt thereof:[Chemical Formula 61]whereinD is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect,Rst1 is optionally substituted C1-12 alkylene, or optionally substituted C1-50 heteroalkylene,CLL is a partial structure cleavable in vivo,Sp is a spacer unit and is connected to CLL and D, t is 0 or 1, andSp is bonded to a nitrogen atom of amine or an oxygen atom of -OH contained in D to form N-Sp or O-Sp, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to Sp to form quaternary ammonium.

[0037]

[38] The drug-linker conjugate or the salt thereof according to

[37] , whereinD is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (II):[Chemical Formula 62]A is CRA or N,RA is H or C1-3 alkyl,X1 is -CH2- or -O-,R1 is naphthyl optionally substituted by OH, or a group represented by the following formula (III):[Chemical Formula 63]R1a is H, methyl, F, or Cl,R1b is F, Cl, methyl, or ethyl,R2 is H, halogen, cyclopropyl, vinyl, or C1-3 alkyl optionally substituted by a group selected from the group consisting of OH and OCH3,R3 is a group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII):[Chemical Formula 64]R3a is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 5- or 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,R3b is H or C1-3 alkyl,each of R3c and R3d is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,on the proviso that when R3c is -(CH2)pCHR3f-NRN1RN2, X2 in formula (V) is -O-, -NH-, or -N(C2-3 alkyl)-,R3e is -O-C2-3 alkylene-NRN1RN2,R3f is H, F, or C1-3 alkyl,R3g is H or C1-3 alkyl,R3h is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms,R3i are the same or different from each other and each is a group selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, -NH-optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)2, halogen, -CN, and oxo, ortwo R3i present on the same carbon atom optionally form, together with the adjacent carbon atom, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a spiro ring as the group of formula (XIII), wherein the spiro ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two adjacent carbon atoms optionally form, together with the two carbon atoms, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a condensed ring as the group of formula (XIII), wherein the condensed ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two non-adjacent carbon atoms optionally form, together with the two carbon atoms, a bridged structure of 1 or 2 carbon atoms, wherein the group of formula (XIII) which is a ring having the bridged structure is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl, orRN1 and RN2 optionally form, together with the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, orR3f and RN1 optionally form, together with the carbon atom and the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,X2 is -O-, -NH-, or -N(C1-3 alkyl)-,X3 is O or S,X4 is -CH2-, -CH2-CH2-, or -O-CH2-,n is 1 or 2,p is 1 or 2,q is an integer of 1 to 8,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, R4a, cyclopropyl, N(R4a)2, pyrrolidinyl optionally substituted by R4a, and tetrahydrofuranyl optionally substituted by R4a; piperidinyl optionally substituted by R4b; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl optionally substituted by F,R4b is C1-3 alkyl substituted by 1 to 3 F,Y is phenylene optionally substituted by F or Cl, or pyridinediyl,LP is a group that chemically bonds Y to EUB,EUB is a group having the ability to bind to E3 ubiquitin ligase,CLL is a partial structure cleavable in vivo,Sp is a spacer unit and is connected to CLL and D, t is 0 or 1,Sp is bonded to a nitrogen atom of amine or an oxygen atom of -OH contained in the group R3, R4, or EUB of D to form N-Sp or O-Sp, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to Sp to form quaternary ammonium,whereini) Rst1 is optionally substituted C1-12 alkylene, -optionally substituted C1-6 alkylene-C(=O)-NH-C1-6 alkylene-(OCH2CH2)a-, or -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-, a is an integer of 1 to 10,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-1'), *CO represents a site of connection to a carbonyl group,[Chemical Formula 65]RAA are each independently one group selected from the group consisting of H, methyl, isopropyl, benzyl, and -(CH2)3-NH-C(=O)-NH2,d is an integer of 2 to 4,Sp is a spacer unit represented by formula (SP-1), formula (SP-2), or formula (SP-3), t is 1, *CLL represents a site of connection to CLL,[Chemical Formula 66]andRSP is H,orii) Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-2'), *CO represents a site of connection to a carbonyl group,[Chemical Formula 67]andt is 0.

[0038]

[39] The drug-linker conjugate or the salt thereof according to

[38] , whereinEUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 68]R5 is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, C3-6 cycloalkylmethyl, or C3-6 cycloalkyl,R6a and R6b are the same or different from each other and each is H or C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, and N(CH3)2, orR6a and R6b optionally form, together with the carbon bonded thereto, optionally substituted C3-6 cycloalkane, or an optionally substituted 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,R7 is an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or 6-membered heteroaryl containing 1 to 3 nitrogen atoms,W is optionally substituted phenylene or optionally substituted 6-membered heteroarenediyl containing 1 to 3 nitrogen atoms as ring-constituting atom,LP is -(L1-L2-L3-L4)-,L1, L2, L3, and L4 are the same or different from each other and each is a group selected from the group consisting of a bond, -O-, -NRL1-, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3 alkylene, and C=O,RL1 is H or C1-3 alkyl, andZ is NH or 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom.

[0039]

[40] The drug-linker conjugate or the salt thereof according to

[39] , whereinA is CRA or N,RA is H,X1 is -O-,R1 is a group represented by the following formula (III-a):[Chemical Formula 69]R2 is cyclopropyl,R3 is a group selected from the group consisting of the following formula (IV), formula (V), and formula (XI):[Chemical Formula 70]R3a is -(CH2)pCHR3f-NRN1RN2,R3b is H,R3c is C3-6 cycloalkyl optionally substituted by -NRN1RN2,R3f is H,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl,X2 is -O- or -NH-,X3 is O,n is 1,p is 1,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of OCH3, N(R4a)2, and pyrrolidinyl optionally substituted by R4a; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl, andY is phenylene.

[0040]

[41] The drug-linker conjugate or the salt thereof according to

[40] , whereinEUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 71]R5 is isopropyl or tert-butyl,R6a and R6b are different from each other and each is H, or C1-6 alkyl optionally substituted by OH,R7 is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen,W is phenylene,LP is a bond,Z is 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, andSp is bonded to a nitrogen atom of amine contained in the group R3 or R4 of D, or an oxygen atom of -OH contained in EUB to form N-Sp or O-Sp, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded Sp to form quaternary ammonium.

[0041]

[42] The drug-linker conjugate or the salt thereof according to

[41] , whereinA is N,R3 is a group represented by the following formula (XI):[Chemical Formula 72]R4 is C1-6 alkyl substituted by N(R4a)2,R4a is C1-3 alkyl,R7 is a group represented by the following formula (XVI):[Chemical Formula 73]W is a group represented by the following formula (XVII-a):[Chemical Formula 74]Z is a group represented by the following formula (XVIII):[Chemical Formula 75]Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-2'), *CO represents a site of connection to a carbonyl group,[Chemical Formula 76]t is 0, andSp is bonded to a nitrogen atom of N(R4a)2 contained in the group R4 of D to form -N+(R4a)2-Sp.

[0042]

[43] The drug-linker conjugate or the salt thereof according to

[37] , wherein the drug-linker conjugate is represented by the following formula (LD-2), (LD-3), or (LD-4):[Chemical Formula 77-1][Chemical Formula 77-2][Chemical Formula 77-3]wherein b is an integer of 2 to 20.

[0043]

[44] The drug-linker conjugate or the salt thereof according to

[43] , wherein b is 12.

[0044] [44-2] A drug-linker conjugate represented by formula (LD-8) or a salt thereof:[Chemical Formula 78]whereinD is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (II):[Chemical Formula 79]A is CRA or N,RA is H or C1-3 alkyl,X1 is -CH2- or -O-,R1 is naphthyl optionally substituted by OH, or a group represented by the following formula (III):[Chemical Formula 80]R1a is H, methyl, F, or Cl,R1b is F, Cl, methyl, or ethyl,R2 is H, halogen, cyclopropyl, vinyl, or C1-3 alkyl optionally substituted by a group selected from the group consisting of OH and OCH3,R3 is a group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII):[Chemical Formula 81]R3a is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 5- or 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,R3b is H or C1-3 alkyl,each of R3c and R3d is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,on the proviso that when R3c is -(CH2)pCHR3f-NRN1RN2, X2 in formula (V) is -O-, -NH-, or -N(C2-3 alkyl)-,R3e is -O-C2-3 alkylene-NRN1RN2,R3f is H, F, or C1-3 alkyl,R3g is H or C1-3 alkyl,R3h is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms,R3i are the same or different from each other and each is a group selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, -NH-optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)2, halogen, -CN, and oxo, ortwo R3i present on the same carbon atom optionally form, together with the adjacent carbon atom, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a spiro ring as the group of formula (XIII), wherein the spiro ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two adjacent carbon atoms optionally form, together with the two carbon atoms, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a condensed ring as the group of formula (XIII), wherein the condensed ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two non-adjacent carbon atoms optionally form, together with the two carbon atoms, a bridged structure of 1 or 2 carbon atoms, wherein the group of formula (XIII) which is a ring having the bridged structure is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl, orRN1 and RN2 optionally form, together with the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, orR3f and RN1 optionally form, together with the carbon atom and the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,X2 is -O-, -NH-, or -N(C1-3 alkyl)-,X3 is O or S,X4 is -CH2-, -CH2-CH2-, or -O-CH2-,n is 1 or 2,p is 1 or 2,q is an integer of 1 to 8,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, R4a, cyclopropyl, N(R4a)2, pyrrolidinyl optionally substituted by R4a, and tetrahydrofuranyl optionally substituted by R4a; piperidinyl optionally substituted by R4b; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl optionally substituted by F,R4b is C1-3 alkyl substituted by 1 to 3 F,Y is phenylene optionally substituted by F or Cl, or pyridinediyl,LP is a group that chemically bonds Y to EUB,EUB is a group having the ability to bind to E3 ubiquitin ligase,CLL is a partial structure cleavable in vivo represented by formula (CL-3):[Chemical Formula 82](wherein*STR represents a site of connection to Str),Sp is a spacer unit represented by formula (SP-4):[Chemical Formula 83](wherein*CLL represents a site of connection to CLL) and is connected to CLL and D, t is 1, andSp is bonded to an oxygen atom of -OH contained in the group EUB of D to form O-Sp.

[0045] [44-3] The drug-linker conjugate or the salt thereof according to

[37] , whereinD is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (II):[Chemical Formula 84]A is N,X1 is -O-,R1 is a group represented by the following formula (III-a):[Chemical Formula 85]R2 is cyclopropyl,R3 is a group represented by the following formula (XI):[Chemical Formula 86]R4 is C1-6 alkyl represented by N(R4a)2,R4a is C1-3 alkyl,Y is phenylene,LP is a bond,EUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 87]R5 is isopropyl or tert-butyl,R6a and R6b are different from each other and each is H, or C1-6 alkyl optionally substituted by OH,R7 is a group represented by the following formula (XVI):[Chemical Formula 88]W is a group represented by the following formula (XVII-a):[Chemical Formula 89]andZ is a group represented by the following formula (XVIII):[Chemical Formula 90]

[0046]

[45] A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being selected from the group consisting of(4R)-1-[(2S)-2-{4-[4-({[(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide,(4R)-1-[(2S)-2-(4-{4-[({(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-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-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide,(4R)-1-[(2S)-2-{4-[4-({[(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide, and(4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-[(1-{[2-(methylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide.

[0047] [45-2] A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being selected from the group consisting of(4R)-1-[(2S)-2-{4-[4-({[4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide,(4R)-1-[(2S)-2-(4-{4-[({4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-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-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide,(4R)-1-{(2S)-2-[4-(4-{[(4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}quinazolin-8-yl)oxy]methyl}phenyl)-1H-1,2,3-triazol-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide, and(4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-[(1-{[2-(methylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide.

[0048] When a symbol in a chemical formula in the present specification is also used in another chemical formula, the same symbol represents the same meaning, unless otherwise specified. ADVANTAGEOUS EFFECTS OF INVENTION

[0049] An antibody-drug conjugate of formula (I) or a salt thereof and a heterocyclic compound of formula (II) or a salt thereof have a mutant KRAS protein degradation-inducing effect, particularly, a G12V mutant, G12D mutant, and G12C mutant KRAS protein degradation-inducing effect, and can be used as therapeutic agents for cancers, particularly, cancers expressing mutant KRAS, particularly, G12V mutant, G12D mutant, and G12C mutant KRAS. Also, the drug-linker conjugate of the present invention contains a compound having a mutant KRAS protein degradation-inducing effect, particularly, a G12V mutant, G12D mutant, and G12C mutant KRAS protein degradation-inducing effect, and can be used for synthesizing the antibody-drug conjugate of the present invention or the salt thereof. DESCRIPTION OF EMBODIMENTS

[0050] Hereinafter, the present invention will be described in detail.

[0051] In the present specification, "optionally substituted" means unsubstituted or having 1 to 5 substituents. In certain embodiments, it means unsubstituted or having 1 to 3 substituents. In the case of having a plurality of substituents, these substituents may be the same or may be different from each other.

[0052] "C1-12 alkyl" is linear or branched alkyl having 1 to 12 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or dodecyl (hereinafter, the number of carbon atoms is similarly expressed). It is ethyl or dodecyl in certain embodiments.Likewise, "C1-6 alkyl" is linear or branched alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl, is methyl, ethyl, n-propyl, isopropyl, or sec-butyl in certain embodiments, is methyl, ethyl, isopropyl, or tert-butyl in certain embodiments, and is methyl, ethyl, n-propyl, isopropyl, or n-butyl in certain embodiments.Likewise, "C1-3 alkyl" is linear or branched alkyl having 1 to 3 carbon atoms, for example, methyl, ethyl, n-propyl, or isopropyl, is methyl or ethyl in certain embodiments, is n-propyl or isopropyl in certain embodiments, is methyl or isopropyl in certain embodiments, is ethyl or isopropyl in certain embodiments, is methyl in certain embodiments, is ethyl in certain embodiments, is isopropyl in certain embodiments, and is n-propyl in certain embodiments.Likewise, "C2-3 alkyl" is linear or branched alkyl having 2 or 3 carbon atoms, for example, ethyl, n-propyl, or isopropyl, is ethyl in certain embodiments, is isopropyl in certain embodiments, and is n-propyl in certain embodiments.

[0053] "C3-6 cycloalkyl" is cycloalkyl having 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. It is cyclobutyl, cyclopentyl, or cyclohexyl in certain embodiments, is cyclobutyl or cyclopentyl in certain embodiments, is cyclopentyl or cyclohexyl in certain embodiments, is cyclopropyl or cyclobutyl in certain embodiments, is cyclopropyl in certain embodiments, is cyclobutyl in certain embodiments, is cyclopentyl in certain embodiments, and is cyclohexyl in certain embodiments.

[0054] "C1-12 alkylene" is a divalent group formed by removing a hydrogen atom from C1-12 alkyl and is linear or branched C1-12 alkylene, for example, methylene, ethylene, trimethylene, methylmethylene, methylethylene, 1,1-dimethylmethylene, or pentamethylene. It is linear or branched C1-6 alkylene in certain embodiments, is linear or branched C1-3 alkylene in certain embodiments, is methylene, ethylene, or trimethylene in certain embodiments, is methylene or ethylene in certain embodiments, is methylene in certain embodiments, and is ethylene in certain embodiments. Likewise, "C2-3 alkylene" is a divalent group formed by removing a hydrogen atom from C2-3 alkyl and is linear or branched C2-3 alkylene, for example, ethylene, trimethylene, methylmethylene, methylethylene, or 1,1-dimethylmethylene. It is ethylene or trimethylene in certain embodiments, is ethylene in certain embodiments, and is trimethylene in certain embodiments.

[0055] "Heteroalkylene" is a group in which at least one carbon atom of linear or branched alkyl is replaced with a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen. C1-50 heteroalkylene is C1-50 alkylene, at least one carbon atom of which is replaced with a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen. C1-6 heteroalkylene is C1-6 alkylene, at least one carbon atom of which is replaced with a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen.

[0056] "Saturated heterocyclic group" is a saturated hydrocarbon ring group containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom. The sulfur atom as ring-constituting atom of the saturated heterocyclic group may be oxidized.Thus, "4- to 6-membered saturated heterocyclic group" is a 4- to 6-membered saturated heterocyclic group containing heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom. "4- to 6-Membered saturated heterocyclic group" is a 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom in certain embodiments. The 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom is a 4- to 6-membered saturated heterocyclic group containing 1 heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring-constituting atom in certain embodiments, is a 5- or 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom in certain embodiments, is a 4-membered saturated heterocyclic group containing 1 heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring-constituting atom in certain embodiments, is a 5-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom in certain embodiments, is a 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom in certain embodiments, is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, oxazolidinyl, imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or dioxothiomorpholinyl in certain embodiments, is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or dioxothiomorpholinyl in certain embodiments, is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, or morpholinyl in certain embodiments, is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or piperidinyl in certain embodiments, is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl in certain embodiments, is pyrrolidinyl or piperidinyl in certain embodiments, is oxetanyl in certain embodiments, is tetrahydrofuranyl in certain embodiments, is tetrahydropyranyl in certain embodiments, is pyrrolidinyl in certain embodiments, is piperidinyl in certain embodiments, is morpholinyl in certain embodiments, and is oxazolidinyl in certain embodiments.

[0057] "Heteroaryl" is an aromatic hydrocarbon ring group containing heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom.Thus, "5-membered heteroaryl" is a 5-membered aromatic hydrocarbon ring group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom."5-Membered heteroaryl" is a 5-membered aromatic hydrocarbon ring group containing 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom in certain embodiments, is pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl in certain embodiments, is pyrazolyl, imidazolyl, triazolyl, oxazolyl, or thiazolyl in certain embodiments, is pyrazolyl, imidazolyl, oxazolyl, or thiazolyl in certain embodiments, is pyrazolyl, imidazolyl, triazolyl, or isoxazolyl in certain embodiments, is pyrazolyl, oxazolyl, or thiazolyl in certain embodiments, is pyrazolyl, triazolyl, or isoxazolyl in certain embodiments, is pyrazolyl or thiazolyl in certain embodiments, is pyrazolyl or triazolyl in certain embodiments, is pyrazolyl in certain embodiments, is imidazolyl in certain embodiments, is oxazolyl in certain embodiments, is thiazolyl in certain embodiments, and is triazolyl in certain embodiments. "5-Membered heteroarenediyl" is a divalent group obtained by removing any one hydrogen from "5-membered heteroaryl".

[0058] "6-Membered heteroaryl" is a 6-membered aromatic hydrocarbon ring group containing 1 to 3 nitrogen atoms as ring-constituting atom. "6-Membered heteroaryl" is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl in certain embodiments, is pyridyl or pyridazinyl in certain embodiments, is pyridyl or pyrimidinyl in certain embodiments, is pyridyl in certain embodiments, and is pyrimidinyl in certain embodiments. "6-Membered heteroarenediyl" is a divalent group obtained by removing any one hydrogen from "6-membered heteroaryl".

[0059] "C3-6 cycloalkane" is cycloalkane having 3 to 6 carbon atoms, for example, cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0060] "Saturated heterocyclic ring" is a saturated hydrocarbon ring containing heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom. The sulfur atom as a ring-constituting atom of the saturated heterocyclic ring may be oxidized. Thus, "4- to 6-membered saturated heterocyclic ring" is a saturated hydrocarbon ring of a 4- to 6-membered ring containing heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom. The sulfur atom as a ring-constituting atom of the saturated heterocyclic ring may be oxidized. "4- to 6-Membered saturated heterocyclic ring" is a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom in certain embodiments. "4- to 6-Membered saturated heterocyclic ring" is oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, oxazolidine, imidazolidine, piperazine, morpholine, thiomorpholine, or dioxothiomorpholine in certain embodiments.

[0061] "Spiro ring" is a polycyclic ring structure in which two ring structures are bonded by sharing one spiro atom which is quaternary carbon.

[0062] "Ring having a bridged structure" is a ring structure having a divalent chain structure linked to two non-adjacent atoms among ring-constituting atoms of one ring. "Ring having a bridged structure" is azabicyclo[3.2.1]octane, azabicyclo[3.1.1]heptane, azabicyclo[2.2.1]heptane, or azaoxabicyclo[3.2.1]octane in certain embodiments.

[0063] "Halogen" means F, Cl, Br, and I. It is F, Cl, or Br in certain embodiments, is F or Cl in certain embodiments, is F or Br in certain embodiments, is F in certain embodiments, is Cl in certain embodiments, and is Br in certain embodiments.

[0064] The substituent acceptable for "optionally substituted C1-6 alkyl" and "optionally substituted C1-3 alkyl" is F, OH, OCH3, N(CH3)2, optionally substituted C3-6 cycloalkyl, azabicyclo[3.3.0]octanyl, or an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen in certain embodiments. It is F, OH, OCH3, N(CH3)2, hydroxymethyl, methoxymethyl, difluoroethyl, optionally substituted cyclopropyl, tetrahydrofuranyl, optionally substituted tetrahydropyranyl, morpholinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, or azabicyclo[3.3.0]octanyl in certain embodiments, is F, OH, OCH3, N(CH3)2, hydroxymethyl, methoxymethyl, optionally substituted cyclopropyl, tetrahydrofuranyl, optionally substituted tetrahydropyranyl, or optionally substituted pyrrolidinyl in certain embodiments, is F, OH, OCH3, N(CH3)2, hydroxymethyl, methoxymethyl, cyclopropyl, (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyranyl, pyrrolidinyl, or methylpyrrolidinyl in certain embodiments, is F, OH, OCH3, (methoxymethyl)cyclopropyl, tetrahydrofuranyl, or methylpyrrolidinyl in certain embodiments, is F, OH, or cyclopropyl in certain embodiments, is F, OH, or OCH3 in certain embodiments, is OH or OCH3 in certain embodiments, is F or OCH3 in certain embodiments, is OH in certain embodiments, is F in certain embodiments, and is OCH3 in certain embodiments.

[0065] The substituent acceptable for "optionally substituted 5-membered heteroaryl", "optionally substituted 6-membered heteroaryl", "optionally substituted 6-membered heteroarenediyl", "optionally substituted C3-6 cycloalkyl", "optionally substituted pyrazolyl", "optionally substituted pyridyl", "optionally substituted pyrimidinyl", "optionally substituted phenylene", and "optionally substituted cyclopropyl" is C1-3 alkyl optionally substituted by a group selected from the group consisting of OH and OCH3, -SO2CH3, halogen, OH, OCH3, or C3-6 cycloalkyl in certain embodiments. It is C1-3 alkyl optionally substituted by a group selected from the group consisting of OH and OCH3 in certain embodiments, is C1-3 alkyl optionally substituted by OH in certain embodiments, is C1-3 alkyl optionally substituted by OCH3 in certain embodiments, is C1-3 alkyl or halogen in certain embodiments, is methyl, ethyl, methoxymethyl, or F in certain embodiments, and is methyl, ethyl, or F in certain embodiments.

[0066] The substituent acceptable for "optionally substituted 4- to 6-membered saturated heterocyclic group", "optionally substituted pyrrolidinyl", "optionally substituted piperidinyl", "optionally substituted oxetanyl", "optionally substituted tetrahydrofuranyl", and "optionally substituted tetrahydropyranyl" is C1-3 alkyl optionally substituted by a group selected from the group consisting of F, OH, and OCH3, F, OH, OCH3, oxo, or oxetanyl in certain embodiments. It is F, OH, or OCH3 in certain embodiments, is OH or methyl in certain embodiments, is C1-3 alkyl optionally substituted by a group selected from the group consisting of F, OH, and OCH3, F, oxo, or oxetanyl in certain embodiments, is C1-3 alkyl optionally substituted by a group selected from the group consisting of F, OH, and OCH3 or oxo in certain embodiments, is C1-3 alkyl optionally substituted by a group selected from the group consisting of F, OH, and OCH3 in certain embodiments, is C1-3 alkyl optionally substituted by F in certain embodiments, is C1-3 alkyl optionally substituted by OH in certain embodiments, is C1-3 alkyl optionally substituted by OCH3 in certain embodiments, and is C1-3 alkyl in certain embodiments.

[0067] The substituent acceptable for "optionally substituted pyrrolidinediyl", "optionally substituted piperidinediyl", "optionally substituted piperazinediyl", and "optionally substituted C1-3 alkylene" is F, OH, OCH3, or optionally substituted C1-3 alkyl in certain embodiments. It is F, OH, OCH3, methyl, ethyl, hydroxymethyl, or methoxymethyl in certain embodiments, and is F, OH, OCH3, or methyl in certain embodiments.

[0068] "C1-3 alkyl optionally substituted by F" is methyl optionally substituted by F or ethyl optionally substituted by F in certain embodiments. It is, for example, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, or trifluoroethyl. It is methyl, ethyl, monofluoromethyl, difluoromethyl, or difluoroethyl in certain embodiments, is monofluoromethyl or difluoromethyl in certain embodiments, is monofluoromethyl or difluoroethyl in certain embodiments, is difluoromethyl or difluoroethyl in certain embodiments, is monofluoromethyl in certain embodiments, is difluoromethyl in certain embodiments, is difluoroethyl in certain embodiments, and is 2,2-difluoroethyl in certain embodiments.

[0069] "C1-3 alkyl optionally substituted by OH" is methyl optionally substituted by 1 OH or ethyl optionally substituted by 1 or 2 OH in certain embodiments. It is, for example, methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, or 1,2-dihydroxyethyl. It is methyl, ethyl, or hydroxymethyl in certain embodiments, is methyl or hydroxymethyl in certain embodiments, is hydroxymethyl or hydroxyethyl in certain embodiments, is hydroxymethyl in certain embodiments, and is hydroxyethyl in certain embodiments.

[0070] "C1-3 alkyl optionally substituted by OCH3" is methyl optionally substituted by 1 OCH3, ethyl optionally substituted by 1 or 2 OCH3, or propyl optionally substituted by 1 to 3 OCH3 in certain embodiments. It is, for example, methyl, ethyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1,2-dimethoxyethyl, or 2-methoxypropyl. It is methoxymethyl or methoxyethyl in certain embodiments, is methoxymethyl in certain embodiments, is methoxyethyl in certain embodiments, and is 2-methoxypropyl in certain embodiments.

[0071] "Phenylene optionally substituted by F" is phenylene optionally substituted by 1 or 2 F in certain embodiments. It is phenylene optionally substituted by 1 F in certain embodiments, is phenylene or fluorophenylene in certain embodiments, is phenylene in certain embodiments, is 2-fluoro-1,4-phenylene in certain embodiments, and is 3-fluoro-1,4-phenylene in certain embodiments.

[0072] "Halogeno C1-6 alkyl" is C1-6 alkyl substituted by 1 or more halogen. It is C1-6 alkyl substituted by 1 or more F in certain embodiments, is C1-6 alkyl substituted by 1 to 3 F in certain embodiments, is difluoromethyl in certain embodiments, and is trifluoromethyl in certain embodiments.

[0073] "EUB" is a group having the ability to bind to E3 ubiquitin ligase. It is a group having the ability to bind to one E3 ubiquitin ligase selected from the group consisting of VHL (von Hippel-Lindau), CRBN (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 finger protein 114), FEM1B (Protein fem-1 homolog B), and AhR (Aryl hydrocarbon receptor) in certain embodiments. It is a group having the ability to bind to one E3 ubiquitin ligase selected from the group consisting of VHL, IAP, and MDM2 in certain embodiments. It is a group having the ability to bind to VHL or CRBN in certain embodiments. It is a group having the ability to bind to VHL in certain embodiments. It is a group having the ability to bind to CRBN in certain embodiments. Those skilled in the art can understand it with reference to the following documents, though not limited thereto.[Reference]Current Research in Chemical Biology., 2022, 2, 100020Front. Chem., 2021, 9, 707317J. Am. Chem. Soc., 2021, 143, 5141Signal Transduct. Target. Ther., 2020, 5, 129Nat. Chem. Biol., 2019, 15(7), 737Communications Biology., 2020, 3, 140Sci. Rep., 2020, 10(1), 15543ACS Chem. Biol., 2019, 14, 2430Cell Chem. Biol., 2021, 28(4), 559J. Am. Chem. Soc., 2022, 144, 701ACS Chem. Biol., 2019, 14, 2822

[0074] "RAS protein" refers to RAS family protein including KRAS, HRAS, and NRAS and is KRAS, HRAS, and / or NRAS in certain embodiments, and is KRAS in certain embodiments. In this context, the RAS protein includes mutant RAS protein, particularly, mutant KRAS, for example, G12V, G12D, and G12C mutant KRAS.

[0075] "Mutant KRAS" is KRAS having a mutation and refers to, for example, G12V mutant KRAS, G12D mutant KRAS, and G12C mutant KRAS. The mutant KRAS is G12V mutant KRAS, G12D mutant KRAS, and / or G12C mutant KRAS in certain embodiments, is G12V mutant KRAS in certain embodiments, is G12D mutant KRAS in certain embodiments, and is G12C mutant KRAS in certain embodiments.

[0076] "G12V mutation" refers to a mutation that converts an amino acid residue corresponding to the 12th position of the wild-type protein from glycine to valine.

[0077] "G12V mutant KRAS" refers to KRAS having "G12V mutation" described above.

[0078] "G12D mutation" refers to a mutation that converts an amino acid residue corresponding to the 12th position of the wild-type protein from glycine to aspartic acid.

[0079] "G12D mutant KRAS" refers to KRAS having "G12D mutation" described above.

[0080] "G12C mutation" refers to a mutation that converts an amino acid residue corresponding to the 12th position of the wild-type protein from glycine to cysteine.

[0081] "G12C mutant KRAS" refers to KRAS having "G12C mutation" described above.

[0082] "ZN1" is one group selected from the group consisting of the following formulas (ZN1-1) to (ZN1-15) (wherein *LGZ represents a site of connection to LGZ or LP, RZ1' are each independently optionally substituted C1-6 alkyl, halogen, cyano, -OH, -O-(optionally substituted C1-6 alkyl), -S-(optionally substituted C1-6 alkyl), -NH-(optionally substituted C1-6 alkyl), or -N-(optionally substituted C1-6 alkyl)2, n' is an integer of 0 to 2, RZ2', RZ3', and RZ4' are each independently H or optionally substituted C1-6 alkyl, and ring B1' is a benzene ring or a 6-membered hetero ring, wherein RZ1' and -*LGZ form bonds with the carbon atoms constituting ring B1'). [Chemical Formula 91]

[0083] "ZN2" is one group selected from the group consisting of the following formulas (ZN2-1) to (ZN2-15) (wherein *LGZ represents a site of connection to LGZ or LP, RZ1' are each independently optionally substituted C1-6 alkyl, halogen, cyano, -OH, -O-(optionally substituted C1-6 alkyl), -S-(optionally substituted C1-6 alkyl), -NH-(optionally substituted C1-6 alkyl), or -N-(optionally substituted C1-6 alkyl)2, n' is an integer of 0 to 2, RZ2' and RZ3' are each independently H or optionally substituted C1-6 alkyl, and ring B1' is a benzene ring or a 6-membered hetero ring, wherein RZ1' and -*LGZ form bonds with the carbon atoms constituting ring B1').[Chemical Formula 92]

[0084] "ZC" is one group selected from the group consisting of the following formulas (ZC-16) to (ZC-27) (wherein *LGZ represents a site of connection to LGZ or LP, RZ1' are each independently optionally substituted C1-6 alkyl, halogen, cyano, -OH, -O-(optionally substituted C1-6 alkyl), -S-(optionally substituted C1-6 alkyl), -NH-(optionally substituted C1-6 alkyl), or -N-(optionally substituted C1-6 alkyl)2, n' is an integer of 0 to 2, RZ2', RZ4', and RZ5' are each independently H or optionally substituted C1-6 alkyl, M' is a bond, -O-, -S-, -N(RM')-, or optionally substituted C1-3 alkylene, RM' is H or optionally substituted C1-3 alkyl, ring B1' is a benzene ring or a 6-membered hetero ring, and ring B2' is a benzene ring or a 5- or 6-membered hetero ring, wherein RZ1' and -*LGZ form bonds with the carbon atoms constituting ring B1', and M', RZ1', and -*LGZ form bonds with the carbon atoms constituting ring B2').[Chemical Formula 93]

[0085] "Antigen" is used as a term that refers to a molecule or a portion of a molecule to which an antigen binding protein such as an antibody or an antigen binding fragment is capable of specifically binding. The antigen can be a molecule such as a protein or a nucleic acid. One antigen may have one or more epitopes that can interact with different antibodies or the like.

[0086] An antibody (or immunoglobulin) is a glycoprotein having, as a basic structure, a four-chain structure of a symmetric Y-shaped structure composed of two heavy chains having a single sequence and two light chains having a single sequence. The antibody has five classes, IgG, IgM, IgA, IgD, and IgE. The heavy chain usually consists of a polypeptide chain containing approximately 440 amino acids, has a structure characteristic to each class, and is designated as Igγ, Igμ, Igα, Igδ, and Igε corresponding to IgG, IgM, IgA, IgD, and IgE, respectively. Besides, IgG has subclasses IgG1, IgG3, IgG3, and IgG4, and heavy chains corresponding to these subclasses are designated as Igγ1, Igγ2, Igγ3, and Igγ4, respectively. The light chain usually consists of a polypeptide chain containing approximately 220 amino acids, is known to have two types, λ and κ light chains, which are designated as Igλ and Igκ, respectively. The two types of light chains can pair with any type of heavy chains.

[0087] The heavy chain has four (or five in Igμ and Igε) intrachain disulfide bonds of an antibody molecule, and the light chain has two intrachain disulfide bonds, with one loop formed every 100 to 110 amino acid residues. The three-dimensional structure is similar among loops and called structural unit or domain. In both the heavy chain and the light chain, a domain positioned at the N terminus is called variable region, which is known to have diverse amino acid sequences even among antibodies produced from the same class (or subclass) of animals of the same species, and to participate in the binding specificity of the antibody for an antigen. The amino acid sequence of a domain on the C-terminal side downstream from the variable region is substantially constant in each class or subclass, and this domain is called constant region. The heavy chain has, from the N terminus toward the C terminus, a heavy chain variable region (VH) and a heavy chain constant region (CH). CH is further divided into three domains, CH1 domain, CH2 domain, and CH3 domain in the presented order from the N-terminal side. The light chain has, from the N terminus toward the C terminus, a light chain variable region (VL) and a light chain constant region (CL).

[0088] Three complementarity determining regions (CDRs) present in each of VH and VL vary very largely in amino acid sequence, and contribute to the variability of the variable regions. CDRs are regions of approximately 5 to 10 amino acid residues present at the N terminus of each of the heavy chain and the light chain in the order of CDR1, CDR2, and CDR3, and form an antigen binding site. On the other hand, moieties except for CDRs in the variable region are called framework regions (FRs), which consist of FR1 to FR4 and vary relatively small in amino acid sequence.

[0089] The treatment of the antibody with a proteolytic enzyme papain produces three antibody fragments. Two fragments on the N-terminal side are designated as Fab (fragment, antigen binding) regions, and a fragment on the C-terminal side is designated as an Fc (fragment, crystallizable) region.

[0090] In the present specification, "antibody" is a polypeptide that specifically binds to an antigen and may have any structure as long as being capable of specifically binding to an antigen. The antibody includes, for example, a polypeptide having a four-chain structure as a basic structure, such as IgG, as well as polypeptides in various shapes such as an antigen binding fragment and a multispecific antibody (e.g., a bispecific antibody) mentioned later.

[0091] "Antigen binding fragment" is a molecule containing at least one polypeptide chain having antigen binding activity derived from an antibody. Representative examples of the antigen binding fragment include a single-chain variable region fragment (scFv), a Fab fragment, a Fab' fragment, and a F(ab')2 fragment. scFv is a monovalent antigen binding fragment constituted by VH and VL linked through a linker. The Fab fragment is a monovalent antigen binding fragment constituted by a fragment containing a light chain and the VH and CH1 domains of a heavy chain. The Fab' fragment is a monovalent antigen binding fragment constituted by a fragment containing a light chain, the VH and CH1 domains of a heavy chain, and a portion of a hinge region, and this moiety of the hinge region contains a cysteine residue constituting the S-S bond between the heavy chains. The F(ab')2 fragment is a bivalent molecule of Fab' fragments linked through a disulfide bond. Monovalence means that one antigen binding site is included, and bivalence means that two antigen binding sites are included.

[0092] "Polypeptide" means a plurality of amino acids linked through peptide bonds. The amino acids for use in the polypeptide may be natural amino acids or artificial amino acids. The number of amino acid residues contained in the polypeptide can be 2 or more and is preferably 10 or more.

[0093] "Multispecific antibody" is an antibody that can specifically bind to two or more different antigens or two or more different epitopes on one antigen, and is called bispecific antibody or trispecific antibody, for example, depending on the number of antigens to be bound. The multispecific antibody contains a complex of two or more antibodies and / or antigen binding fragments that can bind to different antigens. "Antibody" used in the present specification includes the multispecific antibody, unless otherwise specified in the context.

[0094] "Human antibody" refers to an antibody having a human immunoglobulin amino acid sequence. In the present specification, "humanized antibody" refers to an antibody in which a portion of, most of, or all of amino acid residues excluding CDRs are replaced with amino acid residues derived from a human immunoglobulin molecule. A humanization method is not particularly limited, and the humanized antibody can be prepared with reference to, for example, U.S. Patent Nos. 5225539 and 6180370.

[0095] "Post-translational modification" means that an antibody expressed in a cell is modified after translation. Examples of the post-translational modification include N-linked or O-linked glycosylation, N-terminal or C-terminal processing, deamidation, isomerization of aspartic acid, and oxidation of methionine. Such post-translational modification is known to occur in various antibodies (J. Pharma. Sci., 2008; Vol. 97: p. 2426-2447).

[0096] An amino acid residue number of the antibody used in the present specification can be prescribed by specifying Kabat numbering or EU index (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed., 1991, NIH Publication No. 91-3242) in accordance with these numbering systems.

[0097] "Identity" means a value of identity obtained using EMBOSS Needle (Nucleic Acids Res., 2015; Vol. 43, p. W580-W584) with parameters provided as default. The parameters described above are as follows.Gap Open Penalty = 10 Gap Extend Penalty = 0.5Matrix = EBLOSUM62 End Gap Penalty = false

[0098] In the present specification, the antibody and the antigen binding fragment are also collectively referred to as "Ab".

[0099] "Antibody-drug conjugate" is a conjugate of an antibody and a drug connected via a linker. It can transport the drug to cells or tissues targeted by the antibody. The antibody-drug conjugate is a conjugate of the antibody and the drug connected via a linker cleavable in vivoin certain embodiments. The antibody-drug conjugate is a conjugate of the antibody and the drug connected via a non-cleavable linker in certain embodiments.

[0100] "Compound-to-antibody ratio" refers to an average number of compounds conjugated per antibody in the antibody-drug conjugate. The compound-to-antibody ratio can be measured and calculated by an approach known in the art such as hydrophobic interaction HPLC or LC-MS.

[0101] "Linker" is a divalent chemical group that connects a functional compound to another functional compound.

[0102] "Linker cleavable in vivo" is a linker having a partial structure cleavable in vivo. "Partial structure cleavable in vivo" is a partial structure that can be cleaved by the action of an enzyme or the like in vivo. Examples of the enzyme that cleaves the partial structure cleavable in vivoinclude protease, glycosidase, esterase, and phosphatase. Examples of the protease include, but are not limited to, cathepsin B, cathepsin S, plasmin, and legumain. Examples of the glycosidase include, but are not limited to, β-glucuronidase and β-galactosidase. Examples of the esterase include, but are not limited to, carboxyesterase.

[0103] "Non-cleavable linker" means a linker that is degraded neither under intralysosomal acidic conditions nor by any action of glycosidase or protease in vivo. It is, for example, C=O, C1-6 alkylene, C(=O)NH-C1-6 alkylene, or polyethylene glycol.

[0104] "Subject" means a human or other animals in need of prevention or treatment. It is a human in need of treatment or prevention in certain embodiments.

[0105] Embodiments of the antibody-drug conjugate of the present invention or the salt thereof, and drug (D), linker (LA), and antibody (Ab) constituting the antibody-drug conjugate or the salt thereof will be shown below. One or two or more embodiments can be combined with other embodiments unless a specific combination is described. In short, all embodiments can be freely combined.

[0106] 1. Drug (D)Drug (D) constituting the antibody-drug conjugate of the present invention or the salt thereof is a heterocyclic compound having a RAS protein degradation-inducing effect, particularly, a mutant KRAS protein degradation-inducing effect, particularly, a G12V mutant, G12D mutant, and G12C mutant KRAS protein degradation-inducing effect. Some or all of linkers (LA) constituting the antibody-drug conjugate of the present invention or the salt thereof are cleaved in tumor cells so that drugs (D) are liberated to exert an effect. Certain embodiments of drug (D) according to the present invention will be shown below.

[0107] (1-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof.(1-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II):[Chemical Formula 94](1-3) A heterocyclic compound having a RAS protein degradation-inducing effect or a salt thereof.

[0108] (2-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein A is CRA or N, and RA is H or C1-3 alkyl.(2-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein A is CRA or N, and RA is H.(2-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein A is N.(2-4) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein A is CH.

[0109] (3-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein X1 is -CH2- or -O-.(3-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein X1 is -O-.

[0110] (4-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinR1 is naphthyl optionally substituted by 1 or 2 groups selected from the group consisting of cyano, OH, halogen, and optionally substituted C1-3 alkyl, or is one group selected from the group consisting of the following formula (III), formula (III-b), and formula (III-c):[Chemical Formula 95]andR1a, R1b, and R1c are each independently H, vinyl, halogen, or optionally substituted C1-3 alkyl.(4-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinR1 is naphthyl optionally substituted by OH, or a group represented by the following formula (III):[Chemical Formula 96]R1a is H, methyl, F, or Cl, andR1b is F, Cl, methyl, or ethyl.(4-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinR1 is a group represented by formula (III):[Chemical Formula 97]R1a is H, methyl, F, or Cl, andR1b is F, Cl, methyl, or ethyl.(4-4) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinR1 is a group represented by formula (III):[Chemical Formula 98]R1a is H, methyl, F, or Cl,R1b is methyl.(4-5) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R1 is a group represented by the following formula (III-a):[Chemical Formula 99]

[0111] (5-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R2 is H, halogen, cyclopropyl, vinyl, or C1-3 alkyl optionally substituted by a group selected from the group consisting of OH and OCH3.(5-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R2 is halogen, cyclopropyl, vinyl, or C1-3 alkyl optionally substituted by a group selected from the group consisting of OH and OCH3.(5-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R2 is halogen, C1-3 alkyl, cyclopropyl, or vinyl.(5-4) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R2 is cyclopropyl.

[0112] (6-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3 is a group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII):[Chemical Formula 100](6-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3 is a group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), and formula (XII):[Chemical Formula 101](6-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3 is a group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (IX-a), and formula (XI):[Chemical Formula 102](6-4) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3 is a group selected from the group consisting of the following formula (IV-a), formula (V-a), formula (VI-a), formula (IX-a), and formula (XI):[Chemical Formula 103](6-5) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3 is a group selected from the group consisting of the following formula (IV-a), formula (V-a), and formula (VI-a):[Chemical Formula 104](6-6) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3 is a group selected from the group consisting of the following formula (IV-a), formula (V-a), and formula (XI):[Chemical Formula 105](6-7) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3 is a group selected from the group consisting of the following formula (IV-a) and formula (V-a):[Chemical Formula 106](6-8) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3 is a group selected from the group consisting of the following formula (IV-a) and formula (XI):[Chemical Formula 107](6-9) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3 is a group represented by the following formula (XI):[Chemical Formula 108](6-10) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3 is a group selected from the group consisting of the following formula (IV), formula (V), and formula (XI):[Chemical Formula 109](6-11) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3 is a group represented by the following formula (IV-a):[Chemical Formula 110]

[0113] (7-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3a is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 5- or 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2.(7-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3a is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; pyrrolidinyl optionally substituted by C1-3 alkyl; piperidinyl optionally substituted by C1-3 alkyl; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2.(7-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3a is -(CH2)pCHR3f-NRN1RN2 or -(CH2)pCHR3f-OR3g.(7-4) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3a is -(CH2)pCHR3f-NRN1RN2.

[0114] (8-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3b is H or C1-3 alkyl.(8-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3b is H or methyl.(8-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3b is H.

[0115] (9-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein each of R3c and R3d is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2, on the proviso that when R3c is -(CH2)pCHR3f-NRN1RN2, X2 in formula (V) is -O-, -NH-, or -N(C2-3 alkyl)-.(9-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3c is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; pyrrolidinyl optionally substituted by C1-3 alkyl; piperidinyl optionally substituted by C1-3 alkyl; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2, on the proviso that when R3c is -(CH2)pCHR3f-NRN1RN2, X2 in formula (V-a) is -O- or -NH-.(9-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3c is -(CH2)pCHR3f-NRN1RN2; pyrrolidinyl optionally substituted by C1-3 alkyl; or C3-6 cycloalkyl optionally substituted by -NRN1RN2, and X2 in formula (V-a) is -O- or -NH-.(9-4) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3c is C3-6 cycloalkyl optionally substituted by -NRN1RN2.(9-5) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3d is -(CH2)pCHR3f-NRN1RN2 or a 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-NRN1RN2, and -NRN1RN2.

[0116] (10-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3e is -O-C2-3 alkylene-NRN1RN2.

[0117] (11-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3f is H, F, or C1-3 alkyl.(11-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3f is H or C1-3 alkyl.(11-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3f is H.

[0118] (12-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3g is H or C1-3 alkyl.(12-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3g is H.

[0119] (13-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3h is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms.(13-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R3h is optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms.

[0120] (14-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinR3i are the same or different from each other and each is a group selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, -NH-optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)2, halogen, -CN, and oxo, ortwo R3i present on the same carbon atom optionally form, together with the adjacent carbon atom, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a spiro ring as the group of formula (XIII), wherein the spiro ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two adjacent carbon atoms optionally form, together with the two carbon atoms, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a condensed ring as the group of formula (XIII), wherein the condensed ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two non-adjacent carbon atoms optionally form, together with the two carbon atoms, a bridged structure of 1 or 2 carbon atoms, wherein the group of formula (XIII) which is a ring having the bridged structure is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo.

[0121] (15-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or salt thereof, the heterocyclic compound being represented by formula (II), whereinRN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl, orRN1 and RN2 optionally form, together with the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, orR3f and RN1 optionally form, together with the carbon atom and the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom.(15-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinRN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl, orRN1 and RN2 optionally form, together with the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom.(15-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl.(15-4) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein RN1 and RN2 are the same or different from each other and both are C1-3 alkyl.(15-5) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein RN1 is C1-3 alkyl, and RN2 is H.

[0122] (16-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein X2 is -O-, -NH-, or -N(C1-3 alkyl)-.(16-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein X2 is -O- or -NH-, or -N(CH3)-.(16-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein X2 is -O- or -NH-.(16-4) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein X2 is -NH-.(16-5) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein X2 is -O-.

[0123] (17-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein X3 is O or S.(17-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein X3 is O.

[0124] (18-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein X4 is -CH2-, -CH2-CH2-, or -O-CH2-.

[0125] (19-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein n is 1 or 2.(19-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein n is 1.(19-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein n is 2.

[0126] (20-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein p is 1 or 2.(20-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein p is 1.(20-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein p is 2.

[0127] (21-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein q is an integer of 1 to 8.

[0128] (22-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinR4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3,R4a, cyclopropyl, N(R4a)2, pyrrolidinyl optionally substituted by R4a, and tetrahydrofuranyl optionally substituted by R4a; piperidinyl optionally substituted by R4b; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl optionally substituted by F, andR4b is C1-3 alkyl substituted by 1 to 3 F.(22-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinR4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3,R4a, cyclopropyl, N(R4a)2, pyrrolidinyl optionally substituted by R4a, and tetrahydrofuranyl; piperidinyl optionally substituted by R4b; or tetrahydropyranyl,R4a is C1-3 alkyl, andR4b is C1-3 alkyl substituted by 1 to 3 F.(22-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinR4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of OCH3,R4a, N(R4a)2, pyrrolidinyl optionally substituted by R4a, and tetrahydrofuranyl; piperidinyl optionally substituted by R4b; or tetrahydropyranyl,R4a is C1-3 alkyl, andR4b is C1-3 alkyl substituted by 1 to 3 F.(22-4) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of OCH3 and tetrahydrofuranyl; or tetrahydropyranyl.(22-5) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R4 is C1-6 alkyl optionally substituted by OCH3, or tetrahydropyranyl.(22-6) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R4 is C1-6 alkyl optionally substituted by OCH3.(22-7) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of OCH3, N(R4a)2, and pyrrolidinyl optionally substituted by R4a; or tetrahydropyranyl optionally substituted by R4a, and R4a is C1-3 alkyl.(22-8) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of N(R4a)2, and pyrrolidinyl optionally substituted by R4a, and R4a is C1-3 alkyl.(22-9) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R4 is C1-6 alkyl substituted by N(R4a)2, and R4a is C1-3 alkyl.

[0129] (23-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein EUB is a group having the ability to bind to E3 ubiquitin ligase.(23-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein EUB is a group having the ability to bind to VHL.(23-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein EUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 111]whereinR5 is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, C3-6 cycloalkylmethyl, or C3-6 cycloalkyl,R6a and R6b are the same or different from each other and each is H or C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, and N(CH3)2, orR6a and R6b optionally form, together with the carbon bonded thereto, optionally substituted C3-6 cycloalkane, or an optionally substituted 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,R7 is an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or 6-membered heteroaryl containing 1 to 3 nitrogen atoms,W is optionally substituted phenylene or optionally substituted 6-membered heteroarenediyl containing 1 to 3 nitrogen atoms as ring-constituting atom, andZ is NH or 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom.(23-4) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein EUB is a group having the ability to bind to CRBN.(23-5) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein EUB is a group having the ability to bind to VHL or CRBN.(23-6) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinEUB is a group having the ability to bind to CRBN, wherein the group having the ability to bind to CRBN is a group represented by the following formula (E-1):[Chemical Formula 112]G is CRG or N,RG is H or C1-6 alkyl,ZAr is one group selected from the group consisting of the following formulas (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), whereinring B1 and ring B2 in formulas (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) form a bond with LP,on the proviso that when G is N, ZAr is one group selected from the group consisting of formulas (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):[Chemical Formula 113-1][Chemical Formula 113-2]RZ1 are each independently optionally substituted C1-6 alkyl, halogen, cyano, -OH, -O-(optionally substituted C1-6 alkyl), -S-(optionally substituted C1-6 alkyl), -NH-(optionally substituted C1-6 alkyl), or -N-(optionally substituted C1-6 alkyl)2,p' is an integer of 0 to 2,RZ2, RZ3, RZ4, and RZ5 are each independently H or optionally substituted C1-6 alkyl,M is a bond, -O-, -S-, -N(RM)-, or optionally substituted C1-3 alkylene,RM is H or optionally substituted C1-3 alkyl,ring B1 is a benzene ring or a 6-membered hetero ring, whereinRZ1 and LP form bonds with the carbon atoms constituting ring B1, andring B2 is a benzene ring or a 5- or 6-membered hetero ring, whereinM, RZ1, and LP form bonds with the carbon atoms constituting ring B2.(23-7) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinEUB is a group having the ability to bind to CRBN, wherein the group having the ability to bind to CRBN is a group represented by the following formula (E-1):[Chemical Formula 114]G is CH or N, andZAr is one group selected from the group consisting of the following formulas (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):[Chemical Formula 115]whereinthe benzene ring or the 6-membered hetero ring in formulas (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 LP, and the benzene ring in (Z-24A) forms a bond with LP,on the proviso that when G is N, ZAr 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).(23-8) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinEUB is a group having the ability to bind to CRBN, wherein the group having the ability to bind to CRBN is a group represented by the following formula (E-1):[Chemical Formula 116-1]G is CH or N, andZAr is one group selected from the group consisting of the following formulas (Z-1A) and (Z-16A):[Chemical Formula 116-2]whereinthe benzene ring in formulas (Z-1A) and (Z-16A) form a bond with LP.(23-9) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein EUB is a group having the ability to bind to one E3 ubiquitin ligase selected from the group consisting of VHL, CRBN, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR.

[0130] (24-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R5 is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, C3-6 cycloalkylmethyl, or C3-6 cycloalkyl.(24-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R5 is ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, or C3-6 cycloalkyl.(24-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R5 is isopropyl or sec-butyl.(24-4) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R5 is isopropyl or tert-butyl.(24-5) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R5 is isopropyl.

[0131] (25-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinR6a and R6b are the same or different from each other and each is H or C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, and N(CH3)2, orR6a and R6b optionally form, together with the carbon bonded thereto, optionally substituted C3-6 cycloalkane, or an optionally substituted 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom.(25-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinR6a and R6b are the same or different from each other and each is H or C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, and N(CH3)2, orR6a and R6b optionally form, together with the carbon bonded thereto, optionally substituted C3-6 cycloalkane, or an optionally substituted 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom.(25-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinR6a and R6b are the same or different from each other and each is H or C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, and N(CH3)2, orR6a and R6b optionally form, together with the carbon bonded thereto, optionally substituted C3-6 cycloalkane.(25-4) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R6a and R6b are different from each other and each is H or C1-6 alkyl optionally substituted by OH.(25-5) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R6a is H, and R6b is C1-6 alkyl optionally substituted by OH.(25-6) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R6a is H, and R6b is hydroxymethyl.

[0132] (26-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R7 is an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or 6-membered heteroaryl containing 1 to 3 nitrogen atoms.(26-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R7 is a group selected from the group consisting of the following formula (XIX), formula (XX), formula (XXI), formula (XXII), formula (XXIII), formula (XXIV), formula (XXV), formula (XXVI), formula (XXVII), formula (XXVIII), and formula (XXIX):[Chemical Formula 117]R7a and R7b are the same or different from each other and each is H or C1-3 alkyl optionally substituted by OH.(26-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R7 is a group selected from the group consisting of the following formula (XIX), formula (XX), formula (XXII), formula (XXIV), and formula (XXIX):[Chemical Formula 118]R7a and R7b are the same or different from each other and each is H or C1-3 alkyl optionally substituted by OH.(26-4) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R7 is a group selected from the group consisting of formula (XIX), formula (XX), formula (XXII), formula (XXIV), and formula (XXIX):[Chemical Formula 119]R7a and R7b are the same or different from each other and each is H or C1-3 alkyl.(26-5) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R7 is a group selected from the group consisting of the following formula (XIX), formula (XX), and formula (XXIV):[Chemical Formula 120]R7a and R7b are the same or different from each other and each is H or C1-3 alkyl.(26-6) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R7 is a group selected from the group consisting of the following formula (XIX-a), formula (XX-a), and formula (XVI):[Chemical Formula 121](26-7) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R7 is a group represented by the following formula (XIX-a):[Chemical Formula 122](26-8) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R7 is a group represented by the following formula (XVI):[Chemical Formula 123](26-9) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R7 is a group represented by the following formula (XX-a):[Chemical Formula 124](26-10) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R7 is a group selected from the group consisting of the following formula (XIX-a) and formula (XVI):[Chemical Formula 125](26-11) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein R7 is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen.

[0133] (27-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein W is optionally substituted phenylene or optionally substituted 6-membered heteroarenediyl containing 1 to 3 nitrogen atoms as ring-constituting atom.(27-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinW is a group represented by the following formula (XVII):[Chemical Formula 126]W1 is CH, CF, CCl, or CCH3, andW2 is CH, CF, CCl, CCH3, or N.(27-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein W is a group represented by formula (XVII), W1 is CH, and W2 is CH or N.(27-4) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein W is phenylene.(27-5) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein W is a group represented by formula (XVII-a):[Chemical Formula 127]

[0134] (28-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein Y is phenylene optionally substituted by F or Cl, or pyridinediyl.(28-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein Y is phenylene optionally substituted by F or Cl.(28-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein Y is phenylene.

[0135] (29-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein LP is a group that chemically bonds Y to EUB.(29-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinLP is -(L1-L2-L3-L4)-,L1, L2, L3, and L4 are the same or different from each other and each is a group selected from the group consisting of a bond, -O-, -NRL1-, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3 alkylene, and C=O, andRL1 is H or C1-3 alkyl.(29-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinLP is a bond, C1-3 alkylene, C=O, or a group selected from the group consisting of the following formula (XXXI), formula (XXXII), formula (XXXIII), formula (XXXIV), formula (XXXV), and formula (XXXVI):[Chemical Formula 128]RL1 is H or C1-3 alkyl,RL2 and RL3 are the same or different from each other and each is H, F, OH, OCH3, or optionally substituted C1-3 alkyl,RL is CH or N, andm2 is 1 or 2.(29-4) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinLP is a bond, C=O, or a group selected from the group consisting of the following formula (XXXI) and formula (XXXII);[Chemical Formula 129]RL1 is H or C1-3 alkyl,RL2 and RL3 are the same or different from each other and each is H, F, OH, OCH3, or optionally substituted C1-3 alkyl, andm2 is 1 or 2.(29-5) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinLP is a bond, C=O, or a group selected from the group consisting of formula (XXXI) and formula (XXXII):[Chemical Formula 130]RL1 is C1-3 alkyl,both RL2 and RL3 are H, andm2 is 1.(29-6) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein LP is a bond, or C=O.(29-7) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein LP is a bond.(29-8) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein LP is C=O.(29-9) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinLP is -(L5-L6-L7-L8)-,L5, L6, L7, and L8 are each independently one group selected from the group consisting of a bond, C=O, -O-, -S-, -SO2-, -NRL-, acetylene-1,2-diyl, optionally substituted hetero cycloalkylene, optionally substituted heteroarylene, 7- to 9-membered saturated spiro hetero cycloalkylene containing 1 or 2 nitrogen atoms, 7- to 9-membered saturated bridged hetero cycloalkylene containing 2 nitrogen atoms, and optionally substituted C1-6 alkylene, andRL is H or C1-6 alkyl.(29-10) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinLP is -(L5-L6-L7-L8)-,L5 is C=O,L6 is piperidinediyl optionally substituted by C1-3 alkyl, piperazinediyl optionally substituted by C1-3 alkyl, pyrrolidinediyl optionally substituted by C1-3 alkyl, bridged piperazinediyl, or 2,6-diazaspiro[3.4]octanediyl,L7 is a bond, -N(RL7)-, C1-3 alkylene, or piperazinediyl,L8 is a bond, -N(RL8)-, -O-, piperazinediyl, or C1-3 alkylene,RL7 is H or C1-3 alkyl, andRL8 is H or C1-3 alkyl.(29-11) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), whereinLP is one group selected from the group consisting of the following formulas (L-1), (L-2), (L-3), (L-4), (L-5), (L-6), and (L-7), whereinC=O in formulas (L-1), (L-2), (L-3), (L-4), (L-5), (L-6), and (L-7) forms a bond with Y,[Chemical Formula 131]L' is -O-, -(C1-3 alkylene)-NH-, -N(CH3)(C1-3 alkylene)-, piperazinediyl, or -(C1-3 alkylene)-piperazinediyl,L'' is a bond, C1-3 alkylene, or -(C1-3 alkylene)-O-, andRL6 is H or C1-3 alkyl.(29-12) A heterocyclic compound represented by formula (II) or a salt thereof, whereinLP is one group selected from the group consisting of the following formulas (L-1), (L-2), (L-3), (L-4), (L-5), and (L-7), whereinC=O in formulas (L-1), (L-2), (L-3), (L-4), (L-5), and (L-7) forms a bond with Y,[Chemical Formula 132]L' is -O-, -(C1-3 alkylene)-NH-, -N(CH3)(C1-3 alkylene)-, piperazinediyl, or -(C1-3 alkylene)-piperazinediyl,L'' is a bond, C1-3 alkylene, or -(C1-3 alkylene)-O-, andRL6 is H or C1-3 alkyl.(29-13) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein LP is the following formula (L-5A) or (L-7A), wherein C=O in formula (L-5A) and (L-7A) forms a bond with Y,[Chemical Formula 133](29-14) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein LP is formula (L-5A), wherein C=O in formula (L-5A) forms a bond with Y,[Chemical Formula 134]

[0136] (30-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein Z is NH or 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom.(30-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein Z is NH or a group selected from the group consisting of the following formula (XXXVII), formula (XVIII), formula (XXXIX), and formula (XXXX):[Chemical Formula 135](30-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein Z is NH or a group selected from the group consisting of the following formula (XXXVII-a), formula (XVIII-a), formula (XXXIX-a), and formula (XXXX-a):[Chemical Formula 136]wherein * represents a site of connection to LP.(30-4) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein Z is a group selected from the group consisting of formula (XXXVII), formula (XVIII), formula (XXXIX), and formula (XXXX):[Chemical Formula 137](30-5) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein Z is a group selected from the group consisting of formula (XXXVII-a), formula (XVIII-a), formula (XXXIX-a), and formula (XXXX-a):[Chemical Formula 138](30-6) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein Z is a group represented by the following formula (XVIII):[Chemical Formula 139](30-7) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein Z is a group represented by the following formula (XVIII-a):[Chemical Formula 140]wherein * represents a site of connection to LP.(30-8) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein Z is NH.(30-9) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein Z is 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom.

[0137] (31) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being represented by formula (II), wherein two or more of the embodiments described in (1-1) to (30-9) above are combined without contradicting each other. Examples thereof include, but are not limited to, the following heterocyclic compounds having a mutant KRAS protein degradation-inducing effect or salts thereof.

[0138] (31-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (II):[Chemical Formula 141]whereinA is CRA or N,RA is H or C1-3 alkyl,X1 is -CH2- or -O-,R1 is naphthyl optionally substituted by OH, or a group represented by the following formula (III):[Chemical Formula 142]R1a is H, methyl, F, or Cl,R1b is F, Cl, methyl, or ethyl,R2 is H, halogen, cyclopropyl, vinyl, or C1-3 alkyl optionally substituted by a group selected from the group consisting of OH and OCH3,R3 is a group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII):[Chemical Formula 143]R3a is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 5- or 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,R3b is H or C1-3 alkyl,each of R3c and R3d is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,on the proviso that when R3c is -(CH2)pCHR3f-NRN1RN2, X2 in formula (V) is -O-, -NH-, or -N(C2-3 alkyl)-,R3e is -O-C2-3 alkylene-NRN1RN2,R3f is H, F, or C1-3 alkyl,R3g is H or C1-3 alkyl,R3h is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms,R3i are the same or different from each other and each is a group selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, -NH-optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)2, halogen, -CN, and oxo, ortwo R3i present on the same carbon atom optionally form, together with the adjacent carbon atom, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a spiro ring as the group of formula (XIII), wherein the spiro ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two adjacent carbon atoms optionally form, together with the two carbon atoms, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a condensed ring as the group of formula (XIII), wherein the condensed ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two non-adjacent carbon atoms optionally form, together with the two carbon atoms, a bridged structure of 1 or 2 carbon atoms, wherein the group of formula (XIII) which is a ring having the bridged structure is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl, orRN1 and RN2 optionally form, together with the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, orR3f and RN1 optionally form, together with the carbon atom and the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,X2 is -O-, -NH-, or -N(C1-3 alkyl)-,X3 is O or S,X4 is -CH2-, -CH2-CH2-, or -O-CH2-,n is 1 or 2,p is 1 or 2,q is an integer of 1 to 8,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, R4a, cyclopropyl, N(R4a)2, pyrrolidinyl optionally substituted by R4a, and tetrahydrofuranyl optionally substituted by R4a; piperidinyl optionally substituted by R4b; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl optionally substituted by F,R4b is C1-3 alkyl substituted by 1 to 3 F,Y is phenylene optionally substituted by F or Cl, or pyridinediyl,LP is a group that chemically bonds Y to EUB,EUB is a group having the ability to bind to E3 ubiquitin ligase.

[0139] (31-2) The antibody-drug conjugate or the salt thereof according to (31-2), whereinA is CRA or N,RA is H,X1 is -O-,R1 is a group represented by the following formula (III-a):[Chemical Formula 144]R2 is cyclopropyl,R3 is a group selected from the group consisting of the following formula (IV), formula (V), and formula (XI):[Chemical Formula 145]R3a is -(CH2)pCHR3f-NRN1RN2,R3b is H,R3c is C3-6 cycloalkyl optionally substituted by -NRN1RN2, R3f is H,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl,X2 is -O- or -NH-,X3 is O,n is 1,p is 1,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of OCH3, N(R4a)2, and pyrrolidinyl optionally substituted by R4a; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl, andY is phenylene.

[0140] (31-3) The antibody-drug conjugate or the salt thereof according to (31-2), whereinA is N,R3 is a group represented by the following formula (XI):[Chemical Formula 146]R4 is C1-6 alkyl substituted by N(R4a)2, andR4a is C1-3 alkyl.

[0141] (31-4) The antibody-drug conjugate or the salt thereof according to (31-1), wherein EUB is a group having the ability to bind to VHL.

[0142] (31-5) The antibody-drug conjugate or the salt thereof according to (31-4), whereinEUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 147]R5 is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, C3-6 cycloalkylmethyl, or C3-6 cycloalkyl,R6a and R6b are the same or different from each other and each is H or C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, and N(CH3)2, orR6a and R6b optionally form, together with the carbon bonded thereto, optionally substituted C3-6 cycloalkane, or an optionally substituted 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,R7 is an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or 6-membered heteroaryl containing 1 to 3 nitrogen atoms,W is optionally substituted phenylene or optionally substituted 6-membered heteroarenediyl containing 1 to 3 nitrogen atoms as ring-constituting atom,LP is -(L1-L2-L3-L4)-,L1, L2, L3, and L4 are the same or different from each other and each is a group selected from the group consisting of a bond, -O-, -NRL1-, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3 alkylene, and C=O,RL1 is H or C1-3 alkyl, andZ is NH or 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom.

[0143] (31-6) The antibody-drug conjugate or the salt thereof according to (31-5), whereinEUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 148]R5 is isopropyl or tert-butyl,R6a and R6b are different from each other and each is H, or C1-6 alkyl optionally substituted by OH,R7 is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen,W is phenylene,LP is a bond, andZ is 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom.

[0144] (31-7) The antibody-drug conjugate or the salt thereof according to (31-6), whereinR7 is a group represented by the following formula (XVI):[Chemical Formula 149]W is a group represented by the following formula (XVII-a):[Chemical Formula 150]andZ is a group represented by the following formula (XVIII):[Chemical Formula 151]

[0145] (31-8) The heterocyclic compound having a mutant KRAS protein degradation-inducing effect or the salt thereof according to (31-1), the heterocyclic compound being represented by formula (II), whereinA is CRA or N,RA is H,X1 is -O-,R1 is a group represented by the following formula (III-a):[Chemical Formula 152]R2 is cyclopropyl,R3 is a group selected from the group consisting of the following formula (IV), formula (V), and formula (XI):[Chemical Formula 153]R3a is -(CH2)pCHR3f-NRN1RN2,R3b is H,R3c is C3-6 cycloalkyl optionally substituted by -NRN1RN2,R3f is H,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl,X2 is -O- or -NH-,X3 is O,n is 1,p is 1,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of OCH3, N(R4a)2, and pyrrolidinyl optionally substituted by R4a; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl,Y is phenylene,EUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 154]R5 is isopropyl or tert-butyl,R6a and R6b are different from each other and each is H, or C1-6 alkyl optionally substituted by OH,R7 is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen,W is phenylene,LP is a bond, andZ is 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom.

[0146] (31-9) The heterocyclic compound having a mutant KRAS protein degradation-inducing effect or the salt thereof according to (31-8), the heterocyclic compound being represented by formula (II), whereinA is N,R3 is a group represented by the following formula (XI):[Chemical Formula 155]R4 is C1-6 alkyl substituted by N(R4a)2,R4a is C1-3 alkyl,R7 is a group represented by the following formula (XVI):[Chemical Formula 156]W is a group represented by the following formula (XVII-a):[Chemical Formula 157]andZ is a group represented by the following formula (XVIII):[Chemical Formula 158]

[0147] (31-10) The heterocyclic compound having a mutant KRAS protein degradation-inducing effect or the salt thereof according to (31-1), the heterocyclic compound being represented by formula (II), whereinA is CRA or N,RA is H,X1 is -O-,R1 is a group represented by the following formula (III-a):[Chemical Formula 159]R2 is cyclopropyl,R3 is a group selected from the group consisting of the following formula (IV-a) and formula (V-a):[Chemical Formula 160]R3a is -(CH2)pCHR3f-NRN1RN2,R3b is H,R3c is C3-6 cycloalkyl optionally substituted by -NRN1RN2,R3f is H,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl,X2 is -O- or -NH-,X3 is O,p is 1,n is 1,R4 is C1-6 alkyl optionally substituted by OCH3,Y is phenylene,LP is a bond,EUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 161]R5 is isopropyl,R6a is H, R6b is hydroxymethyl,R7 is a group selected from the group consisting of the following formula (XIX-a) and formula (XVI):[Chemical Formula 162]W is a group represented by formula (XVII-a):[Chemical Formula 163]andZ is a group represented by the following formula (XVIII-a):[Chemical Formula 164]wherein * represents a site of connection to LP.

[0148] Specific examples of certain embodiments of the heterocyclic compound having a mutant KRAS protein degradation-inducing effect for use as a drug constituting the antibody-drug conjugate of the present invention or the salt thereof include a heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being selected from the following group:(4R)-1-[(2S)-2-{4-[4-({[(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide,(4R)-1-[(2S)-2-(4-{4-[({(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-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-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide,(4R)-1-[(2S)-2-{4-[4-({[(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide, and(4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-[(1-{[2-(methylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide.

[0149] Specific examples of other embodiments of the heterocyclic compound having a mutant KRAS protein degradation-inducing effect for use as a drug constituting the antibody-drug conjugate of the present invention or the salt thereof include a heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being selected from the following group:(4R)-1-[(2S)-2-{4-[4-({[4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide,(4R)-1-[(2S)-2-(4-{4-[({4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-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-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide,(4R)-1-{(2S)-2-[4-(4-{[(4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}quinazolin-8-yl)oxy]methyl}phenyl)-1H-1,2,3-triazol-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide, and(4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-[(1-{[2-(methylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide.

[0150] Other examples of the heterocyclic compound having a mutant KRAS protein degradation-inducing effect, particularly, a G12V mutant, G12D mutant, and G12C mutant KRAS protein degradation-inducing effect, for use as a drug constituting the antibody-drug conjugate of the present invention or the salt thereof will be shown below.

[0151] (31-1-1) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (TP-1), (TP-2), or (TP-3):[Chemical Formula 165]whereinA is CRA or N,RA is H or C1-3 alkyl,X1 is -CH2- or -O-,R1 is naphthyl optionally substituted by OH, or a group represented by the following formula (III):[Chemical Formula 166]R1a is H, methyl, F, or Cl,R1b is F, Cl, methyl, or ethyl,R2 is H, halogen, cyclopropyl, vinyl, or C1-3 alkyl optionally substituted by a group selected from the group consisting of OH and OCH3,R3 is a group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII):[Chemical Formula 167]R3a is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 5- or 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,R3b is H or C1-3 alkyl,each of R3c and R3d is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,on the proviso that when R3c is -(CH2)pCHR3f-NRN1RN2, X2 in formula (V) is -O-, -NH-, or -N(C2-3 alkyl)-,R3e is -O-C2-3 alkylene-NRN1RN2,R3f is H, F, or C1-3 alkyl,R3g is H or C1-3 alkyl,R3h is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms,R3i are the same or different from each other and each is a group selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, -NH-optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)2, halogen, -CN, and oxo, ortwo R3i present on the same carbon atom optionally form, together with the adjacent carbon atom, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a spiro ring as the group of formula (XIII), wherein the spiro ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two adjacent carbon atoms optionally form, together with the two carbon atoms, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a condensed ring as the group of formula (XIII), wherein the condensed ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two non-adjacent carbon atoms optionally form, together with the two carbon atoms, a bridged structure of 1 or 2 carbon atoms, wherein the group of formula (XIII) which is a ring having the bridged structure is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl, orRN1 and RN2 optionally form, together with the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, orR3f and RN1 optionally form, together with the carbon atom and the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,X2 is -O-, -NH-, or -N(C1-3 alkyl)-,X3 is O or S,X4 is -CH2-, -CH2-CH2-, or -O-CH2-,n is 1 or 2,p is 1 or 2,q is an integer of 1 to 8,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, R4a, cyclopropyl, N(R4a)2, pyrrolidinyl optionally substituted by R4a, and tetrahydrofuranyl optionally substituted by R4a; piperidinyl optionally substituted by R4b; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl optionally substituted by F,R4b is C1-3 alkyl substituted by 1 to 3 F,Y is phenylene optionally substituted by F or Cl, or pyridinediyl,LP is a group that chemically bonds Y to EUB,EUB is a group having the ability to bind to E3 ubiquitin ligase, andR8 is H or halogen.

[0152] (31-1-2) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (TP-1).(31-1-3) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (TP-2).(31-1-4) A heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (TP-3).

[0153] Heterocyclic compounds having a mutant KRAS protein degradation-inducing effect, the heterocyclic compounds being represented by the following formulas (TP-4) to (TP-11) (see International Publication No. WO 2023 / 099620; for the symbols in the formulas, see the patent literature):[Chemical Formula 168-1][Chemical Formula 168-2][Chemical Formula 168-3][Chemical Formula 168-4][Chemical Formula 168-5][Chemical Formula 168-6][Chemical Formula 168-7][Chemical Formula 168-8]

[0154] Heterocyclic compounds having a mutant KRAS protein degradation-inducing effect, the heterocyclic compounds being represented by the following formulas (TP-12) to (TP-16) (see International Publication No. WO 2023 / 141570; for the symbols in the formulas, see the patent literature):[Chemical Formula 169-1][Chemical Formula 169-2][Chemical Formula 169-3][Chemical Formula 169-4][Chemical Formula 169-5]

[0155] A heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by the following formula (TP-17) or (TP-18) (see International Publication No. WO 2023 / 130012; for the symbols in the formulas, see the patent literature):[Chemical Formula 170-1][Chemical Formula 170-2]

[0156] 2. Linker (LA)In the present specification, linker (LA) constituting the antibody-drug conjugate of the present invention or the salt thereof is a bifunctional partial structure that connects one or more drugs (D) to antibody (Ab) to form an antibody-drug conjugate. Linker (LA) is a linker cleavable in vivo or a non-cleavable linker in certain embodiments and is a linker cleavable in vivo in certain embodiments. The linker cleavable in vivo is a linker having a partial structure cleavable in vivo and is, but not particularly limited to, a linker having a partial structure cleavable by an enzyme such as protease, glycosidase, esterase, or phosphatase. Examples of the protease include, but are not limited to, cathepsin B, cathepsin S, plasmin, and legumain. Examples of the glycosidase include, but are not limited to, β-glucuronidase and β-galactosidase. Examples of the esterase include, but are not limited to, carboxyesterase. The linker is cleaved so that drug (D) is released in vivo.

[0157] Certain embodiments of the pattern of connection between LA and D according to the present invention will be shown below.(32-1) LA is bonded to an arbitrary nitrogen atom or oxygen atom of -OH contained in D, wherein when the nitrogen atom is tertiary amine, the nitrogen atom is bonded to LA to form quaternary ammonium.(32-2) LA is bonded to a nitrogen atom of amine or an oxygen atom of -OH contained in the group R3, R4, or EUB of D to form N-LA or O-LA, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to LA to form quaternary ammonium.(32-3) LA is bonded to a nitrogen atom of amine contained in the group R3 or R4 of D, or an oxygen atom of -OH contained in EUB to form N-LA or O-LA, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to LA to form quaternary ammonium.(32-4) LA is bonded to a nitrogen atom of amine contained in the group R3 or R4 of D to form N-LA, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to LA to form quaternary ammonium.(32-5) LA is bonded to a nitrogen atom of amine contained in the group R3 of D to form N-LA, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to LA to form quaternary ammonium.(32-6) LA is bonded to a nitrogen atom of amine contained in the group R4 of D to form N-LA, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to LA to form quaternary ammonium.(32-7) LA is bonded to a nitrogen atom of N(R4a)2 contained in the group R4 of D to form -N+(R4a)2-LA.(32-8) LA is bonded to an oxygen atom of -OH contained in the group EUB of D to form O-LA.(32-9) LA is bonded to an arbitrary nitrogen atom contained in D, wherein when the nitrogen atom is tertiary amine, the nitrogen atom is bonded to LA to form quaternary ammonium.

[0158] Certain embodiments of linker (LA) according to the present invention will be shown below.(33-1) A linker for connecting Ab and D.(33-2) A linker represented by the following formula (XV):[Chemical Formula 171]whereinStr is a stretcher unit and is connected to Ab and CLL,CLL is a partial structure cleavable in vivo,Sp is a spacer unit and is connected to CLL and D, t is 0 or 1, and*Ab represents a site of connection to Ab.(34-1) The linker according to (33-2), wherein r is 1.(34-2) The linker according to (33-2), wherein r is 0.(35-1) The linker according to (33-2), wherein t is 1.(35-2) The linker according to (33-2), wherein t is 0.

[0159] In the present specification, "stretcher unit (Str)", if present, is a structural unit that connects antibody (Ab) and CLL. The stretcher unit forms a covalent bond with a functional group contained in antibody (Ab). Examples of the functional group contained in antibody (Ab), which forms a covalent bond with the stretcher unit, include, but are not particularly limited to, a mercapto group, an amino group, a hydroxyl group, and a carboxyl group. It is a mercapto group in certain embodiments. A mercapto group that can be used in covalent bond formation with a drug-linker conjugate may be generated by reducing an intramolecular disulfide bond contained in the antibody.

[0160] Certain embodiments of stretcher unit (Str) will be shown below.(36-1) A stretcher unit represented by formula (ST-1):[Chemical Formula 172]wherein Rst1 is optionally substituted C1-12 alkylene, or -optionally substituted C1-50 heteroalkylene, and *Ab represents a site of connection to Ab.(36-1-2) The stretcher unit according to (36-1), wherein Rst1 is optionally substituted C1-12 alkylene, -optionally substituted C1-6 alkylene-C(=O)-NH-C1-6 alkylene-(OCH2CH2)a-, or -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-, and a is an integer of 1 to 10.(36-1-3) The stretcher unit according to (36-1), wherein Rst1 is -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-.(36-2) The stretcher unit according to (36-1), whereinRst1 is optionally substituted C1-12 alkylene, or -optionally substituted C1-6 alkylene-C(=O)-NH-C1-6 alkylene-(OCH2CH2)a-, anda is an integer of 1 to 10.(36-3) The stretcher unit according to (36-1), wherein Rst1 is C1-12 alkylene.(36-4) The stretcher unit according to (36-1), wherein Rst1 is C3-8 alkylene.(36-5) The stretcher unit according to (36-1), wherein Rst1 is C5 alkylene.(36-6) The stretcher unit according to (36-1), wherein Rst1 is optionally substituted C1-50 heteroalkylene.(36-7) The stretcher unit according to (36-1), wherein Rst1 is -optionally substituted C1-6 alkylene-C(=O)-NH-C1-6 alkylene-(OCH2CH2)a-, and a is an integer of 1 to 10.(36-8) The stretcher unit according to (36-7), wherein a is an integer of 3 to 9.(36-9) The stretcher unit according to (36-7), wherein a is an integer of 5 to 8.(36-10) A stretcher unit represented by formula (ST-2) or (ST-3):[Chemical Formula 173]wherein Rst1 is optionally substituted C1-12 alkylene, or -optionally substituted C1-50 heteroalkylene, and *Ab represents a site of connection to Ab.(36-10-2) The stretcher unit according to (36-10), wherein Rst1 is optionally substituted C1-12 alkylene, -optionally substituted C1-6 alkylene-C(=O)-NH-C1-6 alkylene-(OCH2CH2)a-, or -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-, and a is an integer of 1 to 10.(36-10-3) The stretcher unit according to (36-10), wherein Rst1 is -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-.(36-11) The stretcher unit according to (36-10), wherein Rst1 is optionally substituted C1-12 alkylene, or -optionally substituted C1-6 alkylene-C(=O)-NH-C1-6 alkylene-(OCH2CH2)a-, and a is an integer of 1 to 10.(36-12) The stretcher unit according to (36-10), wherein Rst1 is C1-12 alkylene.(36-13) The stretcher unit according to (36-10), wherein Rst1 is C3-8 alkylene.(36-14) The stretcher unit according to (36-10), wherein Rst1 is C5 alkylene.(36-15) The stretcher unit according to (36-10), wherein Rst1 is optionally substituted C1-50 heteroalkylene.(36-16) The stretcher unit according to (36-10), wherein Rst1 is -optionally substituted C1-6 alkylene-C(=O)-NH-C1-6 alkylene-(OCH2CH2)a-, and a is an integer of 1 to 10.(36-17) The stretcher unit according to (36-16), wherein a is an integer of 3 to 9.(36-18) The stretcher unit according to (36-16), wherein a is an integer of 5 to 8.(36-19) A stretcher unit represented by formula (ST-1):[Chemical Formula 174]wherein Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20, and *Ab represents a site of connection to Ab.(36-20) The stretcher unit according to (36-19), wherein Rst1 is optionally substituted C1-12 alkylene-NH-.(36-21) The stretcher unit according to (36-19), wherein Rst1 is optionally substituted C3-8 alkylene-NH-.(36-22) The stretcher unit according to (36-19), wherein Rst1 is optionally substituted C5 alkylene-NH-.(36-23) The stretcher unit according to (36-19), wherein Rst1 is -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-.(36-24) The stretcher unit according to (36-19), wherein Rst1 is -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-.(36-25) The stretcher unit according to (36-19), wherein Rst1 is -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-.(36-26) The stretcher unit according to (36-1-2), (36-1-3), (36-10-2), (36-10-3), (36-19), (36-23), (36-24), or (36-25), wherein RPEG is -C(=O)-(CH2CH2O)b-CH3.(36-26-2) The stretcher unit according to (36-1-2), (36-1-3), (36-10-2), (36-10-3), (36-19), (36-23), (36-24), or (36-25), wherein b is an integer of 2 to 20.(36-27) The stretcher unit according to (36-1-2), (36-1-3), (36-10-2), (36-10-3), (36-19), (36-23), (36-24), or (36-25), wherein b is an integer of 5 to 15.(36-28) The stretcher unit according to (36-1-2), (36-1-3), (36-10-2), (36-10-3), (36-19), (36-23), (36-24), or (36-25), wherein b is an integer of 10 to 12.(36-29) The stretcher unit according to (36-1-2), (36-1-3), (36-10-2), (36-10-3), (36-19), (36-23), (36-24), or (36-25), wherein b is 12.

[0161] Embodiments of "partial structure cleavable in vivo (CLL)" according to the present invention will be shown below.(37-1) A partial structure cleavable in vivo represented by formula (CL-1):[Chemical Formula 175]wherein RAA are each independently 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 formula (RAA-1) and (RAA-2):[Chemical Formula 176]d is an integer of 1 to 6, and *STR represents a site of connection to Str.(37-2) The partial structure cleavable in vivo according to (37-1), wherein RAA are each 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 of 2 to 4.(37-3) The partial structure cleavable in vivo according to (37-1), wherein RAA are each independently one group selected from the group consisting of H, methyl, isopropyl, benzyl, and -(CH2)3-NH-C(=O)-NH2, and d is an integer of 2 to 4.(37-4) The partial structure cleavable in vivo according to (37-1), wherein RAA are each independently methyl, isopropyl or -(CH2)3-NH-C(=O)-NH2, and d is 2.(37-5) The partial structure cleavable in vivo according to (37-1), wherein RAA are each independently methyl or isopropyl, and d is 2.(37-6) The partial structure cleavable in vivo according to (37-1), wherein RAA are each independently isopropyl or -(CH2)3-NH-C(=O)-NH2, and d is 2.(37-7) A partial structure cleavable in vivo represented by formula (CL-2):[Chemical Formula 177]wherein*STR represents a site of connection to Str.(37-8) A partial structure cleavable in vivo represented by formula (CL-3):[Chemical Formula 178]wherein*STR represents a site of connection to Str.

[0162] In the present specification, "spacer unit (Sp)" is a structural unit that connects CLL and drug (D). The spacer unit is bonded to a nitrogen atom of amine or an oxygen atom of -OH contained in drug (D) to form N-Sp or O-Sp in certain embodiments, bonded to a nitrogen atom of amine or an oxygen atom of -OH contained in R3, R4, or EUB to form N-Sp or O-Sp in certain embodiments, bonded to a nitrogen atom of amine contained in R3 or R4, or an oxygen atom of -OH contained in EUB to form N-Sp or O-Sp in certain embodiments, and bonded to a nitrogen atom of N(R4a)2 contained in R4 to form N-Sp in certain embodiments. When the amine is tertiary amine, the nitrogen atom of the amine is bonded to Sp to form quaternary ammonium. The spacer unit is a self-destruction spacer unit in certain embodiments. When CLL is cleaved, the self-destruction spacer unit is degraded in itself without undergoing further hydrolysis reaction so that free drug (D) is released.

[0163] Certain embodiments of the spacer unit will be shown below.(38-1) A spacer unit represented by formula (SP-1), formula (SP-2), or formula (SP-3):[Chemical Formula 179]wherein RSP is H, C1-6 alkyl, -O-C1-6 alkyl, halogen, or halogeno C1-6 alkyl, and *CLL represents a site of connection to CLL.(38-2) The spacer unit according (38-1), wherein RSP is H.(38-3) A spacer unit represented by formula (SP-1):[Chemical Formula 180]wherein RSP is H, C1-6 alkyl, -O-C1-6 alkyl, halogen, or halogeno C1-6 alkyl, and *CLL represents a site of connection to CLL.(38-4) The spacer unit according (38-3), wherein RSP is H.(38-5) A spacer unit represented by formula (SP-2):[Chemical Formula 181]wherein*CLL represents a site of connection to CLL.(38-6) A spacer unit represented by formula (SP-3):[Chemical Formula 182]wherein RSP is H, C1-6 alkyl, -O-C1-6 alkyl, halogen, or halogeno C1-6 alkyl, and *CLL represents a site of connection to CLL.(38-7) The spacer unit according to (38-6), wherein RSP is H.(38-8) A spacer unit represented by formula (SP-4):[Chemical Formula 183]wherein*CLL represents a site of connection to CLL.

[0164] Although not bound by the following theory, it is considered that self-destruction spacer unit (SP-1) used in the present invention is degraded through the following mechanism after cleavage of the bond between CLL and the nitrogen atom so that drug (D) is released (Journal of Organic Chemistry, 2002, 67, p. 1866-1872).[Chemical Formula 184]CleavageCleavage

[0165] Certain embodiments of linker LA constituting the antibody-drug conjugate of the present invention or the salt thereof will be shown below.(39-1) A linker represented by formula (XV):[Chemical Formula 185]whereinStr is a stretcher unit and is connected to Ab and CLL,CLL is a partial structure cleavable in vivo,Sp is a spacer unit and is connected to CLL and D, t is 0 or 1,whereini) Str is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 186]Rst1 is optionally substituted C1-12 alkylene, or -optionally substituted C1-6 alkylene-C(=O)-NH-C1-6 alkylene-(OCH2CH2)a-, a is an integer of 1 to 10,CLL is a partial structure cleavable in vivo represented by formula (CL-1), *STR represents a site of connection to Str,[Chemical Formula 187]RAA are each independently one group selected from the group consisting of H, methyl, isopropyl, benzyl, and -(CH2)3-NH-C(=O)-NH2,d is an integer of 2 to 4,Sp is a spacer unit represented by formula (SP-1), formula (SP-2), or formula (SP-3), t is 1, *CLL represents a site of connection to CLL,[Chemical Formula 188]andRSP is H,orii) Str is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 189]Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-2), *STR represents a site of connection to Str,[Chemical Formula 190]t is 0, and *Ab represents a site of connection to Ab.(39-2) The linker according to (39-1), whereinStr is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 191]Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-2), *STR represents a site of connection to Str,[Chemical Formula 192]andt is 0.(39-3) The linker according to (39-2), wherein Rst1 is -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-.(39-4) The linker according to (39-3), wherein Rst1 is -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-.(39-5) The linker according to (39-3), wherein Rst1 is -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-.

[0166] (39-6) A linker represented by the following formula (LA-1) (wherein*Ab represents a site of connection to Ab):[Chemical Formula 193]

[0167] (39-7) A linker represented by the following formula (LA-2) (wherein*Ab represents a site of connection to Ab):[Chemical Formula 194]

[0168] (39-8) A linker represented by the following formula (LA-3) (wherein b is an integer of 2 to 20, and *Ab represents a site of connection to Ab):[Chemical Formula 195]

[0169] (39-9) A linker represented by the following formula (LA-4) (wherein b is an integer of 2 to 20, and *Ab represents a site of connection to Ab):[Chemical Formula 196](39-10) A linker represented by the following formula (LA-5) (wherein*Ab represents a site of connection to Ab):[Chemical Formula 197](39-11) The linker according to (39-8) or (39-9), wherein b is an integer of 5 to 15.(39-12) The linker according to (39-8) or (39-9), wherein b is an integer of 10 to 12.(39-13) The linker according to (39-8) or (39-9), wherein b is 12.

[0170] Other examples of linker LA constituting the antibody-drug conjugate of the present invention or the salt thereof will be shown below.

[0171] A linker represented by the following formula (LA-6) or formula (LA-7) (see International Publication No. WO 2015 / 095124; in the formulas, *Ab represents a site of connection to Ab):[Chemical Formula 198-1][Chemical Formula 198-2]

[0172] A linker represented by the following formula (LA-8) (see International Publication No. WO 2015 / 095223; in the formula, *Ab represents a site of connection to Ab):[Chemical Formula 199]

[0173] A linker represented by the following formula (LA-9) (see International Publication No. WO 2015 / 095227; in the formula, *Ab represents a site of connection to Ab):[Chemical Formula 200]

[0174] A linker represented by the following formula (LA-10) (see International Publication No. WO 2014 / 057687; in the formula, *Ab represents a site of connection to Ab):[Chemical Formula 201]

[0175] A linker represented by the following formula (LA-11) (see International Publication No. WO 2013 / 173337; in the formula, *Ab represents a site of connection to Ab):[Chemical Formula 202]

[0176] A linker represented by the following formula (LA-12) (see International Publication No. WO 2022 / 220625; in the formula, *Ab represents a site of connection to Ab):[Chemical Formula 203]

[0177] A linker represented by the following formula (LA-13) (see International Publication No. WO 2016 / 040684; in the formula, *Ab represents a site of connection to Ab):[Chemical Formula 204]

[0178] A linker represented by the following formula (LA-14) or formula (LA-15) (see International Publication No. WO 2015 / 057699; in the formulas, e represents an integer of 2 to 24, and *Ab represents a site of connection to Ab):[Chemical Formula 205-1][Chemical Formula 205-2]

[0179] 3. Drug-linker conjugate (LA-D)In the present specification, "drug-linker conjugate" is a compound of linker (LA) and drug (D) connected to each other through a covalent bond. The drug-linker conjugate of the present invention or a salt thereof has a reactive site, is capable of forming a covalent bond through reaction with a functional group contained in antibody (Ab), and is useful as an intermediate for synthesizing the antibody-drug conjugate. In this context, in the antibody-drug conjugate, at least one drug-linker conjugate of the present invention is connected to antibody (Ab). In certain embodiments, the antibody moiety and / or the linker moiety of the antibody-drug conjugate may be further connected to at least another drug (anticancer agent, protein degradation inducer, immunostimulator, or label, etc.) via a linker.Examples of the functional group contained in antibody (Ab), which forms a covalent bond with the drug-linker conjugate of the present invention or the salt thereof, include, but are not particularly limited to, a mercapto group, an amino group, a hydroxyl group, and a carboxyl group. It is a mercapto group in certain embodiments. A mercapto group that can be used in covalent bond formation with the drug-linker conjugate may be generated by reducing an intramolecular disulfide bond contained in the antibody.For example, when the drug-linker conjugate of the present invention or the salt thereof has a maleimide structure, the antibody-drug conjugate of the present invention or the salt thereof can be synthesized by forming the following partial structure through reaction with a mercapto group contained in the antibody (wherein Ab'-SH represents an antibody having a mercapto group).[Chemical Formula 206]

[0180] Certain embodiments of the pattern of connection between Sp and D according to the present invention will be shown below. When t is 0, Sp is absent and CLL is connected, instead of Sp in the following aspects, directly to D.(40-1) Sp is bonded to an arbitrary nitrogen atom or oxygen atom of -OH contained in D, wherein when the nitrogen atom is tertiary amine, the nitrogen atom is bonded to Sp to form quaternary ammonium.(40-2) Sp is bonded to a nitrogen atom of amine or an oxygen atom of -OH contained in the group R3, R4, or EUB of D to form N-Sp or O-Sp, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to Sp to form quaternary ammonium.(40-3) Sp is bonded to a nitrogen atom of amine contained in the group R3 or R4 of D, or an oxygen atom of -OH contained in EUB to form N-Sp or O-Sp, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to Sp to form quaternary ammonium.(40-4) Sp is bonded to a nitrogen atom of amine contained in the group R3 or R4 of D to form N-Sp, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to Sp to form quaternary ammonium.(40-5) Sp is bonded to a nitrogen atom of amine contained in the group R3 of D to form N-Sp, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to Sp to form quaternary ammonium.(40-6) Sp is bonded to a nitrogen atom of amine contained in the group R4 of D to form N-Sp, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to Sp to form quaternary ammonium.(40-7) Sp is bonded to a nitrogen atom of N(R4a)2 contained in the group R4 of D to form -N+(R4a)2-Sp.(40-8) Sp is bonded to an oxygen atom of -OH contained in the group EUB of D to form O-Sp.(40-9) Sp is bonded to an arbitrary nitrogen atom contained in D, wherein when the nitrogen atom is tertiary amine, the nitrogen atom is bonded to Sp to form quaternary ammonium.

[0181] Embodiments of the drug-linker conjugate of the present invention or the salt thereof will be shown below.(41-1) A drug-linker conjugate represented by formula (LD-1) or a salt thereof:[Chemical Formula 207]whereinD is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect,Rst1 is optionally substituted C1-12 alkylene, or optionally substituted C1-50 heteroalkylene,CLL is a partial structure cleavable in vivo,Sp is a spacer unit and is connected to CLL and D, t is 0 or 1, andSp is bonded to a nitrogen atom of amine or an oxygen atom of -OH contained in D to form N-Sp or O-Sp, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to Sp to form quaternary ammonium.

[0182] (41-2) The drug-linker conjugate or the salt thereof according to (41-1), whereinD is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (II):[Chemical Formula 208]A is CRA or N,RA is H or C1-3 alkyl,X1 is -CH2- or -O-,R1 is naphthyl optionally substituted by OH, or a group represented by the following formula (III):[Chemical Formula 209]R1a is H, methyl, F, or Cl,R1b is F, Cl, methyl, or ethyl,R2 is H, halogen, cyclopropyl, vinyl, or C1-3 alkyl optionally substituted by a group selected from the group consisting of OH and OCH3,R3 is a group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII):[Chemical Formula 210]R3a is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 5- or 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,R3b is H or C1-3 alkyl,each of R3c and R3d is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,on the proviso that when R3c is -(CH2)pCHR3f-NRN1RN2, X2 in formula (V) is -O-, -NH-, or -N(C2-3 alkyl)-,R3e is -O-C2-3 alkylene-NRN1RN2,R3f is H, F, or C1-3 alkyl,R3g is H or C1-3 alkyl,R3h is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms,R3i are the same or different from each other and each is a group selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, -NH-optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)2, halogen, -CN, and oxo, ortwo R3i present on the same carbon atom optionally form, together with the adjacent carbon atom, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a spiro ring as the group of formula (XIII), wherein the spiro ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two adjacent carbon atoms optionally form, together with the two carbon atoms, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a condensed ring as the group of formula (XIII), wherein the condensed ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two non-adjacent carbon atoms optionally form, together with the two carbon atoms, a bridged structure of 1 or 2 carbon atoms, wherein the group of formula (XIII) which is a ring having the bridged structure is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl, orRN1 and RN2 optionally form, together with the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, orR3f and RN1 optionally form, together with the carbon atom and the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,X2 is -O-, -NH-, or -N(C1-3 alkyl)-,X3 is O or S,X4 is -CH2-, -CH2-CH2-, or -O-CH2-,n is 1 or 2,p is 1 or 2,q is an integer of 1 to 8,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, R4a, cyclopropyl, N(R4a)2, pyrrolidinyl optionally substituted by R4a, and tetrahydrofuranyl optionally substituted by R4a; piperidinyl optionally substituted by R4b; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl optionally substituted by F,R4b is C1-3 alkyl substituted by 1 to 3 F,Y is phenylene optionally substituted by F or Cl, or pyridinediyl,LP is a group that chemically bonds Y to EUB,EUB is a group having the ability to bind to E3 ubiquitin ligase,CLL is a partial structure cleavable in vivo,Sp is a spacer unit and is connected to CLL and D, t is 0 or 1,Sp is bonded to a nitrogen atom of amine or an oxygen atom of -OH contained in the group R3, R4, or EUB of D to form N-LA or O-LA, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to Sp to form quaternary ammonium,whereini) Rst1 is optionally substituted C1-12 alkylene, -optionally substituted C1-6 alkylene-C(=O)-NH-C1-6 alkylene-(OCH2CH2)a-, or -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-, a is an integer of 1 to 10,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-1'), *CO represents a site of connection to a carbonyl group,[Chemical Formula 211]RAA are each independently one group selected from the group consisting of H, methyl, isopropyl, benzyl, and -(CH2)3-NH-C(=O)-NH2,d is an integer of 2 to 4,Sp is a spacer unit represented by formula (SP-1), formula (SP-2), or formula (SP-3), t is 1, *CLL represents a site of connection to CLL,[Chemical Formula 212]andRSP is H,or ii) Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20, CLL is a partial structure cleavable in vivo represented by formula (CL-2'), *CO represents a site of connection to a carbonyl group,[Chemical Formula 213]andt is 0.

[0183] (41-3) The drug-linker conjugate or the salt thereof according to (41-2), whereinEUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 214]R5 is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, C3-6 cycloalkylmethyl, or C3-6 cycloalkyl,R6a and R6b are the same or different from each other and each is H or C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, and N(CH3)2, orR6a and R6b optionally form, together with the carbon bonded thereto, optionally substituted C3-6 cycloalkane, or an optionally substituted 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,R7 is an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or 6-membered heteroaryl containing 1 to 3 nitrogen atoms,W is optionally substituted phenylene or optionally substituted 6-membered heteroarenediyl containing 1 to 3 nitrogen atoms as ring-constituting atom,LP is -(L1-L2-L3-L4)-,L1, L2, L3, and L4 are the same or different from each other and each is a group selected from the group consisting of a bond, -O-, -NRL1-, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3 alkylene, and C=O, RL1 is H or C1-3 alkyl, andZ is NH or 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom.

[0184] (41-4) The drug-linker conjugate or the salt thereof according to (41-3), whereinA is CRA or N,RA is H,X1 is -O-,R1 is a group represented by the following formula (III-a):[Chemical Formula 215]R2 is cyclopropyl,R3 is a group selected from the group consisting of the following formula (IV), formula (V), and formula (XI):[Chemical Formula 216]R3a is -(CH2)pCHR3f-NRN1RN2,R3b is H,R3c is C3-6 cycloalkyl optionally substituted by -NRN1RN2,R3f is H,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl,X2 is -O- or -NH-,X3 is O,n is 1,p is 1,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of OCH3, N(R4a)2, and pyrrolidinyl optionally substituted by R4a; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl, andY is phenylene.

[0185] (41-4-1) The drug-linker conjugate or the salt thereof according to (41-4), whereinEUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 217]R5 is isopropyl or tert-butyl,R6a and R6b are different from each other and each is H, or C1-6 alkyl optionally substituted by OH,R7 is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen,W is phenylene,LP is a bond,Z is 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, andSp is bonded to a nitrogen atom of amine contained in the group R3 or R4 of D, or an oxygen atom of -OH contained in EUB to form N-Sp or O-Sp, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to Sp to form quaternary ammonium.

[0186] (41-5) The drug-linker conjugate or the salt thereof according to (41-4), whereinA is N, R3 is a group represented by the following formula (XI):[Chemical Formula 218]R4 is C1-6 alkyl substituted by N(R4a)2,R4a is C1-3 alkyl,R7 is a group represented by the following formula (XVI):[Chemical Formula 219]W is a group represented by the following formula (XVII-a):[Chemical Formula 220]Z is a group represented by the following formula (XVII):[Chemical Formula 221]Rst1 is optionally substituted C1-12 alkylene, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-2'), *CO represents a site of connection to a carbonyl group,[Chemical Formula 222]t is 0, andSp is bonded to a nitrogen atom of N(R4a)2 contained in R4 to form -N+(R4a)2-Sp.

[0187] (41-6) The drug-linker conjugate or the salt thereof according to (41-4), whereinA is CRA or N,RA is H,X1 is -O-,R1 is a group represented by the following formula (III-a):[Chemical Formula 223]R2 is cyclopropyl,R3 is a group selected from the group consisting of the following formula (IV-a) and formula (V-a):[Chemical Formula 224]R3a is -(CH2)pCHR3f-NRN1RN2,R3b is H,R3c is C3-6 cycloalkyl optionally substituted by -NRN1RN2,R3f is H,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl,X2 is -O- or -NH-,X3 is O,p is 1,n is 1,R4 is C1-6 alkyl optionally substituted by OCH3,Y is phenylene,LP is a bond,EUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 225]R5 is isopropyl,R6a is H, R6b is hydroxymethyl,R7 is a group selected from the group consisting of the following formula (XIX-a) and formula (XVI):[Chemical Formula 226]W is a group represented by formula (XVII-a):[Chemical Formula 227]Z is a group represented by the following formula (XVIII-a) (wherein * represents a site of connection to LP),[Chemical Formula 228]andSp is bonded to a nitrogen atom of amine contained in the group R3 of D, or an oxygen atom of -OH contained in EUB to form N-Sp or O-Sp, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to Sp to form quaternary ammonium.

[0188] (41-7) The drug-linker conjugate or the salt thereof according to any of (41-1) to (41-6), wherein D is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by the following formula (PL-1) (wherein*Sp represents a site of connection to Sp):[Chemical Formula 229]

[0189] (41-8) The drug-linker conjugate or the salt thereof according to any of (41-1) to (41-7), wherein the drug-linker conjugate is represented by the following formula (LD-2'):[Chemical Formula 230]wherein b is an integer of 2 to 20.

[0190] (41-9) The drug-linker conjugate or the salt thereof according to any of (41-1) to (41-7), wherein the drug-linker conjugate is represented by the following formula (LD-3'):[Chemical Formula 231]wherein b is an integer of 2 to 20.

[0191] (41-10) The drug-linker conjugate or the salt thereof according to any of (41-1) to (41-7), wherein the drug-linker conjugate is represented by the following formula (LD-4'):[Chemical Formula 232]

[0192] (41-11) A drug-linker conjugate represented by the following formula (LD-2), (LD-3), or (LD-4) or a salt thereof:[Chemical Formula 233-1][Chemical Formula 233-2][Chemical Formula 233-3]wherein b is an integer of 2 to 20.(41-12) The drug-linker conjugate or the salt thereof according to any of (41-2) to (41-11), wherein b is an integer of 5 to 15.(41-13) The drug-linker conjugate or the salt thereof according to any of (41-2) to (41-11), wherein b is an integer of 10 to 12.(41-14) The drug-linker conjugate or the salt thereof according to any of (41-2) to (41-11), wherein b is 12.

[0193] (41-15) A drug-linker conjugate represented by formula (LD-8) or a salt thereof:[Chemical Formula 234]whereinD is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (II):[Chemical Formula 235]A is CRA or N,RA is H or C1-3 alkyl,X1 is -CH2- or -O-,R1 is naphthyl optionally substituted by OH, or a group represented by the following formula (III):[Chemical Formula 236]R1a is H, methyl, F, or Cl,R1b is F, Cl, methyl, or ethyl,R2 is H, halogen, cyclopropyl, vinyl, or C1-3 alkyl optionally substituted by a group selected from the group consisting of OH and OCH3,R3 is a group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII):[Chemical Formula 237]R3a is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 5- or 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,R3b is H or C1-3 alkyl,each of R3c and R3d is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,on the proviso that when R3c is -(CH2)pCHR3f-NRN1RN2, X2 in formula (V) is -O-, -NH-, or -N(C2-3 alkyl)-,R3e is -O-C2-3 alkylene-NRN1RN2,R3f is H, F, or C1-3 alkyl,R3g is H or C1-3 alkyl,R3h is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms,R3i are the same or different from each other and each is a group selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, -NH-optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)2, halogen, -CN, and oxo, ortwo R3i present on the same carbon atom optionally form, together with the adjacent carbon atom, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a spiro ring as the group of formula (XIII), wherein the spiro ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two adjacent carbon atoms optionally form, together with the two carbon atoms, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a condensed ring as the group of formula (XIII), wherein the condensed ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two non-adjacent carbon atoms optionally form, together with the two carbon atoms, a bridged structure of 1 or 2 carbon atoms, wherein the group of formula (XIII) which is a ring having the bridged structure is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl, orRN1 and RN2 optionally form, together with the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, orR3f and RN1 optionally form, together with the carbon atom and the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,X2 is -O-, -NH-, or -N(C1-3 alkyl)-,X3 is O or S,X4 is -CH2-, -CH2-CH2-, or -O-CH2-,n is 1 or 2,p is 1 or 2,q is an integer of 1 to 8,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, R4a, cyclopropyl, N(R4a)2, pyrrolidinyl optionally substituted by R4a, and tetrahydrofuranyl optionally substituted by R4a; piperidinyl optionally substituted by R4b; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl optionally substituted by F,R4b is C1-3 alkyl substituted by 1 to 3 F,Y is phenylene optionally substituted by F or Cl, or pyridinediyl,LP is a group that chemically bonds Y to EUB,EUB is a group having the ability to bind to E3 ubiquitin ligase,CLL is a partial structure cleavable in vivo represented by formula (CL-3):[Chemical Formula 238](wherein*STR represents a site of connection to Str),Sp is a spacer unit represented by formula (SP-4):[Chemical Formula 239](wherein*CLL represents a site of connection to CLL) and is connected to CLL and D, t is 1, andSp is bonded to an oxygen atom of -OH contained in the group EUB to form O-Sp.

[0194] (41-16) The drug-linker conjugate or the salt thereof according to (41-1), whereinD is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (II):[Chemical Formula 240]A is N,X1 is -O-,R1 is a group represented by the following formula (III-a):[Chemical Formula 241]R2 is cyclopropyl,R3 is a group represented by the following formula (XI):[Chemical Formula 242]R4 is C1-6 alkyl represented by N(R4a)2,R4a is C1-3 alkyl,Y is phenylene,LP is a bond,EUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 243]R5 is isopropyl or tert-butyl,R6a and R6b are different from each other and each is H, or C1-6 alkyl optionally substituted by OH,R7 is a group represented by the following formula (XVI):[Chemical Formula 244]W is a group represented by the following formula (XVII-a):[Chemical Formula 245]andZ is a group represented by the following formula (XVIII):[Chemical Formula 246]

[0195] 4. Antibody or antigen binding fragment (Ab)The antibody or the antigen binding fragment (hereinafter, also referred to as "Ab") used in the present invention binds to an antigen protein expressed on cell surface or a modified form (e.g., glycan modification) thereof. In certain embodiments, the antibody or the antigen binding fragment used in the present invention binds to a tumor-associated antigen or a cell surface receptor expressed on cancer cell surface.

[0196] In certain embodiments, the antibody or the antigen binding fragment used in the present invention can be an antibody or an antigen binding fragment that binds to one or two 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, CEACAM5, CEACAM6, CLDN1, CLDN4, CLDN6, CLDN18.2, cMET, EGFR, EphA3, FAP, FGFR3, Fibronectin, FOLRa, Globo H, GPRC5D, HER2, HER3, IGF1R, Integrin αV, KAAG1, LIV1, MSLN, MT1-MMP, MUC1, MUC4, NaPi2b, Nectin-4, PD-L1, PSMA, PTK7, ROR1, ROR2, SEZ6, SialylTn, TF, TROP2, TSPAN8, and VEGF. In certain embodiments, the antibody or the antigen binding fragment used in the present invention is an antibody or an antigen binding fragment that binds to one or two or more antigens selected from the group consisting of 5T4, B7H3, CEACAM5, CEACAM6, CLDN4, CLDN18.2, cMET, EGFR, HER2, HER3, MUC1, TROP2, and TSPAN8. In certain embodiments, the antibody or the antigen binding fragment used in the present invention is an antibody or an antigen binding fragment that binds to one or two or more antigens selected from the group consisting of EGFR, HER2, Nectin-4, and TROP2. In certain embodiments, the antibody or the antigen binding fragment used in the present invention is an antibody or an antigen binding fragment that binds to EGFR.

[0197] In certain embodiments, the antibody or the antigen binding fragment used in the present invention can be an antibody selected from the group consisting of an anti-5T4 antibody, an anti-ADAM9 antibody, an anti-ALPP antibody, an anti-ALPPL2 antibody, an anti-AXL antibody, an anti-B7H3 antibody, an anti-B7H4 antibody, an anti-BCMA antibody, an anti-CA9 antibody, an anti-CCR2 antibody, an anti-CCR7 antibody, an anti-CD123 antibody, an anti-CD166 antibody, an anti-CD19 antibody, an anti-CD20 antibody, an anti-CD22 antibody, an anti-CD25 antibody, an anti-CD30 antibody, an anti-CD33 antibody, an anti-CD37 antibody, an anti-CD38 antibody, an anti-CD45 antibody, an anti-CD46 antibody, an anti-CD70 antibody, an anti-CD74 antibody, an anti-CD79b antibody, an anti-CDH3 antibody, an anti-CDH6 antibody, an anti-CEACAM5 antibody, an anti-CEACAM6 antibody, an anti-CLDN1 antibody, an anti-CLDN4 antibody, an anti-CLDN6 antibody, an anti-CLDN18.2 antibody, an anti-cMET antibody, an anti-EGFR antibody, an anti-EphA3 antibody, an anti-FAP antibody, an anti-FGFR3 antibody, an anti-Fibronectin antibody, an anti-FOLRa antibody, an anti-Globo H antibody, an anti-GPRC5D antibody, an anti-HER2 antibody, an anti-HER3 antibody, an anti-IGF1R antibody, an anti-IntegrinαV antibody, an anti-KAAG1 antibody, an anti-LIV1 antibody, an anti-MSLN antibody, an anti-MT1-MMP antibody, an anti-MUC1 antibody, an anti-MUC4 antibody, an anti-NaPi2b antibody, an anti-Nectin-4 antibody, an anti-PD-L1 antibody, an anti-PSMA antibody, an anti-PTK7 antibody, an anti-ROR1 antibody, an anti-ROR2 antibody, an anti-SEZ6 antibody, an anti-SialylTn antibody, an anti-TF antibody, an anti-TROP2 antibody, an anti-TSPAN8 antibody, and an anti-VEGF antibody, or an antigen binding fragment thereof. In certain embodiments, the antibody or the antigen binding fragment used in the present invention is an antibody selected from the group consisting of an anti-5T4 antibody, an anti-B7H3 antibody, an anti-CEACAM5 antibody, an anti-CEACAM6 antibody, an anti-CLDN4 antibody, an anti-CLDN18.2 antibody, an anti-cMET antibody, anti-EGFR antibody, an anti-HER2 antibody, an anti-HER3 antibody, an anti-MUC1 antibody, an anti-TROP2 antibody, and an anti-TSPAN8 antibody, or an antigen binding fragment thereof. In certain embodiments, the antibody or the antigen binding fragment used in the present invention is an antibody selected from the group consisting of an anti-EGFR antibody, an anti-HER2 antibody, an anti-Nectin-4 antibody, and an anti-TROP2 antibody, or an antigen binding fragment thereof.

[0198] Those skilled in the art can obtain, by a method known in the art, the antibody or the antigen binding fragment thereof used in the present invention. It can be obtained by use of a method that is usually carried out in the art, for example, by immunizing an animal with a polypeptide serving as an antigen, and collecting and purifying an antibody produced in vivo. The origin of the antigen is not limited to a human, and an animal may be immunized with an antigen derived from a non-human animal such as a mouse or a rat. In this case, an antibody applicable to a human disease can be selected by testing the obtained antibody that binds to the heterologous antigen for its cross-reactivity with the human antigen. In accordance with a method known in the art (e.g., Kohler and Milstein, Nature (1975) 256, p. 495-497; and Kennet, R. ed., Monoclonal Antibodies, p. 365-367, Plenum Press, N.Y. (1980)), antibody-producing cells that produce an antibody against the antigen are fused with myeloma cells so that hybridomas may be established to obtain a monoclonal antibody. The immunizing antigen can be obtained, for example, by transferring a gene encoding an arbitrary protein or polypeptide to host cells using a vector or the like, allowing the gene to be expressed, and purifying the expressed protein. Alternatively, the antibody can be obtained by a method of immunizing an animal with cells such as cells allowed to express an arbitrary protein by the gene manipulation described above, or a cell line endogenously expressing the antigen.

[0199] Whether or not the antibody or the antigen binding fragment binds to the antigen can be confirmed by use of a binding activity measurement method known in the art. Examples of the method for measuring binding activity include methods such as enzyme-linked immunosorbent assay (ELISA) and flow cytometry.

[0200] The antibody or the antibody binding fragment used in the present invention may be derived from any species such as a human, a rat, a mouse, or a rabbit. The antibody, when derived from a non-human species, is preferably chimerized or humanized by use of a well-known technique. The antibody or the antibody binding fragment for use in the antibody-drug conjugate of the present invention may be a polyclonal antibody or a monoclonal antibody.

[0201] In certain embodiments, the antibody or the antibody binding fragment used in the present invention is an IgG type antibody or antibody binding fragment. IgG has subtypes of IgG1, IgG2, IgG3, and IgG4 depending on the structures of hinge and Fc regions, and may be appropriately selected by those skilled in the art in consideration of an effector function of the antibody, DAR, or the like. In certain embodiments, the antibody or the antibody binding fragment used in the present invention is an IgG1 or IgG4 type.

[0202] In certain embodiments, the antibody or the antibody binding fragment used in the present invention is an anti-EGFR antibody or an antigen binding fragment thereof.

[0203] In certain embodiments, the antibody or the antibody binding fragment used in the present invention is an anti-EGFR antibody including a heavy chain variable region and a light chain variable region described in the following (1) or (2) or an antigen binding fragment thereof:(1) a heavy chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 31 to 35 of SEQ ID NO: 1, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 65 of SEQ ID NO: 1, and CDR3 consisting of an amino acid sequence from amino acid positions 98 to 108 of SEQ ID NO: 1, anda light chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 24 to 34 of SEQ ID NO: 2, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 56 of SEQ ID NO: 2, and CDR3 consisting of an amino acid sequence from amino acid positions 89 to 97 of SEQ ID NO: 2; or(2) a heavy chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 31 to 35 of SEQ ID NO: 3, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 65 of SEQ ID NO: 3, and CDR3 consisting of an amino acid sequence from amino acid positions 98 to 108 of SEQ ID NO: 3, anda light chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 24 to 34 of SEQ ID NO: 4, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 56 of SEQ ID NO: 4, and CDR3 consisting of an amino acid sequence from amino acid positions 89 to 97 of SEQ ID NO: 4.

[0204] In certain embodiments, the antibody or the antibody binding fragment used in the present invention is an anti-EGFR antibody including a heavy chain variable region and a light chain variable region selected from the group consisting of the following (1) to (3) or an antigen binding fragment thereof:(1) a heavy chain variable region consisting of an amino acid sequence from amino acid positions 1 to 119 of SEQ ID NO: 1 and a light chain variable region consisting of an amino acid sequence from amino acid positions 1 to 107 of SEQ ID NO: 2;(2) a heavy chain variable region consisting of an amino acid sequence from amino acid positions 1 to 119 of SEQ ID NO: 3 and a light chain variable region consisting of an amino acid sequence from amino acid positions 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 higher identity to the heavy chain variable region and the light chain variable region described in (1) or (2) above.

[0205] In certain embodiments, the antibody used in the present invention is an IgG1 or IgG4 type anti-EGFR antibody.

[0206] In certain embodiments, the antibody used in the present invention can be an antibody that binds to EGFR, for example, cetuximab, panitumumab, or matuzumab, or an antibody obtained by engineering a sequence thereof. The antibody obtained by engineering a sequence (hereinafter, also referred to as "engineered form") refers to an antibody obtained by partially engineering the amino acid sequence of a variable region or a constant region on the basis of the amino acid sequence of an antibody known in the art. Examples of the engineered form of cetuximab include antibodies described in WO2007058823, WO2013134743, and WO2014166029. In certain embodiments, preferably, the antibody used in the present invention is cetuximab or an engineered form thereof.

[0207] In certain embodiments, Ab used in the present invention is an anti-EGFR antibody consisting of a heavy chain of SEQ ID NO: 1 and a light chain of SEQ ID NO: 2 or an anti-EGFR antibody consisting of a heavy chain of SEQ ID NO: 3 and a light chain of SEQ ID NO: 4. In certain embodiments, Ab used in the present invention is an anti-EGFR antibody consisting of a heavy chain of SEQ ID NO: 1 and a light chain of SEQ ID NO: 2. In certain embodiments, Ab used in the present invention is an anti-EGFR antibody consisting of a heavy chain of SEQ ID NO: 3 and a light chain of SEQ ID NO: 4.

[0208] In certain embodiments, the antibody or the antigen binding fragment used in the present invention may undergo post-translational modification such as N-linked or O-linked glycosylation, N-terminal or C-terminal processing, deamidation, isomerization of aspartic acid, or oxidation of methionine.

[0209] An arbitrary amino acid residue in the antibody or the antibody binding fragment used in the present invention may be substituted by cysteine or a non-natural amino acid. The substitution by cysteine can employ, for example, a method described in WO2008141044 or WO2016040856. The substitution by a non-natural amino acid can employ, for example, a method described in WO2010081111 or WO2013185115.

[0210] An Fc region of the antibody used in the present invention may have a mutation that reduces antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). L234A is the substitution of leucine at amino acid position 234 based on the EU index in a human Igγ1 constant region by alanine. L235A is the substitution of leucine at amino acid position 235 based on the EU index in a human Igγ1 constant region by alanine. The amino acid mutation of L234A and L235A in the human Igγ1 constant region is called "LALA mutation". This mutation is known to reduce antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity of antibodies (Mol. Immunol., 1992; Vol. 29: p. 633-639). P331G or P331S is the substitution of proline at amino acid position 331 based on the EU index in a human Igγ1 constant region by glycine or serine. This mutation is known to reduce CDC of antibodies (J. Immunol., 2000, Vol / 164 (8), p. 4178-4184).

[0211] 5. Antibody-drug conjugateThe antibody-drug conjugate according to the present invention or the salt thereof is an antibody-drug conjugate represented by the following formula (I) or a salt thereof:[Chemical Formula 247]whereinAb is an antibody or an antigen binding fragment thereof,D is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect,LA is a linker for connecting Ab and D, andm is a number of 1 to 20.

[0212] m represents a compound-to-antibody ratio in the antibody-drug conjugate. Certain embodiments of m will be shown below.(42-1) An antibody-drug conjugate or a salt thereof, wherein m is a number of 1 to 20.(42-2) An antibody-drug conjugate or a salt thereof, wherein m is a number of 1 to 10.(42-3) An antibody-drug conjugate or a salt thereof, wherein m is a number of 2 to 10.(42-4) An antibody-drug conjugate or a salt thereof, wherein m is a number of 3 to 9.(42-5) An antibody-drug conjugate or a salt thereof, wherein m is a number of 2 to 6.(42-6) An antibody-drug conjugate or a salt thereof, wherein m is a number of 3 to 5.(42-7) An antibody-drug conjugate or a salt thereof, wherein m is a number of 6 to 10.(42-8) An antibody-drug conjugate or a salt thereof, wherein m is a number of 7 to 9.

[0213] Embodiments of the antibody-drug conjugate according to the present invention or the salt thereof will be shown below.

[0214] (43-1) The antibody-drug conjugate or the salt thereof, whereinD is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (II):[Chemical Formula 248]whereinA is CRA or N,RA is H or C1-3 alkyl,X1 is -CH2- or -O-,R1 is naphthyl optionally substituted by OH, or a group represented by the following formula (III):[Chemical Formula 249]R1a is H, methyl, F, or Cl,R1b is F, Cl, methyl, or ethyl,R2 is H, halogen, cyclopropyl, vinyl, or C1-3 alkyl optionally substituted by a group selected from the group consisting of OH and OCH3,R3 is a group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII):[Chemical Formula 250]R3a is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 5- or 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,R3b is H or C1-3 alkyl,each of R3c and R3d is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,on the proviso that when R3c is -(CH2)pCHR3f-NRN1RN2, X2 in formula (V) is -O-, -NH-, or -N(C2-3 alkyl)-,R3e is -O-C2-3 alkylene-NRN1RN2,R3f is H, F, or C1-3 alkyl,R3g is H or C1-3 alkyl,R3h is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms,R3i are the same or different from each other and each is a group selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, -NH-optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)2, halogen, -CN, and oxo, ortwo R3i present on the same carbon atom optionally form, together with the adjacent carbon atom, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a spiro ring as the group of formula (XIII), wherein the spiro ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two adjacent carbon atoms optionally form, together with the two carbon atoms, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a condensed ring as the group of formula (XIII), wherein the condensed ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two non-adjacent carbon atoms, optionally form, together with the two carbon atoms, a bridged structure of 1 or 2 carbon atoms, wherein the group of formula (XIII) which is a ring having the bridged structure is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl, orRN1 and RN2 optionally form, together with the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, orR3f and RN1 optionally form, together with the carbon atom and the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,X2 is -O-, -NH-, or -N(C1-3 alkyl)-,X3 is O or S,X4 is -CH2-, -CH2-CH2-, or -O-CH2-,n is 1 or 2,p is 1 or 2,q is an integer of 1 to 8,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, R4a, cyclopropyl, N(R4a)2, pyrrolidinyl optionally substituted by R4a, and tetrahydrofuranyl optionally substituted by R4a; piperidinyl optionally substituted by R4b; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl optionally substituted by F,R4b is C1-3 alkyl substituted by 1 to 3 F,Y is phenylene optionally substituted by F or Cl, or pyridinediyl,LP is a group that chemically bonds Y to EUB,EUB is a group having the ability to bind to E3 ubiquitin ligase, andLA is a linker for connecting Ab and D and is bonded to an arbitrary nitrogen atom or oxygen atom of -OH contained in D, wherein when the nitrogen atom is tertiary amine, the nitrogen atom is bonded to LA to form quaternary ammonium.

[0215] (43-2) The antibody-drug conjugate or the salt thereof according to (43-1), wherein LA is a linker for connecting Ab and D and is bonded to a nitrogen atom of amine or an oxygen atom of -OH contained in the group R3, R4, or EUB of D to form N-LA or O-LA, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to LA to form quaternary ammonium.

[0216] (43-3) The antibody-drug conjugate or the salt thereof according to (43-2), whereinA is CRA or N,RA is H,X1 is -O-,R1 is a group represented by the following formula (III-a):[Chemical Formula 251]R2 is cyclopropyl,R3 is a group selected from the group consisting of the following formula (IV), formula (V), and formula (XI):[Chemical Formula 252]R3a is -(CH2)pCHR3f-NRN1RN2,R3b is H,R3c is C3-6 cycloalkyl optionally substituted by -NRN1RN2,R3f is H,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl,X2 is -O- or -NH-,X3 is O,n is 1,p is 1,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of OCH3, N(R4a)2, and pyrrolidinyl optionally substituted by R4a; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl, andY is phenylene.

[0217] (43-4) The antibody-drug conjugate or the salt thereof according to (43-3), whereinA is N,R3 is a group represented by the following formula (XI):[Chemical Formula 253]R4 is C1-6 alkyl substituted by N(R4a)2, andR4a is C1-3 alkyl.

[0218] (43-5) The antibody-drug conjugate or the salt thereof according to (43-2), wherein EUB is a group having the ability to bind to VHL or CRBN.(43-6) The antibody-drug conjugate or the salt thereof according to (43-2), wherein EUB is a group having the ability to bind to CRBN.(43-7) The antibody-drug conjugate or the salt thereof according to (43-2), wherein EUB is a group having the ability to bind to VHL.

[0219] (43-8) The antibody-drug conjugate or the salt thereof according to (43-7), whereinEUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 254]R5 is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, C3-6 cycloalkylmethyl, or C3-6 cycloalkyl,R6a and R6b are the same or different from each other and each is H or C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, and N(CH3)2, orR6a and R6b optionally form, together with the carbon bonded thereto, optionally substituted C3-6 cycloalkane, or an optionally substituted 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,R7 is an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or 6-membered heteroaryl containing 1 to 3 nitrogen atoms,W is optionally substituted phenylene or optionally substituted 6-membered heteroarenediyl containing 1 to 3 nitrogen atoms as ring-constituting atom,LP is -(L1-L2-L3-L4)-,L1, L2, L3, and L4 are the same or different from each other and each is a group selected from the group consisting of a bond, -O-, -NRL1-, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3 alkylene, and C=O,RL1 is H or C1-3 alkyl, andZ is NH or 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom.

[0220] (43-9) The antibody-drug conjugate or the salt thereof according to (43-8), whereinEUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 255]R5 is isopropyl or tert-butyl,R6a and R6b are different from each other and each is H, or C1-6 alkyl optionally substituted by OH,R7 is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen,W is phenylene,LP is a bond, andZ is 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom.

[0221] (43-10) The antibody-drug conjugate or the salt thereof according to (43-9), whereinR7 is a group represented by the following formula (XVI):[Chemical Formula 256]W is a group represented by the following formula (XVII-a):[Chemical Formula 257]andZ is a group represented by the following formula (XVIII):[Chemical Formula 258]

[0222] (43-11) The antibody-drug conjugate or the salt thereof according to (43-2), wherein LA is a linker represented by formula (XV):[Chemical Formula 259]whereinStr is a stretcher unit and is connected to Ab and CLL,CLL is a partial structure cleavable in vivo,Sp is a spacer unit and is connected to CLL and D, t is 0 or 1, and*Ab represents a site of connection to Ab.

[0223] (43-12) The antibody-drug conjugate or the salt thereof according to (43-11), whereinii) Str is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 260]Rst1 is optionally substituted C1-12 alkylene, -optionally substituted C1-6 alkylene-C(=O)-NH-C1-6 alkylene-(OCH2CH2)a-, or -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-, a is an integer of 1 to 10,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-1), *STR represents a site of connection to Str,[Chemical Formula 261]RAA are each independently one group selected from the group consisting of H, methyl, isopropyl, benzyl, and -(CH2)3-NH-C(=O)-NH2,d is an integer of 2 to 4,Sp is a spacer unit represented by formula (SP-1), formula (SP-2), or formula (SP-3), t is 1, *CLL represents a site of connection to CLL,[Chemical Formula 262]andRSP is H,orii) Str is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 263]Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivorepresented by formula (CL-2), *STR represents a site of connection to Str,[Chemical Formula 264]andt is 0.

[0224] (43-13) The antibody-drug conjugate or the salt thereof according to (43-12), whereinStr is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 265]Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-2), *STR represents a site of connection to Str,[Chemical Formula 266]andt is 0.

[0225] (43-14) The antibody-drug conjugate or the salt thereof according to (43-2), whereinA is CRA or N,RA is H,X1 is -O-,R1 is a group represented by the following formula (III-a):[Chemical Formula 267]R2 is cyclopropyl,R3 is a group selected from the group consisting of the following formula (IV), formula (V), and formula (XI):[Chemical Formula 268]R3a is -(CH2)pCHR3f-NRN1RN2,R3b is H,R3c is C3-6 cycloalkyl optionally substituted by -NRN1RN2,R3f is H,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl,X2 is -O- or -NH-,X3 is O,n is 1,p is 1,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of OCH3, N(R4a)2, and pyrrolidinyl optionally substituted by R4a; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl,Y is phenylene,EUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 269]R5 is isopropyl or tert-butyl,R6a and R6b are different from each other and each is H, or C1-6 alkyl optionally substituted by OH,R7 is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen,W is phenylene,LP is a bond,Z is 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,LA is a linker represented by formula (XV) (wherein *Ab represents a site of connection to Ab):[Chemical Formula 270]Str is a stretcher unit and is connected to Ab and CLL,CLL is a partial structure cleavable in vivo,Sp is a spacer unit and is connected to CLL and D, t is 0 or 1,whereini) Str is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 271]Rst1 is optionally substituted C1-12 alkylene, -optionally substituted C1-6 alkylene-C(=O)-NH-C1-6 alkylene-(OCH2CH2)a-, or -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-, a is an integer of 1 to 10,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-1), *STR represents a site of connection to Str,[Chemical Formula 272]RAA are each independently one group selected from the group consisting of H, methyl, isopropyl, benzyl, and -(CH2)3-NH-C(=O)-NH2,d is an integer of 2 to 4,Sp is a spacer unit represented by formula (SP-1), formula (SP-2), or formula (SP-3), t is 1, *CLL represents a site of connection to CLL,[Chemical Formula 273]andRSP is H,orii) Str is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 274]Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-2), *STR represents a site of connection to Str,[Chemical Formula 275]t is 0,LA is bonded to a nitrogen atom of amine contained in R3 or R4, or an oxygen atom of -OH contained in EUB to form N-LA or O-LA, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded LA to form quaternary ammonium,and m is a number of 2 to 10.

[0226] (43-15) The antibody-drug conjugate or the salt thereof according to (43-14), whereinA is N,R3 is a group represented by the following formula (XI):[Chemical Formula 276]R4 is C1-6 alkyl substituted by N(R4a)2,R4a is C1-3 alkyl,R7 is a group represented by the following formula (XVI):[Chemical Formula 277]W is a group represented by the following formula (XVII-a):[Chemical Formula 278]Z is a group represented by the following formula (XVIII):[Chemical Formula 279]Str is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 280]Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-2), *STR represents a site of connection to Str,[Chemical Formula 281]t is 0, andLA is a linker for connecting Ab and D and is bonded to a nitrogen atom of N(R4a)2 contained in the group R4 of D to form -N+(R4a)2-LA.

[0227] (43-16) The antibody-drug conjugate or the salt thereof according to (43-2), whereinA is N,X1 is -O-,R1 is a group represented by the following formula (III-a):[Chemical Formula 282]R2 is cyclopropyl,R3 is a group represented by the following formula (XI):[Chemical Formula 283]R4 is C1-6 alkyl substituted by N(R4a)2,R4a is C1-3 alkyl,Y is phenylene,LP is a bond,EUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 284]R5 is isopropyl or tert-butyl,R6a and R6b are different from each other and each is H, or C1-6 alkyl optionally substituted by OH,R7 is a group represented by the following formula (XVI):[Chemical Formula 285]W is a group represented by the following formula (XVII-a):[Chemical Formula 286]andZ is a group represented by the following formula (XVIII):[Chemical Formula 287]

[0228] (43-17) The antibody-drug conjugate or the salt thereof according to (43-2), whereinA is CRA or N,RA is H,X1 is -O-,R1 is a group represented by the following formula (III-a):[Chemical Formula 288]R2 is cyclopropyl,R3 is a group selected from the group consisting of the following formula (IV-a) and formula (V-a):[Chemical Formula 289]R3a is -(CH2)pCHR3f-NRN1RN2,R3b is H,R3c is C3-6 cycloalkyl optionally substituted by -NRN1RN2,R3f is H,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl,X2 is -O- or -NH-,X3 is O,p is 1,R4 is C1-6 alkyl optionally substituted by OCH3,Y is phenylene,LP is a bond,EUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 290]R5 is isopropyl,R6a is H, R6b is hydroxymethyl,R7 is a group selected from the group consisting of the following formula (XIX-a) and formula (XVI):[Chemical Formula 291]W is a group represented by formula (XVII-a):[Chemical Formula 292]andZ is a group represented by the following formula (XVIII-a):[Chemical Formula 293]wherein * represents a site of connection to LP.

[0229] (43-18) The antibody-drug conjugate or the salt thereof according to (43-2), whereinLA is a linker represented by formula (XV) (wherein *Ab represents a site of connection to Ab):[Chemical Formula 294]Str is a stretcher unit and is connected to Ab and CLL, r is 0,CLL is a partial structure cleavable in vivo represented by formula (CL-3):[Chemical Formula 295](wherein *STR represents a site of connection to Str),Sp is a spacer unit represented by formula (SP-4):[Chemical Formula 296](wherein*CLL represents a site of connection to CLL) and is connected to CLL and D, t is 1, andLA is bonded to an oxygen atom of -OH contained in the group EUB of D to form O-LA.(43-19) The antibody-drug conjugate or the salt thereof according to any of (43-1) to (43-18), wherein D is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (PL-1') (wherein*LA represents a site of connection to LA):[Chemical Formula 297](43-20) The antibody-drug conjugate or the salt thereof according to any of (43-1) to (43-19), wherein LA is represented by the following formula (LA-3) (wherein b is an integer of 2 to 20, and *Ab represents a site of connection to Ab):[Chemical Formula 298]

[0230] (43-21) The antibody-drug conjugate or the salt thereof according to any of (43-1) to (43-19), wherein LA is represented by the following formula (LA-4) (wherein b is an integer of 2 to 20, and *Ab represents a site of connection to Ab):[Chemical Formula 299](43-22) The antibody-drug conjugate or the salt thereof according to any of (43-1) to (43-19), wherein LA is represented by the following formula (LA-5) (wherein *Ab represents a site of connection to Ab):[Chemical Formula 300]

[0231] (43-23) The antibody-drug conjugate or the salt thereof according to (43-2), wherein the antibody-drug conjugate is represented by the following formula (AD-1), (AD-2), or (AD-3):[Chemical Formula 301-1][Chemical Formula 301-2][Chemical Formula 301-3]wherein b is an integer of 2 to 20, and m is a number of 2 to 10.(43-24) The antibody-drug conjugate or the salt thereof according to (43-2), wherein the antibody-drug conjugate is represented by the following formula (AD-1):[Chemical Formula 302]wherein b is an integer of 2 to 20, and m is a number of 2 to 10.(43-25) The antibody-drug conjugate or the salt thereof according to (43-2), wherein the antibody-drug conjugate is represented by the following formula (AD-2):[Chemical Formula 303]wherein b is an integer of 2 to 20, and m is a number of 2 to 10.(43-26) The antibody-drug conjugate or the salt thereof according to (43-2), wherein the antibody-drug conjugate is represented by the following formula (AD-3):[Chemical Formula 304]wherein m is a number of 2 to 10.

[0232] (43-27) The antibody-drug conjugate or the salt thereof according to any of (43-1) to (43-26), wherein Ab is an antibody or an antigen binding fragment that binds to an antigen 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, CEACAM5, CEACAM6, CLDN1, CLDN4, CLDN6, CLDN18.2, cMET, EGFR, EphA3, FAP, FGFR3, Fibronectin, FOLRa, Globo H, GPRC5D, HER2, HER3, IGF1R, Integrin αV, KAAG1, LIV1, MSLN, MT1-MMP, MUC1, MUC4, NaPi2b, Nectin-4, PD-L1, PSMA, PTK7, ROR1, ROR2, SEZ6, SialylTn, TF, TROP2, TSPAN8, and VEGF.(43-28) The antibody-drug conjugate or the salt thereof according to any of (43-1) to (43-26), wherein Ab is an antibody or an antigen binding fragment that binds to an antigen selected from the group consisting of EGFR, HER2, Nectin-4, and TROP2.(43-29) The antibody-drug conjugate or the salt thereof according to any of (43-1) to (43-26), wherein Ab is an anti-EGFR antibody or an antigen binding fragment thereof.(43-30) The antibody-drug conjugate or the salt thereof according to (43-29), wherein Ab is an anti-EGFR antibody including a heavy chain variable region and a light chain variable region described in the following (1) or (2) or an antigen binding fragment thereof:(1) a heavy chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 31 to 35 of SEQ ID NO: 1, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 65 of SEQ ID NO: 1, and CDR3 consisting of an amino acid sequence from amino acid positions 98 to 108 of SEQ ID NO: 1, anda light chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 24 to 34 of SEQ ID NO: 2, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 56 of SEQ ID NO: 2, and CDR3 consisting of an amino acid sequence from amino acid positions 89 to 97 of SEQ ID NO: 2; or(2) a heavy chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 31 to 35 of SEQ ID NO: 3, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 65 of SEQ ID NO: 3, and CDR3 consisting of an amino acid sequence from amino acid positions 98 to 108 of SEQ ID NO: 3, anda light chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 24 to 34 of SEQ ID NO: 4, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 56 of SEQ ID NO: 4, and CDR3 consisting of an amino acid sequence from amino acid positions 89 to 97 of SEQ ID NO: 4.(43-31) The antibody-drug conjugate or the salt thereof according to (43-30), wherein Ab is an anti-EGFR antibody including a heavy chain variable region and a light chain variable region selected from the group consisting of the following (1) to (3) or an antigen binding fragment thereof:(1) a heavy chain variable region consisting of an amino acid sequence from amino acid positions 1 to 119 of SEQ ID NO: 1 and a light chain variable region consisting of an amino acid sequence from amino acid positions 1 to 107 of SEQ ID NO: 2;(2) a heavy chain variable region consisting of an amino acid sequence from amino acid positions 1 to 119 of SEQ ID NO: 3 and a light chain variable region consisting of an amino acid sequence from amino acid positions 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 higher identity to the heavy chain variable region and the light chain variable region described in (1) or (2) above.(43-32) The antibody-drug conjugate or the salt thereof according to (43-31), wherein Ab is an IgG1 or IgG4 type anti-EGFR antibody.(43-33) The antibody-drug conjugate or the salt thereof according to (43-32), wherein Ab is cetuximab or an engineered form thereof.(43-34) The antibody-drug conjugate or the salt thereof according to (43-32), wherein Ab is cetuximab.(43-35) The antibody-drug conjugate or the salt thereof according to (43-32), wherein 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.(43-36) The antibody-drug conjugate or the salt thereof according to any of (43-14) to (43-35), wherein Ab is a post-translationally modified antibody or an antigen binding fragment, or an antibody or an antigen binding fragment with an arbitrary amino acid residue substituted by cysteine or a non-natural amino acid.(43-37) The antibody-drug conjugate or the salt thereof according to any of (43-1) to (43-36), wherein b is an integer of 5 to 15.(43-38) The antibody-drug conjugate or the salt thereof according to any of (43-1) to (43-36), wherein b is an integer of 10 to 12.(43-39) The antibody-drug conjugate or the salt thereof according to any of (43-1) to (43-36), wherein b is 12.(43-40) The antibody-drug conjugate or the salt thereof according to any of (43-1) to (43-39), wherein m is a number of 2 to 10.(43-41) The antibody-drug conjugate or the salt thereof according to any of (43-1) to (43-39), wherein m is a number of 3 to 9.(43-42) The antibody-drug conjugate or the salt thereof according to any of (43-1) to (43-39), wherein m is a number of 2 to 6.(43-43) The antibody-drug conjugate or the salt thereof according to any of (43-1) to (43-39), wherein m is a number of 3 to 5.(43-44) The antibody-drug conjugate or the salt thereof according to any of (43-1) to (43-39), wherein m is a number of 6 to 10.(43-45) The antibody-drug conjugate or the salt thereof according to any of (43-1) to (43-39), wherein m is a number of 7 to 9.(43-46) An antibody-drug conjugate represented by formula (I) or a salt thereof:[Chemical Formula 305]whereinAb is an anti-EGFR antibody including a heavy chain variable region and a light chain variable region described in the following (1) or (2) or an antigen binding fragment thereof:(1) a heavy chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 31 to 35 of SEQ ID NO: 1, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 65 of SEQ ID NO: 1, and CDR3 consisting of an amino acid sequence from amino acid positions 98 to 108 of SEQ ID NO: 1, anda light chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 24 to 34 of SEQ ID NO: 2, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 56 of SEQ ID NO: 2, and CDR3 consisting of an amino acid sequence from amino acid positions 89 to 97 of SEQ ID NO: 2; or(2) a heavy chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 31 to 35 of SEQ ID NO: 3, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 65 of SEQ ID NO: 3, and CDR3 consisting of an amino acid sequence from amino acid positions 98 to 108 of SEQ ID NO: 3, anda light chain variable region including CDR1 consisting of an amino acid sequence from amino acid positions 24 to 34 of SEQ ID NO: 4, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 56 of SEQ ID NO: 4, and CDR3 consisting of an amino acid sequence from amino acid positions 89 to 97 of SEQ ID NO: 4,LA is a linker represented by formula (LA-3) (wherein *Ab represents a site of connection to Ab):[Chemical Formula 306]b is 12,D is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (PL-1') (wherein*LA represents a site of connection to LA)[Chemical Formula 307]andm is a number of 3 to 9.

[0233] The antibody-drug conjugate of formula (I) or the salt thereof may have tautomers or geometric isomers depending on the types of substituents. In the present specification, the compound of formula (I) may be described in only one form of isomers. The present invention encompasses the other isomers and also encompasses separated isomers or mixtures thereof.The antibody-drug conjugate of formula (I) or the salt thereof may have a chiral carbon atom or a chiral axis and may have diastereomers based thereon. The present invention also encompasses separated diastereomers of the antibody-drug conjugate of formula (I) or the salt thereof or mixtures thereof.

[0234] The antibody-drug conjugate of formula (I) or the salt thereof is an antibody-drug conjugate of formula (I) or a pharmaceutically acceptable salt of a salt thereof and may form an acid-addition salt or a salt with a base depending on the types of substituents. Examples thereof include salts described in P. Heinrich Stahl, Handbook of Pharmaceutical Salts Properties, Selection, and Use, Wiley-VCH, 2008. Specific examples thereof include acid-addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid or organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric 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.

[0235] The present invention further encompasses various hydrates or solvates and crystalline polymorphic substances of the antibody-drug conjugate of formula (I) or the salt thereof.

[0236] The present invention also encompasses every antibody-drug conjugate of formula (I) or salt thereof labeled with one or more pharmaceutically acceptable radioactive or non-radioactive isotopes. Preferred examples of the isotope for use in the isotope label for the compound of the present invention include isotopes of hydrogen (2H and 3H, etc.), carbon (11C, 13C, and 14C, etc.), nitrogen (13N and 15N, etc.), oxygen (15O, 17O, and 18O, etc.), fluorine (18F, etc.), chlorine (36Cl, etc.), iodine (123I and 125I, etc.), and sulfur (35S, etc.).The isotope-labeled compound of the present invention may be used in, for example, a study such as tissue distribution study of a drug and / or a substrate. For example, a radioactive isotope such as tritium (3H) or carbon-14 (14C) may be used for this purpose because of easy labeling and convenient detection.Substitution by a heavier isotope, for example, substitution of hydrogen by deuterium (2H), may be therapeutically advantageous (e.g.,in vivoincrease in half-life, decrease in necessary dose, and decrease in drug interaction) through improvement in metabolic stability.Substitution by a positron-emitting isotope (11C, 18F, 15O, and 13N, etc.) may be used in a positron emission tomography (PET) test in order to test a substrate receptor occupancy.The isotope-labeled compound of the present invention can be produced by a conventional approach generally known to those skilled in the art or by, for example, the same or similar production method as in Examples or Production Examples using an appropriate isotope-labeled reagent instead of an unlabeled reagent.

[0237] (Production method)The antibody-drug conjugate of formula (I) or the salt thereof can be produced by the application of various synthesis methods known in the art, through the use of a feature based on its basic structure or the types of substituents. Depending on the type of a functional group, the replacement of the functional group with an appropriate protective group (group easily convertible to the functional group) at a stage from a starting material to an intermediate may be effective for a production technique. Examples of such a protective group can include protective groups described in P. G. M. Wuts and T. W. Greene, "Greene's Protective Groups in Organic Synthesis", 5th edition, John Wiley & Sons Inc., 2014, which can be appropriately selected and used depending on their reaction conditions. In such a method, the protective group can be introduced and, after reaction, removed, if necessary, to obtain the desired compound.Hereinafter, representative methods for producing the antibody-drug conjugate of formula (I) or the salt thereof as well as drug (D), drug-linker conjugate (LA-D), and antibody (Ab) constituting the antibody-drug conjugate or the salt thereof will be described. Each production method may be performed with reference to a reference document given in the description. The production method of the present invention is not limited to the following examples.

[0238] In the present specification, the following abbreviations may be used.DMF: N,N-dimethylformamide, DMA: N,N-dimethylacetamide, NMP: N-methyl-2-pyrrolidone, THF: tetrahydrofuran, MeCN: acetonitrile, MeOH: methanol, EtOH: ethanol, iPrOH: isopropyl alcohol, tBuOH: tert-butyl alcohol, DOX: 1,4-dioxane, DMSO: dimethyl sulfoxide, iPr2O: diisopropyl ether, TEA: triethylamine, DIPEA: N,N-diisopropylethylamine, NMM: N-methylmorpholine, DMEDA: N,N'-dimethylethylenediamine, DBU: 1,8-diazabicyclo[5.4.0]-7-undecene, DABCO: 1,4-diazabicyclo[2.2.2]octane, Triton B: benzyl trimethylammonium hydroxide, tBuOK: potassium tert-butoxide, LHMDS: lithium bis(trimethylsilyl)amide, NHMDS: sodium bis(trimethylsilyl)amide, PdCl2(dppf)⋅CH2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride⋅dichloromethane adduct, Pd / C: palladium carbon, SPhos Pd G3: (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, SPhos: 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, RuPhos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, PyBOP: (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, PyAOP: (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, COMU: N-[({[(1Z)-1-cyano-2-ethoxy-2-oxoethylidene]amino}oxy)(morpholin-4-yl)methylene]-N-methylmethanamium hexafluorophosphate, CDI: 1,1'-carbonyldiimidazole, TFA: trifluoroacetic acid, TfOH: trifluoromethanesulfonic acid, NMO: N-methylmorpholine N-oxide, TBAF: tetrabutylammonium fluoride, TCEP: tris(2-carboxyethyl)phosphine, TSTU: N,N,N'N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate, TBTA: tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine, TMAD: N,N,N',N'-tetramethylazodicarboxamide, EDTA: ethylenediaminetetraacetic acid, NBS: N-bromosuccinimide, DMAP: 4-dimethylaminopyridine, TBSOTf: tert-butyldimethylsilyl trifluoromethanesulfonate, ADMP: 2-azido-1,3-dimethylimidazolinium hexafluorophosphate, Me: methyl, TBS: tert-butyldimethylsilyl, FMOC: 9-fluorenylmethyloxycarbonyl, Ac: acetyl, PPTS: pyridinium p-toluenesulfonate, BOC: tert-butoxycarbonyl.

[0239] I. Production method for drug (D)

[0240] (Drug production method 1)[Chemical Formula 308]wherein R1A and R3A represent divalent groups obtained by eliminating H from functional groups that permit introduction of protective groups from R1 and R3, PG1 and PG2 each represent a protective group, and any one of the protective groups may be absent (the same holds true for the description below).

[0241] This production method is a production method for a heterocyclic compound represented by formula (II). The heterocyclic compound of formula (II) can be obtained by subjecting compound (1) to deprotection reaction. It may be obtained by subjecting NH2 contained in R3 to alkylation reaction after deprotection reaction. In this context, examples of the protective group include a tert-butoxycarbonyl group, a triphenylmethyl group, a tetrahydro-2H-pyran-2-yl group, a methoxymethyl group, a dimethylmethanediyl group, and a tert-butylsulfinyl group.The deprotection reaction involves stirring usually for 0.1 hours to 5 days under cooling to under heating to reflux. In this context, examples of the solvent used include, but are not particularly limited to, alcohols such as MeOH, EtOH, and iPrOH, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, ethers such as diethyl ether, THF, DOX, and dimethoxyethane, DMF, DMSO, MeCN, water, and mixtures thereof. Examples of the deprotection reagent include, but are not particularly limited to, acids such as hydrogen chloride (DOX solution), trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and phosphoric acid.The deprotection may be performed through catalytic hydrogenation reaction by selecting a protective group. Examples of the protective group include a benzyl group, a p-methoxybenzyl group, and a benzyloxycarbonyl group. The deprotection may be performed with a fluoride ion source such as tetra-n-butylammonium fluoride. Examples of the protective group include a tert-butyl(dimethyl)silyl group and a (trimethylsilyl)ethoxymethyl group. Examples of the protective group that may be deprotected under basic conditions include an acetyl group, a trifluoroacetyl group, and a benzoyl group. The deprotection may be performed in stages by selecting protective groups that can be deprotected under different deprotection conditions as PG1 and PG2, respectively.The alkylation reaction involves stirring at -45°C to under heating to reflux, preferably at 0°C to room temperature, usually for 0.1 hours to 5 days in a solvent inert to the reaction in the presence of a reducing agent using formaldehyde or alkyl having a formyl group. In this context, examples of the solvent used include, but are not particularly limited to, alcohols such as methanol and ethanol, ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, and mixtures thereof. Examples of the reducing agent include sodium cyanoborohydride, sodium triacetoxyborohydride, and sodium borohydride. It may be preferred to perform the reaction in the presence of a dehydrating agent such as a molecular sieve, or an acid such as acetic acid, hydrochloric acid, or a titanium(IV) isopropoxide complex.For a reference document, see the following, for example.P. G. M. Wuts and T. W. Greene, "Greene's Protective Groups in Organic Synthesis", fifth edition, John Wiley & Sons Inc., 2014A. R. Katritzky and R. J. K. Taylor, "Comprehensive Organic Functional Group Transformations II", vol. 2, Elsevier Pergamon, 2005When starting material compound (1) has axial chirality, this reaction may be performed using a stereoisomer obtained by temporarily separating compound (1).

[0242] Hydrochloride of the heterocyclic compound of formula (II) can be obtained by subjecting the heterocyclic compound of formula (II) to, for example, the following operation as salification reaction.A heterocyclic compound of formula (II) considered to form a salt with hydrochloric acid owing to a feature of its chemical structure is dissolved in CH2Cl2 and MeOH, and hydrogen chloride (4 M DOX solution, 10 equivalents) is added thereto under ice cooling and stirred for 30 minutes under ice cooling. The reaction mixture is concentrated under reduced pressure. To the obtained residue, diethyl ether is added, and the formed solid is collected by filtration and dried under reduced pressure to obtain hydrochloride of the heterocyclic compound of formula (II).

[0243] The heterocyclic compound of formula (II) can be obtained by subjecting the hydrochloride of the heterocyclic compound of formula (II) to, for example, the following operation as desalting reaction, though not limited to this method.The hydrochloride of the heterocyclic compound of formula (II) is purified by ODS column chromatography (MeCN / 0.1% aqueous formic acid solution) to collect a fraction containing the compound of interest, which is then rendered basic with a saturated aqueous solution of sodium bicarbonate, followed by extraction with CHCl3 / MeOH (5 / 1). A combined organic layer is dried over anhydrous sodium sulfate, and the solution is concentrated under reduced pressure. The obtained solid is washed with diethyl ether and dried under reduced pressure to obtain the heterocyclic compound of formula (II).

[0244] (Drug production method 2)[Chemical Formula 309]This production method is a production method for a heterocyclic compound represented by formula (II-b) as the heterocyclic compound represented by formula (II). The heterocyclic compound represented by formula (II-b) can be obtained through cycloaddition reaction of compound (2) and compound (3).This reaction involves using compound (2) and compound (3) in equal amounts or one of them in an excessive amount, and stirring a mixture thereof under cooling to under heating to reflux, preferably at 0°C to 100°C, usually for 0.1 hours to 5 days in a solvent inert to the reaction or without a solvent, preferably in the presence of a copper salt, further preferably in the presence of a copper salt and a reducing agent. In this context, examples of the solvent used include, but are not particularly limited to, 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 the copper salt include CuI, CuSO4, and copper(I) trifluoromethanesulfonate (CuOTf). Examples of the reducing agent include sodium ascorbate. Reaction in the presence of TEA, DIPEA, NMM, 2,6-lutidine, TBTA, or the like may be advantageous for allowing the reaction to proceed smoothly.[Reference]Angew. Chem. Int. Ed. 2002, 41, p. 2596-2599

[0245] (Drug starting material synthesis 1)[Chemical Formula 310]Step 1Step 1

[0246] This production method is the first method for producing compound (1)-1 included in starting material compound (1).

[0247] (Step 1)This step is a method for producing compound (1)-1 through cycloaddition reaction of compound (2)-1 with R3 and R4 of compound (2) protected with protective groups, and compound (3). The reaction conditions are the same as those for the cycloaddition reaction of drug production method 2.This reaction may be performed using a compound obtained by initially subjecting PG2 of compound (2)-1 to deprotection reaction.

[0248] (Drug starting material synthesis 2)[Chemical Formula 311]Step 3Step 3Step 2Step 2Step 1Step 1wherein R represents a C1-3 alkyl group (the same holds true for the description below).

[0249] This production method is the second method for producing compound (1)-1 included in starting material compound (1).

[0250] (Step 1)This step is a method for producing compound (5) through cycloaddition reaction of compound (2)-1 and compound (4).The reaction conditions are the same as those for step 1 of drug starting material synthesis 1.

[0251] (Step 2)This step is a method for producing compound (6) by hydrolyzing compound (5).This reaction is performed by stirring compound (5) usually for 0.1 hours to 5 days under cooling to under heating to reflux. In this context, examples of the solvent used include, but are not particularly limited to, alcohols, acetone, DMF, and THF. A mixed solvent of the solvent described above with water may be suitable for the reaction. Examples of the hydrolysis reagent include, but are not particularly limited to, an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, and trimethyltin hydroxide.For a reference document of this reaction, see the following, for example.The Chemical Society of Japan ed., "Jikken Kagaku Koza (Courses in Experimental Chemistry in English) (fifth edition)" Vol. 16 (2005) (Maruzen Co., Ltd.)Angew. Chem. Int. Ed. 2005, 44, p. 1378-1382.

[0252] (Step 3)This step is a method for producing compound (1)-1 through amidation reaction of compound (6) and compound (7).This reaction involves using compound (6) and compound (7) in equal amounts or one of them in an excessive amount, and stirring a mixture thereof under cooling to under heating, preferably at -20°C to 60°C, usually for 0.1 hours to 5 days in a solvent inert to the reaction in the presence of a condensing agent. Examples of the solvent include, but are not particularly limited to, 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 the condensing agent include PyBOP, HATU, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and hydrochloride thereof, N,N'-dicyclohexylcarbodiimide (DCC), CDI, and diphenylphosphorylazide (DPPA). It may be preferred for the reaction to use an additive (e.g., 1-hydroxybenzotriazole). The reaction in the presence of an organic base such as TEA, DIPEA, or NMM, or an inorganic base such as potassium carbonate, sodium carbonate, or potassium hydroxide may be advantageous for allowing the reaction to proceed smoothly.A method of converting compound (6) to a reactive derivative, followed by acylation reaction may be used. Examples of the reactive derivative of carboxylic acid include acid halide obtained through reaction with a halogenating agent such as phosphorus oxychloride or thionyl chloride, mixed acid anhydride obtained through reaction with isobutyl chloroformate or the like, and active ester obtained by condensation with 1-hydroxybenzotriazole or the like. The reaction of compound (7) with such a reactive derivative can be performed under cooling to under heating, preferably at -20°C to 120°C, in a solvent inert to the reaction, such as a halogenated hydrocarbon, an aromatic hydrocarbon, or an ether.[Reference]S. R. Sandler and W. Karo, "Organic Functional Group Preparations", 2nd edition, vol. 1, Academic Press Inc., 1991The Chemical Society of Japan ed., "Jikken Kagaku Koza (Courses in Experimental Chemistry in English) (fifth edition)" vol. 16 (2005) (Maruzen Co., Ltd.)

[0253] (Drug starting material synthesis 3)[Chemical Formula 312]Step 1Step 1Step 2Step 2Step 3Step 3wherein R3B represents NR3aaR3bb, OR3cc, or R3dd, PG1A and PG3 each represent a protective group, R3B represents a divalent group obtained by eliminating H from each of a functional group that permits introduction of a protective group and a functional group that permits introduction of a carbonyl group or a carboxyl group from any of NR3aR3b, OR3c, and R3d, and R1 optionally has PG2 (the same holds true for the description below).

[0254] This production method is the second method for producing compound (1)-2 included in starting material compound (1).

[0255] (Step 1)This step is a method for producing compound (9) through cycloaddition reaction of compound (8) and compound (3).The reaction conditions are the same as those for step 1 of drug starting material synthesis 1.

[0256] (Step 2)This step is ...

Claims

1. An antibody-drug conjugate represented by formula (I) or a salt thereof:[Chemical Formula 1]whereinAb is an antibody or an antigen binding fragment thereof,D is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect,LA is a linker for connecting Ab and D, andm is a number of 1 to 20. 2. The antibody-drug conjugate or the salt thereof according to claim 1, whereinD is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (II):[Chemical Formula 2]whereinA is CRA or N,RA is H or C1-3 alkyl,X1 is -CH2- or -O-,R1 is naphthyl optionally substituted by OH, or a group represented by the following formula (III):[Chemical Formula 3]R1a is H, methyl, F, or Cl,R1b is F, Cl, methyl, or ethyl,R2 is H, halogen, cyclopropyl, vinyl, or C1-3 alkyl optionally substituted by a group selected from the group consisting of OH and OCH3,R3 is a group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII):[Chemical Formula 4]R3a is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 5- or 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,R3b is H or C1-3 alkyl,each of R3c and R3d is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,on the proviso that when R3c is -(CH2)pCHR3f-NRN1RN2, X2 in formula (V) is -O-, -NH-, or -N(C2-3 alkyl)-,R3e is -O-C2-3 alkylene-NRN1RN2,R3f is H, F, or C1-3 alkyl,R3g is H or C1-3 alkyl,R3h is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms,R3i are the same or different from each other and each is a group selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, -NH-optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)2, halogen, -CN, and oxo, ortwo R3i present on the same carbon atom optionally form, together with the adjacent carbon atom, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a spiro ring as the group of formula (XIII), wherein the spiro ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two adjacent carbon atoms optionally form, together with the two carbon atoms, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a condensed ring as the group of formula (XIII), wherein the condensed ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two non-adjacent carbon atoms, optionally form, together with the two carbon atoms, a bridged structure of 1 or 2 carbon atoms, wherein the group of formula (XIII) which is a ring having the bridged structure is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl, orRN1 and RN2 optionally form, together with the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, orR3f and RN1 optionally form, together with the carbon atom and the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,X2 is -O-, -NH-, or -N(C1-3 alkyl)-,X3 is O or S,X4 is -CH2-, -CH2-CH2-, or -O-CH2-,n is 1 or 2,p is 1 or 2,q is an integer of 1 to 8,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, R4a, cyclopropyl, N(R4a)2, pyrrolidinyl optionally substituted by R4a, and tetrahydrofuranyl optionally substituted by R4a; piperidinyl optionally substituted by R4b; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl optionally substituted by F,R4b is C1-3 alkyl substituted by 1 to 3 F,Y is phenylene optionally substituted by F or Cl, or pyridinediyl,LP is a group that chemically bonds Y to EUB,EUB is a group having the ability to bind to E3 ubiquitin ligase, andLA is a linker for connecting Ab and D and is bonded to an arbitrary nitrogen atom or oxygen atom of -OH contained in D, wherein when the nitrogen atom is tertiary amine, the nitrogen atom is bonded to LA to form quaternary ammonium. 3. The antibody-drug conjugate or the salt thereof according to claim 2, wherein LA is a linker for connecting Ab and D and is bonded to a nitrogen atom of amine or an oxygen atom of -OH contained in the group R3, R4, or EUB of D to form N-LA or O-LA, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to LA to form quaternary ammonium. 4. The antibody-drug conjugate or the salt thereof according to claim 3, whereinA is CRA or N,RA is H,X1 is -O-,R1 is a group represented by the following formula (III-a):[Chemical Formula 5]R2 is cyclopropyl,R3 is a group selected from the group consisting of the following formula (IV), formula (V), and formula (XI):[Chemical Formula 6]R3a is -(CH2)pCHR3f-NRN1RN2,R3b is H,R3c is C3-6 cycloalkyl optionally substituted by -NRN1RN2,R3f is H,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl,X2 is -O- or -NH-,X3 is O,n is 1,p is 1,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of OCH3, N(R4a)2, and pyrrolidinyl optionally substituted by R4a; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl, andY is phenylene. 5. The antibody-drug conjugate or the salt thereof according to claim 4, whereinA is N,R3 is a group represented by the following formula (XI):[Chemical Formula 7]R4 is C1-6 alkyl substituted by N(R4a)2, andR4a is C1-3 alkyl. 6. The antibody-drug conjugate or the salt thereof according to claim 3, wherein EUB is a group having the ability to bind to VHL. 7. The antibody-drug conjugate or the salt thereof according to claim 3, whereinEUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 8]R5 is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, C3-6 cycloalkylmethyl, or C3-6 cycloalkyl,R6a and R6b are the same or different from each other and each is H or C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, and N(CH3)2, orR6a and R6b optionally form, together with the carbon bonded thereto, optionally substituted C3-6 cycloalkane, or an optionally substituted 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,R7 is an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or 6-membered heteroaryl containing 1 to 3 nitrogen atoms,W is optionally substituted phenylene or optionally substituted 6-membered heteroarenediyl containing 1 to 3 nitrogen atoms as ring-constituting atom,LP is -(L1-L2-L3-L4)-,L1, L2, L3, and L4 are the same or different from each other and each is a group selected from the group consisting of a bond, -O-, -NRL1-, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3 alkylene, and C=O,RL1 is H or C1-3 alkyl, andZ is NH or 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom. 8. The antibody-drug conjugate or the salt thereof according to claim 7, whereinEUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 9]R5 is isopropyl or tert-butyl,R6a and R6b are different from each other and each is H, or C1-6 alkyl optionally substituted by OH,R7 is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen,W is phenylene,LP is a bond, andZ is 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom. 9. The antibody-drug conjugate or the salt thereof according to claim 8, whereinR7 is a group selected from the group consisting of the following formula (XIX-a), formula (XX-a), and formula (XVI):[Chemical Formula 10]W is a group represented by the following formula (XVII-a):[Chemical Formula 11]andZ is a group represented by the following formula (XVIII):[Chemical Formula 12] 10. The antibody-drug conjugate or the salt thereof according to claim 9, wherein R7 is a group represented by the following formula (XVI):[Chemical Formula 13] 11. The antibody-drug conjugate or the salt thereof according to claim 3, wherein LA is a linker represented by formula (XV):[Chemical Formula 14]whereinStr is a stretcher unit and is connected to Ab and CLL,CLL is a partial structure cleavable in vivo,Sp is a spacer unit and is connected to CLL and D, t is 0 or 1, and*Ab represents a site of connection to Ab. 12. The antibody-drug conjugate or the salt thereof according to claim 11, whereini) Str is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 15]Rst1 is optionally substituted C1-12 alkylene, -optionally substituted C1-6 alkylene-C(=O)-NH-C1-6 alkylene-(OCH2CH2)a-, or -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-, a is an integer of 1 to 10,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-1), *STR represents a site of connection to Str,[Chemical Formula 16]RAA are each independently one group selected from the group consisting of H, methyl, isopropyl, benzyl, and -(CH2)3-NH-C(=O)-NH2,d is an integer of 2 to 4,Sp is a spacer unit represented by formula (SP-1), formula (SP-2), or formula (SP-3), t is 1, *CLL represents a site of connection to CLL,[Chemical Formula 17]andRSP is H,orii) Str is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 18]Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivorepresented by formula (CL-2), *STR represents a site of connection to Str,[Chemical Formula 19]andt is 0. 13. The antibody-drug conjugate or the salt thereof according to claim 12, whereinStr is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 20]Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-2), *STR represents a site of connection to Str,[Chemical Formula 21]andt is 0. 14. The antibody-drug conjugate or the salt thereof according to claim 3, whereinA is CRA or N,RA is H,X1 is -O-,R1 is a group represented by the following formula (III-a):[Chemical Formula 22]R2 is cyclopropyl,R3 is a group selected from the group consisting of the following formula (IV), formula (V), and formula (XI):[Chemical Formula 23]R3a is -(CH2)pCHR3f-NRN1RN2,R3b is H,R3c is C3-6 cycloalkyl optionally substituted by -NRN1RN2,R3f is H,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl,X2 is -O- or -NH-,X3 is O,n is 1,p is 1,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of OCH3, N(R4a)2, and pyrrolidinyl optionally substituted by R4a; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl,Y is phenylene,EUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 24]R5 is isopropyl or tert-butyl,R6a and R6b are different from each other and each is H, or C1-6 alkyl optionally substituted by OH,R7 is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen,W is phenylene,LP is a bond,Z is 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,LA is a linker represented by formula (XV) (wherein *Ab represents a site of connection to Ab):[Chemical Formula 25]Str is a stretcher unit and is connected to Ab and CLL,CLL is a partial structure cleavable in vivo,Sp is a spacer unit and is connected to CLL and D, t is 0 or 1,whereini) Str is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 26]Rst1 is optionally substituted C1-12 alkylene, -optionally substituted C1-6 alkylene-C(=O)-NH-C1-6 alkylene-(OCH2CH2)a-, or -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-, a is an integer of 1 to 10,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-1), *STR represents a site of connection to Str,[Chemical Formula 27]RAA are each independently one group selected from the group consisting of H, methyl, isopropyl, benzyl, and -(CH2)3-NH-C(=O)-NH2,d is an integer of 2 to 4,Sp is a spacer unit represented by formula (SP-1), formula (SP-2), or formula (SP-3), t is 1, *CLL represents a site of connection to CLL,[Chemical Formula 28]andRSP is H,orii) Str is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 29]Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-2), *STR represents a site of connection to Str,[Chemical Formula 30]t is 0,LA is bonded to a nitrogen atom of amine contained in R3 or R4, or an oxygen atom of -OH contained in EUB to form N-LA or O-LA, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded LA to form quaternary ammonium,and m is a number of 2 to 10. 15. The antibody-drug conjugate or the salt thereof according to claim 14, whereinA is N,R3 is a group represented by the following formula (XI):[Chemical Formula 31]R4 is C1-6 alkyl substituted by N(R4a)2,R4a is C1-3 alkyl,R7 is a group represented by the following formula (XVI):[Chemical Formula 32]W is a group represented by the following formula (XVII-a):[Chemical Formula 33]Z is a group represented by the following formula (XVIII):[Chemical Formula 34]Str is a stretcher unit represented by formula (ST-1), r is 1, *Ab represents a site of connection to Ab,[Chemical Formula 35]Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-2), *STR represents a site of connection to Str,[Chemical Formula 36]t is 0, andLA is bonded to a nitrogen atom of N(R4a)2 contained in R4 to form -N+(R4a)2-LA. 16. The antibody-drug conjugate or the salt thereof according to claim 3, wherein the antibody-drug conjugate is represented by the following formula (AD-1), (AD-2), or (AD-3):[Chemical Formula 37-1][Chemical Formula 37-2][Chemical Formula 37-3]wherein b is an integer of 2 to 20, and m is a number of 2 to 10. 17. The antibody-drug conjugate or the salt thereof according to claim 16, wherein b is 12, and m is a number of 3 to 9. 18. The antibody-drug conjugate or the salt thereof according to claim 1, wherein Ab is an antibody or an antigen binding fragment that binds to an antigen 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, CEACAM5, CEACAM6, CLDN1, CLDN4, CLDN6, CLDN18.2, cMET, EGFR, EphA3, FAP, FGFR3, Fibronectin, FOLRa, Globo H, GPRC5D, HER2, HER3, IGF1R, Integrin αV, KAAG1, LIV1, MSLN, MT1-MMP, MUC1, MUC4, NaPi2b, Nectin-4, PD-L1, PSMA, PTK7, ROR1, ROR2, SEZ6, SialylTn, TF, TROP2, TSPAN8, and VEGF. 19. The antibody-drug conjugate or the salt thereof according to claim 1, wherein Ab is an antibody or an antigen binding fragment that binds to an antigen selected from the group consisting of EGFR, HER2, Nectin-4, and TROP2. 20. The antibody-drug conjugate or the salt thereof according to claim 1, wherein Ab is an anti-EGFR antibody or an antigen binding fragment thereof. 21. The antibody-drug conjugate or the salt thereof according to claim 20, wherein Ab is an anti-EGFR antibody comprising a heavy chain variable region and a light chain variable region described in the following (1) or (2) or an antigen binding fragment thereof:(1) a heavy chain variable region comprising CDR1 consisting of an amino acid sequence from amino acid positions 31 to 35 of SEQ ID NO: 1, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 65 of SEQ ID NO: 1, and CDR3 consisting of an amino acid sequence from amino acid positions 98 to 108 of SEQ ID NO: 1, anda light chain variable region comprising CDR1 consisting of an amino acid sequence from amino acid positions 24 to 34 of SEQ ID NO: 2, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 56 of SEQ ID NO: 2, and CDR3 consisting of an amino acid sequence from amino acid positions 89 to 97 of SEQ ID NO: 2; or(2) a heavy chain variable region comprising CDR1 consisting of an amino acid sequence from amino acid positions 31 to 35 of SEQ ID NO: 3, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 65 of SEQ ID NO: 3, and CDR3 consisting of an amino acid sequence from amino acid positions 98 to 108 of SEQ ID NO: 3, anda light chain variable region comprising CDR1 consisting of an amino acid sequence from amino acid positions 24 to 34 of SEQ ID NO: 4, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 56 of SEQ ID NO: 4, and CDR3 consisting of an amino acid sequence from amino acid positions 89 to 97 of SEQ ID NO: 4. 22. The antibody-drug conjugate or the salt thereof according to claim 21, wherein Ab is an anti-EGFR antibody comprising a heavy chain variable region and a light chain variable region selected from the group consisting of the following (1) to (3) or an antigen binding fragment thereof:(1) a heavy chain variable region consisting of an amino acid sequence from amino acid positions 1 to 119 of SEQ ID NO: 1 and a light chain variable region consisting of an amino acid sequence from amino acid positions 1 to 107 of SEQ ID NO: 2;(2) a heavy chain variable region consisting of an amino acid sequence from amino acid positions 1 to 119 of SEQ ID NO: 3 and a light chain variable region consisting of an amino acid sequence from amino acid positions 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 higher identity to the heavy chain variable region and the light chain variable region described in (1) or (2) above. 23. The antibody-drug conjugate or the salt thereof according to claim 22, wherein Ab is an IgG1 or IgG4 type anti-EGFR antibody. 24. The antibody-drug conjugate or the salt thereof according to claim 23, wherein Ab is cetuximab. 25. The antibody-drug conjugate or the salt thereof according to claim 23, wherein 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. 26. The antibody-drug conjugate or the salt thereof according to claim 18, wherein Ab is a post-translationally modified antibody or an antigen binding fragment, or an antibody or an antigen binding fragment with an arbitrary amino acid residue substituted by cysteine or a non-natural amino acid. 27. An antibody-drug conjugate represented by formula (I) or a salt thereof:[Chemical Formula 38]whereinAb is an anti-EGFR antibody comprising a heavy chain variable region and a light chain variable region described in the following (1) or (2) or an antigen binding fragment thereof:(1) a heavy chain variable region comprising CDR1 consisting of an amino acid sequence from amino acid positions 31 to 35 of SEQ ID NO: 1, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 65 of SEQ ID NO: 1, and CDR3 consisting of an amino acid sequence from amino acid positions 98 to 108 of SEQ ID NO: 1, anda light chain variable region comprising CDR1 consisting of an amino acid sequence from amino acid positions 24 to 34 of SEQ ID NO: 2, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 56 of SEQ ID NO: 2, and CDR3 consisting of an amino acid sequence from amino acid positions 89 to 97 of SEQ ID NO: 2; or(2) a heavy chain variable region comprising CDR1 consisting of an amino acid sequence from amino acid positions 31 to 35 of SEQ ID NO: 3, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 65 of SEQ ID NO: 3, and CDR3 consisting of an amino acid sequence from amino acid positions 98 to 108 of SEQ ID NO: 3, anda light chain variable region comprising CDR1 consisting of an amino acid sequence from amino acid positions 24 to 34 of SEQ ID NO: 4, CDR2 consisting of an amino acid sequence from amino acid positions 50 to 56 of SEQ ID NO: 4, and CDR3 consisting of an amino acid sequence from amino acid positions 89 to 97 of SEQ ID NO: 4,LA is a linker represented by formula (LA-3) (wherein *Ab represents a site of connection to Ab):[Chemical Formula 39]b is 12,D is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (PL-1') (wherein*LA represents a site of connection to LA)[Chemical Formula 40]andm is a number of 3 to 9. 28. A pharmaceutical composition comprising an antibody-drug conjugate or a salt thereof according to claim 1 and a pharmaceutically acceptable excipient. 29. The pharmaceutical composition according to claim 28 for use in the treatment of a cancer. 30. The pharmaceutical composition according to claim 29, wherein the cancer is blood cancer or solid cancer. 31. The pharmaceutical composition according to claim 29, wherein the cancer is colorectal cancer, pancreatic cancer, or lung cancer. 32. The pharmaceutical composition according to claim 29, wherein the cancer is a cancer expressing mutant KRAS. 33. The pharmaceutical composition according to claim 32, wherein the mutant KRAS is G12V mutant, G12D mutant, or G12C mutant KRAS. 34. The antibody-drug conjugate or the salt thereof according to claim 1 for use in the treatment of a cancer. 35. The antibody-drug conjugate or a salt thereof according to claim 1 for use in the production of a pharmaceutical composition for the treatment of a cancer. 36. A drug-linker conjugate represented by formula (LD-1) or a salt thereof:[Chemical Formula 41]whereinD is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect,Rst1 is optionally substituted C1-12 alkylene, or optionally substituted C1-50 heteroalkylene,CLL is a partial structure cleavable in vivo,Sp is a spacer unit and is connected to CLL and D, t is 0 or 1, andSp is bonded to a nitrogen atom of amine or an oxygen atom of -OH contained in D to form N-Sp or O-Sp, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to Sp to form quaternary ammonium. 37. The drug-linker conjugate or the salt thereof according to claim 36, whereinD is a heterocyclic compound having a mutant KRAS protein degradation-inducing effect, the heterocyclic compound being represented by formula (II):[Chemical Formula 42]A is CRA or N,RA is H or C1-3 alkyl,X1 is -CH2- or -O-,R1 is naphthyl optionally substituted by OH, or a group represented by the following formula (III):[Chemical Formula 43]R1a is H, methyl, F, or Cl,R1b is F, Cl, methyl, or ethyl,R2 is H, halogen, cyclopropyl, vinyl, or C1-3 alkyl optionally substituted by a group selected from the group consisting of OH and OCH3,R3 is a group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII):[Chemical Formula 44]R3a is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 5- or 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,R3b is H or C1-3 alkyl,each of R3c and R3d is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted by a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g, and -NRN1RN2,on the proviso that when R3c is -(CH2)pCHR3f-NRN1RN2, X2 in formula (V) is -O-, -NH-, or -N(C2-3 alkyl)-,R3e is -O-C2-3 alkylene-NRN1RN2,R3f is H, F, or C1-3 alkyl,R3g is H or C1-3 alkyl,R3h is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms,R3i are the same or different from each other and each is a group selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, -NH-optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)2, halogen, -CN, and oxo, ortwo R3i present on the same carbon atom optionally form, together with the adjacent carbon atom, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a spiro ring as the group of formula (XIII), wherein the spiro ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two adjacent carbon atoms optionally form, together with the two carbon atoms, a ring selected from the group consisting of C3-6 cycloalkane, and a 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, and form a condensed ring as the group of formula (XIII), wherein the condensed ring is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two non-adjacent carbon atoms optionally form, together with the two carbon atoms, a bridged structure of 1 or 2 carbon atoms, wherein the group of formula (XIII) which is a ring having the bridged structure is optionally substituted by 1 or 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl, orRN1 and RN2 optionally form, together with the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, orR3f and RN1 optionally form, together with the carbon atom and the nitrogen atom bonded thereto, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,X2 is -O-, -NH-, or -N(C1-3 alkyl)-,X3 is O or S,X4 is -CH2-, -CH2-CH2-, or -O-CH2-,n is 1 or 2,p is 1 or 2,q is an integer of 1 to 8,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, R4a, cyclopropyl, N(R4a)2, pyrrolidinyl optionally substituted by R4a, and tetrahydrofuranyl optionally substituted by R4a; piperidinyl optionally substituted by R4b; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl optionally substituted by F,R4b is C1-3 alkyl substituted by 1 to 3 F,Y is phenylene optionally substituted by F or Cl, or pyridinediyl,LP is a group that chemically bonds Y to EUB,EUB is a group having the ability to bind to E3 ubiquitin ligase,CLL is a partial structure cleavable in vivo,Sp is a spacer unit and is connected to CLL and D, t is 0 or 1,Sp is bonded to a nitrogen atom of amine or an oxygen atom of -OH contained in R3, R4, or EUB to form N-Sp or O-Sp, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded to Sp to form quaternary ammonium,whereini) Rst1 is optionally substituted C1-12 alkylene, -optionally substituted C1-6 alkylene-C(=O)-NH-C1-6 alkylene-(OCH2CH2)a-, or -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-, a is an integer of 1 to 10,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-1'), *CO represents a site of connection to a carbonyl group,[Chemical Formula 45]RAA are each independently one group selected from the group consisting of H, methyl, isopropyl, benzyl, and -(CH2)3-NH-C(=O)-NH2,d is an integer of 2 to 4,Sp is a spacer unit represented by formula (SP-1), formula (SP-2), or formula (SP-3), t is 1, *CLL represents a site of connection to CLL,[Chemical Formula 46]andRSP is H,orii) Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -(CH2CH2O)b-CH3, -C(=O)-C1-6 alkylene-NH-C(=O)-(CH2CH2O)b-CH3, or -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-2'), *CO represents a site of connection to a carbonyl group,[Chemical Formula 47]andt is 0. 38. The drug-linker conjugate or the salt thereof according to claim 37, whereinEUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 48]R5 is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, C3-6 cycloalkylmethyl, or C3-6 cycloalkyl,R6a and R6b are the same or different from each other and each is H or C1-6 alkyl optionally substituted by a group selected from the group consisting of F, OH, OCH3, and N(CH3)2, orR6a and R6b optionally form, together with the carbon bonded thereto, optionally substituted C3-6 cycloalkane, or an optionally substituted 4- to 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom,R7 is an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or 6-membered heteroaryl containing 1 to 3 nitrogen atoms,W is optionally substituted phenylene or optionally substituted 6-membered heteroarenediyl containing 1 to 3 nitrogen atoms as ring-constituting atom,LP is -(L1-L2-L3-L4)-,L1, L2, L3, and L4 are the same or different from each other and each is a group selected from the group consisting of a bond, -O-, -NRL1-, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3 alkylene, and C=O,RL1 is H or C1-3 alkyl, andZ is NH or 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom. 39. The drug-linker conjugate or the salt thereof according to claim 38, whereinA is CRA or N,RA is H,X1 is -O-,R1 is a group represented by the following formula (III-a):[Chemical Formula 49]R2 is cyclopropyl,R3 is a group selected from the group consisting of the following formula (IV), formula (V), and formula (XI):[Chemical Formula 50]R3a is -(CH2)pCHR3f-NRN1RN2,R3b is H,R3c is C3-6 cycloalkyl optionally substituted by -NRN1RN2,R3f is H,RN1 and RN2 are the same or different from each other and each is H or C1-3 alkyl,X2 is -O- or -NH-,X3 is O,n is 1,p is 1,R4 is C1-6 alkyl optionally substituted by a group selected from the group consisting of OCH3, N(R4a)2, and pyrrolidinyl optionally substituted by R4a; or tetrahydropyranyl optionally substituted by R4a,R4a is C1-3 alkyl, andY is phenylene. 40. The drug-linker conjugate or the salt thereof according to claim 39, whereinEUB is a group having the ability to bind to VHL, wherein the group having the ability to bind to VHL is a group represented by formula (XIV):[Chemical Formula 51]R5 is isopropyl or tert-butyl,R6a and R6b are different from each other and each is H, or C1-6 alkyl optionally substituted by OH,R7 is optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen,W is phenylene,LP is a bond,Z is 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atom, andSp is bonded to a nitrogen atom of amine contained in R3 or R4, or an oxygen atom of -OH contained in EUB to form N-Sp or O-Sp, wherein when the amine is tertiary amine, the nitrogen atom of the amine is bonded Sp to form quaternary ammonium. 41. The drug-linker conjugate or the salt thereof according to claim 40, whereinA is N,R3 is a group represented by the following formula (XI):[Chemical Formula 52]R4 is C1-6 alkyl substituted by N(R4a)2,R4a is C1-3 alkyl,R7 is a group represented by the following formula (XVI):[Chemical Formula 53]W is a group represented by the following formula (XVII-a):[Chemical Formula 54]Z is a group represented by the following formula (XVIII):[Chemical Formula 55]Rst1 is optionally substituted C1-12 alkylene-NH-, -C1-6 alkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-, or -C1-6 heteroalkylene-NH-C(=O)-C1-6 alkylene-N(RPEG)-C1-6 alkylene-C(=O)-NH-C1-6 alkylene-NH-,RPEG is -C(=O)-(CH2CH2O)b-CH3, b is an integer of 2 to 20,CLL is a partial structure cleavable in vivo represented by formula (CL-2'), *CO represents a site of connection to a carbonyl group,[Chemical Formula 56]t is 0, andSp is bonded to a nitrogen atom of N(R4a)2 contained in R4 to form -N+(R4a)2-Sp. 42. The drug-linker conjugate or the salt thereof according to claim 36, wherein the drug-linker conjugate is represented by the following formula (LD-2), (LD-3), or (LD-4):[Chemical Formula 57-1][Chemical Formula 57-2][Chemical Formula 57-3]wherein b is an integer of 2 to 20. 43. The drug-linker conjugate or the salt thereof according to claim 42, wherein b is 12. 44. A heterocyclic compound having a mutant KRAS protein degradation-inducing effect or a salt thereof, the heterocyclic compound being selected from the group consisting of(4R)-1-[(2S)-2-{4-[4-({[(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide,(4R)-1-[(2S)-2-(4-{4-[({(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-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-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide,(4R)-1-[(2S)-2-{4-[4-({[(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide, and(4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-[(1-{[2-(methylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide. 

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