Conjugates of drug units and targeting units, and their precursor compounds.

Abstract

This specification includes formula (I) [Formula 1] A drug linker or a pharmaceutically acceptable salt thereof is provided, where D is a drug unit, K1 is selected from (i) a peptide unit, (ii) an oligosaccharide, and (iii) a polyether, and M1 is a group that can react with a ligand to form a connector unit. Such compounds may be useful as anticancer agents.

Description

[Technical Field]

[0001] cross reference This application claims benefits under U.S. Provisional Patent Application No. 63 / 512,428 filed July 7, 2023, U.S. Provisional Patent Application No. 63 / 606,519 filed December 5, 2023, U.S. Provisional Patent Application No. 63 / 558,540 filed February 27, 2024, U.S. Provisional Patent Application No. 63 / 640,733 filed April 30, 2024, and U.S. Provisional Patent Application No. 63 / 667,649 filed July 3, 2024, the contents of each of these applications are incorporated herein by reference. [Background technology]

[0002] Currently, cytotoxic small molecules for antibody-drug conjugates can include camptothecin derivatives that exert antitumor effects by inhibiting topoisomerase I. Camptothecin derivatives can be used in antibody-drug conjugates (ADCs). However, there is still a need to develop camptothecin derivatives and ADC drugs with better efficacy and / or safety. [Overview of the project]

[0003] In one aspect, this disclosure relates to formula (X)

[0004] [ka] Provides a drug linker or a pharmaceutically acceptable salt thereof, in the formula, D is a drug unit, Y 1 It does not exist, or -OT 1 and -NH-T 2 Selected from, T 1 This is a sugar cleavable unit, T 2 This is a peptide-cleaving unit, S 1is (i) optionally substituted C1-C 30 alkylene, one or more alkylene units of which are independently optionally -N(R 20 )-, -N(R 20 )C(O)-, -C(O)N(R 20 )-, -N(R 20 )S(O)2-, -S(O)2N(R 20 )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, a 5- to 6-membered heterocycle, or -P(O)(R 20 )2-substituted optionally substituted C1-C 30 alkylene, (ii) optionally substituted C3-C 30 alkenylene, one or more alkenylene units of which are independently optionally -N(R 20 )-, -N(R 20 )C(O)-, -C(O)N(R 20 )-, -N(R 20 )S(O)2-, -S(O)2N(R 20 )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, or -P(O)(R 20 )2-substituted optionally substituted C3-C 30 alkenylene, (iii) one or more amino acids, (iv) one or more N-substituted amino acids, (v) optionally substituted polyether, (vi) optionally substituted C3-C 10 carbocyclene, (vii) selected from optionally substituted 5- to 10-membered heterocycles, S 2 is optionally substituted C1-C 30 alkylene, one or more alkylene units of which are independently optionally -N(R 20 )-, -N(R 20 )C(O)-, -C(O)N(R 20 )-, -N(R 20 )S(O)2-, -S(O)2N(R 20-P(O)(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, 5-6 member heterorings, or -P(O)(R) 20 )2- Replaced by optionally replaced C1-C 30 Selected from alkylenes, S 3 It is selected from the spacers, and at this time, S 3 Does it exist or does it not exist? M 1 , K 1 S 1 S 2 , and S 3 Each of the above optional substituents, independently, (i) Halogen, -OR 30 , -N(R 30 )2, -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 -OS(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), and -CN, (ii)C 1-10 Alkyl, C 2-10 Alkenil, C 2-10 Alkinyl (each of these is a halogen, -OR 30 , -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30,-O-S(O)2OR 30 ,-P(O)(OR 30 )2,-OP(O)(OR 30 )2,-NO2,=O,=S,=N(R 30 ),-CN,C 3-10 a carbon ring, and one or more substituents independently selected from 3- to 10-membered heterocyclic rings, optionally substituted), and (iii)C 3-10 a carbon ring and 3- to 10-membered heterocyclic rings (each of which is halogen, -OR 30 ,-SR 30 ,-N(R 30 )2,-C(O)R 30 ,-C(O)N(R 30 )2,-N(R 30 )C(O)R 30 ,-C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 ,-S(O)2R 30 ,-P(O)(OR 30 )2,-OP(O)(OR 30 )2,-NO2,=O,=S,=N(R 30 ),-CN,C 1-6 alkyl,C 2-6 alkenyl, and C 2-6 alkynyl, optionally substituted with one or more substituents independently selected therefrom) selected from, M 1 is a group capable of reacting with a ligand to form a linker unit, K 1 is (i) a peptide unit, (ii) an oligosaccharide, and (iii) a polyether selected from, R 20 is, independently of each other, hydrogen, and C 1-6 alkyl,C 2-6 alkenyl,C 2-6 alkynyl,C 3-12Carbon rings and 3- to 12-membered heterocycles (each of these being halogens, -OH, -CN, -NO2, -NH2, -N(C) 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 Selected from carbon rings and 3- to 12-membered heterocycles, (optionally substituted with one or more substituents independently selected from these rings), R 30 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-12 Carbon rings and 3- to 12-membered heterocycles (each of these being halogens, -OH, -CN, -NO2, -NH2, -N(C) 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 It is selected from a carbon ring and one or more substituents that are optionally substituted with substituents independently selected from 3- to 12-membered heterocycles.

[0005] In one aspect, this disclosure relates to formula (XX)

[0006] [ka] Provides a conjugate of or a pharmaceutically acceptable salt thereof, in the formula, D is a drug unit, Y 1 It does not exist, or -OT 1 and -NH-T 2 Selected from, T 1 It is a glucose-cleaving unit, T 2 This is a peptide-cleaving unit, L is the targeting unit, S 1 (i) C1-C replaced by arbitrary selection30 Alkylene, wherein one or more alkylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 -P(O)(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, 5-6 member heterorings, or -P(O)(R) 20 )2- Replaced by optionally replaced C1-C 30 (ii) C3-C substituted by any choice 30 An alkenylene in which one or more alkenylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, or -P(O)(R 20 )2, optionally replaced C3-C 30 (iii) one or more amino acids, (iv) one or more N-substituted amino acids, (v) a polyether with optional substitution, (vi) a C3-C 10 Carbocyclene, (vii) Selected from 5-10 member heterocyclenes that have been optionally substituted, S 2 C1-C, which were replaced by arbitrary selection. 30 Alkylene, wherein one or more alkylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20-P(O)(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, 5-6 member heterorings, or -P(O)(R) 20 )2- Replaced by optionally replaced C1-C 30 Selected from alkylenes, S 3 It is selected from the spacers, and at this time, S 3 Does it exist or does it not exist? M 1 , K 1 S 1 S 2 , and S 3 Each of the above optional substituents, independently, (i) Halogen, -OR 30 , -N(R 30 )2, -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 -OS(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), and -CN, (ii)C 1-10 Alkyl, C 2-10 Alkenil, C 2-10 Alkinyl (each of these is a halogen, -OR 30 , -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30-OS(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), -CN, C 3-10 (Optionally substituted with one or more substituents independently selected from a carbon ring and a 3- to 10-membered heterocycle), and (iii) C 3-10 Carbon rings and 3- to 10-membered heterocycles (each of these being halogens, -OR) 30 , -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 (Optionally substituted with one or more substituents independently selected from the alkynyl molecule.) Selected from, M 2 This is a connector unit, K 1 teeth, (i) peptide unit, (ii) Oligosaccharides, and (iii) Polyether Selected from, R 20 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-12 Carbon rings and 3- to 12-membered heterocycles (each of these being halogens, -OH, -CN, -NO2, -NH2, -N(C)1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 Selected from carbon rings and 3- to 12-membered heterocycles, (optionally substituted with one or more substituents independently selected from these rings), R 30 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-12 Carbon rings and 3- to 12-membered heterocycles (each of these being halogens, -OH, -CN, -NO2, -NH2, -N(C) 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 It is selected from a carbon ring and one or more substituents that are optionally substituted with substituents independently selected from 3- to 12-membered heterocycles.

[0007] Reference All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent as each individual publication, patent, or patent application is specifically and individually referenced. Where any publication or patent or patent application referenced herein conflicts with any disclosure contained herein, this specification is intended to supersede and / or take precedence over any such conflicting material. [Brief explanation of the drawing]

[0008] Novel features of the present invention are specifically stated in the appended claims. The features and advantages of the present invention will be better understood by referring to the following detailed description, which specifies exemplary embodiments in which the principles of the present invention are utilized, and to the appended drawings (also referred to herein as “figure” and “FIG.”).

[0009] [Figure 1] This figure shows the stability of different ADCs in mouse plasma. [Figure 2] This figure shows the stability of different ADCs in human plasma. [Figure 3] This figure shows the percentage of cell binding for different ADCs. [Figure 4] This figure shows the median fluorescence intensity (MFI) of different ADCs that bind to JeKo cells. [Figure 5] This figure shows the percentage of inhibition of Jeko-1 cell growth for different ADCs. [Figure 6] This diagram shows the internalization of different ADCs. [Figure 7] This figure shows the release of exatecan from the ADC. [Figure 8] This figure shows the pharmacokinetic parameters of various ADCs. [Figure 9] This figure shows the in vivo antitumor activity of ADC in the H1975 xenograft model. [Figure 10] This figure shows the in vivo antitumor activity of ADC in an H520 xenograft model. [Figure 11] This figure shows the in vivo antitumor activity of ADC in an LCLC-103H xenograft model. [Figure 12] This figure shows the in vivo antitumor activity of ADC in a CTG-2215 xenograft model. [Figure 13] This figure shows the in vivo antitumor activity of ADC in a SA4121 xenograft model. [Figure 14] This figure shows the in vivo antitumor activity of ADC in an NCI-H526 xenograft model. [Figure 15] This figure shows the in vivo antitumor activity of ADC in an H520 xenograft model. [Figure 16] This figure shows the in vivo antitumor activity of ADC in an LCLC-103H xenograft model. [Figure 17] The graph shows the binding of the indicated ADCs to non-small cell lung cancer H1155 tumor cells, and the table shows the EC50 values ​​of each ADC. MFI: Median Fluorescence Intensity. [Figure 18] This line graph shows that the ADCs shown bind to non-small cell lung cancer H1155 tumor cells. MFI: Median fluorescence intensity. [Figure 19A] This is a set of line graphs showing the percentage of ADCs (antibody-derived cells) that are internalized in non-small cell lung cancer H1155 tumor cells. MFI: Median fluorescence intensity. [Figure 19B] This is a set of line graphs showing the percentage of ADCs (antibody-derived cells) that are internalized in non-small cell lung cancer H1155 tumor cells. MFI: Median fluorescence intensity. [Figure 20] This figure shows the in vivo antitumor activity of ADC in an LCLC-103H xenograft model. [Figure 21] This figure shows the in vivo antitumor activity of ADC in an H520 xenograft model. [Modes for carrying out the invention]

[0010] The following description includes numerous exemplary configurations, methods, parameters, etc. However, please note that such descriptions are not intended to limit the scope of this disclosure, but rather are provided as illustrative examples of embodiments.

[0011] The following description provides certain specific details to give a thorough understanding of the various embodiments of this disclosure. However, those skilled in the art will understand that this disclosure can be carried out without these details.

[0012] definition Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art in which this invention pertains. All patents and publications referenced herein are invoked by reference.

[0013] "Alkyl" consists only of carbon and hydrogen atoms, is unsaturated, and preferably has 1 to 15 carbon atoms (for example, C1-C 15 Alkyl) refers to a linear or branched hydrocarbon chain radical. In certain embodiments, alkyl contains 1 to 13 carbon atoms (i.e., C1-C13). 13 Alkyl). In certain embodiments, the alkyl group contains 1 to 8 carbon atoms (i.e., C1-C8 alkyl). In other embodiments, the alkyl group contains 1 to 5 carbon atoms (i.e., C1-C5 alkyl). In other embodiments, the alkyl group contains 1 to 4 carbon atoms (i.e., C1-C4 alkyl). In other embodiments, the alkyl group contains 1 to 3 carbon atoms (i.e., C1-C3 alkyl). In other embodiments, the alkyl group contains 1 to 2 carbon atoms (i.e., C1-C2 alkyl). In other embodiments, the alkyl group contains 1 carbon atom (i.e., C1 alkyl). In other embodiments, the alkyl group contains 5 to 15 carbon atoms (i.e., C5-C 15 Alkyl). In other embodiments, the alkyl group contains 5 to 8 carbon atoms (i.e., C5-C8 alkyl). In other embodiments, the alkyl group contains 2 to 5 carbon atoms (i.e., C2-C5 alkyl). In other embodiments, the alkyl group contains 3 to 5 carbon atoms (i.e., C3-C5 alkyl). In certain embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl group is bonded to the remainder of the molecule by a single bond.

[0014] "C x-y The term "C" means a group containing x to y carbon atoms in the chain, when used with chemical parts such as alkyl, alkenyl, or alkynyl. For example, "C 1-6The term "alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including linear and branched alkyl groups containing 1 to 6 carbon atoms. -C x-y The term "alkylene-" refers to a substituted or unsubstituted alkylene chain having x to y carbon atoms in the alkylene chain. For example, -C 1-6 The alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, and any one of these may be optionally substituted.

[0015] "Alkoxy" refers to a radical bonded via the oxygen atom of the formula -O-alkyl, in which case alkyl is the alkyl chain as defined above.

[0016] "Alkenyl" consists only of carbon and hydrogen atoms, contains at least one carbon-carbon double bond, and preferably has 2 to 12 carbon atoms (i.e., C2-C 12 An alkenyl refers to a linear or branched hydrocarbon chain radical group. In certain embodiments, an alkenyl contains 2 to 8 carbon atoms (i.e., a C2-C8 alkenyl). In certain embodiments, an alkenyl contains 2 to 6 carbon atoms (i.e., a C2-C6 alkenyl). In other embodiments, an alkenyl contains 2 to 4 carbon atoms (i.e., a C2-C4 alkenyl). Alkenyls are bonded to the remainder of the molecule by single bonds, such as ethenyl (i.e., vinyl), propa-1-enyl (i.e., allyl), buta-1-enyl, penta-1-enyl, penta-1,4-dienyl, etc.

[0017] "Alkynyl" consists only of carbon and hydrogen atoms, contains at least one carbon-carbon double bond, and preferably has 2 to 12 carbon atoms (i.e., C2-C 12Alkynnyl refers to a linear or branched hydrocarbon chain radical group. In certain embodiments, the alkynyl contains 2 to 8 carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, the alkynyl contains 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, the alkynyl contains 2 to 4 carbon atoms (i.e., C2-C4 alkynyl). The alkynyl is bonded to the remainder of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0018] "C x-y "Alkenil" and "C x-y The term "alkynyl" refers to a substituted or unsubstituted unsaturated aliphatic group that is similar in length and possible substitutions to the alkyl groups described above, but each contains at least one double or triple bond. -C x-y The term "-alkenylene" refers to a substituted or unsubstituted alkenylene chain having x to y carbon atoms. For example, -C 2-6 The alkenylene- may be selected from etenylene, propenylene, butenylene, pentenylene, and hexenylene, and any one of these may be optionally substituted. The alkenylene chain may have one or more triple bonds. -C x-y The term -alkynylene refers to a substituted or unsubstituted alkynylene chain having x to y carbon atoms. For example, -C 2-6 The alkenylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, and one of these may be optionally substituted. The alkynylene chain may have one or more triple bonds.

[0019] An "alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, unsaturated, and preferably having 1 to 12 carbon atoms, with the remainder of the molecule linked to a radical group, such as methylene, ethylene, propylene, and n-butylene. The alkylene chain is bonded to the remainder of the molecule via single bonds and to the radical group via single bonds. The points of bond between the alkylene chain and the remainder of the molecule and the radical group may be via any two carbon atoms in the chain. In certain embodiments, the alkylene contains 1 to 10 carbon atoms (i.e., C1-C8 alkylene). In certain embodiments, the alkylene contains 1 to 8 carbon atoms (i.e., C1-C8 alkylene). In other embodiments, the alkylene contains 1 to 5 carbon atoms (i.e., C1-C5 alkylene). In other embodiments, the alkylene contains 1 to 4 carbon atoms (i.e., C1-C4 alkylene). In other embodiments, the alkylene contains 1 to 3 carbon atoms (i.e., C1-C3 alkylene). In other embodiments, the alkylene contains 1 to 2 carbon atoms (i.e., C1-C2 alkylene). In other embodiments, the alkylene contains 1 carbon atom (i.e., C1 alkylene). In other embodiments, the alkylene contains 5 to 8 carbon atoms (i.e., C5-C8 alkylene). In other embodiments, the alkylene contains 2 to 5 carbon atoms (i.e., C2-C5 alkylene). In other embodiments, the alkylene contains 3 to 5 carbon atoms (i.e., C3-C5 alkylene).

[0020] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having 2 to 12 carbon atoms, with the remainder of the molecule linked to a radical group. The alkenylene chain is bonded to the remainder of the molecule via single bonds and to the radical group via single bonds. The points where the alkenylene chain is bonded to the remainder of the molecule and to the radical group may be via any two carbon atoms in the chain. In certain embodiments, the alkenylene contains 2 to 8 carbon atoms (i.e., C2-C2). 10Alkenylenes). In certain embodiments, alkenylenes contain 2 to 8 carbon atoms (i.e., C2-C8 alkenylenes). In other embodiments, alkenylenes contain 2 to 5 carbon atoms (i.e., C2-C5 alkenylenes). In other embodiments, alkenylenes contain 2 to 4 carbon atoms (i.e., C2-C4 alkenylenes). In other embodiments, alkenylenes contain 2 to 3 carbon atoms (i.e., C2-C3 alkenylenes). In other embodiments, alkenylenes contain 2 carbon atoms (i.e., C2 alkenylenes). In other embodiments, alkenylenes contain 5 to 8 carbon atoms (i.e., C5-C8 alkenylenes). In other embodiments, alkenylenes contain 3 to 5 carbon atoms (i.e., C3-C5 alkenylenes).

[0021] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having 2 to 12 carbon atoms, with the remainder of the molecule linked to a radical group. The alkynylene chain is bonded to the remainder of the molecule via single bonds and to the radical group via single bonds. The points where the alkynylene chain is bonded to the remainder of the molecule and to the radical group may be via any two carbon atoms in the chain. In certain embodiments, the alkynylene contains 2 to 8 carbon atoms (i.e., C2-C2). 10 Alkynylene). In certain embodiments, the alkynylene contains 2 to 8 carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, the alkynylene contains 2 to 5 carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, the alkynylene contains 2 to 4 carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, the alkynylene contains 2 to 3 carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, the alkynylene contains 2 carbon atoms (i.e., C2 alkynylene). In other embodiments, the alkynylene contains 5 to 8 carbon atoms (i.e., C5-C8 alkynylene). In other embodiments, the alkynylene contains 3 to 5 carbon atoms (i.e., C3-C5 alkynylene).

[0022] The term "aryl" refers to a radical derived from an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system by removing a hydrogen atom from a cyclic carbon atom. An aromatic monocyclic or aromatic polycyclic hydrocarbon ring system contains only hydrogen, carbon, and 5 to 18 carbon atoms, and at least one ring in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n+2)π-electron system according to Hückel's theory. Examples of ring systems from which an aryl group is derived include, but are not limited to, benzene, fluorene, indan, indene, tetralin, and naphthalene.

[0023] "Aralkill" is formula -R c -aryl(in the formula, R) c This refers to the radicals of the alkylene chain (as defined above), such as methylene and ethylene.

[0024] "Aralkenyl" is expressed by formula -R d -aryl(in the formula, R) d "Aralkynyl" refers to the radical of the alkenylene chain (as defined above). e -aryl(in the formula, R) e This refers to the radical of the alkynylene chain (as defined above).

[0025] A "carbocyclic ring" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocyclic rings may include monocyclic rings with 3 to 10 members, bicyclic rings with 6 to 12 members, and bridging rings with 6 to 12 members. Each ring in a bicyclic carbocyclic ring may be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, such as phenyl, may be condensed with a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of a carbocyclic ring, as long as the valence allows. Exemplary carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Bicyclic carbocyclic rings can be condensed, bridging, or spirocyclic. In some cases, a spirocyclic carbocyclic ring has at least two molecular rings with only one common atom.

[0026] "Carbocyclene" refers to a divalent carbon ring that links the rest of the molecule to a radical group.

[0027] The term "unsaturated carbocyclic ring" refers to a carbocyclic ring with a degree of unsaturation of at least 1, excluding aromatic carbocyclic rings. Examples of unsaturated carbocyclic rings include cyclohexadiene, cyclohexene, and cyclopentene.

[0028] "Cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, including a fused or bridging ring system, and preferably having 3 to 12 carbon atoms. In certain embodiments, a cycloalkyl contains 3 to 10 carbon atoms. In other embodiments, a cycloalkyl contains 5 to 7 carbon atoms. A cycloalkyl can be bonded to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norborneyl, decalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl.

[0029] A "cycloalkenyl" refers to an unsaturated, non-aromatic, monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, including a fused or bridging ring system, preferably having 3 to 12 carbon atoms and containing at least one double bond. In certain embodiments, a cycloalkenyl contains 3 to 10 carbon atoms. In other embodiments, a cycloalkenyl contains 5 to 7 carbon atoms. The rest of the molecule may be bonded by single bonds. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0030] "Cycloalkylalkyl" is defined by formula -R c -Cycloalkyl(wherein R) c This refers to the radical of the alkylene chain mentioned above.

[0031] "Cycloalkylalkoxy" is a compound of the formula -OR c -Cycloalkyl(wherein R) c This refers to a radical bonded via the oxygen atom of the alkyl chain (mentioned above).

[0032] "Halo" or "halogen" refers to halogen substituents such as bromo substituents, chloro substituents, fluoro substituents, and iodo substituents.

[0033] As used herein, the terms “haloalkyl” or “haloalkane” refer to the alkyl radicals defined above, which are substituted with one or more halogen radicals, such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, and 1-fluoromethyl-2-fluoroethyl. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally further substituted. Examples of halogen-substituted alkanes ("haloalkanes") include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), dihalomethanes and trihalomethanes (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethanes, 2-haloethanes, 1,2-dihaloethanes, 1-halopropanes, 2-halopropanes, 3-halopropanes, 1,2-dihalopropanes, 1,3-dihalopropanes, 2,3-dihalopropanes, 1,2,3-trihalopropanes, as well as any other suitable combination of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with one or more halogen radicals, the halogens can be independently selected from, for example, 1-chloro and 2-fluoroethanes.

[0034] "Fluoroalkyl" refers to an alkyl radical as defined above, which is substituted by one or more fluororadicals, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, and 1-fluoromethyl-2-fluoroethyl.

[0035] "Hydroxyalkyl" refers to the alkyl radical defined above, which is substituted by one or more hydroxyl radicals, such as propan-1-ol, butane-1,4-diol, and pentane-1,2,4-triol.

[0036] "Alkoxyalkyl" refers to the alkyl radical defined above, which is substituted by one or more alkoxy radicals, such as methoxymethane, 1,3-dimethoxybutane, 1-methoxypropane, and 2-ethoxypentane.

[0037] The term "activated C≡C group" refers to a cyclic alkyne that forms a triazole due to its high reactivity caused by ring strain on the azide group.

[0038] An "activated disulfide group" refers to a disulfide that can react with a thiol to form a new disulfide bond.

[0039] As used herein, "cyanoalkyl" refers to an alkyl group as defined above, which is substituted with one or more cyano radicals, such as acetonitrile, 2-ethyl-3-methylsuccinonitrile, and butyronitrile.

[0040] A "heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include monocyclic rings with 3 to 10 members, bicyclic rings with 6 to 12 members, and bridging rings with 6 to 12 members. Each ring in a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. Bicyclic heterocycles can be fused, bridging, or spirocycle systems. A spirocycle heterocycle may have at least two molecular rings sharing only one common atom. A spirocycle heterocycle contains at least one heteroatom.

[0041] A "heterocyclene" refers to a divalent heterocycle in which the remainder of a molecule is linked to a radical group.

[0042] A “heteroaryl” or “aromatic heterocycle” refers to a radical derived from a heteroaromatic ring radical containing 1 to 11 carbon atoms and at least one heteroatom, each heteroatom may be selected from N, O, and S. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic rings and from fused or bridging ring systems, at least one of the rings in the ring system being aromatic, i.e., containing a delocalized (4n+2)π-electron system of the ring according to Hückel's theory. The heteroatoms in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be bonded to the remainder of the molecule by any atom of the heteroaryl, such as the carbon or nitrogen atoms of the heteroaryl, if the valence allows. Examples of heteroaryls include, but are not limited to, pyridine, pyrimidine, oxazole, furan, pyran, thiophene, isoxazole, benzimidazole, benzthiazole, and imidazopyridine.

[0043] "X-membered heteroaryl" refers to the number of ring atoms in the ring, i.e., X. For example, a 5-membered heteroaryl ring or a 5-membered aromatic heterocycle has 5 ring atoms, such as triazole, oxazole, thiophene, etc.

[0044] The term "unsaturated heterocycle" refers to a heterocycle having a degree of unsaturation of at least 1, excluding aromatic heterocycles. Examples of unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine. The heterocycle may be optionally substituted with one or more substituents, such as those described herein.

[0045] The term "substituted" refers to a moiety in a structure that has substituents that substitute hydrogen atoms on one or more carbon atoms or substituteable heteroatoms, such as NH groups. "Substitution" or "substituted with" will be understood to imply that such substitutions are subject to the allowable valencies of the substituted atom and substituent, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, or excretion. In certain embodiments, "substituted" refers to a moiety that has substituents that substitute two hydrogen atoms on the same carbon atom, such as substituting two hydrogen atoms on a single carbon atom with an oxo, imino, or thioxo group.

[0046] As used herein, the term “substituted” is intended to include all acceptable substituents of an organic compound. In a broad range of embodiments, acceptable substituents include acyclic and cyclic substituents, branched and unbranched substituents, cyclic and heterocyclic substituents, and aromatic and non-aromatic substituents of an organic compound. There may be one or more acceptable substituents in a given organic compound, and they may be the same or different. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or all acceptable substituents of the organic compounds described herein that satisfy the valence of the heteroatom. In some embodiments, substituents may include all substituents described herein, e.g., halogen, hydroxyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxymo (=N-OH), hydrazino (=N-NH2), -R b -OR a ,-R b -OC(O)R a ,-R b -OC(O)OR a ,-R b -OC(O)N(R a )2, -R b -N(R a )2, -R b -C(O)OR a ,-Rb -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a ,-R b -N(R a )C(O)R a ,-R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t Ure a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2), and may include alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralquinyl, cycloalkyl, cycloalkylalkyl, and heterocycles, any of which may include alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxymo (=N-OH), hydrazine (=N-NH2), -R b -OR a ,-R b -OC(O)R a ,-R b -OC(O)OR a ,-R b -OC(O)N-(R a )2, -R b -N(R a )2, -R b -C(O)R a ,-R b -C(O)OR a ,-R b -C(O)N(R a )2, -R b -OR c -C(O)N(Ra )2, -R b -N(R a )C(O)OR a ,-R b -N(R a )C(O)R a ,-R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t Ure a (t is 1 or 2), and -R b -S(O) t N(R a )2(t is 1 or 2) may be optionally substituted by, and Ra is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, R a These are, respectively, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxymo (=N-OH), hydrazine (=N-NH2), and -R, depending on the valency. b -OR a ,-R b -OC(O)-R a ,-R b -OC(O)-OR a ,-R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a ,-R b -C(O)OR a ,-R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a)2, -R b -N(R a )C(O)OR a ,-R b -N(R a )C(O)R a ,-R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t Ure a (t is 1 or 2), and -R b -S(O) t N(R a ) may be optionally replaced by 2 (where t is 1 or 2), R b Each is independently selected from directly linked, or linear or branched alkylene, alkenylene, or alkynylene chains, and R c These are linear or branched alkylene, alkenylene, or alkynylene chains, respectively.

[0047] As used herein and in the claims, the singular forms "a," "an," and "the" include the plural form unless otherwise evident from the context.

[0048] The terms "salt" or "pharmaceutically acceptable salt" refer to salts derived from various organic and inorganic counterions known in the art. Pharmacopoecitable acid addition salts can be formed from inorganic and organic acids. Examples of inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids from which salts can be derived include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmacopoecitable base addition salts can be formed from inorganic and organic acids. Examples of inorganic bases from which salts can be derived include sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Examples of organic bases from which salts can be derived include primary amines, secondary amines, tertiary amines, and substituted amines (including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins), specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0049] As used herein, the terms “parenteral administration” and “administered parenterally” refer to a form of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, injections and infusions by vein, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal.

[0050] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of appropriate medical common sense, and that are balanced by a reasonable benefit-risk ratio.

[0051] As used herein, the terms “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” mean a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as core butter and suppository wax; (9) peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and dextrose oil. Examples include oils such as tung oil, (10) glycols such as propylene glycol, (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) esters such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) water free of pyrogens, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffer, and (21) other suitable nontoxic substances used in pharmaceutical formulations.

[0052] In certain embodiments, the terms “prevent” or “preventing” in relation to a disease or disorder may refer to a compound that, in a statistical sample, reduces the incidence of the disorder or disease in a treated sample compared to an untreated control sample, or reduces the severity of one or more symptoms of the disorder or disease compared to an untreated control sample.

[0053] As used herein, the terms “treat,” “treating,” or “treatment” may include alleviating, reducing, or improving the symptoms of a disease or illness; preventing further symptoms; inhibiting a disease or illness, for example, halting the progression of a disease or illness; alleviating a disease or illness; causing regression of a disease or illness; alleviating a condition caused by a disease or illness; or preventing and / or curatively stopping the symptoms of a disease or illness.

[0054] The term "ligand" generally refers to a macromolecule capable of recognizing and binding to an antigen or receptor associated with a target cell. Ligands include, but are not limited to, protein hormones, lectins, growth factors, antibodies, or other substances capable of binding to cells, receptors, and / or antigen molecules, and can be used to bring drugs to target cell populations to which they bind. A ligand can be an antibody. A ligand can be an antigen-binding fragment.

[0055] The term "targeting moiety" or "targeting unit" refers to a structure that has a selective affinity for a target molecule compared to other non-target molecules. The targeting moiety binds to the target molecule. The targeting unit may include, for example, an antibody, a peptide, a ligand, a receptor, or their binding sites. The target biological molecule may be a biological receptor or other cellular structure such as a tumor antigen.

[0056] The term "antibody" refers to the whole antibody and any antigen-binding fragment (i.e., the "antigen-binding portion") or its single-chain variant. A whole antibody is a protein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain contains a heavy chain variable region (VH) and a heavy chain constant region containing three domains, namely CH1, CH2, and CH3. Each light chain contains a light chain variable region (VL or Vk) and a light chain constant region containing a single domain CL. The VH and VL regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), which are interspersed with more conserved framework regions (FRs). VH and VL, respectively, consist of three CDRs (HCDRs as used herein, where HCDRs represent heavy chain-derived CDRs and LCDRs represent light chain-derived CDRs) and four FRs arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable region contains a binding domain that interacts with the antigen. The constant region can mediate the binding of immunoglobulins to various cells of the immune system (e.g., effector cells) and to host tissues or host factors, including the first component (Clq) of the classical complement system.

[0057] The antibody reacted with antigen X in a 5 × 10 -8 M or less, more preferably 1 × 10 -8 M or less, more preferably 6 × 10 -9 M or less, more preferably 3 × 10 -9 M or less, more preferably 2 × 10 -9When binding occurs with a KD of M or less, it is said to "specifically bind" to antigen X. The antibody may be a chimeric antibody, a humanized antibody, or preferably a human antibody. The heavy chain constant region can be manipulated to affect the type or degree of glycosylation, extend the antibody half-life, enhance or reduce interaction with effector cells or the complement system, or modulate some other properties. This manipulation can be achieved by substitution, addition, or deletion of one or more amino acids, or by substituting a domain with a domain derived from another immunoglobulin type, or by a combination of the foregoing.

[0058] The terms "antigen-binding fragment" and "antigen-binding moiety" (or simply "antibody moiety" or "antibody fragment") refer to one or more fragments of an antibody that have the ability to specifically bind to an antigen. Antibody antigen-binding function can be performed by fragments of full-length antibodies, such as (i) Fab fragments, which are monovalent fragments consisting of a VL domain, VH domain, CL domain, and CH1 domain; (ii) F(ab')2 fragments, which are bivalent fragments containing two Fab fragments linked by disulfide crosslinks in the hinge region; (iii) Fab' fragments, which are essentially Fab fragments having part of the hinge region (see, for example, Cellular and Molecular Immunology, 6th Ed., Saunders Elsevier 2007 by Abbas et al.); (iv) Fd fragments consisting of a VH domain and a CH1 domain; (v) Fv fragments consisting of the VL domain and VH domain of a single arm of the antibody; (vi) dAb fragments consisting of a VH domain (Nature 341: pp. 544-546 by Ward et al. (1989)); (vii) isolated complementarity-determining regions (CDRs); and (viii) nanobodies, which are heavy-chain variable regions containing a single variable domain and two constant domains. Preferred antigen-binding fragments are the Fab fragment, F(ab')2 fragment, Fab' fragment, Fv fragment, and Fd fragment. Furthermore, the two domains of the Fv fragment, VL and VH, are encoded by separate genes, but they can be linked by a synthetic linker that allows the VL and VH regions to pair up using recombination to form a single protein chain that forms a monovalent molecule (known as single-chain Fv, or scFv). See, for example, Bird et al. (1988), Science 242: pp. 423-426, and Huston et al. (1988), Proc. Natl. Acad. Sci. USA 85: pp. 5879-5883. Such single-chain antibodies are also encompassed within the term "antigen-binding portion" of an antibody.

[0059] The term "isolated antibody" means an antibody that substantially contains no other antibodies with different antigen specificities (for example, an isolated antibody that specifically binds to antigen X substantially contains no antibodies that specifically bind to antigens other than antigen X). However, an isolated antibody that specifically binds to antigen X may cross-react to other antigens, such as antigen X molecules from other species. In certain embodiments, an isolated antibody specifically binds to human antigen X but does not cross-react with other (non-human) antigen X antigens. Furthermore, an isolated antibody may substantially contain no other cellular material and / or chemical substances.

[0060] The terms "monoclonal antibody" or "monoclonal antibody composition" refer to a single-molecule antibody composition preparation that exhibits a single binding specificity and binding affinity to a specific epitope.

[0061] The terms “antibody-drug conjugate,” “conjugate,” “ADC,” or “immune conjugate” refer to an antibody or its antigen-binding portion covalently or noncovalently bound to one or more biologically active molecules, with or without a linker.

[0062] The term "human antibody" refers to an antibody in which both the framework region and the CDR region (and, if present, the constant region) have variable regions derived from human germline immunoglobulin sequences. Human antibodies may include later modifications, including innate or synthetic modifications. Human antibodies may contain amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro, or somatic mutations in vivo). However, "human antibodies" do not include antibodies in which CDR sequences derived from the germline of another mammalian species, such as mouse, have been transplanted onto a human framework sequence.

[0063] The term "human monoclonal antibody" refers to an antibody exhibiting single binding specificity, in which both the framework region and the CDR region have variable regions derived from human germline immunoglobulin sequences. In one embodiment, human monoclonal antibodies are produced by a non-human transgenic animal having a genome containing human heavy chain and light chain transgenes fused to immortalized cells, such as a hybridoma containing B cells obtained from a transgenic mouse.

[0064] The term “epitope” refers to an amino acid conventionally bound by an immunoglobulin VH / VL pair, such as an antibody, its antigen-binding moiety, and other binders described herein. Other binders include non-antibody scaffolds. Epitopes can be formed on polypeptides from consecutive amino acids or from discontinuous amino acids juxtaposed by tertiary folding of the protein. Epitopes formed from consecutive amino acids are typically retained upon exposure to denaturing solvents, while epitopes formed by tertiary folding are typically lost upon processing with denaturing solvents. Epitopes typically contain at least 3, more commonly at least 5, about 9, or about 8–10 amino acids in a unique spatial conformation. Epitopes define the minimum binding site for an antibody, its antigen-binding moiety, and other binders, and thus represent the target of the specificity of the antibody, its antigen-binding moiety, or other immunoglobulin binder. In the case of a single-domain antibody, the epitope represents a structural unit bound by an isolated variable domain.

[0065] The "mutant" antibody or antigen-binding moiety may have amino acid substitutions (which may be conserved or non-conserved) derived from the reference antibody or antigen-binding moiety, but the biological activity derived from the reference antibody or antigen-binding moiety is substantially unchanged. For example, the mutant antibody or antigen-binding moiety may retain at least 50%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding affinity of the reference antibody or antigen-binding moiety, or it may even exceed the binding affinity of the reference antibody or antigen-binding moiety.

[0066] The term "specifically binds" means that the molecules described herein (e.g., antibodies or their antigen-binding moieties or non-antibody scaffolds) bind specifically to 10 -5 M (10000 nM) or less, for example, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 This refers to the ability to bind to a target with a KD of M or less. Specific binding can be influenced by factors such as the affinity and binding strength of the antibody, antigen-binding moiety, or other binder, as well as the concentration of the target polypeptide.

[0067] The term "about" can mean ±1% when used in relation to percentages.

[0068] The term "cleavage unit" refers to a chemical group that can be cleaved by an internal or external, preferably external, stimulus. The stimulus that induces the cleavage of a cleavage unit may be, for example, pH or temperature conditions, or the presence of an enzyme.

[0069] Linkers, drug linkers, and conjugates as disclosed herein In one embodiment, this disclosure relates to formula (B)

[0070] [ka] Provides a drug linker or a pharmaceutically acceptable salt thereof, in the formula, R 40 teeth,

[0071] [ka] and C1-C 30 Alkylene, wherein one or more alkylene units are optionally and independently -N(R 20 )-,-N(R20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 -P(O)(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, 5-6 member heterorings, or -P(O)(R) 20 )2- is substituted by C1-C 30 Selected from alkylenes, D is a drug unit, Y 1 It does not exist, or -OT 1 and -NH-T 2 Selected from, T 1 It is a glucose-cleaving unit, T 2 This is a peptide-cleaving unit, S 1 (i) C1-C replaced by arbitrary selection 30 Alkylene, wherein one or more alkylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 -P(O)(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, 5-6 member heterorings, or -P(O)(R) 20 )2- Replaced by optionally replaced C1-C 30 (ii) C3-C substituted by any choice 30 An alkenylene in which one or more alkenylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, or -P(O)(R20 )2, optionally replaced C3-C 30 (iii) one or more amino acids, (iv) one or more N-substituted amino acids, (v) a polyether with optional substitution, (vi) a C3-C 10 Carbocyclene, (vii) Selected from 5-10 member heterocyclenes that have been optionally substituted, S 2 C1-C, which were replaced by arbitrary selection. 30 Alkylene, wherein one or more alkylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 -P(O)(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, 5-6 member heterorings, or -P(O)(R) 20 )2- Replaced by optionally replaced C1-C 30 Selected from alkylenes, S 3 It is selected from the spacers, and at this time, S 3 Does it exist or does it not exist? M 1 , K 1 S 1 S 2 , and S 3 Each of the above optional substituents, independently, (i) Halogen, -OR 30 , -N(R 30 )2, -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 -OS(O)2OR 30, -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), and -CN, (ii)C 1-10 Alkyl, C 2-10 Alkenil, C 2-10 Alkinyl (each of these is a halogen, -OR 30 , -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 -OS(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), -CN, C 3-10 (Optionally substituted with one or more substituents independently selected from a carbon ring and a 3- to 10-membered heterocycle), and (iii) C 3-10 Carbon rings and 3- to 10-membered heterocycles (each of these being halogens, -OR) 30 , -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6(Optionally substituted with one or more substituents independently selected from the alkynyl molecule.) Selected from, M 1 This is a group that can react with a ligand to form a connector unit. K 1 teeth, (i) peptide unit, (ii) Oligosaccharides, and (iii) Polyether Selected from, R 20 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-12 Carbon rings and 3- to 12-membered heterocycles (each of these being halogens, -OH, -CN, -NO2, -NH2, -N(C) 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 Selected from carbon rings and 3- to 12-membered heterocycles, (optionally substituted with one or more substituents independently selected from these rings), R 30 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-12 Carbon rings and 3- to 12-membered heterocycles (each of these being halogens, -OH, -CN, -NO2, -NH2, -N(C) 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 It is selected from a carbon ring and one or more substituents that are optionally substituted with substituents independently selected from 3- to 12-membered heterocycles.

[0072] In some embodiments, the drug linker of formula (B) is represented by formula (X). In some cases, the drug linker of formula (B) is represented by formula (X). In some cases, the drug linker further comprises a targeting unit, M 1 It reacts with the targeting unit and M 2 It forms.

[0073] In one aspect, this disclosure relates to formula (X)

[0074] [ka] Provides a drug linker or a pharmaceutically acceptable salt thereof, in the formula, D is a drug unit, Y 1 It does not exist, or -OT 1 and -NH-T 2 Selected from, T 1 It is a glucose-cleaving unit, T 2 This is a peptide-cleaving unit, S 1 (i) C1-C replaced by arbitrary selection 30 Alkylene, wherein one or more alkylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 -P(O)(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, 5-6 member heterorings, or -P(O)(R) 20 )2- Replaced by optionally replaced C1-C 30 (ii) C3-C substituted by any choice 30 An alkenylene in which one or more alkenylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20)-,-N(R 20 )S(O)2-, -S(O)2N(R 20 )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, or -P(O)(R 20 )2, optionally replaced C3-C 30 (iii) one or more amino acids, (iv) one or more N-substituted amino acids, (v) a polyether with optional substitution, (vi) a C3-C 10 Carbocyclene, (vii) Selected from 5-10 member heterocyclenes that have been optionally substituted, S 2 C1-C, which were replaced by arbitrary selection. 30 Alkylene, wherein one or more alkylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 -P(O)(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, 5-6 member heterorings, or -P(O)(R) 20 )2- Replaced by optionally replaced C1-C 30 Selected from alkylenes, S 3 It is selected from the spacers, and at this time, S 3 Does it exist or does it not exist? M 1 , K 1 S 1 S 2 , and S 3 Each of the above optional substituents, independently, (i) Halogen, -OR 30 , -N(R 30 )2, -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 -OS(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), and -CN, (ii)C 1-10 Alkyl, C 2-10 Alkenil, C 2-10 Alkinyl (each of these is a halogen, -OR 30 , -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 -OS(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), -CN, C 3-10 (Optionally substituted with one or more substituents independently selected from a carbon ring and a 3- to 10-membered heterocycle), and (iii) C 3-10 Carbon rings and 3- to 10-membered heterocycles (each of these being halogens, -OR) 30 , -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 , -P(O)(OR 30)2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 (Optionally substituted with one or more substituents independently selected from the alkynyl molecule.) Selected from, M 1 This is a group that can react with a ligand to form a connector unit. K 1 teeth, (i) peptide unit, (ii) Oligosaccharides, and (iii) Polyether Selected from, R 20 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-12 Carbon rings and 3- to 12-membered heterocycles (each of these being halogens, -OH, -CN, -NO2, -NH2, -N(C) 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 Selected from carbon rings and 3- to 12-membered heterocycles, (optionally substituted with one or more substituents independently selected from these rings), R 30 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-12 Carbon rings and 3- to 12-membered heterocycles (each of these being halogens, -OH, -CN, -NO2, -NH2, -N(C) 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12It is selected from a carbon ring and one or more substituents that are optionally substituted with substituents independently selected from 3- to 12-membered heterocycles.

[0075] In some embodiments, equation (X) is,

[0076] [ka] or represented by a pharmaceutically acceptable salt thereof.

[0077] In one embodiment, this disclosure relates to formula (C)

[0078] [ka] Provides a conjugate of or a pharmaceutically acceptable salt thereof, in the formula, R 40 teeth,

[0079] [ka] and C1-C 30 Alkylene, wherein one or more alkylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 -P(O)(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, 5-6 member heterorings, or -P(O)(R) 20 )2- is substituted by C1-C 30 Selected from alkylenes, D is a drug unit, Y 1 It does not exist, or -OT 1 and -NH-T 2 Selected from, T 1 It is a glucose-cleaving unit, T2 This is a peptide-cleaving unit, L is the targeting unit, S 1 (i) C1-C replaced by arbitrary selection 30 Alkylene, wherein one or more alkylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 -P(O)(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, 5-6 member heterorings, or -P(O)(R) 20 )2- Replaced by optionally replaced C1-C 30 (ii) C3-C substituted by any choice 30 An alkenylene in which one or more alkenylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, or -P(O)(R 20 )2, optionally replaced C3-C 30 (iii) one or more amino acids, (iv) one or more N-substituted amino acids, (v) a polyether with optional substitution, (vi) a C3-C 10 Carbocyclene, (vii) Selected from 5-10 member heterocyclenes that have been optionally substituted, S 2 C1-C, which were replaced by arbitrary selection. 30 Alkylene, wherein one or more alkylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20)-,-N(R 20 )S(O)2-, -S(O)2N(R 20 -P(O)(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, 5-6 member heterorings, or -P(O)(R) 20 )2- Replaced by optionally replaced C1-C 30 Selected from alkylenes, S 3 It is selected from the spacers, and at this time, S 3 Does it exist or does it not exist? M 1 , K 1 S 1 S 2 , and S 3 Each of the above optional substituents, independently, (i) Halogen, -OR 30 , -N(R 30 )2, -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 -OS(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), and -CN, (ii)C 1-10 Alkyl, C 2-10 Alkenil, C 2-10 Alkinyl (each of these is a halogen, -OR 30 , -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R30 ,-S(O)R 30 -S(O)2R 30 -OS(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), -CN, C 3-10 (Optionally substituted with one or more substituents independently selected from a carbon ring and a 3- to 10-membered heterocycle), and (iii) C 3-10 Carbon rings and 3- to 10-membered heterocycles (each of these being halogens, -OR) 30 , -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 (Optionally substituted with one or more substituents independently selected from the alkynyl molecule.) Selected from, M 2 This is a connector unit, K 1 teeth, (i) peptide unit, (ii) Oligosaccharides, and (iii) Polyether Selected from, R 20 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-12Carbon rings and 3- to 12-membered heterocycles (each of these being halogens, -OH, -CN, -NO2, -NH2, -N(C) 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 Selected from carbon rings and 3- to 12-membered heterocycles, (optionally substituted with one or more substituents independently selected from these rings), R 30 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-12 Carbon rings and 3- to 12-membered heterocycles (each of these being halogens, -OH, -CN, -NO2, -NH2, -N(C) 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 It is selected from a carbon ring and one or more substituents that are optionally substituted with substituents independently selected from 3- to 12-membered heterocycles.

[0080] In some embodiments, the conjugate of formula (C) is represented by formula (XX). In some cases, formula (C) is represented by formula (A).

[0081] In one aspect, this disclosure relates to formula (XX)

[0082] [ka] Provides a conjugate of or a pharmaceutically acceptable salt thereof, in the formula, D is a drug unit, Y 1 It does not exist, or -OT 1 and -NH-T 2 Selected from, T 1 It is a glucose-cleaving unit, T2 This is a peptide-cleaving unit, L is the targeting unit, S 1 (i) C1-C replaced by arbitrary selection 30 Alkylene, wherein one or more alkylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 -P(O)(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, 5-6 member heterorings, or -P(O)(R) 20 )2- Replaced by optionally replaced C1-C 30 (ii) C3-C substituted by any choice 30 An alkenylene in which one or more alkenylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, or -P(O)(R 20 )2, optionally replaced C3-C 30 (iii) one or more amino acids, (iv) one or more N-substituted amino acids, (v) a polyether with optional substitution, (vi) a C3-C 10 Carbocyclene, (vii) Selected from 5-10 member heterocyclenes that have been optionally substituted, S 2 C1-C, which were replaced by arbitrary selection. 30 Alkylene, wherein one or more alkylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20)-,-N(R 20 )S(O)2-, -S(O)2N(R 20 -P(O)(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, 5-6 member heterorings, or -P(O)(R) 20 )2- Replaced by optionally replaced C1-C 30 Selected from alkylenes, S 3 It is selected from the spacers, and at this time, S 3 Does it exist or does it not exist? M 1 , K 1 S 1 S 2 , and S 3 Each of the above optional substituents, independently, (i) Halogen, -OR 30 , -N(R 30 )2, -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 -OS(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), and -CN, (ii)C 1-10 Alkyl, C 2-10 Alkenil, C 2-10 Alkinyl (each of these is a halogen, -OR 30 , -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R30 ,-S(O)R 30 -S(O)2R 30 -OS(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), -CN, C 3-10 (Optionally substituted with one or more substituents independently selected from a carbon ring and a 3- to 10-membered heterocycle), and (iii) C 3-10 Carbon rings and 3- to 10-membered heterocycles (each of these being halogens, -OR) 30 , -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 (Optionally substituted with one or more substituents independently selected from the alkynyl molecule.) Selected from, M 2 This is a connector unit, K 1 teeth, (i) peptide unit, (ii) Oligosaccharides, and (iii) Polyether Selected from, R 20 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-12Carbon rings and 3- to 12-membered heterocycles (each of these being halogens, -OH, -CN, -NO2, -NH2, -N(C) 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 Selected from carbon rings and 3- to 12-membered heterocycles, (optionally substituted with one or more substituents independently selected from these rings), R 30 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-12 Carbon rings and 3- to 12-membered heterocycles (each of these being halogens, -OH, -CN, -NO2, -NH2, -N(C) 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 It is selected from a carbon ring and one or more substituents that are optionally substituted with substituents independently selected from 3- to 12-membered heterocycles.

[0083] In some embodiments, formula (XX) is,

[0084] [ka] or represented by a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, with respect to drug linkers or salts of formula (B), formula (X), or formula (I), S 1 -S 2 -K 1 teeth,

[0086] [ka] Selected from, S 2 teeth,

[0087] [ka] Selected from, S 3 It does not exist, Y 1 It is either absent or selected from cleavable sugars and cleavable peptides (e.g., dipeptides), M 1 teeth,

[0088] [ka] And, K 1 These are selected from peptide units and oligosaccharides. D is

[0089] [ka] That is the case.

[0090] In some embodiments, with respect to drug linkers or salts of formula (B), formula (X), or formula (I), S 1 -S 2 -K 1 teeth,

[0091] [ka] Selected from, S 3 It does not exist, Y 1 teeth,

[0092] [ka] Selected from, M 1 teeth,

[0093] [ka] And, K 1 teeth,

[0094] [ka] Selected from, D is

[0095] [ka] That is the case.

[0096] In some embodiments, with respect to drug linkers or salts of formula (B), formula (X), or formula (I), S 1 -S 2 -K 1 teeth,

[0097] [ka] Selected from, S 3 It does not exist, Y 1 teeth,

[0098] [ka] Selected from, M 1 teeth,

[0099] [ka] And, K 1 teeth,

[0100] [ka] Selected from, D is

[0101] [ka] That is the case.

[0102] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), K 1 This is a hydrophilic spacer. In some cases, K 1 The components are selected from polyethylene glycol units, cyclodextrin units, polyamides, hydrophilic peptides, polysaccharides, and dendrimers. In some cases, K 1 This is selected from polyamides, hydrophilic peptides, and polysaccharides. In some cases, K 1 These are selected from hydrophilic peptides and polysaccharides. In some cases, K 1 It is selected from hydrophilic peptides. In some cases, K 1 It is selected from polysaccharides.

[0103] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), S 1 (i) C1-C replaced by arbitrary selection 30 Alkylene, wherein one or more alkylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, or -P(O)(R 20 )2, optionally replaced C1-C 30 Selected from alkylenes. In some cases, S 1 (i) C6-C replaced by any choice 10An alkylene in which one or more alkylene units are independently optionally selected from -N(R 20 )-, -N(R 20 )C(O)-, -C(O)N(R 20 )-, or -C(O)-substituted optionally substituted C6-C 10 alkylene. Optionally, S 1 is optionally substituted C1 alkylene. Optionally, S 1 is optionally substituted C2 alkylene. Optionally, S 1 is optionally substituted C3 alkylene. Optionally, S 1 is optionally substituted C4 alkylene. Optionally, S 1 is optionally substituted C5 alkylene. Optionally, S 1 is optionally substituted C6 alkylene. Optionally, S 1 is optionally substituted C7 alkylene. Optionally, S 1 is optionally substituted C8 alkylene. Optionally, S 1 is optionally substituted C9 alkylene. Optionally, S 1 is optionally substituted C 10 alkylene. Optionally, S 1 is optionally substituted C 11 alkylene. Optionally, S 1 is optionally substituted C 12 alkylene. Optionally, S 1 is optionally substituted C 13 alkylene. Optionally, S 1 is optionally substituted C 14 alkylene. Optionally, S 1 is optionally substituted C 15 alkylene. Optionally, S 1 is optionally substituted C 16 alkylene. Optionally, S 1 is optionally substituted C 17It is alkylene. Depending on the case, S 1 This is C, which has been replaced by an optional substitution. 18 It is alkylene. Depending on the case, S 1 This is C, which has been replaced by an optional substitution. 19 It is alkylene. Depending on the case, S 1 This is C, which has been replaced by an optional substitution. 20 It is alkylene. Depending on the case, S 1 One or more alkylene units of the alkylene are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, or -P(O)(R 20 ) is replaced by 2-. Depending on the case, S 1 One or more alkylene units of the alkylene are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 Substituted by -C(O)-, or -C(O)-. In some cases, S 1 One or more alkylene units of the alkylene are optionally and independently -N(R 20 )- is replaced by. Depending on the case, S 1 One or more alkylene units of the alkylene are optionally and independently -N(R 20 ) is replaced by C(O)-. In some cases, S 1 One or more alkylene units of the alkylene are optionally and independently -C(O)N(R 20 )- is replaced by. Depending on the case, S 1 One or more alkylene units of the alkylene are optionally and independently substituted by -C(O)-. In some cases, S 1One or more alkylene units of the alkylene are optionally and independently substituted with -O-. In some cases, when alkylene units of an alkylene are substituted, the alkylene may be referred to as the resulting alkylene. In some cases, S 1 If two or more alkylene units are replaced, the replaced alkylene units are not adjacent alkylene units. In some cases, S 1 If two or more alkylene units are substituted, adjacent alkylene units of the resulting alkylene are not substituted. 1 If two or more alkylene units are substituted, the resulting alkylene does not have the heteroatom repeats of adjacent alkylene units. In some cases, S 1 If two or more alkylene units are substituted, the resulting alkylene does not have the same heteroatom repeats of adjacent alkylene units. In some cases, S 1 If two or more alkylene units are substituted, the resulting alkylene units will not have -NN- or -OO-. In some cases, S 1 If two or more alkylene units are substituted, the resulting alkylene units are stable alkylenes. In some cases, S 1If two or more of the alkylene units are substituted, the resulting alkylene units are unreactive alkylenes. In some cases, the resulting alkylene has only one heteroatom. In some cases, the resulting alkylene has only two heteroatoms, and these two heteroatoms are distinct from each other. In some cases, the resulting alkylene has only two heteroatoms, and these two heteroatoms are not adjacent to each other. In some cases, the resulting alkylene has only three heteroatoms, and these three heteroatoms are not adjacent to each other. In some cases, the alkylene has zero substituted units. In some cases, the alkylene has one substituted unit. In some cases, the alkylene has two substituted units. In some cases, the alkylene has three substituted units. In some cases, the alkylene has four substituted units. In some cases, the alkylene has five substituted units. In some cases, the alkylene has six substituted units. In some cases, adjacent alkylene units of an alkylene are not substituted. In some cases, adjacent alkylene units resulting in two or more adjacent heteroatoms are not present in the resulting alkylene (e.g., adjacent -N(R 20 )S(O)2- and -N(R 20 )2- is not allowed, but the singular -N(R 20 )S(O)2- is acceptable). In some cases, two heteroatoms may be present in the resulting alkylene if they arise from a single substituted alkylene unit. In some cases, two heteroatoms may be present in the resulting alkylene if they arise from a single substituted alkylene unit. In some cases, the resulting alkylene has two heteroatoms, and these two heteroatoms originate from a single substituted alkylene unit. In some cases, two heteroatoms are present in the resulting alkylene if it arises from a single substitution of an alkylene unit.

[0104] In some embodiments, for the linker of formula (XXX) or formula (II), the drug linker or salt of formula (B), formula (X), formula (I), or formula (I-A), or the conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), S 1 is selected from -N(R 20 )C(O)-C1-C3 alkylene-N(R 20 )C(O)-C1-C3 alkylene-N(R 20 )C(O)-C1-C3 alkylene. Optionally, S 1 is selected from -NHC(O)-C1-C3 alkylene-NHC(O)-C1-C3 alkylene-NHC(O)-C1-C3 alkylene.

[0105] In some embodiments, for the linker of formula (XXX) or formula (II), the drug linker or salt of formula (B), formula (X), formula (I), or formula (I-A), or the conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), S 1 Each optional substituent above is independently, each time it appears, (i) halogen, -OR 30 , -N(R 30 )2, -SR 30 , -N(R 30 )2, -C(O)R 30 , -C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 , -OC(O)R 30 , -S(O)R 30 , -S(O)2R 30 , -O-S(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), and -CN, (ii) C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl (each optionally, halogen, -OR 30 , -SR 30 , -N(R 30)2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 -OS(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), -CN, C 3-10 Selected from a carbon ring and one or more substituents independently selected from 3- to 10-membered heterocycles. 1 Each of the above optional substituents is independent, and each instance is (i) halogen, -OR 30 , -N(R 30 )2, -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 -OS(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), and -CN are selected. Depending on the case, S 1 Each of the above optional substituents is independent, and each instance is a halogen, -OR 30 , -N(R 30 )2, =O, and -CN are selected. Depending on the case, S 1 Each of the above optional substituents is independently selected from =O each time it appears. In some cases, S 1 This is a non-substitution.

[0106] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), S 1 C1-C replaced by any choice 30 Alkylenes are linear. In some cases, S 1 C1-C replaced by any choice 30 Alkylenes are branched-chain alkylenes.

[0107] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), S 1 C1-C, which were replaced by arbitrary selection. 30 An alkylene in which one or more alkylene units are optionally and independently substituted by -N(H)C(O)-, an optionally substituted C1-C 30 Selected from alkylenes.

[0108] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), S 1 is -NH-C(O)-C 1- C6 Alkylene-NH-C(O)-C 1- C6 Alkylene-NH-C(O)-C 1- Selected from C6 alkylenes.

[0109] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), S 1 is -NH-C(O)-C 1-C6 Alkylene-NH-C(O)-C 1- C6 Alkylene-NH-C(O)-C 1- Selected from C6 alkylene, -S 2 -K 1 It binds to one of the alkylenes. In some cases, S 1 teeth,

[0110] [ka] Selected from, -S 2 -K 1 It binds to one of the alkylenes. In some cases, S 1 teeth,

[0111] [ka] Selected from, -S 2 -K 1 It binds to one of the alkylenes, S 2 It is -C(O)-.

[0112] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), -S 1 -S 2 -K 1 teeth,

[0113] [ka] Selected from. Depending on the case, -S 1 -S 2 -K 1 teeth,

[0114] [ka] Selected from. Depending on the case, -S 1 -S 2 -K 1 teeth,

[0115] [ka] Selected from. Depending on the case, -S 1 -S 2 -K 1 teeth,

[0116] [ka] Selected from. Depending on the case, -S 1 -S 2 -K 1 teeth,

[0117] [ka] Selected from. Depending on the case, -S 1 -S 2 -K 1 teeth,

[0118] [ka] Selected from.

[0119] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), S 2 C1-C, which were replaced by arbitrary selection. 30 Alkylene, wherein one or more alkylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 C1-C is optionally substituted by -, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.30 Selected from alkylenes. In some embodiments, S 2 C1-C, which were replaced by arbitrary selection. 30 Alkylene, wherein one or more alkylene units are optionally and independently -N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 C1-C is optionally substituted by -, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-. 30 Selected from alkylenes. In some embodiments, S 2 C1-C, which were replaced by arbitrary selection. 30 Alkylene, wherein one or more alkylene units are optionally and independently -C(O)N(R) 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 C1-C is optionally substituted by -, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-. 30 Selected from alkylenes. In some embodiments, S 2 C1-C, which were replaced by arbitrary selection. 30 Alkylene, wherein one or more alkylene units are optionally and independently -N(R 20 )S(O)2-, -S(O)2N(R 20 C1-C is optionally substituted by -, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-. 30 Selected from alkylenes. In some embodiments, S 2 C1-C, which were replaced by arbitrary selection. 30 An alkylene in which one or more alkylene units are optionally and independently -S(O)2N(R 20C1-C is optionally substituted by -, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-. 30 Selected from alkylenes. In some embodiments, S 2 C1-C, which were replaced by arbitrary selection. 30 An alkylene in which one or more alkylene units are optionally and independently substituted with -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-, an optionally substituted C1-C 30 Selected from alkylenes. In some embodiments, S 2 C1-C, which were replaced by arbitrary selection. 30 An alkylene in which one or more alkylene units are optionally and independently substituted with -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-, an optionally substituted C1-C 30 Selected from alkylenes.

[0120] In some embodiments, with respect to a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), S 2 C1-C, which were replaced by arbitrary selection. 30 An alkylene in which one or more alkylene units are optionally and independently substituted with -C(O)-, an optionally substituted C1-C 30 Selected from alkylenes.

[0121] In some embodiments, with respect to linkers of formula (XXX), formula (II), drug linkers or salts of formula (B), formula (X), formula (I), or formula (IA), or conjugates or salts of formula (C), formula (XX), formula (A), or formula (A-1), S 2This is an optionally substituted C1-C6 alkylene, in which one or more alkylene units are optionally and independently substituted with -C(O)-, selected from optionally substituted C1-C6 alkylenes. In some cases, S 2 This is an optionally substituted C1-C2 alkylene, in which one or more alkylene units are optionally and independently substituted with -C(O)-, selected from optionally substituted C1-C2 alkylenes. In some cases, S 2 teeth,

[0122] [ka] That is the case.

[0123] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), S 2 is -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 -P(O)(R) 20 )2- Selected. Depending on the case, S 2 These include -NH-, -NHC(O)-, -C(O)NH-, -NHS(O)2-, -S(O)2NH-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, 5-6 member heterocyclenes, and -P(O)(R 20 )2- Selected. Depending on the case, S 2 The following are selected from -NH-, -NHC(O)-, -C(O)NH-, and -C(O)-. Depending on the case, S 2The following are selected from -NHC(O)-, -C(O)NH-, and -C(O)-. Depending on the case, S 2 It is selected from -C(O)-.

[0124] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), -S 1 -S 2 -K 1 is, -S 1 -C(O)-K 1 It is represented by [this].

[0125] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), S 2 is selected from -C1-C6 alkylene-C(O)-. In some embodiments, S 2 The C1-C5 alkylene is selected from C(O)-. In some embodiments, S 2 is selected from -C1-C4 alkylene-C(O)-. In some embodiments, S 2 is selected from -C1-C3 alkylene-C(O)-. In some embodiments, S 2 is selected from -C1-C2 alkylene-C(O)-. In some embodiments, S 2 is selected from -C2 alkylene-C(O)-. In some embodiments, S 2 The component is selected from -C1 alkylene-C(O)-.

[0126] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), -S 1 -S 2-K 1 teeth,

[0127] [ka] Selected from.

[0128] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), -S 1 -S 2 -K 1 teeth,

[0129] [ka] That is the case.

[0130] In some embodiments, the drug linker or salt of formula (B), formula (X), or formula (I) is formula (IA)

[0131] [ka] It is represented by: In some embodiments, formula (X) or formula (I) is formula (IB)

[0132] [ka] It is represented by . Depending on the case, D is exatecan. Depending on the case, D is MMAE. Depending on the case, Y 1 teeth,

[0133] [ka] Selected from. In some cases, Y 1 teeth,

[0134] [ka] That is the case.

[0135] In some embodiments, with respect to a drug linker of formula (IA) or formula (IB), Y 1 teeth,

[0136] [ka] Selected from, K 1 It is selected from the peptide units. In some cases, the peptide units are

[0137] [ka] Represented by, m is selected from 1 to 3. n is selected from 1 to 30. R 5 These are, independently, hydrogen and C 1-6 Selected from alkyl groups, R 10 These are, independently, hydrogen, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -CH2CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2 )3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-, phenyl, cyclohexyl, and

[0138] [ka] Selected from, T is -OH, -NH2, and

[0139] [ka] Selected from. Depending on the case, R 10 It is selected from hydrogen and methyl. In some cases, the peptide unit is

[0140] [ka] It is represented by . Depending on the case, n is selected from 7 to 12. Depending on the case, n is selected from 8 to 10. Depending on the case, n is 8. Depending on the case, n is 9. Depending on the case, n is 10. Depending on the case, R 10 These are hydrogen atoms, respectively. Depending on the case, R 5 These are independently selected from hydrogen and methyl. In some cases, Y 1 teeth,

[0141] [ka] That is the case.

[0142] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), K 1 teeth,

[0143] [ka] Selected from. Depending on the case, K 1 teeth,

[0144] [ka] Selected from. In some cases, K 1 teeth,

[0145] [ka] Selected from. In some cases, K 1 teeth,

[0146] [ka] It is selected from. Depending on the case, n is selected from 7 to 12. Depending on the case, n is selected from 8 to 10. Depending on the case, n is 8. Depending on the case, n is 9. Depending on the case, n is 10.

[0147] In some embodiments, with respect to a drug linker or salt of formula (B), formula (X), or formula (I), or a conjugate or salt of formula (C), formula (XX), or formula (A), S 3 It exists and is phenylene.

[0148] In some embodiments, with respect to a drug linker or salt of formula (X) or formula (I), or a conjugate or salt of formula (C), formula (XX), or formula (A), S 3 It does not exist.

[0149] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), the sugar-cleaving unit may refer to a sugar moiety, preferably a glucuronide or galactoside.

[0150] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), cleavage of the cleavage unit induces the self-sacrifice of the phenyl-containing linker and the release of drug unit (D) among the compounds of the present invention.

[0151] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), the peptide-cleaving unit may refer to a polypeptide, preferably a dipeptide or tripeptide.

[0152] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), T 1 The sugar-cleaving unit contains a sugar. In some cases, the sugar is a glucuronide. In some cases, the sugar is selected from fructose, galactose, glucose, xylose, and ribose. In some cases, the sugar is a monosaccharide. In some cases, the sugar is a disaccharide.

[0153] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), or formula (A), or formula (A-1), Y 1 teeth,

[0154] [ka] In some cases, Y 1 This is the sugar portion. In some cases, Y 1 It does not exist.

[0155] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), T 2The peptide unit contains one or more amino acids selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-alanine. In some cases, T 2 The peptide unit contains one or more amino acids selected from the group consisting of alanine, arginine, asparagine, aspartic acid, glutamine, glycine, lysine, methionine, phenylalanine, proline, serine, valine, citrulline, and β-alanine. In some cases, T 2 The peptide unit may include a dipeptide or a tripeptide. 2 The peptide unit contains a dipeptide. The dipeptide may be selected from Val-Cit, Val-Ala, and Phe-Lys.

[0156] In some embodiments, with respect to linkers of formula (XXX), formula (II), drug linkers or salts of formula (B), formula (X), formula (I), or formula (IA), or conjugates or salts of formula (C), formula (XX), formula (A), or formula (A-1), T 2 The peptide unit includes a capping moiety. In some cases, the capping moiety is a moiety capable of reacting with the amine of the peptide to form an amide, carbamate, or sulfonamide. In some cases, the capping moiety, as a result of reacting with the amine, forms an amide, carbamate, or sulfonamide. In some cases, the capping moiety, as a result of reacting with the amine, forms an amide. In some cases, the capping moiety is a moiety that caps the end of the peptide / amino acid. In some cases, the capping moiety is

[0157] [ka] In some cases, Y 1 teeth,

[0158] [ka] That is the case.

[0159] In some embodiments, with respect to linkers of formula (XXX), formula (II), drug linkers or salts of formula (B), formula (X), formula (I), or formula (IA), or conjugates or salts of formula (C), formula (XX), formula (A), or formula (A-1), T 2 The peptide unit includes a capping moiety. In some cases, the capping moiety is a moiety capable of reacting with the amine of the peptide to form an amide, carbamate, or sulfonamide. In some cases, the capping moiety, as a result of reacting with the amine, forms an amide. In some cases, the capping moiety, as a result of reacting with the amine, forms an amide. In some cases, the capping moiety is a moiety that caps the end of the peptide / amino acid. In some cases, the capping moiety is an acyl moiety. In some cases, the capping moiety is

[0160] [ka] (In the formula, R* is C 1-6 (Selected from) In some cases, the capping portion is

[0161] [ka] In some cases, Y is

[0162] [ka] (In the formula, R* is C 1-6 (selected from) In some cases, Y is

[0163] [ka] That is the case.

[0164] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), K 1 It is selected from peptide units. In some cases, a peptide unit is a residue.

[0165] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), K 1 The peptide unit has 1 to 50 amino acids. In some cases, K 1 The peptide unit has 1 to 20 amino acids. In some cases, K 1 The peptide unit has 1 to 10 amino acids. In some cases, K 1 The peptide unit has 2 to 50 amino acids. In some cases, K 1 The peptide unit has 2 to 40 amino acids. In some cases, K 1 The peptide unit has 2 to 30 amino acids. In some cases, K 1 The peptide unit has 2 to 20 amino acids. In some cases, K 1 The peptide unit has 2 to 10 amino acids. In some cases, K 1 The peptide unit has 5 to 10 amino acids. In some cases, K 1 The peptide unit has at least one amino acid. In some cases, K 1 The peptide unit has one amino acid. In some cases, K 1 The peptide unit has at least two amino acids. In some cases, K 1 The peptide unit has at least 5 amino acids. In some cases, K 1The peptide unit has at least 8 amino acids. In some cases, K 1 The peptide unit has at least 10 amino acids. In some cases, K 1 The peptide unit has up to 10 amino acids. In some cases, K 1 The peptide unit has 10 amino acids. In some cases, K 1 The peptide unit has at least 12 amino acids. In some cases, K 1 The peptide unit has up to 12 amino acids. In some cases, K 1 The peptide unit has at least 20 amino acids. In some cases, K 1 The peptide unit has up to 20 amino acids. In some cases, K 1 The peptide unit has 20 amino acids. In some cases, K 1 The peptide unit has up to 30 amino acids. In some cases, K 1 The peptide unit has at least 30 amino acids. In some cases, K 1 The amino acids are selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-alanine. In some cases, K 1 The amino acids are selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-alanine. In some cases, K 1 The amino acids are selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-alanine. In some cases, K1 The amino acids are selected from the group consisting of glycine, sarcosine, proline, serine, alanine, and β-alanine. In some cases, K 1 The amino acids are selected from the group consisting of glycine, proline, serine, alanine, and β-alanine. In some cases, K 1 The amino acids are selected from the group consisting of glycine, proline, serine, alanine, and β-alanine. In some cases, K 1 It contains at least one glycine. In some cases, K 1 It contains at least one proline. In some cases, K 1 It contains at least one serine. In some cases, K 1 It contains at least one alanine. In some cases, K 1 It contains at least one β-alanine. In some cases, K 1 It is polysarcosine. In some cases, K 1 It is a polysarcosine having 10 repeating sarcosine units.

[0166] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), K 1 It is selected from peptide units, and the peptide unit has a terminal -NH2. In some cases, K 1 It is selected from peptide units, and the peptide units have a terminal -OH. In some cases, K 1 It is selected from peptides, and the peptide has a terminal -NH2. In some cases, K 1 It is selected from peptides, and the peptides have a terminal -OH group.

[0167] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), K 1It is selected from the peptide unit. In some cases, K 1 The peptide unit has 1 to 50 amino acids. In some cases, K 1 The peptide unit has 1 to 20 amino acids. In some cases, K 1 The peptide unit has 1 to 10 amino acids. In some cases, K 1 The peptide unit has 2 to 50 amino acids. In some cases, K 1 The peptide unit has 2 to 40 amino acids. In some cases, K 1 The peptide unit has 2 to 30 amino acids. In some cases, K 1 The peptide unit has 2 to 20 amino acids. In some cases, K 1 The peptide unit has 2 to 10 amino acids. In some cases, K 1 The peptide unit has 5 to 10 amino acids. In some cases, K 1 The peptide unit has at least one amino acid. In some cases, K 1 The peptide unit has one amino acid. In some cases, K 1 The peptide unit has at least two amino acids. In some cases, K 1 The peptide unit has at least 5 amino acids. In some cases, K 1 The peptide unit has at least 8 amino acids. In some cases, K 1 The peptide unit has at least 10 amino acids. In some cases, K 1 The peptide unit has up to 10 amino acids. In some cases, K 1 The peptide unit has 10 amino acids. In some cases, K 1 The peptide unit has at least 12 amino acids. In some cases, K 1 The peptide unit has up to 12 amino acids. In some cases, K 1 The peptide unit has at least 20 amino acids. In some cases, K 1 The peptide unit has up to 20 amino acids. In some cases, K 1The peptide unit has 20 amino acids. In some cases, K 1 The peptide unit has up to 30 amino acids. In some cases, K 1 The peptide unit has at least 30 amino acids. In some cases, K 1 It is a peptide unit selected from glycine and two adjacent sarcosines. In some cases, K 1 It is a peptide unit selected from glycine and three adjacent sarcosines. In some cases, K 1 It is a peptide unit selected from glycine and four adjacent sarcosines. In some cases, when the peptide unit contains adjacent sarcosines, at least one other amino acid is present. In some cases, K 1 It contains glycine and two adjacent sarcosines. In some cases, K 1 It contains glycine and three adjacent sarcosines. In some cases, K 1 It contains glycine and four adjacent sarcosines. In some cases, K 1 It is a peptide unit selected from glycine and two adjacent sarcosines. In some cases, K 1 It is a peptide unit selected from glycine and three adjacent sarcosines. In some cases, K 1 It is a peptide unit selected from glycine and four adjacent sarcosines. In some cases, K 1 It contains two glycines and eight sarcosines. In some cases, K 1 It contains three glycine molecules and eight sarcosine molecules. In some cases, K 1 It contains four glycine molecules and seven sarcosine molecules. In some cases, K 1 It contains three glycine molecules and seven sarcosine molecules. In some cases, K 1 It contains three glycine molecules and six sarcosine molecules. In some cases, K 1 It contains three glycine molecules and five sarcosine molecules. In some cases, K 1 It contains three glycine molecules and four sarcosine molecules. In some cases, K 1It contains three glycine molecules and three sarcosine molecules. In some cases, K 1 It contains three glycine molecules and nine sarcosine molecules. In some cases, K 1 It contains three glycine molecules and ten sarcosine molecules. In some cases, K 1 It contains five glycine molecules and five sarcosine molecules. In some cases, K 1 It contains four glycine molecules and four sarcosine molecules. In some cases, K 1 It contains four glycine molecules and five sarcosine molecules. In some cases, K 1 It contains five glycine molecules and four sarcosine molecules. In some cases, K 1 It has up to 9 sarcosines. In some cases, K 1 It has up to 8 sarcosines. In some cases, K 1 It has up to 7 sarcosines. In some cases, K 1 It has up to 6 sarcosines. In some cases, K 1 It has up to 5 sarcosines. In some cases, K 1 It has up to 4 sarcosines. In some cases, K 1 It has up to 3 sarcosines. In some cases, K 1 It has a maximum of two sarcosines. In some cases, K 1 It has a maximum of one sarcosine. In some cases, K 1 It has up to 9 glycines. In some cases, K 1 It has up to 8 glycines. In some cases, K 1 It has up to 7 glycine molecules. In some cases, K 1 It has up to 6 glycines. In some cases, K 1 It has up to 5 glycines. In some cases, K 1 It has up to 4 glycines. In some cases, K 1 It has up to 3 glycine molecules. In some cases, K 1 It has a maximum of two glycine molecules. In some cases, K 1 It has a maximum of one glycine. In some cases, K 1The amino acids are selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-alanine. In some cases, K 1 The amino acids are selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-alanine. In some cases, K 1 The amino acids are selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-alanine. In some cases, K 1 The amino acids are selected from the group consisting of glycine, sarcosine, proline, serine, alanine, and β-alanine. In some cases, K 1 The amino acids are selected from the group consisting of glycine, proline, serine, alanine, and β-alanine. In some cases, K 1 The amino acids are selected from the group consisting of proline, serine, alanine, and β-alanine. In some cases, K 1 The amino acids include at least one glycine and at least one other amino acid. In some cases, K 1 The amino acids include at least one glycine and at least one sarcosine. In some cases, K 1 The amino acids include at least one glycine and at least one other amino acid selected from proline, serine, alanine, and β-alanine. In some cases, K 1 The amino acids are selected from the group consisting of glycine, proline, serine, alanine, and β-alanine. In some cases, K 1It contains at least one glycine. In some cases, K 1 It contains at least one proline. In some cases, K 1 It contains at least one serine. In some cases, K 1 It contains at least one alanine. In some cases, K 1 It contains at least one β-alanine.

[0168] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), K 1 This includes PASylation. In some cases, PASylation is a peptide containing proline, alanine, and serine. In some cases, PASylation is a peptide consisting only of proline, alanine, and serine. In some cases, K 1 This includes PAS formulations with less than PAS100. For example, PAS100 refers to a peptide having 100 amino acids, where the amino acids are selected from proline, alanine, and serine. In some cases, K 1 This includes PAS conversions below PAS50. In some cases, K 1 This includes PAS conversions below PAS25. In some cases, K 1 This includes PAS implementations beyond PAS5. In some cases, K 1 This includes PAS implementations beyond PAS9. In some cases, K 1 This includes PAS conversion beyond PAS15. In some cases, K 1 This includes PAS conversion of PAS5 to PAS25. Depending on the case, K 1 This includes the PAS conversion of PAS10 to PAS20. Depending on the case, K 1 This includes the PAS conversion of PAS10. Depending on the case, K 1 This includes the PAS conversion of PAS20. Depending on the case, K 1It contains β-alanine, which links the PAS compound to the drug linker. In some cases, PAS compounding is used to extend the plasma half-life. In some cases, PAS compounding is used to increase solubility. Barrier PAS compounding is used to increase solubility without creating secondary structures. In some cases, PAS compounding is used

[0169] [ka] In some cases, PAS implementation is possible.

[0170] [ka] That is the case.

[0171] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), K 1 The peptide unit has a terminal unit. In some cases, K 1 teeth,

[0172] [ka] (In the formula, the terminal unit is R 6 Represented by (where j is selected from 1 to 30). In some cases, j is 1. In some cases, j is 3. In some cases, j is 5. In some cases, j is 10. In some cases, j is 20. In some cases, R 6 is -OR 7 and -NHR 7 Selected from, R 7 is hydrogen, C 1-10 Alkyl, C 2-10 Alkenil, C 2-10 Alkinyl (each of these is a halogen, -OR 30 , -SR 30 , -N(R 30)2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 -OS(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), -CN, C 3-10 Selected from carbon rings and (optionally substituted with one or more substituents independently selected from 3- to 10-membered heterocycles). In some cases, R 6 These are -OH, -NH2, and

[0173] [ka] Selected from. Depending on the case, R 6 It is -OH. Depending on the case, R 6 It is -NH2. Depending on the case, R 6 teeth,

[0174] [ka] That is the case.

[0175] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), K 1 The peptide unit has a terminal unit. In some cases, K 1 teeth,

[0176] [ka] (In the formula, the terminal unit is R 6It is represented by (where j is selected from 1 to 30). In some cases, K 1 teeth,

[0177] [ka] (In the formula, the terminal unit is R 6 Represented by (where j is selected from 1 to 30). In some cases, j is 1. In some cases, j is 3. In some cases, j is 5. In some cases, j is 10. In some cases, j is 20. In some cases, R 6 is -OR 7 and -NHR 7 Selected from, R 7 is hydrogen, C 1-10 Alkyl, C 2-10 Alkenil, C 2-10 Alkinyl (each of these is a halogen, -OR 30 , -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 -OS(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), -CN, C 3-10 Selected from carbon rings and (optionally substituted with one or more substituents independently selected from 3- to 10-membered heterocycles). In some cases, R 6 It is selected from -OH and -NH2. In some cases, R 6 These are -OH, -NH2, and

[0178] [ka] Selected from. Depending on the case, R 6 It is -OH. Depending on the case, R 6 It is -NH2. Depending on the case, R 6 teeth,

[0179] [ka] That is the case.

[0180] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), K 1 teeth,

[0181] [ka] Selected from. In some cases, K 1 teeth,

[0182] [ka] Selected from. In some cases, K 1 teeth,

[0183] [ka] Selected from. In some cases, K 1 teeth,

[0184] [ka] Selected from. In some cases, K 1 teeth,

[0185] [ka] Selected from. In some cases, K 1 teeth,

[0186] [ka] Selected from. In some cases, K 1 teeth,

[0187] [ka] Selected from. In some cases, K 1 teeth,

[0188] [ka] In some cases, K 1 teeth,

[0189] [ka] In some cases, K 1 teeth,

[0190] [ka] In some cases, K 1 teeth,

[0191] [ka] In some cases, K 1 teeth,

[0192] [ka] In some cases, K 1 teeth,

[0193] [ka] In some cases, K 1 teeth,

[0194] [ka] In some cases, K 1 teeth,

[0195] [ka] That is the case.

[0196] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), K 1 teeth,

[0197] [ka] Selected from. In some cases, K 1 teeth,

[0198] [ka] Selected from.

[0199] In some embodiments, with respect to a linker of formula (XXX) or formula (II), a drug linker or salt of formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), K 1 Each is selected from oligosaccharides. In some cases, the oligosaccharide will contain a connector unit that binds the oligosaccharide to the rest of the molecule. In some cases, the connector unit is beta-alanine. In some cases, the connector unit is

[0200] [ka] In some cases, K 1 These are,

[0201] [ka] (In the formula, k is selected from 2 to 10). In some cases, k is 2. In some cases, k is 3. In some cases, k is 4. In some cases, k is 5. In some cases, k is 6. In some cases, K 1 These are,

[0202] [ka] Selected from. Depending on the case, S 2 teeth,

[0203] [ka] In some cases, S 2 -K 1 teeth,

[0204] [ka] That is the case.

[0205] In some embodiments, with respect to a drug linker or salt of formula (X), formula (I), or formula (IA), M 1This group is capable of forming a connector unit by reacting with a targeting unit. The group capable of forming a connector unit by reacting with a targeting unit may refer to any chemical moiety that is reactive for covalent bonding with the targeting unit (e.g., an antibody, ligand, or antigen-binding fragment). This group may react with thiol groups present on the targeting unit. This group may react with thiol groups present on the antibody or its antigen-binding fragment. This group may react with thiol groups present on the ligand. Depending on the case, the chemical moieties that are reactive for covalent bonding to a ligand include carboxylic acids, primary amines, secondary amines, tertiary amines, hydroxyls, halogens, activated esters (such as N-hydroxysuccinimide esters, perfluoroesters, nitrophenyl esters, aza-benzotriazole, and benzotriazole activated esters), acylureas, alkynyls, alkenyls, azides, isocyanates, isothiocyanates, aldehydes, thiol reactive moieties (such as maleimide, halomaleimide, haloacetyl, pyridyl disulfide), thiols, acrylates, mesylates, tosylates, triflates, hydroxylamines, chlorosulfonyls, and boronic acid-B(OR')2 derivatives (wherein R' is hydrogen or alkyl). Depending on the case, M 1 It is maleimide, halogen, COOH,

[0206] [ka] , azide, -C≡CH, activated C≡C group,

[0207] [ka] Selected from OH, SH, activated disulfide group, NH2, and -ONH2. In some cases, M 1 It is maleimide. In some cases, M 1 It is a halogen. Depending on the case, M 1 It is COOH. In some cases, M 1 teeth,

[0208] [ka] In some cases, M 1 It is Azid. Depending on the case, M 1 -C≡CH. In some cases, M 1 The activated C≡C group is

[0209] [ka] Selected from. Depending on the case, M 1 teeth,

[0210] [ka] In some cases, M 1 teeth,

[0211] [ka] In some cases, M 1 It is OH. Depending on the case, M 1 It is SH. Depending on the case, M 1 The activated disulfide is,

[0212] [ka] Selected from. Depending on the case, M 1 teeth,

[0213] [ka] In some cases, M 1 It is NH2. Depending on the case, M 1 It is -ONH2. Depending on the case, M 1 These are suitable for click reactions (e.g., cyclic alkynes, azides).

[0214] In some embodiments, with respect to a drug linker or salt of formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), the drug unit is selected from cytotoxic agents, immunomodulators, nucleic acids, growth inhibitors, PROTACs, toxins, radioisotopes, and chelated ligands. In some cases, the drug unit is selected from cytotoxic agents.

[0215] In some embodiments, with respect to a drug linker or salt of formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), the drug unit is selected from cytotoxic agents, camptothecin derivatives, and immunomodulators.

[0216] In some cases, the drug unit is selected from exatecan, SN-38, and monomethyl auristatin E (MMAE). In some cases, the drug unit is a camptothecin derivative. In some cases, the drug unit is exatecan. In some cases, the drug unit is SN-38. In some cases, the drug unit is selected from MMAF and MMAE. In some cases, the cytotoxic agent is selected from the group consisting of auristatin, meitansinoids, camptothecin, duocalmycin, and calicheamycin. In some cases, the cytotoxic agent is a drug that has a cytotoxic effect on cells. In some cases, the cytotoxic agent includes, for example, tubulin disruptors, topoisomerase inhibitors, DNA minor groove binders, and DNA alkylating agents. In some cases, tubulin-destroying agents include, for example, auristatin, dorastatin, tubulicin, colchicine, vinca alkaloids, taxanes, cryptophycin, meitansinoids, hemiasterin, and other tubulin-destroying agents. In some cases, auristatin is a derivative of the natural product dorastatin 10. In some cases, auristatin is selected from MMAE (N-methylvaline-valine-dry soleicin-doraproin-norephedrine), MMAF (N-methylvaline-valine-dry soleicin-doraproin-phenylalanine), and AFP. In some cases, the cytotoxic agent may be a topoisomerase inhibitor. In some cases, the drug is an immunomodulator, such as a TLR7 agonist and / or a TLR8 agonist. In some cases, the immunomodulator is a STING agonist. In some cases, the drug is a radioactive atom. In some cases, the drug is a proteolytically targeted chimeric molecule (PROTAC).

[0217] In some embodiments, with respect to a drug linker or salt of formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), S 3The spacer is selected from the spacers. In some cases, the spacer is a divalent moiety that covalently bonds to two components of the conjugate or drug linker. In some cases, S 3 It exists. Depending on the case, S 3 There is no such thing. Depending on the case, the spacer may be selected from alkylenes, heteroalkylenes (alkylenes having one or more alkylene units substituted with at least one heteroatom selected from Si, N, O, and S at appropriate valencies), alkoxys, polyethers (such as polyalkylene glycols and typically polyethylene glycols), one or more natural or unnatural amino acids (such as glycine, alanine, proline, valine, and N-methylglycine), C3-C8 heterocyclos, C3-C8 carbocyclos, and any combination thereof. Depending on the case, the spacer may be a divalent linear alkylene group. Depending on the case, the spacer may be -C1-C 10 Alkylene-,-C1-C 10 Heteroalkylene-,-C3-C8 carbocyclo-,-O-(C1C8 alkyl)-,-arylene-,-C1-C 10 Alkilen-Arirene-,-Arirene-C1-C 10 Alkylene-,-C1-C 10 Alkylene-(C3-C8 carbocyclo)-,-(C3-C8 carbocyclo)-C1-C 10 Alkylene-,-C3-C8 heterocyclo-,-C1-C 10 Alkylene-(C3-C8 heterocyclo)-,-(C3-C8 heterocyclo)-C1-C 10 Alkylene-,-C1-C 10 Alkylene -C(=O)-, -C1-C 10 Heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O-(C1-C8 alkyl)-C(=O)-, -arylene-C(=O)-, -C1-C 10 Alkylene-arirene-C(=O)-,-arirene-C1-C 10 Alkylene -C(=O)-, -C1-C 10 Alkylene-(C3-C8 carbocyclo)-C(=O)-,-(C3-C8 carbocyclo)-C1-C 10Alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, C1-C 10 Alkylene-(C3-C8 heterocyclo)-C(=O)-,-(C3-C8 heterocyclo)-C1-C 10 Alkylene -C(=O)-, -C1-C 10 Alkylene-NH-,-C1-C 10 Heteroalkylene-NH-,-C3-C8carbocyclo-NH-,-O-(C1-C8alkyl)-NH-,-arylene-NH-,-C1-C 10 Alkylene-arylene-NH-,-arylene-C1-C 10 Alkylene-NH-,-C1-C 10 Alkylene-(C3-C8 carbocyclo)-NH-,-(C3-C8 carbocyclo)-C1-C 10 Alkylene-NH-,-C3-C8 heterocyclo-NH-,-C1-C 10 Alkylene-(C3-C8 heterocyclo)-NH-,-(C3-C8 heterocyclo)-C1-C 10 Alkylene-NH-,-C1-C 10 Alkylene-S-,-C1-C 10 Heteroalkylene-S-,-C3-C8carbocyclo-S-,-O-(C1-C8alkyl)-)-S-,-arylene-S-,-C1-C 10 Alkylene-Arirene-S-,-Arirene-C1-C 10 Alkylene-S-,-C1-C 10 Alkylene-(C3-C8 carbocyclo)-S-,-(C3-C8 carbocyclo)-C1-C 10 Alkylene-S-,-C3-C8 heterocyclo-S-,-C1-C 10 Alkylene-(C3-C8 heterocyclo)-S-,-(C3-C8 heterocyclo)-C1-C 10 Alkylene-S-,-C1-C 10 Alkylene-OC(=O)-, -C3-C8 carbocyclo-OC(=O)-, -O-(C1-C8 alkyl)-OC(=O)-, -arylene-OC(=O)-, -C1-C 10 Alkylene-arylene-OC(=O)-,-arylene-C1-C 10Alkylene -OC(=O)-, -C1-C 10 Alkylene-(C3-C8 carbocyclo)-OC(=O)-,-(C3-C8 carbocyclo)-C1-C 10 Alkylene-OC(=O)-, -C3-C8 heterocyclo-OC(=O)-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-OC(=O)- and -(C3-C8 heterocyclo)-C1-C 10 It can be selected from the group consisting of alkylene-OC(=O)-. Depending on the case, S 3 (i) halogen, -OR 30 , -N(R 30 )2, -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -OS(O)2R 30 -S(O)2R 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), and -CN, (ii)C 1-10 Alkyl, C 2-10 Alkenil, C 2-10 Alkinyl (each can be selected as halogen, -OR) 30 , -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 -OS(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30)2, -NO2, =O, =S, =N(R 30 ), -CN, C 3-10 (iii)C 3-10 Carbon rings and 3- to 10-membered heterorings (each can be optionally halogen, -OR) 30 , -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Substituted with one or more substituents selected from (which are independently selected from the alkynyl molecule). In some cases, S 3 (i) halogen, -OR (optional) 30 , -N(R 30 )2, -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -OS(O)2R 30 -S(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), and -CN are selected. Depending on the case, S 3 It is a non-substitution. In some cases, S3 It is replaced. Depending on the case, S 3 It is phenylene. In some cases, S 3 teeth,

[0218] [ka] That is the case.

[0219] In some embodiments, with respect to a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), the targeting unit is M 1 This further includes binding to form a conjugate, and the M of the drug linker 1 The drug linker reacts with the targeting unit to form a covalent bond. In some cases, the targeting unit is selected from the antibody or its antigen-binding portion. In some cases, the conjugate has an average ratio of drug linker to targeting unit of approximately 1 to 10. In some cases, the targeting unit is selected from the antibody or its antigen-binding portion. In some cases, the conjugate has an average ratio of drug linker to targeting unit of approximately 1 to 10. In some cases, the conjugate has an average ratio of drug linker to targeting unit of approximately 1 to 5. In some cases, the conjugate has an average ratio of drug linker to targeting unit of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0220] In some embodiments, with respect to a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), M 2 This is a connector unit. In some cases, a connector unit refers to a component that connects different parts of a conjugate together. In some cases, a connector unit connects a targeting unit to S 3 (if any) or S 1It can be connected to. In some cases, the connector unit forms a bond with the sulfur atom of the targeting unit. In some cases, the connector unit forms a bond with the sulfur atom of the targeting unit via a maleimide group. In some cases, the sulfur atom may originate from, for example, a sulfhydryl group of the targeting unit (e.g., a thiol group in an interchain disulfide bond). In some cases, M 2 teeth,

[0221] [ka] In some cases, M 2 teeth,

[0222] [ka] In some cases, M 2 teeth,

[0223] [ka] In some cases, M 2 teeth,

[0224] [ka] In some cases, M 2 teeth,

[0225] [ka] In some cases, M 2 teeth,

[0226] [ka] In some cases, M 2 It is -CH2-C(O)NH-. Depending on the case, M 2 M 2It is linked to the targeting unit via a disulfide bond between the sulfur atom of the target unit and the sulfur atom of the target unit. In some cases, M 2 teeth,

[0227] [ka] In some cases, the connector unit forms a bond with the primary or secondary amino group of the targeting unit.

[0228] In one aspect, this disclosure relates to formula (XXX)

[0229] [ka] Provides a linker of or a pharmaceutically acceptable salt thereof, in the formula, Y 1 It does not exist, or -OT 1 and -NH-T 2 Selected from, T 1 It is a glucose-cleaving unit, T 2 This is a peptide-cleaving unit, S 1 (i) C1-C replaced by arbitrary selection 30 Alkylene, wherein one or more alkylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 -P(O)(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, 5-6 member heterorings, or -P(O)(R) 20 )2- Replaced by optionally replaced C1-C 30 (ii) C3-C substituted by any choice 30 An alkenylene in which one or more alkenylene units are optionally and independently -N(R 20 )-,-N(R20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, or -P(O)(R 20 )2, optionally replaced C3-C 30 (iii) one or more amino acids, (iv) one or more N-substituted amino acids, (v) a polyether with optional substitution, (vi) a C3-C 10 Carbocyclene, (vii) Selected from 5-10 member heterocyclenes that have been optionally substituted, S 2 C1-C, which were replaced by arbitrary selection. 30 Alkylene, wherein one or more alkylene units are optionally and independently -N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-N(R 20 )S(O)2-, -S(O)2N(R 20 -P(O)(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, 5-6 member heterorings, or -P(O)(R) 20 )2- Replaced by optionally replaced C1-C 30 Selected from alkylenes, S 3 It is selected from the spacers, and at this time, S 3 Does it exist or does it not exist? M 1 , K 1 S 1 S 2 , and S 3 Each of the above optional substituents, independently, (i) Halogen, -OR 30 , -N(R 30 )2, -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 -OS(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), and -CN, (ii)C 1-10 Alkyl, C 2-10 Alkenil, C 2-10 Alkinyl (each of these is a halogen, -OR 30 , -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R 30 -OS(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), -CN, C 3-10 (Optionally substituted with one or more substituents independently selected from a carbon ring and a 3- to 10-membered heterocycle), and (iii) C 3-10 Carbon rings and 3- to 10-membered heterocycles (each of these being halogens, -OR) 30 , -SR 30 , -N(R 30 )2, -C(O)R 30 ,-C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 ,-OC(O)R 30 ,-S(O)R 30 -S(O)2R30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 (Optionally substituted with one or more substituents independently selected from the alkynyl molecule.) Selected from, M 1 This is a group that can react with a ligand to form a connector unit. K 1 teeth, (i) peptide unit, (ii) Oligosaccharides, and (iii) Polyether Selected from, R 20 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-12 Carbon rings and 3- to 12-membered heterocycles (each of these being halogens, -OH, -CN, -NO2, -NH2, -N(C) 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 Selected from carbon rings and 3- to 12-membered heterocycles, (optionally substituted with one or more substituents independently selected from these rings), R 30 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-12 Carbon rings and 3- to 12-membered heterocycles (each of these being halogens, -OH, -CN, -NO2, -NH2, -N(C) 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12Selected from carbon rings and 3- to 12-membered heterocycles, (optionally substituted with one or more substituents independently selected from these rings), R 50 The substituent is selected from those capable of reacting with the nucleophilic group on the drug.

[0230] Depending on the circumstances, the linker of formula (XXX) may be

[0231] [ka] or represented by a pharmaceutically acceptable salt thereof.

[0232] Depending on the case, with respect to the linker of formula (XXX) or formula (II), R 50 is selected from -OH. In some cases, with respect to the linker of formula (II), R 50 teeth,

[0233] [ka] Selected from.

[0234] Depending on the case, with respect to the linker of formula (XXX) or formula (II), R 50 teeth,

[0235] [ka] Selected from.

[0236] In some embodiments, the drug linker of formula (X) or formula (I) is

[0237] [ka] Selected from.

[0238] In some embodiments, the drug linker of formula (X) or formula (I) is

[0239] [ka]

[0240] [ka] Selected from.

[0241] In some embodiments, the drug linker of formula (X) or formula (I) is

[0242] [ka]

[0243] [ka] Selected from.

[0244] In some embodiments, the drug linker of formula (X) or formula (I) is

[0245] [ka]

[0246] [ka]

[0247] [ka]

[0248] [ka] Selected from.

[0249] In some embodiments, the conjugate of formula (XX) or formula (A) is

[0250] [ka]

[0251] [ka] (wherein L is the targeting unit and DAR is the drug-to-antibody ratio) is expressed as follows. In some cases, DAR is determined using RP-HPLC. In some cases, DAR is determined using RP-HPLC as in Example 25. In some cases, DAR is up to approximately 16. In some cases, DAR is approximately 8. In some cases, DAR is up to approximately 10. In some cases, DAR is at least approximately 1. In some cases, DAR is at least approximately 2. In some cases, DAR is at least approximately 4. In some cases, DAR is at least approximately 8. In some cases, DAR is up to approximately 8. In some cases, DAR is approximately 1 to approximately 16. In some cases, DAR is approximately 4 to approximately 12. In some cases, DAR is approximately 6 to approximately 10. In some cases, DAR is approximately 7 to approximately 9. In some cases, DAR is approximately 8 to approximately 10. Depending on the situation, the DAR is approximately 6 to 8.

[0252] In some embodiments, the conjugate of formula (XX) or formula (A) is

[0253] [ka]

[0254] [ka]

[0255] [ka]

[0256] [ka] (wherein L is the targeting unit and DAR is the drug-to-antibody ratio) is expressed as follows. In some cases, DAR is determined using RP-HPLC. In some cases, DAR is determined using RP-HPLC as in Example 25. In some cases, DAR is up to approximately 16. In some cases, DAR is approximately 8. In some cases, DAR is up to approximately 10. In some cases, DAR is at least approximately 1. In some cases, DAR is at least approximately 2. In some cases, DAR is at least approximately 4. In some cases, DAR is at least approximately 8. In some cases, DAR is up to approximately 8. In some cases, DAR is approximately 1 to approximately 16. In some cases, DAR is approximately 4 to approximately 12. In some cases, DAR is approximately 6 to approximately 10. In some cases, DAR is approximately 7 to approximately 9. In some cases, DAR is approximately 8 to approximately 10. In some cases, the DAR is approximately 6 to 8. In some cases, the targeting unit is an antibody selected from PTK7, ROR2, ROR1, and 5T4.

[0257] In some embodiments, the conjugate of formula (XX) or formula (A) is

[0258] [ka] It is expressed by, in the formula,

[0259] [ka]

[0260] [ka] L is the targeting unit, and DAR is the drug-to-antibody ratio. In some cases, DAR is determined using RP-HPLC. In some cases, DAR is determined using RP-HPLC as in Example 25. In some cases, DAR is up to approximately 16. In some cases, DAR is approximately 8. In some cases, DAR is up to approximately 10. In some cases, DAR is down to approximately 1. In some cases, DAR is down to approximately 2. In some cases, DAR is down to approximately 4. In some cases, DAR is down to approximately 8. In some cases, DAR is up to approximately 8. In some cases, DAR is from approximately 1 to approximately 16. In some cases, DAR is from approximately 4 to approximately 12. In some cases, DAR is from approximately 6 to approximately 10. In some cases, DAR is from approximately 7 to approximately 9. In some cases, DAR is from approximately 8 to approximately 10. In some cases, the DAR is approximately 6 to 8. In some cases, the DAR is the ratio of drug (D) to antibody (L). In some cases, the drug in the DAR is exatecan. In some cases, the drug in the DAR is exatecan. In some cases, the targeting unit contains an antibody. In some cases, the targeting unit is a) Sequence numbers 1 and 2 respectively, b) Sequence numbers 11 and 2, respectively c) Sequence numbers 15 and 16, respectively, or d) Sequence IDs 21 and 16, respectively The product contains antibodies comprising heavy chains (HC) and light chains (LC). In some cases, the targeting unit contains a) antibodies comprising heavy chains (HC) and light chains (LC), comprising SEQ ID NOs. 1 and 2, respectively. In some cases, the antibody or antigen-binding portion may a) Sequence numbers 3 and 4 respectively, b) Sequence IDs 12 and 4, respectively, or c) Sequence numbers 17 and 18 respectively It includes the heavy chain variable domain (VH) amino acid sequence and the light chain variable domain (VL) amino acid sequence. In some cases, the antibody or antigen binding moiety is a) Sequence numbers 5, 6, 7, 8, 9, and 10, respectively b) Sequence numbers 13, 6, 14, 8, 9, and 10, respectively, or c) Sequence numbers 19, 6, 20, 8, 9, and 10 respectively It contains the heavy chain complementarity-determining regions (CDRs) 1-3 (HCDR1-3) amino acid sequences and the light chain CDRs 1-3 (LCDR1-3) amino acid sequences. In some cases, the antibody or antigen-binding moiety competes or cross-competes for binding to human ROR2. In some cases, L is a ROR2 antibody. In some cases, L is a ROR2 antibody (Ab1). In some cases, L is a ROR2 antibody (Ab2). In some cases, L is a ROR2 antibody (Ab3). In some cases, L is a ROR2 antibody (Ab4). In some cases, the targeting unit contains an antibody. In some cases, the targeting unit is a) Sequence IDs 40 and 41, respectively Contains antibodies containing heavy chains (HC) and light chains (LC). In some cases, the antibody or antigen-binding moiety is a) Sequence numbers 42 and 43 respectively It includes the heavy chain variable domain (VH) amino acid sequence and the light chain variable domain (VL) amino acid sequence. In some cases, the antibody or antigen binding moiety is a) Sequence numbers 44, 45, 46, 47, 48, and 49 respectively It contains the heavy chain complementarity-determining regions (CDRs) 1-3 (HCDR1-3) amino acid sequences and the light chain CDRs 1-3 (LCDR1-3) amino acid sequences. In some cases, L is the ROR1 antibody. In some cases, L is Ab5. In some cases, L is the UC-961 antibody. In some cases, the targeting unit contains an antibody. In some cases, the targeting unit is a) Sequence IDs 50 and 51, respectively Contains antibodies containing heavy chains (HC) and light chains (LC). In some cases, the antibody or antigen-binding moiety is a) Sequence IDs 52 and 53, respectively It includes the heavy chain variable domain (VH) amino acid sequence and the light chain variable domain (VL) amino acid sequence. In some cases, the antibody or antigen-binding portion may a) Sequence numbers 54, 55, 56, 57, 58, and 59 respectively It contains the heavy chain complementarity-determining regions (CDRs) 1-3 (HCDR1-3) amino acid sequences and the light chain CDRs 1-3 (LCDR1-3) amino acid sequences. In some cases, L is the 5T4 antibody. In some cases, L is Ab6. In some cases, the targeting unit contains an antibody. In some cases, the antibody is PTK7.

[0261] In some embodiments, the conjugate of formula (XX) or formula (A) is

[0262] [ka] It is expressed by, in the formula,

[0263] [ka]

[0264] [ka] L is the targeting unit, and DAR is the drug-to-antibody ratio. In some cases, DAR is determined using RP-HPLC. In some cases, DAR is determined using RP-HPLC as in Example 25. In some cases, DAR is up to approximately 16. In some cases, DAR is approximately 8. In some cases, DAR is up to approximately 10. In some cases, DAR is down to approximately 1. In some cases, DAR is down to approximately 2. In some cases, DAR is down to approximately 4. In some cases, DAR is down to approximately 8. In some cases, DAR is up to approximately 8. In some cases, DAR is from approximately 1 to approximately 16. In some cases, DAR is from approximately 4 to approximately 12. In some cases, DAR is from approximately 6 to approximately 10. In some cases, DAR is from approximately 7 to approximately 9. In some cases, DAR is from approximately 8 to approximately 10. In some cases, the DAR is approximately 6 to 8. In some cases, the DAR is the ratio of drug (D) to antibody (L). In some cases, the drug in the DAR is exatecan. In some cases, the drug in the DAR is exatecan. In some cases, the targeting unit contains an antibody. In some cases, the targeting unit is a) Sequence numbers 1 and 2 respectively, b) Sequence numbers 11 and 2, respectively c) Sequence numbers 15 and 16, respectively, or d) Sequence IDs 21 and 16, respectively The antibody contains heavy chain (HC) and light chain (LC), which may include the following: a) an antibody containing heavy chain (HC) and light chain (LC), which includes SEQ ID NOs. 1 and 2, respectively. The antibody or antigen binding portion may include the following: a) Sequence numbers 3 and 4 respectively, b) Sequence IDs 12 and 4, respectively, or c) Sequence numbers 17 and 18 respectively It includes the heavy chain variable domain (VH) amino acid sequence and the light chain variable domain (VL) amino acid sequence. In some cases, the antibody or antigen binding moiety is a) Sequence numbers 5, 6, 7, 8, 9, and 10, respectively b) Sequence numbers 13, 6, 14, 8, 9, and 10, respectively, or c) Sequence numbers 19, 6, 20, 8, 9, and 10 respectively It contains the heavy chain complementarity-determining regions (CDRs) 1-3 (HCDR1-3) amino acid sequences and the light chain CDRs 1-3 (LCDR1-3) amino acid sequences. In some cases, the antibody or antigen-binding moiety competes or cross-competes for binding to human ROR2. In some cases, L is a ROR2 antibody. In some cases, L is a ROR2 antibody (Ab1). In some cases, L is a ROR2 antibody (Ab2). In some cases, L is a ROR2 antibody (Ab3). In some cases, L is a ROR2 antibody (Ab4). In some cases, the targeting unit contains an antibody. In some cases, the targeting unit is a) Sequence IDs 40 and 41, respectively Contains antibodies containing heavy chains (HC) and light chains (LC). In some cases, the antibody or antigen-binding moiety is a) Sequence numbers 42 and 43 respectively It includes the heavy chain variable domain (VH) amino acid sequence and the light chain variable domain (VL) amino acid sequence. In some cases, the antibody or antigen binding moiety is a) Sequence numbers 44, 45, 46, 47, 48, and 49 respectively It contains the heavy chain complementarity-determining regions (CDRs) 1-3 (HCDR1-3) amino acid sequences and the light chain CDRs 1-3 (LCDR1-3) amino acid sequences. In some cases, L is the ROR1 antibody. In some cases, L is Ab5. In some cases, L is the UC-961 antibody. In some cases, the targeting unit contains the antibody. In some cases, the targeting unit is a) Sequence IDs 50 and 51, respectively Contains antibodies containing heavy chains (HC) and light chains (LC). In some cases, the antibody or antigen-binding moiety is a) Sequence IDs 52 and 53, respectively It includes the heavy chain variable domain (VH) amino acid sequence and the light chain variable domain (VL) amino acid sequence. In some cases, the antibody or antigen binding moiety is a) Sequence numbers 54, 55, 56, 57, 58, and 59 respectively It contains the heavy chain complementarity-determining region (CDR) 1-3 (HCDR1-3) amino acid sequence and the light chain CDR1-3 (LCDR1-3) amino acid sequence. In some cases, L is the 5T4 antibody. In some cases, L is Ab6. In some cases, the targeting unit contains the antibody. In some cases, the antibody is PTK7.

[0265] [Table 1-1]

[0266] [Table 1-2]

[0267] [Table 1-3]

[0268] [Table 1-4]

[0269] [Table 2-1]

[0270] [Table 2-2]

[0271] [Table 2-3]

[0272] [Table 2-4]

[0273] [Table 3-1]

[0274] Table 3-2

[0275] Table 3-3

[0276] Table 3-4

[0277] Table 4-1

[0278] Table 4-2

[0279] Table 4-3

[0280] Table 5

[0281] Table 6

[0282] Table 7

[0283] Table 8

[0284] [Table 9-1]

[0285] [Table 9-2]

[0286] [Table 9-3]

[0287] [Table 9-4]

[0288] [Table 9-5]

[0289] [Table 9-6]

[0290] [Table 9-7]

[0291] [Table 9-8]

[0292] In an alternative embodiment, the exemplary conjugates in Table H are selected from DARs of approximately 1 to approximately 8.

[0293] [Table 10-1]

[0294] [Table 10-2]

[0295] [Table 10-3]

[0296] [Table 10-4]

[0297] [Table 10-5]

[0298] [Table 10-6]

[0299] [Table 10-7]

[0300] [Table 10-8]

[0301] In an alternative embodiment, the exemplary conjugates in Table I are selected from DARs of approximately 1 to approximately 8.

[0302] [Table 11-1]

[0303] [Table 11-2]

[0304] [Table 11-3]

[0305] [Table 11-4]

[0306] [Table 11-5]

[0307] [Table 11-6]

[0308] [Table 11-7]

[0309] [Table 11-8]

[0310] [Table 11-9]

[0311] In an alternative embodiment, the exemplary conjugates in Table HH are selected from DARs of approximately 1 to approximately 8.

[0312] [Table 12-1]

[0313] [Table 12-2]

[0314] [Table 12-3]

[0315] [Table 12-4]

[0316] [Table 12-5]

[0317] [Table 12-6]

[0318] [Table 12-7]

[0319] [Table 12-8]

[0320] [Table 12-9]

[0321] In an alternative embodiment, the exemplary conjugates in Table II are selected from approximately 1 to approximately 8 DAR.

[0322] In some embodiments, the conjugate is given by equation (III*) or equation (IIIa*)

[0323] [ka] or represented by a pharmaceutically acceptable salt thereof, in the formula, Ab is the anti-ROR2 antibody or its antigen-binding portion. n is between 0 and 10. D is the drug part, Y is a cleavable peptide or β-glucuronide-containing moiety. X is a peptide or hydrophilic moiety.

[0324] In some embodiments, n is 2.

[0325] In some embodiments, Y is a cleavable dipeptide moiety, such as a valine-alanine dipeptide.

[0326] In some embodiments, the conjugate is formula (IV*) or formula (IVa*)

[0327] [ka] Alternatively, it may be represented by a pharmaceutically acceptable salt thereof, where D is the drug moiety and X is the peptide or hydrophilic moiety.

[0328] In some embodiments, X is a peptide moiety containing 1 to 50 amino acid residues.

[0329] In some embodiments, the amino acid residues of X are selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-alanine. In certain embodiments, the amino acid residues of X are selected from the group consisting of glycine, sarcosine, proline, serine, alanine, and β-alanine. In some embodiments, X has terminal units such as terminal amide units.

[0330] In some embodiments, X is a hydrophilic portion that includes a sulfate portion.

[0331] In some embodiments, drug portion D comprises exatecan.

[0332] This disclosure includes salts of the compounds described herein, specifically pharmaceutically acceptable salts. Compounds of the present invention having sufficiently acidic functional groups, sufficiently basic functional groups, or both functional groups, can react with several inorganic bases, as well as either inorganic or organic acids, to form salts. Alternatively, intrinsically charged compounds, such as those having tetravalent nitrogen, can form salts with suitable counterions, such as bromides, chlorides, or fluorides, specifically halides such as bromides.

[0333] Chemical entities having a carbon-carbon double bond or a carbon-nitrogen double bond may exist in Z-form or E-form (i.e., cis-form or trans-form). Furthermore, some chemical entities may exist in various tautomerized forms. Unless otherwise specified, the compounds described herein are intended to equally include all Z-form, E-form, and tautomerized forms.

[0334] A "tautomer" refers to a molecule in which proton transfer is possible from one atom to another atom of the same molecule. The compounds presented herein exist as tautomers in certain embodiments. Where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on various factors, including physical state, temperature, solvent, and pH. Some examples of tautomer equilibrium include:

[0335] [ka]

[0336] In some embodiments, the compounds disclosed herein are, for example, 2 H, 3 H, 11 C, 13 C, and / or 14It is used in various enriched isotopic forms that are enriched in the contents of C. In one particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and / or efficacy of the drug, thereby extending the duration of action.

[0337] Unless otherwise specified, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, hydrogen exchange with deuterium or tritium, or 13 C or 14 Apart from carbon exchange by carbon-rich carbon, compounds having this structure are within the scope of this disclosure.

[0338] The compounds of this disclosure contain, by choice, one or more atomic isotopes in an unnatural ratio in one or more atoms constituting such a compound. For example, the compound may contain, for example, deuterium ( 2 H), tritium ( 3 H), Iodine-125( 125 I) or carbon-14 ( 14 It can be labeled with isotopes such as C). 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl,79 Br, 81 Br, and 125 All isotopic substitutions in I are intended. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0339] In certain embodiments, the compounds disclosed herein are 2 It is exchanged with a H atom. 1 It contains some or all of the H atoms. Methods for synthesizing deuterium-containing compounds are known in the art, and non-limiting examples include the following synthesis methods.

[0340] Deuterium-substituted compounds are synthesized using various methods, including those described in *Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development*, edited by Dennis C. Dean [In: Curr., Pharm. Des., 2000; 6(10)], 2000, p. 110; *The Synthesis of Radiolabeled Compounds via Organometallic Intermediates*, Tetrahedron, 1989, 45(21), pp. 6601-21 by George W. Varma, Rajender S.; and *Synthesis of radiolabeled compounds*, J. Radioanal. Chem., 1981, 64(1-2), pp. 9-32 by Evans, E. Anthony.

[0341] Deuterated starting materials are readily available and are subjected to the synthesis methods described herein for the synthesis of deuterium-containing compounds. Numerous deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0342] The compounds of the present invention also include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts and active metabolites of these compounds, and for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0343] The compounds described herein may, as such, exist in diastereomer, enantiomer, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomer, enantiomer, and epimeric forms, as well as suitable mixtures thereof. Separation of stereoisomers may be performed by chromatography, by forming diastereomers and separating them by recrystallization or chromatography, or by any combination thereof (see "Enantiomers, Racemates and Resolutions" by Jean Jacques, Andre Collet, and Samuel H. Wilen, John Wiley and Sons, Inc., 1981, as incorporated herein by reference). Stereoiomers may also be obtained by stereoselective synthesis.

[0344] The methods and compositions described herein include the use of amorphous and crystalline forms (also known as polymorphs). The compounds described herein may also be in the form of pharmaceutically acceptable salts. Similarly, in some embodiments, active metabolites of these compounds having the same type of activity are included within the scope of this disclosure. Furthermore, the compounds described herein may exist in non-solvated forms as well as in solvated forms with pharmaceutically acceptable solvents such as water or ethanol. The solvated forms of the compounds provided herein are also considered to be disclosed herein.

[0345] In certain embodiments, the compound or a salt of said compound may be a prodrug, for example, a hydroxyl group in the parent compound being presented as an ester or carbonate, or a carboxylic acid present in the parent compound being presented as an ester. The term “prodrug” is intended to encompass compounds that are converted into the pharmaceuticals of the present disclosure under physiological conditions. One method of making a prodrug is to include one or more selected parts that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of a host animal, such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids, and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0346] The claims include prodrug forms of the compounds described herein, in which the prodrug is metabolized in vivo to produce the compounds described herein. In some cases, some of the compounds described herein may be prodrugs of other derivatives or active compounds.

[0347] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. For example, a prodrug may be available to the organism by oral administration, whereas the parent drug may not. Prodrugs can help improve the cellular permeability of a compound compared to the parent drug. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. Prodrugs may be designed as reversible drug derivatives used as modifiers to improve drug delivery to site-specific tissues or to increase intracellular drug retention.

[0348] In some embodiments, the design of the prodrug increases the lipophilicity of the pharmaceutical. In some embodiments, the design of the prodrug increases its effective water solubility. For example, see Am.J.Physiol.,269:G210-218 (1995) by Fedorak et al., Gastroenterol,106:405-413 (1994) by McLoed et al., Biomed.Chrom.,6:283-286 (1992) by Hochhaus et al., Int.J.Pharmaceutics,37,87PTK7 (1987) by J.Larsen and H.Bundgaard, Int.J.Pharmaceutics,47,103 (1988) by J.Larsen et al., J.Pharm.Sci.,64:181-210 (1975) by Sinkula et al., Pro-drugs as Novel Delivery Systems,Vol.14 of the ACSSymposium Series by T.Higuchi and V.Stella, and Bioreversible by Edward B.Roche. See Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987 (all incorporated herein for disclosure purposes). According to another embodiment, this disclosure provides a method for producing the compounds defined above. The compounds may be synthesized using conventional techniques. Advantageously, these compounds can be conveniently synthesized from readily available starting materials.

[0349] Useful synthetic chemical transformations and methods for synthesizing the compounds described herein are known in the art, for example, as described in Comprehensive Organic Transformations (1989) by R. Larock, Protective Groups in Organic Synthesis, 2nd Ed. (1991) by TW. Greene and PGMWuts, Fieser and Fieser's Reagents for Organic Synthesis (1994) by L. Fieser and M. Fieser, and Encyclopedia of Reagents for Organic Synthesis (1995) edited by L. Paquette.

[0350] Targeting unit (L) In some embodiments, with respect to a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), L is a targeting unit. The targeting unit may be selected from an antibody or its antigen-binding fragment.

[0351] In some embodiments, with respect to a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), the targeting unit is selected from an antibody or its antigen-binding fragment. The targeting unit may be selected from the group consisting of chimeric antibodies, humanized antibodies, and human antibodies. The targeting unit may perform a targeting function. The targeting unit may specifically bind to a target molecule. Specifically binding may mean that the targeting unit described herein (e.g., an antibody or its antigen-binding portion) binds to a target molecule. -5 M (10000 nM) or less, for example, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12This refers to the ability to bind to a target with M or less KD. In some cases, the targeting unit is said to bind specifically to its target, preferentially recognizing that target in a complex mixture of proteins and / or macromolecules. In some cases, the antibody is a monoclonal antibody. In some cases, the antibody is UC-961. In some cases, the amino acid sequence of the UC-961 antibody is shown in Table S. In some cases, the targeting unit is PTK7. In some cases, L is a PTK7 antibody. In some cases, the antibody is PTK7. In some cases, the antibody is ROR2. In some cases, the antibody is ROR2 antibody. In some cases, the amino acid sequence of the ROR2 antibody is shown in Table S. In some cases, L is a PTK7 antibody. In some cases, L is an anti-5T4 antibody. In some cases, L is a 5T4 antibody. In some cases, the amino acid sequence of the 5T4 antibody is shown in Table S. In some cases, the antibody contains one or more sequences from Table S. In some cases, L is the ROR1 antibody.

[0352] In some embodiments, the targeting unit is an antibody or its antigen-binding portion, and is a bispecific or multispecific binder. Examples of bispecific and multispecific antibodies include scFv1-scFv2, scFv12-Fc-scFv22, IgG-scFv, DVD-Ig, triomab / quadroma, two-in-one IgG, scFv2-Fc, TandAb, and scFv-HSA-scFv. In some embodiments, IgG-scFv is IgG(H)-scFv, scFv-(H)IgG, IgG(L)-scFv, svFc-(L)IgG, 2scFv-IgG, or IgG-2scFv.

[0353] In some embodiments, the targeting unit includes CD19, CD20, CD30, CD33, CD38, CA125, MUC-1, prostate-specific membrane antigen (PSMA), CD44 surface adhesion molecule, mesothelin (MLSN), carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), EGFRvIII, vascular endothelial growth factor receptor-2 (VEGFR2), high molecular weight melanoma-associated antigen (HMW-MAA), MAGE-A1, IL-13R-a2, GD2, 1p19q, ABL1, AKT1, ALK, APC, AR, ATM, BRAF, BRCA1, BRCA2, cKIT, cMET, CSF1R, CTNNB1, FGFR1, FGFR2, FLT3, GNA11, GNAQ, GNAS, HRA S, IDH1, IDH2, JAK2, KDR(VEGFR2), KRAS, MGMT, MGMT-Me, MLH1, MPL, NOTCH1, NRAS, PDGFRA, Pgp, PIK3CA, PR, PTEN, RET, RRM1 , SMO, SPARC, TLE3, TOP2A, TOP1, TP53, TS, TUBB3, VHL, CDH1, ERBB4, FBXW7, HNF1A, JAK3, NPM1, PTPN11, RB1, SMAD4, SMARCB 1, STK1, MLH1, MSH2, MSH6, PMS2, ROS1, ERCC1, 5T4(TPBG), B7-H3, CCR7, CD105, CD22, CD46, CD47, CD56, CD70, CD71, CD79b, C These are cancer-associated antigens such as DH6, CLDN6, CLDN18.2, CLEC12A, DLL3, DR5, ERBB3 (HER3), EPCAM, FOLR1, IGF1R, IL2RA (CD25), IL3RA, ITGB6, LIV-1, LRRC15, mesothelin (MSLN), NaPi2b (SLC34A2), nectin-4, PTK7, ROR1, SEZ6, SLC44A4, SLITRK6, tissue factor (TF), TROP2, or B7-H4.

[0354] In some embodiments, the targeting unit specifically binds to a target such as CD19, CD20, CD30, CD33, CD70, LIV-1, or EGFRv3.

[0355] In some embodiments, with respect to a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA) (each further comprising a targeting unit), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), the targeting unit is an antibody or an antigen.

[0356] In some embodiments, with respect to a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA) (each further comprising a targeting unit), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), the targeting unit comprises at least one amino acid. Alternatively, the targeting unit may comprise one or more amino acids. Alternatively, the targeting unit may comprise one or more native amino acids. Alternatively, the targeting unit may comprise one or more non-native amino acids. Alternatively, non-native amino acids (p-acetylphenylalanine, i.e., pAcF and p-azidomethyl-L-phenylalanine, i.e., pAMF), or short-chain peptide tags. Alternatively, the targeting unit may comprise cysteine. Alternatively, the targeting unit may comprise glutamine. Alternatively, the targeting unit may be a peptide with fewer than 50 amino acids. Alternatively, the targeting unit may be a peptide with fewer than 40 amino acids. In some cases, the targeting unit is a peptide with fewer than 30 amino acids. In some cases, the targeting unit is a peptide with fewer than 20 amino acids. In some cases, the targeting unit is a peptide with more than 50 amino acids. In some cases, the targeting unit is a peptide with more than 40 amino acids. In some cases, the targeting unit is a peptide with more than 30 amino acids. In some cases, the targeting unit is a peptide with more than 20 amino acids. In some cases, the targeting unit is a peptide with more than 10 amino acids. In some cases, the targeting unit is a peptide with more than 5 amino acids. In some cases, the targeting unit is a peptide with approximately 1 to 50 amino acids. In some cases, the targeting unit is a peptide with approximately 2 to 30 amino acids. In some cases, the targeting unit is a peptide with approximately 3 to 15 amino acids. In some cases, the targeting unit includes cyclic peptides.

[0357] In some embodiments, with respect to a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA) (each further comprising a targeting unit), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), the targeting unit has at least one sulfur atom. Optionally, the targeting unit has at least one sulfur atom derived from a cysteine ​​residue. Optionally, the targeting unit has at least one sulfur atom derived from a reduced cysteine ​​residue.

[0358] In some embodiments, with respect to a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA) (each further comprising a targeting unit), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), the targeting unit has an antibody. In some cases, the targeting unit is a) Sequence numbers 1 and 2 respectively, b) Sequence numbers 11 and 2, respectively c) Sequence numbers 15 and 16, respectively, or d) Sequence IDs 21 and 16, respectively The antibody contains heavy chain (HC) and light chain (LC), which may include the following: a) an antibody containing heavy chain (HC) and light chain (LC), which includes SEQ ID NOs. 1 and 2, respectively. The antibody or antigen binding portion may include the following: a) Sequence numbers 3 and 4 respectively, b) Sequence IDs 12 and 4, respectively, or c) Sequence numbers 17 and 18 respectively It includes the heavy chain variable domain (VH) amino acid sequence and the light chain variable domain (VL) amino acid sequence. In some cases, the antibody or antigen binding moiety is a) Sequence numbers 5, 6, 7, 8, 9, and 10, respectively b) Sequence numbers 13, 6, 14, 8, 9, and 10, respectively, or c) Sequence numbers 19, 6, 20, 8, 9, and 10 respectively It contains the heavy chain complementarity-determining regions (CDRs) 1-3 (HCDR1-3) amino acid sequences and the light chain CDRs 1-3 (LCDR1-3) amino acid sequences. In some cases, the antibody or antigen-binding moiety competes or cross-competes for binding to human ROR2. In some cases, L is a ROR2 antibody. In some cases, L is a ROR2 antibody (Ab1). In some cases, L is a ROR2 antibody (Ab2). In some cases, L is a ROR2 antibody (Ab3). In some cases, L is a ROR2 antibody (Ab4). In some cases, the targeting unit contains an antibody. In some cases, the targeting unit is a) Sequence IDs 40 and 41, respectively Contains antibodies containing heavy chains (HC) and light chains (LC). In some cases, the antibody or antigen-binding moiety is a) Sequence numbers 42 and 43 respectively It includes the heavy chain variable domain (VH) amino acid sequence and the light chain variable domain (VL) amino acid sequence. In some cases, the antibody or antigen binding moiety is a) Sequence numbers 44, 45, 46, 47, 48, and 49 respectively It contains the heavy chain complementarity-determining regions (CDRs) 1-3 (HCDR1-3) amino acid sequences and the light chain CDRs 1-3 (LCDR1-3) amino acid sequences. In some cases, L is the ROR1 antibody. In some cases, L is Ab5. In some cases, L is the UC-961 antibody. In some cases, the targeting unit contains an antibody. In some cases, the targeting unit is a) Sequence IDs 50 and 51, respectively Contains antibodies containing heavy chains (HC) and light chains (LC). In some cases, the antibody or antigen-binding moiety is a) Sequence IDs 52 and 53, respectively It includes the heavy chain variable domain (VH) amino acid sequence and the light chain variable domain (VL) amino acid sequence. In some cases, the antibody or antigen binding moiety is a) Sequence numbers 54, 55, 56, 57, 58, and 59 respectively It contains the heavy chain complementarity-determining region (CDR) 1-3 (HCDR1-3) amino acid sequence and the light chain CDR1-3 (LCDR1-3) amino acid sequence. In some cases, L is the 5T4 antibody. In some cases, L is Ab6. In some cases, the targeting unit contains the antibody. In some cases, the antibody is PTK7. In some cases, the heavy chain variable region further contains the heavy chain constant region. In some cases, the heavy chain constant region is the IgG isotype region. In some cases, the heavy chain constant region is the IgG1 constant region. In some cases, the heavy chain constant region is the IgG4 constant region.

[0359] In some embodiments, with respect to a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA) (each further comprising a targeting unit), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), the targeting unit, such as an antibody or its antigen-binding portion, or another targeting unit, has an antibody constant region. The antibody constant region may be a fully human constant region. The antibody constant region may be a humanized constant region. The antibody constant region may be a non-human constant region. The immunoglobulin constant region may refer to a heavy chain constant region or a light chain constant region. The constant region may be any suitable type selected from the classes of immunoglobulin, IgA, IgD, IgE, IgG, and IgM. Some immunoglobulin classes may be further subdivided into isotypes, e.g., IgG1, IgG2, IgG3, IgG4, or IgA1 and IgA2. The heavy chain constant regions (Fc) corresponding to different classes of immunoglobulins can be α, δ, ε, γ, and μ, respectively. The light chain can be either a kappa (κ) or a lambda (λ) light chain.

[0360] In some embodiments, the steady region may have an IgG isotype. In some embodiments, the steady region may have an IgG1 isotype. In some embodiments, the steady region may have an IgG2 isotype. In some embodiments, the steady region may have an IgG3 isotype. In some embodiments, the steady region may have an IgG4 isotype. In some embodiments, the steady region may have a hybrid isotype comprising steady regions derived from two or more isotypes. In some embodiments, the immunoglobulin steady region may be an IgG1 steady region or an IgG4 steady region.

[0361] Exemplary anti-ROR2 antibody The ADCs of the present invention (e.g., formula (C), formula (XX), formula (A), or formula (A-1)) include an antibody or its antigen-binding moiety that specifically binds to ROR2. Depending on the circumstances, the ADCs of the present invention (e.g., formula (C), formula (XX), formula (A), or formula (A-1)) include an antibody or its antigen-binding moiety that specifically binds to ROR2. Unless otherwise specified, "ROR2" refers to human ROR2. The human ROR2 polypeptide sequence is available under UniProt accession number Q01974 (ROR2_HUMAN), as shown below.

[0362] [Table 13] In the sequence described above, the extracellular domain extends from amino acids 34 to 403. The anti-ROR2 antibody described herein binds to the epitope in the extracellular domain.

[0363] The amino acid sequence of an exemplary anti-ROR2 antibody used in the ADC of the present invention is shown in Table Z below.

[0364] [Table 14]

[0365] Ab1 and Ab2 are humanized effectorless versions of the mouse anti-ROR2 antibody 6E6 (see, for example, International Patent Application Publication WO2021 / 102055 and International Patent Application PCT / US2023 / 086552). Ab3 is a chimeric version of 6E6. Ab4 is a chimeric effectorless version of 6E6.

[0366] In some embodiments, the anti-ROR2 antibody or its antigen-binding moiety used in the ADCs of this disclosure (e.g., formula (C), formula (XX), formula (A), or formula (A-1)) competes or cross-competes with antibodies containing the following for binding to human ROR2, or binds to the same human ROR2 epitope as antibodies containing the following. a) A heavy chain (HC) containing the amino acid sequence of SEQ ID NO: 1 and a light chain (LC) containing the amino acid sequence of SEQ ID NO: 2, b) HC containing the amino acid sequence of SEQ ID NO: 11 and LC containing the amino acid sequence of SEQ ID NO: 2 c) HC containing the amino acid sequence of SEQ ID NO: 15 and LC containing the amino acid sequence of SEQ ID NO: 16, or d) HC containing the amino acid sequence of SEQ ID NO: 21 and LC containing the amino acid sequence of SEQ ID NO: 16

[0367] In some embodiments, the anti-ROR2 antibody or antigen-binding moiety is Sequence numbers 5, 6, and 7, respectively Sequence numbers 13, 6, and 14, respectively, or Sequence IDs 19, 6, and 20, respectively. It has HCDR1-3 containing the amino acid sequence.

[0368] In some embodiments, the anti-ROR2 antibody or antigen-binding moiety has a heavy chain variable domain (VH) amino acid sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NOs: 3, 12, or 17.

[0369] In some embodiments, the anti-ROR2 antibody or antigen-binding moiety has a VH containing the amino acid sequence of SEQ ID NO: 3, 12, or 17.

[0370] In some embodiments, the anti-ROR2 antibody has an HC amino acid sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NOs: 1, 11, 15, or 21, or a sequence that does not contain C-terminal lysine.

[0371] In some embodiments, the anti-ROR2 antibody includes the HC amino acid sequence of SEQ ID NOs: 1, 11, 15, or 21, or a sequence that does not contain C-terminal lysine.

[0372] In some embodiments, the anti-ROR2 antibody or antigen-binding moiety has LCDR1-3, each containing the amino acid sequence of SEQ ID NOs. 8-10.

[0373] In some embodiments, the anti-ROR2 antibody or antigen-binding moiety has a light chain variable domain (VL) amino acid sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 4 or 18.

[0374] In some embodiments, the anti-ROR2 antibody or antigen-binding moiety has a VL containing the amino acid sequence of SEQ ID NO: 4 or 18.

[0375] In some embodiments, the anti-ROR2 antibody has an LC amino acid sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 2 or 16.

[0376] In some embodiments, the anti-ROR2 antibody contains the LC amino acid sequence of SEQ ID NO: 2 or 16.

[0377] In a particular embodiment, the anti-ROR2 antibody or antigen-binding moiety includes one of the heavy chain sequences paired with one of the light chain sequences.

[0378] In some embodiments, the anti-ROR2 antibody or antigen-binding moiety of the present disclosure is a) Sequence numbers 5, 6, 7, 8, 9, and 10, respectively b) Sequence numbers 13, 6, 14, 8, 9, and 10, respectively, or c) Sequence numbers 19, 6, 20, 8, 9, and 10 respectively It contains the HCDR1-3 amino acid sequence and the LCDR1-3 amino acid sequence.

[0379] In some embodiments, the anti-ROR2 antibody or antigen-binding moiety of the present disclosure is a) Sequence numbers 3 and 4 respectively, b) Sequence IDs 12 and 4, respectively, or c) Sequence numbers 17 and 18 respectively It includes VH and VL which are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical (e.g., at least 90% identical) to the amino acid sequence of .

[0380] In some embodiments, the anti-ROR2 antibody or antigen-binding moiety of the present disclosure is a) Sequence numbers 3 and 4 respectively, b) Sequence IDs 12 and 4, respectively, or c) Sequence numbers 17 and 18 respectively It contains VH and VL, which have the amino acid sequence of the following.

[0381] In some embodiments, the anti-ROR2 antibody of this disclosure is a) Sequence numbers 1 and 2 respectively, b) Sequence numbers 11 and 2, respectively c) Sequence numbers 15 and 16, respectively, or d) Sequence IDs 21 and 16, respectively It includes HC and LC containing the amino acid sequence, and optionally, the HC amino acid sequence does not contain C-terminal lysine.

[0382] This disclosure also provides an anti-ROR2 antibody or its antigen-binding moiety that, in binding to human ROR2, competes with or cross-competes with any one of Ab1 to Ab4, or binds to the same human ROR2 epitope.

[0383] In some embodiments, the anti-ROR2 antibody or antigen-binding moiety is HCDR1 containing amino acid sequence TY, HCDR2 containing the amino acid sequence SSGGGY (SEQ ID NO: 27), HCDR3 containing the amino acid sequence HPRDSYALDY (SEQ ID NO: 24), and / or LCDR1 containing the amino acid sequence GHY, LCDR2 containing the amino acid sequence WAS (SEQ ID NO: 9), and LCDR3 containing the amino acid sequence QQYNIYPW (SEQ ID NO: 28) Includes.

[0384] In some embodiments, the anti-ROR2 antibody or antigen-binding moiety of this disclosure includes one of the HCDR1-3 amino acid sequences and LCDR1-3 amino acid sequences from Ab1-Ab4. The assignment of the CDR region may follow any method known in the art, such as the definitions of IMGT®, Kabat, Chothia, Martin, Contact, or AHo, or any combination of these definitions (e.g., Kabat and Chothia). Examples of CDR definitions in the IMGT® and Kabat methods are given below for Ab1 (sequence number).

[0385] [Table 15]

[0386] [Table 16]

[0387] Therefore, for example, the sequences of HCDR1-3 and LCDR1-3, which are defined as Ab1 IMGT®, in sequence numbers 5-10, may be replaced by sequence numbers 22, 23, 24, 25, 26, and 10, respectively, in any embodiment described herein.

[0388] Furthermore, a set of Ab1 CDRs is contemplated, in which each of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 can be individually identified according to any of the methods shown above for defining an Ab1 CDR (e.g., HCDR1 as identified by the Kabat definition, HCDR2 as identified by the IMGT® definition, etc.). The same means for defining an Ab1 CDR is contemplated for any of Ab2 to Ab4.

[0389] In some embodiments, the anti-ROR2 antibody or antigen-binding moiety of the Disclosure comprises VH and VL whose amino acid sequence is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of Ab1 to Ab4.

[0390] In some embodiments, the anti-ROR2 antibody or antigen-binding moiety of the present disclosure comprises VH and VL, which are each one of Ab1 to Ab4.

[0391] In some embodiments, the anti-ROR2 antibody is one of Ab1 to Ab4, or an antibody having the same amino acid sequence as the aforementioned antibody.

[0392] In some embodiments, the targeting unit of formula (C), formula (XX), formula (A), or formula (A-1) is an anti-ROR2 antibody or antigen-binding moiety, and is a mutant antibody or antigen-binding moiety.

[0393] In some embodiments, the anti-ROR2 antibody or antigen-binding moiety is a mutant antibody or antigen-binding moiety. In some embodiments, the mutant antibody or its antigen-binding moiety may have mutations that, for example, increase its half-life, alter its immunogenicity, or provide a site for covalent or non-covalent binding to another molecule. In certain embodiments, the mutant antibody or its antigen-binding moiety may have mutations in its FR (e.g., one, two, three, four, five, six, seven, or eight of its FRs). In certain embodiments, the mutant antibody or its antigen-binding moiety may have mutations in its CDR (e.g., one, two, three, four, five, or six of its CDRs). In certain embodiments, the mutant antibody or its antigen-binding moiety may have mutations in its constant region.

[0394] The class of anti-ROR2 antibodies described herein may be changed or switched to another class or subclass. For example, an anti-ROR2 antibody that was originally IgM may be switched to IgG. Furthermore, class switching may be used to convert one IgG subclass to another, for example, from IgG1 to IgG2. The κ light chain constant region can be changed to, for example, the λ light chain constant region, and vice versa.

[0395] The anti-ROR2 antibodies of this disclosure may be IgG molecules, IgM molecules, IgE molecules, IgA molecules, or IgD molecules, but are typically IgG isotypes, for example, IgG subclasses such as IgG1, IgG 2a Or IgG 2b It is either IgG3 or IgG4.

[0396] In some embodiments, an anti-ROR2 antibody may contain at least one mutation in its Fc region. Numerous different Fc mutations are known, and these mutations alter, for example, the effector function or half-life of the antibody. For example, in some embodiments, an anti-ROR2 antibody contains at least one mutation in its Fc region that reduces or eliminates effector function. In certain embodiments, an anti-ROR2 antibody may contain, for example, an L234A mutation, an L235A mutation, and / or a P329A mutation (Eu numbering), and these mutations may appear individually or in any combination. In specific embodiments, an anti-ROR2 antibody may contain an Fc region having all three mutations.

[0397] In some embodiments, the targeting unit of formula (C), formula (XX), formula (A), or formula (A-1) comprises an antibody or a portion thereof that is specific to human ROR2 ("ROR2 ADC") and can therefore function as a superior targeting portion for delivering a conjugated payload to ROR2-positive cancer cells. Where this disclosure refers to an anti-ROR2 antibody or its antigen-binding portion, it is understood that any portion that functions as a means for binding to ROR2 may be used.

[0398] [Table 17]

[0399] In some embodiments, the ROR1 antibody or antigen-binding moiety of the present disclosure comprises VH and VL whose amino acid sequence is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of the VH and VL of Ab5.

[0400] In some embodiments, with respect to a targeting unit of formula (C), formula (XX), formula (A), or formula (A-1), the targeting unit includes Ab6. In some cases, the targeting unit is Ab5.

[0401] [Table 18]

[0402] In some embodiments, with respect to a targeting unit of formula (C), formula (XX), formula (A), or formula (A-1), the targeting unit includes Ab6. In some cases, the targeting unit is Ab6.

[0403] In some embodiments, the targeting unit of formula (C), formula (XX), formula (A), or formula (A-1) comprises one or more sequences as shown in Table S and / or the examples.

[0404] In some embodiments, the conjugates of this disclosure are used to treat cancer in patients (e.g., mammals such as humans) who require it. In certain embodiments, the cancer is a 5T4-expressing cancer. The ADC may be administered alone or in combination with other therapeutic agents. In some cases, the cancer is a 5T4-positive cancer.

[0405] Trophoblast glycoprotein (5T4) is a carcinoembryonic protein. In some cases, 5T4 refers to the 5T4 carcinoembryonic antigen.

[0406] Pharmaceutical preparations / pharmaceutical compositions In certain embodiments herein, compositions are provided that contain a therapeutically effective amount of a drug linker or salt of formula (X), formula (I), or formula (IA), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1) (hereinafter also referred to as “pharmaceuticals”).

[0407] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate the processing of the pharmaceutical into pharmaceutically usable preparations. The appropriate formulation depends on the chosen route of administration. An overview of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995), Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975, Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, edited by Liberman, HA and Lachman, L., and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0408] The compositions and methods of this disclosure may be used to treat individuals that require them. In certain embodiments, the individuals are mammals such as humans, or non-human mammals. When administered to animals such as humans, the compositions or pharmaceuticals are preferably administered as pharmaceutical compositions comprising, for example, a pharmaceutical and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline, or other solvents or vehicles such as glycols, glycerols, oils (such as olive oil), or injectable organic esters. In preferred embodiments, if such a pharmaceutical composition is for administration to humans, specifically for invasive administration routes such as injection or implantation that avoid transport or diffusion across the epithelial barrier, the aqueous solution is pyrogenic or substantially pyrogenic. Excipients may be selected, for example, to achieve delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition may be in the form of dosage units such as tablets, capsules, granules, lyophilized reconstituted agents, powders, liquids, syrups, suppositories, and injections. The pharmaceutical composition may also be present in transdermal delivery systems, such as skin patches. Furthermore, the pharmaceutical composition may be present in solutions suitable for topical administration, such as eye drops.

[0409] Pharmaceutically acceptable excipients may contain physiologically acceptable agents that function to stabilize, increase the solubility of, or increase the absorption of compounds such as pharmaceuticals. Examples of such physiologically acceptable agents include carbohydrates such as glucose, sucrose, or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents; low molecular weight proteins; or other stabilizers or excipients. The selection of pharmaceutically acceptable excipients, including physiologically acceptable agents, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be, for example, a liposome or other polymer matrix that can incorporate the compounds of the present invention. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively simple to prepare and administer.

[0410] Pharmaceutical compositions (preparations) can be administered to a target by any of a number of routes of administration, including, for example, oral routes (e.g., drenches immersed in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue), absorption via the oral mucosa (e.g., absorption via the sublingual, anal, rectal, or vaginal channels, e.g., as pessaries, creams, or foams), parenteral routes (e.g., intramuscular, intravenous, subcutaneous, or intrathecal administration as sterile solutions or suspensions, nasal administration, intraperitoneal administration, subcutaneous administration, transdermal administration as patches applied to the skin), and topical administration (e.g., as creams, ointments, or sprays applied to the skin, or as eye drops). The compound may also be formulated for inhalation. In certain embodiments, the compound may simply be dissolved or suspended in sterile water.

[0411] The pharmaceutical composition may be a sterile aqueous solution or non-aqueous solution, a suspension, or an emulsion, such as a microemulsion. The excipients described herein are illustrative and not limiting. An effective dose or therapeutically effective dose refers to the amount of one or more pharmaceuticals administered to a subject as a single dose or as part of a series of doses that is effective in producing the desired therapeutic effect.

[0412] The therapeutic efficacy of the subject may generally be monitored using assays and methods suitable for the condition being treated, such assays are well known to those skilled in the art and are described herein. The pharmacokinetics of the drug or one or more metabolites administered to the subject may be monitored by determining the levels of the drug or metabolite in biological fluids, e.g., blood, blood fractions (e.g., serum), and / or urine, and / or other biological samples or tissues of the subject. The levels of the drug or metabolite during the course of treatment may be measured using any method for detecting the drug that has been practiced in the art and is described herein.

[0413] The dosage of the medicinal products described herein for treating a disease or disorder may depend on the condition of the subject, i.e., the stage of the disease, the severity of the symptoms caused by the disease, the overall health status, as well as age, sex, and weight, and other factors that are apparent to those skilled in the art of medicine. The medicinal composition may be administered in a form appropriate to the disease being treated, as determined by those skilled in the art of medicine. In addition to the factors described herein and above regarding the use of medicinal products for treating a disease or disorder, the appropriate duration and frequency of administration of the medicinal product may also be determined or adjusted by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. The optimal dose of the drug may generally be determined using experimental models and / or clinical trials. The optimal dose may depend on the subject's body mass, weight, or blood volume. It is usually preferable to use the minimum dose sufficient to provide effective treatment. The design and execution of the preclinical and clinical trials described herein for medicinal products, including when administered for preventive benefit, are within the realm of what those skilled in the art can conceive. When two or more pharmaceuticals are administered to treat a disease or disorder, the optimal dose of each pharmaceutical may differ, for example, be less than when either drug is administered alone as monotherapy. In certain embodiments, the two combined pharmaceuticals may act synergistically or additively, and either drug may be used in a smaller amount than when administered alone. The amount of pharmaceuticals that may be administered per day may be, for example, between about 0.01 mg / kg (body weight) and 100 mg / kg, for example, between about 0.1 and 1 mg / kg, between about 1 and 10 mg / kg, between about 1 and 50 mg / kg, or between about 50 and 100 mg / kg. In other embodiments, the amount of pharmaceuticals that may be administered per day may be between about 0.01 mg / kg (body weight) and 1000 mg / kg, between about 100 and 500 mg / kg, or between about 500 and 1000 mg / kg. The optimal daily dose or per course of treatment may vary depending on the disease or disorder being treated, as well as the route of administration and the treatment regimen.

[0414] Pharmaceutical compositions, including pharmaceuticals, can be formulated in a manner suitable for delivery by using techniques conventionally practiced in the art. The pharmaceutical composition may be in solid (e.g., tablets, capsules), semi-solid (e.g., gels), liquid, or gaseous (e.g., aerosol) form. In other embodiments, the pharmaceutical composition is administered as a bolus injection.

[0415] Pharmaceutically acceptable excipients are well known in the pharmaceutical field and are described, for example, in Rowe et al.'s Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006, and Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed., Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate-buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, etc., may also be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may be used. Generally, the type of excipient is selected based on the mode of administration as well as the chemical composition of the active ingredient. Alternatively, the compositions described herein may be formulated as lyophilized products. The compositions described herein may be lyophilized with one or more suitable excipient solutions to solubilize and / or dilute the pharmaceutical of the composition upon administration, or otherwise formulated as lyophilized products. In other embodiments, the pharmaceutical product may be encapsulated in liposomes using techniques known and practiced in the art. In certain embodiments, the pharmaceutical product is not formulated in liposomes for application to stents used to treat arteries that are mostly, but not entirely, occluded. The pharmaceutical composition may be formulated for any suitable mode of administration described herein and in the art.

[0416] For example, pharmaceutical compositions for oral administration or injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery, or other methods may be in liquid form. Liquid pharmaceutical compositions may contain, for example, one or more of the following: sterile diluents (water, saline, preferably saline, Ringer's solution, isotonic sodium chloride, a fixing oil that can function as a solvent or suspension medium, polyethylene glycol, glycerin, propylene glycol, or other solvents), antimicrobial agents, antioxidants, chelating agents, buffering agents, and isotonic adjusting agents such as sodium chloride or dextrose. Parenteral compositions can be sealed in glass or plastic ampoules, disposable syringes, or vials for multiple doses. The use of saline is preferred, and pharmaceutical compositions for injection are preferably sterile. In another embodiment, for the treatment of eye diseases or disorders, the liquid pharmaceutical composition may be applied to the eye in the form of eye drops. Liquid pharmaceutical compositions may be delivered orally.

[0417] For oral formulations, at least one of the pharmaceuticals described herein may be used alone or in combination with additives suitable for making tablets, powders, granules, or capsules, and optionally in combination with diluents, buffers, wetting agents, preservatives, colorants, and flavoring agents. The pharmaceuticals may be formulated with buffering agents to protect the compound from the low pH of the gastric environment and / or enteric coating. Pharmaceuticals contained in pharmaceutical compositions may be formulated for oral delivery, for example, with flavoring agents in liquid, solid, or semi-solid formulations and / or with enteric coatings.

[0418] Pharmaceutical compositions comprising any of the pharmaceuticals described herein may be formulated for sustained or controlled release, also known as timed release or controlled release. Such compositions are generally prepared using well-known techniques and may be administered, for example, by oral administration, rectal administration, intradermal administration, or subcutaneous implantation, or by implantation at a desired target site. Sustained-release formulations may contain compounds dispersed in a carrier matrix and / or contained within a reservoir surrounded by a rate-regulating membrane. Excipients for use in such formulations may be biocompatible and biodegradable. Preferably, the formulation releases a relatively constant amount of the active ingredient. The amount of pharmaceutical contained in a sustained-release formulation depends on the implantation site, the rate and expected duration of release, and the nature of the disease, disorder, or condition being treated or prevented.

[0419] In certain embodiments, the pharmaceutical composition containing the drug is formulated for transdermal, intradermal, or topical administration. The composition can be administered as a powder / talc, or as other solid, liquid, spray, aerosol, ointment, foam, cream, gel, or paste using a syringe, bandage, transdermal patch, insert, or syringe-like applicator. The composition is preferably in a controlled-release or sustained-release form, either for topical administration or direct injection into the skin adjacent to or within the area to be treated, e.g., intradermal or subcutaneous injection. The active composition can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetipyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.

[0420] Pharmaceutical compositions, including pharmaceuticals, can be formulated as emulsions for topical application. The emulsion contains one liquid as a second liquid distributed within the body. This emulsion may be an oil-in-water emulsion or a water-in-oil emulsion. Either the oil phase or the aqueous phase, or both, may contain one or more surfactants, emulsifiers, emulsifying stabilizers, buffers, and other excipients. The oil phase may contain other pharmaceutically approved oily excipients. Suitable surfactants include, but are not limited to, anionic surfactants, nonionic surfactants, cationic surfactants, and amphoteric surfactants. The composition for topical administration may also contain at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.

[0421] Ointments and creams may be formulated, for example, using an aqueous or oily base with appropriate thickeners and / or gelling agents added. Lotions may also be formulated using an aqueous or oily base and generally contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants. Liquid sprays may be delivered from a pressurized pack, for example, via a specially shaped closure. Oil-in-water emulsions can also be used in compositions, patches, bandages, and articles. These systems are semi-solid emulsions, microemulsions, or foaming emulsion systems.

[0422] In some embodiments, the pharmaceuticals described herein can be formulated as inhalants. Inhalation methods can deliver the drug directly to the airways. Pharmaceuticals can be formulated as aerosols, microspheres, liposomes, or nanoparticles. Pharmaceuticals can be formulated with solvents, gases, nitrates, or any combination thereof. The compositions described herein are optionally formulated for delivery as liquid aerosols or inhalable dry powders. Liquid aerosol formulations are optionally sprayed primarily into particles that can be delivered to terminal bronchioles and respiratory bronchioles. Liquid aerosol and inhalable dry powder formulations are preferably delivered through the endobronchial trees to the terminal bronchioles and ultimately to the parenchymal tissue.

[0423] The aerosolized formulations described herein are preferably delivered using an aerosol-forming device such as a jet, a vibrating porous plate, or an ultrasonic nebulizer, which is selected to enable the formation of aerosol particles having a mass median mean diameter of mainly 1 to 5 μm. Furthermore, the formulations preferably have a balanced osmotic ion strength and chloride concentration, and the minimum aerosolizable volume capable of delivering an effective dose of the drug. Moreover, the aerosolized formulations preferably do not negatively impair airway function and do not cause undesirable side effects.

[0424] Examples of aerosolizing devices suitable for administering the aerosol formulations described herein include jet nebulizers, vibrating perforated plate nebulizers, ultrasonic nebulizers, and energy-applied dry powder inhalers, which can spray the formulations into aerosol particle sizes mainly in the range of 1 to 5 μm. “Mainly” in this application means that at least 70%, preferably more than 90%, of all generated aerosol particles are in the range of 1 to 5 μm. Jet nebulizers are operated by air pressure to break up liquid solutions into aerosol droplets. Vibrating perforated plate nebulizers are operated by using an ultrasonic vacuum generated by a rapidly vibrating perforated plate to push solvent droplets through the perforated plate. Ultrasonic nebulizers are operated by piezoelectric crystals that shear the liquid into small aerosol droplets. For example, a variety of suitable devices are available, including AeroNeb® and AeroDose® vibrating perforated plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream® nebulizers (Medic-Aid Ltd., West Sussex, UK), Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and Aerosonic® (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Hayden, Germany) and UltraAire® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.

[0425] In some embodiments, pharmaceuticals can be formulated with an oily base or ointment to form a semi-solid composition having a desired shape. In addition to the pharmaceutical, these semi-solid compositions may contain dissolved and / or suspended bactericides, preservatives, and / or buffering systems. Possible petrolatum components may be isobutylene, colloidal silica, or any paraffin in the viscosity range from mineral oil to paraffinic wax incorporating stearate. Absorbent bases can be used with oily systems. Additives may include cholesterol, lanolin (lanolin derivatives), beeswax, fatty alcohols, wool wax alcohol, low HLB (hydrophobic-oleophobic balance) emulsifiers, and classified ionic and nonionic surfactants, either alone or in combination.

[0426] Controlled-release or sustained-release transdermal or topical formulations can be achieved by adding sustained-release additives, such as polymer structures or matrices available in the art. For example, compositions may be administered using hot-melt extruded articles, such as bioadhesive hot-melt extruded films. Formulations may include crosslinked polycarboxylic acid polymer formulations. The crosslinking agent may be present in an amount that provides adequate adhesion to keep the system attached to the target epithelial or endothelial cell surface for a sufficient time to allow the desired release of the compound.

[0427] Inserts, transdermal patches, bandages, or articles may contain a mixture or coating of polymers that release a pharmaceutical product at a constant rate over a long period of time. In some embodiments, articles, transdermal patches, or inserts may include a water-soluble pore-forming agent, such as polyethylene glycol (PEG), which can be mixed with a water-insoluble polymer to enhance the durability of the insert and extend the release of the active ingredient.

[0428] Transdermal devices (inserts, patches, bandages) may also contain water-insoluble polymers. Rate-controlled polymers may be useful for administration to sites where release can be induced using pH changes. These rate-controlled polymers can be applied using a continuous coating film during the spraying and drying process of the active compound. In one embodiment, the coating formulation is used to coat pellets containing the active ingredient, which are compressed to form a solid biodegradable insert.

[0429] Polymer formulations can also be used to provide controlled or sustained release. Bioadhesive polymers described in the art may be used. For example, sustained-release gels and compounds may be incorporated into polymer matrices such as hydrophobic polymer matrices. Examples of polymer matrices include microparticles. The microparticles can be microspheres, and the core may be a polymer shell and a core of a different material. Alternatively, the polymer may be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel. The polymer can also be in the form of a coating or part of a bandage, stent, catheter, grafted blood vessel, or other device to facilitate the delivery of pharmaceuticals. The matrix can be formed by solvent evaporation, spray drying, solvent extraction, and other methods known to those skilled in the art.

[0430] A kit is provided having one or more unit doses of the medicinal products described herein, which are typically available in oral or injectable doses. Such a kit may include a container containing the unit dose, an informational package insert describing the use of the drug in the treatment of a disease and the associated benefits, and optionally an instrument or device for delivering the composition.

[0431] Treatment method / Therapeutic use In one embodiment, the disclosure provides a method for treating a subject with cancer. The treatment of the subject with cancer may include administering to the subject in need of treatment a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA) (each further comprising a targeting unit), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), or any one thereof, a pharmaceutical composition.

[0432] In one embodiment, the disclosure provides a method for treating a subject having a tumor. The treatment of a subject having a tumor may include administering to the subject requiring treatment a drug linker or salt of formula (B), formula (X), formula (I), or formula (IA) (each further comprising a targeting unit), or a conjugate or salt of formula (C), formula (XX), formula (A), or formula (A-1), or any one thereof, a pharmaceutical composition. The tumor may be related to cancer. The cancer may be selected from the group consisting of lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, and esophageal cancer.

[0433] In some embodiments, the conjugates described herein are useful for inhibiting the proliferation of tumor or cancer cells, for inducing apoptosis in tumor or cancer cells, or for treating cancer in patients.

[0434] The conjugate provides specific tumor or cancer targeting to the conjugation, thereby reducing the systemic toxicity of these compounds. The linker stabilizes the conjugate in the bloodstream but is still cleavable by intracellular enzymes (e.g., lysosomal enzymes), releasing the drug.

[0435] In some embodiments, the conjugates described herein (e.g., formula (C), formula (XX), formula (A), formula (A-1), Table H, Table I, Table HH, or Table II) include cancers of the head and neck, including tumors of the head, neck, nasal cavity, sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, salivary glands, and paragangliomas; cancers of the liver and gallbladder (specifically hepatocellular carcinoma); intestinal cancer (specifically colorectal cancer); ovarian cancer; small cell lung cancer and non-small cell lung cancer (SCLC and NSCLC); breast carcinosarcoma (fibrosarcoma, malignant fibrous histiocytoma, embryonic rhabdomyosarcoma, leiomyosarcoma, neurofibrosarcoma, osteosarcoma, synovial sarcoma, liposarcoma, and It can be used to treat hyperproliferative disorders, including but not limited to alveolar soft tissue sarcoma, leukemia (acute promyelocytic leukemia (APL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML)), neoplasms of the central nervous system (specifically brain tumors), multiple myeloma (MM), and lymphoma (Hodgkin lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-series large cell lymphoma, Burkitt lymphoma, and T-cell anaplastic large cell lymphoma). Clinically, the implementation of the methods described herein and the use of the compositions described herein result in a reduction in the size or number of cancerous growths and / or a reduction in associated symptoms (where applicable). Pathologically, the implementation of the methods described herein and the use of the compositions described herein result in pathologically relevant responses, including inhibition of cancer cell proliferation, reduction of cancer or tumor size, prevention of further metastasis, and inhibition of tumor angiogenesis. A method for treating such a disease comprises the step of administering the combination of the present invention to a subject in a therapeutically effective dose. This method may be repeated as needed. The cancer may be kidney cancer, lung cancer, gastric cancer, or ovarian cancer.

[0436] In some embodiments, the conjugates of this disclosure are used to treat cancer in patients (e.g., mammals such as humans) who require it. In certain embodiments, the cancer is a cancer that expresses ROR2. The ADC may be administered alone or in combination with other therapeutic agents.

[0437] In some embodiments, the cancer treated by the ADC of this disclosure (formula (III*), formula (IIIa*), formula (IIIb*), formula (IV*), formula (IVa*), formula (IVb*), formula (C), formula (XX), formula (A), or formula (A-1)) may be a solid tumor or a hematopoietic carcinoma. Cancers include, for example, melanoma, basal cell carcinoma, glioblastoma, glioma, gliosarcoma, astrocytoma, meningioma, neuroblastoma, adrenocortical carcinoma, head and neck cancers (e.g., cancers of the head, neck, nasal cavity, sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, and / or salivary glands, as well as paragangliomas), oral cancer, salivary gland cancer, nasopharyngeal cancer, breast cancer (e.g., triple-negative breast cancer), lung cancer (e.g., non-small cell lung cancer (NSCLC), small cell lung cancer, or squamous cell lung cancer), esophageal cancer, gastroesophageal junction cancer, gastric cancer, gastrointestinal cancer, primary peritoneal cancer, liver cancer, hepatocellular carcinoma, gallbladder cancer, biliary tract cancer, bile duct cancer, colon cancer, rectal cancer, and colon • Rectal cancer, ovarian cancer, fallopian tube cancer, bladder cancer, upper urinary tract cancer, urothelial carcinoma, renal cell carcinoma, kidney cancer, urogenital cancer, cervical cancer, testicular cancer, prostate cancer, fibrosarcoma, liposarcoma, rhabdomyosarcoma (e.g., embryonic rhabdomyosarcoma), leiomyosarcoma, neurofibrosarcoma, synovial sarcoma, liposarcoma, alveolar soft tissue sarcoma, osteosarcoma, histiocytoma (e.g., malignant fibrous histiocytoma), pancreatic cancer, endometrial cancer, appendiceal cancer, thyroid cancer, progressive Merkel cell carcinoma, multiple myeloma, sarcoma, choriocarcinoma, leukemia (e.g., erythroleukemia, acute lymphoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, acute myeloid leukemia, acute myeloid leukemia) It may be myelogenous leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or mast cell leukemia), lymphoma (e.g., small lymphocytic lymphoma, Burkitt lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, lymphoplasmacytoid lymphoma, mucosa-associated lymphoid lymphoma, mantle cell lymphoma, anaplastic large cell T-cell lymphoma, follicular lymphoma, monocytic lymphoma, or HTLV-associated T-cell leukemia / lymphoma), or mesothelioma.In certain embodiments, cancer is selected from head and neck cancer, bone cancer (e.g., osteosarcoma), Ewing's sarcoma, squamous cell carcinoma, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, cervical cancer, pancreatic cancer, breast cancer (e.g., triple-negative breast cancer), melanoma, liver cancer, bladder cancer, gastric cancer, esophageal cancer, and chronic myeloid leukemia. In certain embodiments, cancer is selected from the group consisting of head and neck cancer, non-small cell lung cancer, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, breast cancer, endometrial cancer, ovarian cancer, soft tissue sarcoma, bladder cancer, prostate cancer, kidney cancer, and melanoma. Cancer may be, for example, early-stage, intermediate-stage, late-stage, locally advanced, or metastatic, and may be recurrent, refractory to other treatments, or for which no standard of care is available.

[0438] In some embodiments, the therapeutic use of the ADCs described herein (e.g., formula (III*), formula (IIIa*), formula (IIIb*), formula (IV*), formula (IVa*), formula (IVb*), formula (C), formula (XX), formula (A), or formula (A-1)) results in delayed tumor growth, elimination of cancer cells, tumor reduction / regression, improved survival, slowed or reduced metastasis, or other clinical endpoints desired by the medical professional. In certain embodiments, the therapeutic use of the ADCs described herein inhibits tumor growth by at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%. In certain embodiments, the therapeutic use of the ADCs described herein results in partial tumor regression of at least 10, 20, 30, 40, 50, 60, 70, 80, or 90%, or complete tumor regression.

[0439] The ADCs of this disclosure may be administered without additional therapeutic intervention, i.e., as standalone therapy (monotherapy). Alternatively, treatment with the ADCs of this disclosure may include at least one additional therapeutic intervention (combination therapy), such as an immunomodulator, an anticancer agent (such as a chemotherapeutic agent, an antineoplastic agent, or an anti-angiogenic agent), a vaccine (such as an oncological vaccine), or radiotherapy.

[0440] In some embodiments, additional therapeutic treatments may include anticancer agents such as alkylating agents (e.g., platinum derivatives such as cisplatin, carboplatin, and / or oxaliplatin), plant alcoids (e.g., paclitaxel, docetaxel, and / or irinotecan), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, idarubicin, mitoxantrone, dactinomycin, bleomycin, actinomycin, luteomycin, and / or mitomycin), topoisomerase inhibitors (e.g., topotecan), antimetabolites (e.g., fluorouracil and / or other fluoropyrimidines), kinase inhibitors such as tyrosine kinase inhibitors (e.g., acalabrutinib, ibrutinib, imatinib, sorafenib, lapatinib, etc.), or any combination thereof, selected from the group.

[0441] In some embodiments, additional therapeutic treatments include A2AR, A1AR, A2BR, A3AR, ADA, ALP, AXL, BTLA, B7-H3, B7-H4, CD116, CD123, CD27, CD28, CD39, CD40, CD47, CD55, CD73, CD122, CD137, CD160, CGEN-15049, CHK1, CHK2, CTLA-3, CTLA-4, CEACAM (e.g., CEACAM-1 and / or CEACAM-5) This may include, but is not limited to, agents that modulate the expression or activity of EGFR, FLT3, HER2, NKG2A, NKG2AL, GAL9, GITR, HVEM, LAG-3, LILRB1, LY108, LAIR1, MET, NKG2A, ICOS, IDO, IL2R, IL4R, KIR, LAIR1, PAP, PD-1 / PD-L1 / PD-L2, OX40, STING, TIGIT, TIM-3, TGFR-beta, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9 and TLR10, TNFR2, VEGFR, VEGF, VISTA, LILRB2, CMTM6, and / or 2B4, as well as agents that modulate immune system activation. In certain embodiments, the drug is a small molecule inhibitor, antisense oligonucleotide, small interfering RNA, aptamer, peptide, or antibody or its antigen-binding fragment that binds to one of the above molecules.

[0442] In some embodiments, cancer is the second leading cause of death in humans, after heart disease. Receptor tyrosine kinases (RTKs) play a crucial role in cancer growth and metastasis, as well as oncogenic transformation, by regulating cell differentiation, proliferation, migration, angiogenesis, and survival. Receptor tyrosine kinase-like orphan receptor 2 ("ROR2") is a cell membrane protein and the receptor for Wnt5a, a pro-inflammatory factor in human ovarian granulosa cells. ROR2 modulates Wnt signaling through the sequestration of Wnt ligands and can also repress the transcription of Wnt target genes involved in tumor suppression. ROR2 is involved in the progression of numerous cancers, including breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, kidney cancer, head and neck cancer, bone cancer, skin cancer, and prostate cancer. Therefore, ROR2 is of interest as a target for anti-cancer immunotherapy.

[0443] In some embodiments, treatment of a subject with a tumor inhibits tumor growth by at least about 20%, more preferably at least about 40%, even more preferably at least about 60%, and even more preferably at least about 80% compared to an untreated subject. The therapeutically effective dose of the therapeutic compound can reduce tumor size or otherwise alleviate symptoms in a subject that is typically human but may be another mammal.

[0444] In some embodiments, the compositions described herein may be administered in combination with other therapeutic agents, including antibodies, alkylating agents, angiogenesis inhibitors, antimetabolites, DNA cleavage agents, DNA crosslinking agents, DNA insertion agents, DNA minor groove binders, enediynes, heat shock protein 90 inhibitors, histone deacetylase inhibitors, immunomodulators, microtubule stabilizers, nucleoside (purine or pyrimidine) analogs, nuclear export inhibitors, proteasome inhibitors, topoisomerase (I or II) inhibitors, tyrosine kinase inhibitors, and serine / threonine kinase inhibitors. Specific therapeutic agents include adalimumab, anthamitocin P3, auristatin, bendamustine, bevacizumab, bicalutamide, bleomycin, bortezomib, busulfan, calcistatin A, camptothecin, capecitabine, carboplatin, carmustine, cetuximab, cisplatin, cladribine, cytarabine, cryptophycin, dacarbazine, dasatinib, daunorubicin, docetaxel, doxorubicin, duocalmycin, dynemycin A, epotilon, etoposide, phloxuridine, ipilimumab, and hidol. Examples include roxiurea, imatinib, infliximab, interferon, interleukin, β-rapacon, lenalidomide, irinotecan, maytansine, mechloretamine, melphalan, 6-mercaptopurine, methotrexate, mitomycin C, nilotinib, oxaliplatin, paclitaxel, procarbazine, suberoylanilide hydroxamic acid (SAHA), 6-thioguanidine, thiotepa, teniposide, topotecan, trastuzumab, trichostatin A, vinblastine, vincristine, and vindesine.

[0445] Drug linkers or salts of formula (B), formula (X), formula (I), or formula (IA) (each further comprising a targeting unit), or conjugates or salts of formula (C), formula (XX), formula (A), or formula (A-1) can be used in the preparation of agents for the prevention or treatment of diseases or illnesses. Furthermore, a method for treating any of the diseases or illnesses described herein in a subject requiring such treatment comprises administering a therapeutically effective dose to a mammal a pharmaceutical composition comprising at least one of the compounds described herein, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable solvate thereof.

[0446] The drug linkers or salts of formula (B), formula (X), formula (I), or formula (IA) described herein (each further comprising a targeting unit), or the conjugates or salts of formula (C), formula (XX), formula (A), or formula (A-1) may be administered for prophylactic and / or therapeutic purposes. For therapeutic use, the composition is administered to a patient already suffering from a disease or illness in an amount sufficient to cure or at least partially block the symptoms of the disease or illness. The effective amount for this use will depend on the severity and course of the disease or illness, the patient's treatment history, their health status, weight, response to the drug, and the judgment of the attending physician.

[0447] For preventative use, compositions containing the compounds described herein are administered to patients who are susceptible to or otherwise at risk of a particular disease, disorder, or illness. Such amounts are defined as “effective preventative doses.” For this use, the exact amount will further depend on the patient’s health condition, weight, etc. When administered to a patient, the effective amount for this use will depend on the severity and course of the disease, disorder, or illness, treatment history, the patient’s health condition, response to the drug, and the judgment of the attending physician.

[0448] If the patient's disease does not improve, the compound may, at the physician's discretion, be administered chronically, that is, over a long period including the patient's entire lifespan, to improve or otherwise control or limit the patient's disease or symptoms of the disease.

[0449] Once the patient's condition improves, a maintenance dose is administered as needed. Thereafter, the dose, frequency, or both may be reduced, depending on the symptoms, to the extent that improvement in the disease, impairment, or illness is maintained. However, the patient may require long-term, intermittent treatment in response to any recurrence of symptoms.

[0450] The amount of a given drug corresponding to such a quantity will vary depending on factors such as the specific compound, the disease or illness and its severity, and the identity of the subject or host requiring treatment (e.g., body weight), but nevertheless, it will be determined in a manner known in the art according to the specific circumstances surrounding the case, including, for example, the specific drug administered, the route of administration, the condition being treated, and the subject or host being treated. However, the doses generally used for treating adult humans will typically be in the range of about 0.02 to about 5000 mg / day, and in some embodiments, about 1 to about 1500 mg / day. The desired dose may be conveniently provided as a single dose, or as divided doses administered simultaneously (or over a short period) or at appropriate intervals, for example, two, three, four, or more subdoses per day.

[0451] The pharmaceutical compositions described herein may also be in unit dosage forms suitable for single-dose administration of precise dosages. In unit dosage forms, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. Unit doses may also be in the form of packages containing discrete amounts of the formulation. Non-limiting examples include packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions may be packaged in non-resealable containers for single-dose administration. Alternatively, resealable containers for multiple doses are used, in which case the composition is typically preservative-containing. As just one example, formulations for parenteral injection may be provided in unit dosage forms, including ampoules, or in multi-dose containers with added preservatives.

[0452] The toxicity and therapeutic efficacy of such treatment regimens are LD 50 (A lethal dose for 50% of the population) and ED 50 This can be determined by standard pharmaceutical procedures for cell cultures or experimental animals, including but not limited to determining the therapeutically effective dose for 50% of the population. The dose-to-toxicity ratio is the therapeutic index, and this is called the LD (Low-Dose). 50 and ED 50 It can be expressed as a ratio to [a certain value]. Compounds exhibiting a high therapeutic index are preferred. Data obtained from cell culture assays and animal studies can be used to formulate a series of dosages for use in humans. Doses of such compounds are given with minimal toxicity. 50 It is preferable that the blood concentration is within the range that includes [the substance]. This dose may vary within this range depending on the dosage form used and the route of administration used.

[0453] In certain embodiments, the present invention provides a method for treating or preventing a disease, condition, or illness in a patient requiring treatment or prevention of the disease, condition, or illness, comprising the step of administering to the patient an effective amount of a compound described in any one embodiment of the present invention or a pharmaceutically acceptable salt thereof. The disease, condition, or illness may be selected from the group described elsewhere in this specification.

[0454] Preparation of drug linkers and conjugates as disclosed herein The linkers, drug linkers, and conjugates of this disclosure can generally be prepared by several methods well known to those skilled in the art of organic synthesis.

[0455] In some embodiments, the linkers, drug linkers, and conjugates of the present disclosure can be synthesized using the methods described herein, along with synthetic methods known in the field of organic synthesis chemistry, or variations thereof as understood by those skilled in the art. In some embodiments, conjugates can be prepared by several routes utilizing organic chemical reactions, conditions, and reagents known to those skilled in the art, including (1) the formation of a targeting unit-linker intermediate by the reaction of a nucleophile of a targeting unit (e.g., an antibody or its antigen-binding moiety or a non-antibody protein scaffold) with a divalent linker via covalent bonding, followed by a reaction with a drug, and (2) the formation of a drug linker by the reaction of a nucleophile of a drug with a divalent linker via covalent bonding, followed by a reaction with a nucleophile of a targeting unit.

[0456] In some embodiments, a technique may be used to conjugate a drug to a targeting unit (such as an antibody or its antigen-binding portion or a non-antibody scaffold) via a linker. In some cases, the linker is first conjugated to the drug (e.g., a cytotoxic agent, an immunomodulator, or another drug), and then the drug linker is conjugated to the targeting unit (e.g., an antibody or its antigen-binding portion or a non-antibody protein scaffold). In other cases, the linker is first conjugated to the targeting unit (e.g., an antibody or its antigen-binding portion or a non-antibody protein scaffold), and then the drug is conjugated to the linker.

[0457] In some embodiments, the drug is conjugated to a targeting unit via a linker such that the activity of the drug is reduced until it is released from the conjugate (for example, by hydrolysis, proteolysis, or by a cleavage agent).

[0458] In some embodiments, nucleophiles on targeting units such as antibodies, antigen-binding moieties, and other binders (including non-antibody scaffolds) include, but are not limited to, (i) N-terminal amine groups, (ii) side-chain amine groups, e.g., lysine, (iii) side-chain thiol groups, e.g., cysteine, and (iv) sugar hydroxyl or amino groups to which the antibody is glycosylated. The amine groups, thiol groups, and hydroxyl groups are nucleophilic and can react with electrophiles on linkers including (i) active esters such as NHS esters, HOBt esters, haloformates, and acid halides, (ii) alkyl halides and benzyl halides such as haloacetamides, and (iii) aldehyde groups, ketone groups, carboxyl groups, and maleimide groups to form covalent bonds. Optionally, targeting units such as antibodies (as well as antigen-binding moieties and other binders (including non-antibody scaffolds)) have reducible interchain disulfides, i.e., cysteine ​​crosslinks. In some cases, the antibody (as well as the antigen-binding moiety and other binders (including non-antibody scaffolds)) may be made reactive for conjugation with a linker or drug linker by treating it with a reducing agent such as DTT (dithiothreitol) or tricarbonylethylphosphine (TCEP) so that the antibody is completely or partially reduced. Thus, each cysteine ​​crosslink may theoretically form two reactive thiol nucleophiles. In some cases, further nucleophiles can be introduced into a targeting unit such as the antibody (as well as the antigen-binding moiety and other binders (including non-antibody scaffolds)) by modifying the lysine residue, for example by reacting the lysine residue with 2-iminothiolane (Trout's reagent) to result in an amine-to-thiol conversion. In some cases, the reactive thiol group may also be introduced into the targeting unit (such as the antibody, antigen-binding moiety, and other binders (including non-antibody scaffolds)) by introducing one, two, three, four, or more cysteine ​​residues (for example, by preparing the antibody, antigen-binding moiety, and other binders (including non-antibody scaffolds) containing one or more non-natural cysteine ​​amino acid residues).

[0459] In some embodiments, the conjugate may also be produced by the reaction of an electrophile on the targeting unit, such as an aldehyde group or ketone carbonyl group, with a nucleophile on the linker or drug linker. Useful nucleophiles on the linker reagent may include, but are not limited to, hydrazides, oximes, aminos, hydrazines, thiosemicarbazones, hydrazine carboxyls, and arylhydrazides. The antibody (or its antigen-binding moiety or other binder (including non-antibody scaffolds)) may be modified to introduce an electrophilic moiety capable of reacting with a nucleophilic substituent on the linker or drug linker. The sugar of the glycosylated antibody may be oxidized, for example, with a periodic acid oxidizing reagent to form a formaldehyde or ketone group that can react with an amine group on the linker or drug linker. The resulting imine-schiff base group may form a stable bond or may be reduced, for example, with a boron hydride reagent to form a stable amine bond. In some cases, the reaction of the carbohydrate portion of a glycosylated antibody with either galactose oxidase or sodium periodate may result in carbonyl (aldehyde and ketone) groups in the antibody (or its antigen-binding portion or other binders (including non-antibody scaffolds)) that can react with suitable groups on the linker or drug linker (see, for example, Hermanson, Bioconjugate Techniques).

[0460] In some embodiments, exemplary nucleophiles on drugs such as cytotoxic agents include, but are not limited to, amine groups, thiol groups, hydroxyl groups, hydrazide groups, oxime groups, hydrazine groups, thiosemicarbazone groups, hydrazine carboxyl groups, and arylhydrazide groups, which can react with electrophiles on a linker containing (i) active esters such as NHS esters, HOBt esters, haloformates, and acid halides, (ii) alkyl halides and benzyl halides such as haloacetamides, and (iii) aldehyde groups, ketone groups, carboxyl groups, and maleimide groups to form covalent bonds and ultimately form a drug linker or conjugate.

[0461] In some embodiments, the linker or drug linker is bound to an interchain cysteine ​​residue of the antibody (or its antigen-binding moiety or other binder (including non-antibody scaffolds)). In some cases, the linker or drug linker typically contains a maleimide group for the binding of interchain disulfides to cysteine ​​residues. In some cases, the linker or drug linker is bound to a cysteine ​​residue of the antibody or its antigen-binding moiety.

[0462] The compounds of this disclosure may be prepared as described in the schemes and examples set out elsewhere in this specification.

[0463] The following embodiments further illustrate the present invention, but should not be interpreted as limiting its scope in any way. [Examples]

[0464] The following synthesis schemes are provided for illustrative purposes only, not limitation. The following examples illustrate various methods for preparing the compounds described herein. Those skilled in the art will understand that these compounds may also be prepared by similar methods or by combining other methods known to those skilled in the art. They will also understand that they may be prepared in the same manner as described below by using appropriate starting materials and modifying the synthesis route as necessary. Generally, starting materials and reagents can be obtained from commercial suppliers, synthesized according to sources known to those skilled in the art, or prepared as described herein. Throughout the description of this invention, as used below, the following abbreviations should be understood to have the following meanings unless otherwise specified.

[0465] [Table 19-1]

[0466] [Table 19-2]

[0467] [Table 19-3]

[0468] Preparation of drug linkers Example 1: Synthesis of drug linker compound 12 The drug linker compound 12 was prepared as shown in schemes 1 and 2.

[0469] [ka]

[0470] To a solution of Fmoc-Sar6-COOH (1, synthesized on Cl-Trt resin using the standard Fmoc SPPS protocol, 66 mg, 0.1 mmol) and compound 2 (HCl salt, 22 mg, 0.1 mmol) in anhydrous DMF (2 mL), PyAOP (52 mg, 0.1 mmol), followed by DIEA (0.07 mL), was added. The mixture was stirred at room temperature for 10 minutes. Piperidine (0.1 mL) was added, and the reaction was stirred at room temperature for 20 minutes. The crude reaction mixture was directly purified by RP-HPLC to obtain compound 3 as a white solid (TFA salt, 66 mg).

[0471] Fmoc-Glu(tBu)-Sar3-COOH (4, synthesized on Cl-Trt resin using the standard Fmoc SPPS protocol, 60 mg) and compound 3 (66 mg) were dissolved in anhydrous DMF (2 mL). AOP (44 mg) and DIEA (0.05 mL) were added, and the reaction mixture was stirred at room temperature. After 15 minutes, the mixture was directly purified by RP-HPLC to obtain compound 5 as a white solid (110 mg).

[0472] Compound 5 (110 mg) was treated with TFA / DCM (1 / 1, v / v, 3 mL) at room temperature for 20 minutes. The mixture was concentrated to dryness under reduced pressure to obtain compound 6 as a white solid.

[0473] [ka]

[0474] To a solution of compound 7 (46 mg, Bioconjugate Chem. 2006, 17, pp. 831-840) and exatecan mesylate (27 mg) in DMF (2 mL), DIEA (18 μL) was added. The reaction mixture was stirred at room temperature (22 °C) for 5 hours, and then piperidine (0.1 mL) was added. The mixture was stirred at room temperature for 15 minutes, and the crude product was directly purified by RP-HPLC to obtain compound 8 as a yellow solid (45 mg).

[0475] Compound 6 (24 mg) and compound 8 (TFA salt, 22 mg) were dissolved in anhydrous DMF (1 mL). AOP (9 mg), followed by DIEA (0.014 mL), was added, and the mixture was stirred at room temperature. After 30 minutes, the crude product was purified by RP-HPLC to obtain compound 9 as a yellow solid (29 mg).

[0476] Compound 9 (28 mg) was suspended in MeOH / water (2 / 1, v / v, 3 mL), and sodium carbonate (12 mg) was added. The mixture was stirred at room temperature for 3 hours. HCl (1N aqueous solution, 0.2 mL) was added, and the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in DMF (2 mL), and piperidine (0.04 mL) was added. After stirring at room temperature for 20 minutes, the crude product was purified by RP-HPLC to obtain compound 10 (13 mg) as a yellow solid.

[0477] Compound 10 (13 mg) and NHS ester 11 (3 mg) were dissolved in DMF (1 mL), and DIEA (0.005 mL) was added. After stirring at room temperature for 2 hours, the mixture was purified by RP-HPLC, and after lyophilization, compound 12 was obtained as a yellow solid (11 mg). MS: m / z 1839.7[M+H + ]

[0478] Example 2: Synthesis of drug linker compound 25 The drug linker compound 25 was prepared as shown in Scheme 3.

[0479] [ka]

[0480] To a suspension of compound 13 (2.36 g, 7.59 mmol) in anhydrous DCM (30 mL), oxalyl chloride (3.85 mL, 45.5 mmol) and DMF (65 μL) were added. The mixture was stirred at room temperature for 1 hour. The solvent was removed under vacuum to obtain compound 14 as a yellow solid (2.5 g).

[0481] Compound 15 (390 mg, 1.2 mmol) was added to a solution of compound 14 (200 mg, 1.2 mmol) in DCM (10 mL) and pyridine (3 mL). The mixture was stirred at room temperature for 1 hour. The mixture was then evaporated and purified by RP-HPLC to obtain compound 16 as a yellowish-brown solid (251 mg).

[0482] To a solution of compound 16 (251 mg, 0.54 mmol) in methanol (10 mL), formic acid (1 mL) and zinc powder (500 mg) were added. The mixture was stirred for 20 minutes, then filtered and purified by RP-HPLC to obtain compound 17 as a clear oily substance (60 mg).

[0483] Compound 18 (7.5 mg, 0.03 mmol) and EEDQ (8.0 mg, 0.03 mmol) were added to a solution of compound 17 (14 mg, 0.03 mmol) in 5 mL of anhydrous DCM. The mixture was stirred at room temperature for 24 hours. The solvent was then evaporated, and the resulting residue was purified by RP-HPLC to obtain compound 19 as a pale yellow solid (8.6 mg).

[0484] To a solution of compound 19 (8.6 mg, 13.4 μmol) in anhydrous DMF (1.0 mL), bis(pentafluorophenyl) carbonate (10.6 mg, 26.8 μmol) and DIEA (2.3 μL, 13.4 μmol) were added. The mixture was stirred at room temperature for 24 hours. The mixture was then purified by RP-HPLC to obtain compound 20 as a yellowish-brown solid (10 mg).

[0485] To a solution of compound 20 (10 mg, 11.7 μmol) in anhydrous DMF (1.0 mL), exatecan mesylate (6.22 mg, 11.7 μmol) and DIEA (10 μL) were added. The mixture was stirred at room temperature for 16 hours. Then, piperidine (50 μL) was added, and stirring was continued for a further 10 minutes. The mixture was then purified by RP-HPLC to obtain compound 21 as the TFA salt (9.6 mg).

[0486] Compound 6 (11.3 mg, 9.6 μmol), PyAOP (4.3 mg, 9.6 μmol), and DIEA (10 μL) were added to a solution of compound 21 (TFA salt, 9.6 mg, 9.6 μmol) in anhydrous DMF (1 mL). The mixture was stirred at room temperature for 20 minutes. Then, piperidine (50 μL) was added, and stirring was continued for a further 10 minutes. The mixture was then directly purified by RP-HPLC to obtain compound 22 as a yellowish-brown solid (14.8 mg).

[0487] To a solution of compound 22 (TFA salt, 14.8 mg, 7.7 μmol) in ACN (1.6 mL) and water (1.4 mL), 1N NaOH in water (77 μL, 77 μmol) was added, and the mixture was stirred at room temperature for 60 minutes. The mixture was then directly purified by RP-HPLC to obtain compound 23 as a white solid (9.6 mg).

[0488] Compound 24 (1.75 mg, 5.2 μmol) and DIEA (4 μL) were added to a solution of compound 23 (9.6 mg, 5.2 μmol) in anhydrous DMF (1 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was then directly purified by RP-HPLC to obtain compound 25 as an off-white solid (6.8 mg). MS: m / z 1874.0[M+H + ].

[0489] Example 3: Synthesis of drug linker compound 28 Drug linker compound 28 was prepared as shown in Scheme 4.

[0490] [ka]

[0491] Compound 26 (28 mg, 26 μmol), PyAOP (14 mg, 26 μmol), and DIEA (18 μL) were added to a solution of compound 21 (TFA salt, 26 mg, 26 μmol) in anhydrous DMF (2 mL). The mixture was stirred at room temperature for 30 minutes. Then, piperidine (150 μL) was added, and stirring was continued for a further 10 minutes. The mixture was then directly purified by RP-HPLC to obtain compound 27 as TFA salt (33 mg, 69%). RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (0.1% TFA), B) Acetonitrile; and Gradient: 2-45% B over 20 minutes, flow rate 50 mL / min. The desired compound was eluted in 20 minutes.

[0492] Compound 24 (6 mg, 18 μmol) and DIEA (8 μL) were added to a solution of compound 27 (TFA salt, 33 mg, 18 μmol) in anhydrous DMF (1 mL). The mixture was stirred at room temperature for 20 minutes. The mixture was then directly purified by RP-HPLC to obtain compound 28 as a pale yellow solid (25 mg, 74%). MS: m / z 937.3[M+2H + ] / 2. RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (0.1% TFA), B) Acetonitrile; and gradient: 5-60% B over 20 minutes, flow rate 50 mL / min. The desired compound was eluted in 17 minutes.

[0493] Example 4: Synthesis of drug linker compound 31 The drug linker compound 31 was prepared as shown in Scheme 5.

[0494] [ka]

[0495] Compound 29 (61 mg, 60 μmol), PyAOP (32 mg, 60 μmol), and DIEA (42 μL) were added to a solution of compound 21 (TFA salt, 60 mg, 60 μmol) in anhydrous DMF (2 mL). The mixture was stirred at room temperature for 40 minutes. Then, piperidine (150 μL) was added, and stirring was continued for a further 10 minutes. The mixture was then directly purified by RP-HPLC to obtain compound 30 as TFA salt (68 mg, 64%). RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (0.1% TFA), B) Acetonitrile; and Gradient: 2-45% B over 20 minutes, flow rate 50 mL / min. The desired compound was eluted in 19 minutes.

[0496] Compound 24 (13 mg, 39 μmol) and DIEA (14 μL) were added to a solution of compound 30 (TFA salt, 68 mg, 39 μmol) in anhydrous DMF (2 mL). The mixture was stirred at room temperature for 20 minutes. The mixture was then directly purified by RP-HPLC to obtain compound 31 as a pale yellow solid (53 mg, 75%). MS: m / z 1804.1[M+H + RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (0.1% TFA), B) Acetonitrile; and gradient: 5–55% B over 20 minutes, flow rate 50 mL / min. The desired compound was eluted in 18 minutes.

[0497] Example 5: Synthesis of drug linker compound 34 Drug linker compound 34 was prepared as shown in Scheme 6.

[0498] [ka]

[0499] Compound 29 (110 mg) and compound 8 (TFA salt, 110 mg) were dissolved in anhydrous DMF (4 mL). AOP (52 mg), followed by DIEA (0.06 mL), was added, and the mixture was stirred at room temperature. After 90 minutes, the crude product was purified by RP-HPLC to obtain compound 32 as a yellow solid (116 mg). RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (0.1% TFA), B) Acetonitrile; and Gradient: 2–65% B over 20 minutes, flow rate 50 mL / min. The desired compound was eluted in 19 minutes.

[0500] Compound 32 (116 mg) was suspended in MeOH / water (2 / 1, v / v, 6 mL), and sodium carbonate (36 mg) was added. The mixture was stirred at room temperature for 3 hours. HCl (1N aqueous solution, 0.5 mL) was added, and the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in DMF (3 mL), and piperidine (0.06 mL) was added. After stirring at room temperature for 20 minutes, the crude product was purified by RP-HPLC to obtain compound 33 (52 mg) as a yellow solid. RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (0.1% TFA), B) Acetonitrile; and gradient: 5-40% B over 20 minutes, flow rate 50 mL / min. The desired compound was eluted in 18 minutes.

[0501] Compound 33 (51 mg) and NHS ester (11, 9 mg) were dissolved in DMF (2 mL), and DIEA (0.018 mL) was added. After stirring at room temperature for 2 hours, the mixture was purified by RP-HPLC, and compound 34 was obtained as a yellow solid (33 mg) after lyophilization. MS: m / z 1768.7[M+H +RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (0.1% TFA), B) Acetonitrile; and gradient: 5-60% B over 20 minutes, flow rate 50 mL / min. The desired compound was eluted in 17 minutes.

[0502] Example 6: Synthesis of drug linker compound 37 Drug linker compound 37 was prepared as shown in Scheme 7.

[0503] [ka]

[0504] Compound 35 (70 mg, 90 μmol), PyAOP (47 mg, 90 μmol), and DIEA (80 μL) were added to a solution of compound 21 (TFA salt, 90 mg, 90 μmol) in anhydrous DMF (10 mL). The mixture was stirred at room temperature for 50 minutes. Then, piperidine (700 μL) was added, and stirring was continued for a further 10 minutes. The mixture was then directly purified by RP-HPLC to obtain compound 36 as TFA salt (57 mg, 48%). RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (0.1% TFA), B) Acetonitrile; and Gradient: 2-50% B over 20 minutes, flow rate 50 mL / min. The desired compound was eluted in 20 minutes.

[0505] Compound 24 (15 mg, 43 μmol) and DIEA (30 μL) were added to a solution of compound 36 (TFA salt, 57 mg, 43 μmol) in anhydrous DMF (2 mL). The mixture was stirred at room temperature for 20 minutes. The mixture was then directly purified by RP-HPLC to obtain compound 37 as a pale yellow solid (53 mg, 75%). MS: m / z 1357.0[M+H +RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (0.1% TFA), B) Acetonitrile; and gradient: 5–55% B over 20 minutes, flow rate 50 mL / min. The desired compound was eluted in 18 minutes.

[0506] Example 7: Synthesis of drug linker compound 40 The drug linker compound 40 was prepared as shown in Scheme 8.

[0507] [ka]

[0508] Compound 35 (127 mg) and compound 8 (TFA salt, 220 mg) were dissolved in anhydrous DMF (5 mL). AOP (100 mg), followed by DIEA (0.14 mL), was added, and the mixture was stirred at room temperature. After 2 hours, the crude product was purified by RP-HPLC to obtain compound 38 as a yellow solid (144 mg). RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (0.1% TFA), B) Acetonitrile; and Gradient: 10–70% B over 20 minutes, flow rate 50 mL / min. The desired compound was eluted at 18 minutes.

[0509] Compound 38 (144 mg) was suspended in MeOH / water (2 / 1, v / v, 8 mL), and sodium carbonate (45 mg) was added. The mixture was stirred at room temperature for 3 hours. HCl (1N aqueous solution, 0.7 mL) was added, and the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in DMF (3 mL), and piperidine (0.046 mL) was added. After stirring at room temperature for 20 minutes, the crude product was purified by RP-HPLC to obtain compound 39 (68 mg) as a yellow solid. RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (0.1% TFA), B) Acetonitrile; and gradient: 5-45% B over 20 minutes, flow rate 50 mL / min. The desired compound was eluted at 18 minutes.

[0510] Compound 39 (68 mg) and NHS esters (11, 17 mg) were dissolved in DMF (2 mL), and DIEA (0.03 mL) was added. After stirring at room temperature for 1 hour, the mixture was purified by RP-HPLC, and compound 40 was obtained as a yellow solid (51 mg) after lyophilization. MS: m / z 1322.5[M+H + RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (10 mM NH4OAc), B) Acetonitrile; and gradient: 10–65% B over 20 minutes, flow rate 50 mL / min. The desired compound was eluted in 18 minutes.

[0511] Example 8: Synthesis of drug linker compound 43 Drug linker compound 43 was prepared as shown in Scheme 9.

[0512] [ka]

[0513] Compound 41 (33 mg, 26 μmol), PyAOP (14 mg, 26 μmol), and DIEA (18 μL) were added to a solution of compound 21 (TFA salt, 26 mg, 26 μmol) in anhydrous DMF (2 mL). The mixture was stirred at room temperature for 20 minutes. Then, piperidine (150 μL) was added, and stirring was continued for a further 10 minutes. The mixture was then directly purified by RP-HPLC to obtain compound 42 as TFA salt (30 mg, 58%). RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (0.1% TFA), B) Acetonitrile; and gradient: 2-45% B over 20 minutes, flow rate 50 mL / min. The desired compound was eluted in 20 minutes.

[0514] Compound 24 (4 mg, 12 μmol) and DIEA (6 μL) were added to a solution of compound 42 (TFA salt, 24 mg, 12 μmol) in anhydrous DMF (1 mL). The mixture was stirred at room temperature for 20 minutes. The mixture was then directly purified by RP-HPLC to obtain compound 43 as a pale yellow solid (20 mg, 81%). MS: m / z 1027.4[M+2H + ] / 2. RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (0.1% TFA), B) Acetonitrile; and gradient: 5–65% B over 20 minutes, flow rate 50 mL / min. The desired compound was eluted in 16 minutes.

[0515] Example 9: Synthesis of drug linker compound 45 Drug linker compound 45 was prepared as shown in schemes 10 and 11.

[0516] [ka]

[0517] To a solution of Fmoc-Gly-Sar-OH (1-1, 3.68 g, 10 mmol) in anhydrous DMF (40 mL), TSTU (3.04 g, 10 mmol), followed by DIEA (3.5 mL), was added. The mixture was stirred at room temperature for 10 minutes. A solution of sarcosine (2-1, 1 g) in acetonitrile / water (1 / 1, 5 mL), followed by DIEA (1.8 mL), was added. The reaction mixture was stirred at room temperature for 30 minutes, and the crude product was directly purified by RP-HPLC. After lyophilization, compound 3-1 was obtained as a white powder (3.34 g).

[0518] Resin-bound peptide 5-1 was synthesized on Fmoc-Rink Amide MBHA resin (0.7 mmol / g, 2 g) according to the standard Fmoc SPPS strategy, using Fmoc Gly-OH, compound 3-1, and Fmoc-Glu(tBu)-COOH as building blocks. Resin-bound compound 5-1 was treated with neat TFA at room temperature for 30 minutes. The polymer was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC to obtain compound 6-1 as a white powder (0.75 g). RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (0.1% TFA), B) Acetonitrile; and Gradient: 10-70% B over 20 minutes, flow rate 50 mL / min.

[0519] [ka]

[0520] Compound 6-1 (19.5 mg, 19 mg), PyAOP (10 mg, 19 mg), and DIEA (13 μL) were added to a solution of compound 21 (TFA salt, 19 mg, 19 mg) in anhydrous DMF (1 mL). The mixture was stirred at room temperature for 10 minutes. Then, piperidine (80 μL) was added, and stirring was continued for another 10 minutes. The mixture was then directly purified by RP-HPLC to obtain compound 44 as TFA salt (29 mg, 88%). RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (0.1% TFA), B) Acetonitrile; and Gradient: 2-45% B over 20 minutes, flow rate 50 mL / min. The desired compound was eluted in 19 minutes.

[0521] Compound 24 (6 mg, 18 mg) and DIEA (15 μL) were added to a solution of compound 44 (TFA salt, 29 mg, 16 μL) in anhydrous DMF (1 mL). The mixture was stirred at room temperature for 10 minutes. The mixture was then directly purified by RP-HPLC to obtain compound 45 as a pale yellow solid (27 mg, 93%). RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (0.1% TFA), B) Acetonitrile; and Gradient: 5–55% B over 20 minutes, flow rate 50 mL / min. The desired compound was eluted at 18 minutes.

[0522] Example 10: Synthesis of drug linker compound 47 Drug linker compound 47 was prepared as shown in schemes 12 and 13.

[0523] [ka]

[0524] To a solution of Fmoc-Gly-Sar-OH (1-1, 3.68 g, 10 mmol) in anhydrous DMF (40 mL), TSTU (3.04 g, 10 mmol), followed by DIEA (3.5 mL), was added. The mixture was stirred at room temperature for 10 minutes. A solution of NH2-Sar-Sar-OH (2-2, 2 g) in acetonitrile / water (1 / 1, 5 mL), followed by DIEA (2 mL), was added. The reaction mixture was stirred at room temperature for 30 minutes, and the crude product was directly purified by RP-HPLC. After lyophilization, compound 3-2 was obtained as a white powder (3.8 g).

[0525] Resin-bound peptide 5-2 was synthesized on Fmoc-Rink Amide MBHA resin (0.7 mmol / g, 2 g) according to the standard Fmoc SPPS strategy, using Fmoc Gly-OH, compound 3-2, and Fmoc-Glu(tBu)-COOH as building blocks. Resin-bound compound 5-2 was treated with neat TFA at room temperature for 30 minutes. The polymer was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC to obtain compound 6-2 as a white powder (0.72 g). RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (0.1% TFA), B) Acetonitrile; and Gradient: 10-70% B over 20 minutes, flow rate 50 mL / min.

[0526] [ka]

[0527] Compound 6-2 (18.3 mg, 19 mg), PyAOP (10 mg, 19 mg), and DIEA (13 μL) were added to a solution of compound 21 (TFA salt, 19 mg, 19 mg) in anhydrous DMF (1 mL). The mixture was stirred at room temperature for 10 minutes. Then, piperidine (80 μL) was added, and stirring was continued for another 10 minutes. The mixture was then directly purified by RP-HPLC to obtain compound 46 as TFA salt (28 mg, 84%). RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (0.1% TFA), B) Acetonitrile; and Gradient: 2-45% B over 20 minutes, flow rate 50 mL / min. The desired compound was eluted in 20 minutes.

[0528] Compound 24 (6 mg, 18 mg) and DIEA (15 μL) were added to a solution of compound 46 (TFA salt, 28 mg, 16 μL) in anhydrous DMF (1 mL). The mixture was stirred at room temperature for 10 minutes. The mixture was then directly purified by RP-HPLC to obtain compound 47 as a pale yellow solid (25 mg, 86%). RP-HPLC method: Column: Phenomenex Gemini NX5, C18, 110 Å, 150 × 50 mm; Instrument: Shimadzu LC with CTC IFC; Mobile phase: A) Water (0.1% TFA), B) Acetonitrile; and Gradient: 5–55% B over 20 minutes, flow rate 50 mL / min. The desired compound was eluted at 18 minutes.

[0529] Example 11: Preparation of antibody-drug conjugates The conjugate was prepared using appropriate drug linkers and antibodies under the following conditions.

[0530] 50 mg of mAb for conjugation in various formulations was pH-adjusted or the buffer was changed to a 5% (v / v) 0.5 M Tris, 0.025 M EDTA, pH 8.5 formulation for reduction. 0.025 M EDTA was added to the formulation buffer to prevent metal-catalyzed disulfide reoxidation. 10 mM TCEP (7 M equivalent) was added to reduce the number of target interchain disulfide bonds, generating the desired average number of free thiols per mAb over 90 minutes at 25°C. The free thiols were conjugated with an additional maleimide (MC)-containing toxin linker dissolved in a water-miscible solvent (12 equivalents of 20 mM MC linker in 10% DMA) over 60 minutes at 25°C. Additional solvent was added before the toxin linker to maintain its solubility after addition, and mixing was performed using a stirring flask. The conjugation was terminated by adding additional NAC (110 mM), and the mixture was stirred for a further 30 minutes to quench the unreacted maleimide. The quenched additional toxin linker was removed by incubation with activated carbon at 15 rpm for 60 minutes at room temperature and / or by dialysfiltration. The conjugate (yield 93–97%) was replaced with final formulation buffer (0.1 M Arg / PBS, pH 7.4), filtered through a 0.22 μm PES, divided, and stored at -60°C or below.

[0531] Example 12: Preparation of ADC-1 using deruxtecan and UC-961 antibody ADC-1 was synthesized using deruxtecan combined with the UC-961 antibody. Deruxtecan is a drug linker composed of a DX-8951 derivative (DXd) and a maleimide-GGFG peptide linker.

[0532] [ka]

[0533] ADC-1 was prepared using Example 11 and deruxtecan and UC-961 antibody.

[0534] [ka] The DAR value determined by RP-HPLC was 7.8. The heavy and light chain regions of the UC-961 antibody are shown in Example 31 (e.g., SEQ ID NOs. 40 and 41, respectively).

[0535] Example 13: Preparation of antibody-drug conjugate (ADC)-2 using drug linker 25 and UC-961 antibody ADC-2 was prepared using Example 11, drug linker 25, and UC-961 antibody.

[0536] [ka] The DAR value determined by RP-HPLC was 7.9. The heavy and light chain regions of the UC-961 antibody are shown in Example 31 (e.g., SEQ ID NOs. 40 and 41, respectively).

[0537] Example 14: Preparation of antibody-drug conjugate (ADC)-3 using drug linker 12 and UC-961 antibody ADC-3 was prepared using Example 11, drug linker 12, and UC-961 antibody.

[0538] [ka] The DAR value determined by RP-HPLC was 8. The heavy and light chain regions of the UC-961 antibody are shown in Example 31 (e.g., SEQ ID NOs. 40 and 41, respectively).

[0539] Example 15: Preparation of antibody-drug conjugate (ADC)-4 using drug linker 37 and ROR2 antibody ADC-4 was prepared using Example 11, drug linker 37, and ROR2 antibody (Ab1).

[0540] [ka] The DAR value determined by RP-HPLC was 8. The sequences of the heavy and light chain regions of the ROR2 antibody are shown in Example 32 (e.g., SEQ ID NO: 1 and SEQ ID NO: 2, respectively).

[0541] Example 16: Preparation of antibody-drug conjugate (ADC)-5 using drug linker 31 and ROR2 antibody ADC-5 was prepared using Example 11, drug linker 31, and ROR2 antibody (Ab1).

[0542] [ka] The DAR value determined by RP-HPLC was 8. The sequences of the heavy and light chain regions of the ROR2 antibody are shown in Example 32 (e.g., SEQ ID NO: 1 and SEQ ID NO: 2, respectively).

[0543] Example 17: Preparation of antibody-drug conjugate (ADC)-6 using deruxtecan and 5T4 antibody ADC-6 was prepared using Example 11 and deruxtecan and 5T4 antibody.

[0544] [ka] The DAR value determined by RP-HPLC was 7.8. The heavy and light chain regions of the 5T4 antibody are shown in Example 33 (e.g., SEQ ID NO: 50 and SEQ ID NO: 51, respectively).

[0545] Example 18: Preparation of antibody-drug conjugate (ADC)-7 using drug linker 31 and 5T4 antibody ADC-7 was prepared using Example 11, drug linker 31, and 5T4 antibody.

[0546] [ka] The DAR value determined by RP-HPLC was 8. The sequences of the heavy and light chain regions of the 5T4 antibody are shown in Example 33 (e.g., SEQ ID NO: 50 and SEQ ID NO: 51, respectively).

[0547] Example 19: Preparation of antibody-drug conjugate (ADC)-8 using drug linker 31 and PTK7 ADC-8 was prepared using Example 11, drug linker 31, and PTK7 antibody.

[0548] [ka] The DAR value determined by RP-HPLC was 8.

[0549] Example 20: Preparation of antibody-drug conjugate (ADC)-9 using drug linker 37 and PTK7 ADC-9 was prepared using Example 11, drug linker 37, and PTK7 antibody.

[0550] [ka] The DAR value determined by RP-HPLC was 8.

[0551] Conjugate Feature Analysis Example 21: Plasma stability Plasma stability tests demonstrate the stability of various ADCs in mouse and human plasma. ADC1-3 were tested in both mouse and human plasma.

[0552] ADC was incubated in 300 μL of IgG-depleted plasma at a concentration of 50 μg / mL. IgG depletion was performed using a HiTrap Protein G Column (Cytiva). Samples were incubated in Eppendorf tubes at 37°C for 0, 1, 3, 7, and 15 days. After appropriate incubation time, samples were transferred to a -80°C freezer until ready for processing. Samples were incubated in pairs at each time point.

[0553] To separate ADCs from plasma, 100 μL of each sample was mixed with 100 μL of Protein A magnetic bead slurry (Thermo Pierce) and 900 μL of sodium phosphate (50 mM, pH 7) at room temperature with shaking for 2 hours. Afterward, it was necessary to bind the ADCs to the beads and discard any excess plasma. The beads were then washed to remove nonspecific binding with 1 mL of 0.1% Triton and 0.1% IPA, followed by two washes in 1 mL of PBS with shaking for 30 minutes each. Next, the ADCs were eluted from the beads over 60 minutes in 100 μL of a low-pH, high-organic mixture (40 mM glycine, 2% formic acid, 50% acetonitrile). The bead slurry was then centrifuged, and 50 μL of the supernatant was injected into an LC-MS.

[0554] For LC, a 50 mm × 2.1 bioZen XB-C8 column was used over a 7-minute gradient of H2O and acetonitrile containing 0.1% formic acid, respectively. MS was performed in intact protein mode with a source temperature of 500°C, a delustering potential of 200 V, and a mass range of 900–4500 m / z.

[0555] The processing was carried out using Sciex OS, which allows for the addition of up to four payload linkers per protein. The stability results for mouse plasma are shown in Figure 1, and for human plasma in Figure 2.

[0556] As shown in Figure 1, the stability of ADC-1, ADC-2, and ADC-3 in mouse plasma was achieved. Furthermore, as shown in Figure 2, the stability of ADC-1, ADC-2, and ADC-3 in human plasma was achieved.

[0557] Example 22: Cell binding The ability of the anti-UC-961 conjugate to bind to Jeko-1 cells was measured using an in vitro cell binding assay.

[0558] For each Jeko-1 cell line, 500,000 cells were seeded in 50 μL in each well of a 96-well deep-well plate (Thermo Scientific #249946). A 1:3 dilution series of primary antibody was prepared, starting with a 1 μg / mL starting stock. Subsequently, 50 μL of primary antibody at different concentrations (final concentrations from 17 pg / mL to 1000 ng / mL) was placed on top of 50 μL of the cells. The cells and antibodies were mixed and incubated on ice for 20 minutes. For the first wash, 300 μL of FACS buffer was added, and the cells were centrifuged at 500xg for 5 minutes at 4°C. The supernatant was discarded, and the cells were resuspended in 400 μL of FACS buffer and washed again. After the second wash, the cells were resuspended in 100 μL of goat anti-human IgG secondary phycoerythrin (PE) antibody (ThermoFisher Scientific #12-4998-82) at a final concentration of 1 μg / mL and incubated on ice (in the dark) for 20 minutes. The cells were washed twice as described above and analyzed on BD FACSVerse with Flowjo software version 10. The percentage of maximum binding relative to the highest concentration was graphed, and the maximum effective concentration (EC2) was calculated using GraphPad Prism version 7. 50 The values ​​were determined and are shown in Table 1, and the binding percentage of each ADC was plotted in Figure 3. Figure 4 shows the average fluorescence intensity of each ADC.

[0559] [Table 20]

[0560] Example 23: Cytotoxicity Measurement The ability of anti-UC-961 conjugates to inhibit cell growth was measured using an in vitro cytotoxicity assay.

[0561] Jeko-1 cells were cultured in the logarithmic growth phase and divided into 96-well plates. Each cell line was seeded at slightly different concentrations, but the range was 5 × 10⁶. 3 ~50×10 4 Cells were divided into cells / well. Cells were incubated in a double-row at 37°C and 5% CO2 for 72 hours with 3-fold series dilutions of specific immune complexes starting at 3000 or 1000 nanomoles (3000, 1000, 333, 111, 37, 12.3, 4.1, 1.37, 0.46, 0.15 nanomoles). After treatment, cells were incubated at room temperature for 15 minutes with an equal volume of CellTiter-Glo® reagent (Promega), and viability was determined by luminometer. EC50 values ​​are shown in Table 2, and the percentage of inhibition is plotted in Figure 5.

[0562] [Table 21]

[0563] Example 24: Internalization MDA-MB-468 cells were harvested, washed with cold PBS, and placed in cold FACS buffer containing PBS and 2% FBS (1 × 10⁶ cells). 7 The solution was resuspended at a concentration of cells / mL. 1 × 10 6 Aliquots of cells were added to microcentrifuge tubes or wells. Primary antibodies were diluted to prepare 10-fold stock solutions of 300 μg / mL or 1 mg / mL, and 10 μl of each solution was added to appropriate tubes.

[0564] The control group consisted only of unstained secondary antibody (goat anti-human IgG-PE, Fc-γ specific) (ThermoFisher Scientific #12-4998-82). The test group included cells subjected to the following conditions, with evaluation using either 30 μg / mL (203 nM) or 100 μg / mL (676 nM) primary antibody, depending on the experiment. In addition to centrifugation of controls at 300 x g for 4 minutes, cells were kept on ice for 20 minutes, washed twice with 200 μl of FACS buffer, resuspended in 100 μl of FACS buffer, and incubated at 37°C for 30, 60, 120, or 240 minutes. After incubation, cells were centrifugated at 250 x g, washed twice with FACS buffer, and resuspended in 100 μl of FACS buffer. A 10-fold stock of the secondary antibody was diluted 1:2000 in FACS buffer, and 10 μl was added to each appropriate tube. Cells were incubated on ice for 20 minutes, washed twice with FACS buffer, and resuspended in 100 μl of fixation buffer (4% paraformaldehyde in PBS). FACS analysis was then performed, and the median fluorescence intensity (MFI) was evaluated. The relative magnitude of primary antibody internalization was determined by comparing the MFI value at each time point with the MFI value of the primary antibody control at time 0, and this is shown in Figure 6.

[0565] Example 25: DAR by RP-HPLC The drug-to-antibody ratio (DAR) of each ADC was determined using RP-HPLC. The drug-to-antibody ratio (DAR) of the ADCs was obtained using reverse-phase HPLC, as shown in Table 4 below.

[0566] RP-HPLC conditions: Column - Phenomenex Kinetex 100 Å, 50 × 4.6 mm, 2.6 μm, part number: PL1912-1502. MPA - 0.1% TFA / H2O, MPB - 0.1% TFA / CAN

[0567] Method: Flow rate - 1 mL / min, gradient - refer to Table 3. Column temperature - 50°C.

[0568] Sample temperature - RT. DAD 214nm, BW 16nm; reference 440nm, BW 80nm; peak width >0.4 min (response time 8 seconds (0.62 Hz)); spectrum: 200~600nm, step 1.2nm, slit 8nm.

[0569] Sample - Neat injection, approximately 5 μg.

[0570] [Table 22]

[0571] [Table 23]

[0572] Example 26: Hydrophobicity of drug linkers by RP-HPLC analysis As shown in Table 5, the relative hydrophobicity of the drug linker was determined using reverse-phase HPLC analysis.

[0573] Column - Phenomenex Kinetex 100 Å, 50 × 4.6 mm, 2.6 μm, Part Number: 00B-4497-E0. MPA-0.05% TFA / H2O, MPB-0.05% TFA / CAN.

[0574] Method: Flow rate - 2 mL / min. Gradient - See Table 6. Column temperature - 60°C. Sample temperature - RT. DAD 214 nm, BW 4 nm + 360 nm, BW 4 nm. Reference 440 nm, BW 40 nm. Peak width > 0.1 min (response time 2 seconds (2.5 Hz)). Spectrum: 200 ~ 400 nm, step 2 nm, slit 2 nm

[0575] Sample - Injection mass: 5-100 pmol, DMA toxin stock diluted in MeOH.

[0576] Table 6 shows the retention times of various drug linkers. Two retention time values ​​were obtained by synthesizing the drug linkers deruxtecan, 18, 25, 34, 37, 40, 43, and 58 as enantiomers. Based on the first retention time of each drug linker from RP-HPLC, the hydrophobicity increases as follows: 12 < 25 < 45 < 47 < deruxtecan. The benefit of increasing hydrophilicity due to the short sulfate side chain of drug linker 25 is that of ADC T 1 / 2 This increases lifetime and AUC, ultimately enhancing its in vivo efficacy, demonstrating greater overall ionic effects and less physical masking effects from larger side chains.

[0577] [Table 24]

[0578] [Table 25]

[0579] Example 27: Payload Release The conjugates were incubated overnight with papain or β-glucuronidase buffer, and the release of exatecan was monitored. A 10 mg / ml papain stock was prepared in 1.1 mM EDTA, 0.067 mM DTT, and 5.5 mM cysteine. 50 μg ADC (10 μl) and 1 μl papain stock were prepared to a final concentration of 1 mg / ml and incubated at 37°C for 4 hours before analysis. As shown in Figure 7, the XIC of all samples showed a strong signal in payload release. All six ADCs peaked at 436.16 (consistent with the MSMS fragment assigned to exatecan).

[0580] Example 28: Pharmacokinetic preparation Anti-HuROR1 ELISA ("Total ADC") Procedure: Wells of a 96-well plate were coated with biotin-ROR1 antigen (biotinylated human / cynomolgus / rhesus monkey ROR1 protein, Avitag®; 200 μg / ml, AcroBiosystem) at 0.2 μg / well / 25 μl and allowed to stand overnight at 4°C. The wells were then washed four times with 100 μl / well of wash buffer and blocked with 5% milk + PBS at 37°C for 90 minutes. Diluted mouse plasma PK samples were added in addition to standard curves for ADC-Dxd and / or ADC-exatecan (25 μl / well). The plates were incubated at 37°C for 60 minutes and then washed. 25 μl / well of goat anti-human kappa-HRP (Sothernbiotech, cat#2061-05, Lot#i1519-YD22B) was added at a dilution of 1:5,000 to 1:20,000, and the plates were incubated at 37°C for 60 minutes. The plates were then washed, colored in TMB / stop solution, and read at 450 OD on Spectramax.

[0581] Anti-Dxd ELISA ("Free Payload") Procedure: 0.2 μg / well / 25 μl of biotin-ROR1 (biotinylated human / cynomolgus / rhesus monkey ROR1 protein, Avitag®; 200 μg / ml, AcroBiosystems) for antigen coating at 4°C. Wash each well four times with 100 μl of wash buffer. Block with 5% milk + PBS at 37°C for 90 minutes. Add 25 μl of ADC-Dxd and / or ADC-exatecan as standard and mouse plasma sample. Incubate at 37°C for 60 minutes. Wash. Add anti-Dxd (0.025 ug / 25 ul / well; AcroBiosystems, cat#DXD-S222) at 37°C for 60 minutes. Then wash. Goat α-mouse-κ-HRP was added at a ratio of 1:5K to 1:20 (Bethyl Lab, 1 mg / ml, Lot #33, Cat #A90-119P). Washing was then performed. The samples were color-developed in TMB / stop solution and read using OD450. "Free payload" = anti-HuROR1 ELISA value ("total" ADC) - anti-Dxd ELISA value (ADC containing payload).

[0582] Example 29: Calculation of pharmacokinetic parameters Pharmacokinetic analyses were performed on plasma concentration-vs-time data for all analytes using the Phoenix WinNonlin (v7.0) non-compartmental analysis function (linear trapezoidal rule for AUC calculation). Nominal dose values ​​and sampling times were used for calculation. For the purpose of PK calculation, any concentration reported as "BLQ" was set to be equivalent to zero. The terminal rate constant (lambda z, λz) for each analyte was determined as acceptable data. The value of λz was calculated by the slope of the natural logarithmic-transformed concentration-vs-time regression line, subject to the following constraints: data points were randomly distributed around a single line, at least three data points after Cmax were used for regression, the correlation coefficient (R2) of the regression was greater than 0.90, and the period over which the regression was determined was at least twice as long as the calculated half-life itself.

[0583] To optimize the reliability of the identified terminal phase (λz), data points used to define λz were manually selected. If the lambda z profile did not meet the above guidelines, the AUCINF, t1 / 2, CL, or Vz parameters for that animal profile were not reported. Where possible, AUCINF was calculated as AUClast + (Clast / λz). CL was calculated as dose / (AUCINF), and Vz was calculated as dose / (AUCINF*λz). Terminal phase half-life (t1 / 2) was calculated as ln(2) / λz. Mean plasma concentration versus time data were presented as mean only (N=2) and reported with 3 significant figures. PK parameter values ​​were presented as mean only (N=2). Individual Tmax (where applicable) and t1 / 2 values ​​were reported with 2 significant figures, and all remaining values ​​with 3 significant figures. Pharmacokinetic data are shown in Figure 8.

[0584] Example 30: In Vivo Efficacy The antitumor activity of ADC was evaluated in xenograft models of H1975 (non-small cell lung tumor (NSCLC)), H520 (NSCLC), LCLC-103H (NSCLC), CTG-2215 (TNBC), SA4121 (sarcoma), and NCI-H526 (SCLC). Mice with tumors were randomized based on their individual tumors and administered intravenous doses. As shown in Figure 9, ADC showed antitumor activity in the H1975 model when administered intravenously at a dose of 10 mg / kg once a week for 3 weeks (days 0, 8, and 16). On the other hand, as shown in Figures 10 and 21, ADC showed antitumor activity in the H520 model when administered intravenously at a dose of 10 mg / kg once a week for 3 weeks (days 0, 8, and 16). Figures 11 and 20 show that when ADC is administered intravenously at a dose of 10 mg / kg once a week for three weeks (days 0, 8, and 16), it exhibits antitumor activity in the LCLC-103H model. Figure 12 shows that when ADC is administered intravenously at a dose of 5 mg / kg or 10 mg / kg once a week for four weeks (days 1, 8, 15, and 22), it exhibits antitumor activity in the CTG-2215 model. Figure 13 shows that when ADC is administered intravenously at a dose of 10 mg / kg once a week for four weeks (days 1, 8, 15, and 22), it exhibits antitumor activity in the SA4121 model. On the other hand, Figure 14 shows that when ADC is administered intravenously at a dose of 10 mg / kg once a week for three weeks (days 1, 8, and 15), it exhibits antitumor activity in the NCI-H526 model. On the other hand, Figure 15 shows that when ADC is administered intravenously at a dose of 10 mg / kg once a week for three weeks (days 0, 8, and 16), it exhibits antitumor activity in the H520 model. Figure 16 shows that when ADC is administered intravenously at a dose of 10 mg / kg once a week for three weeks (days 0, 8, and 16), it exhibits antitumor activity in the LCLC-103H model.

[0585] Example 31: UC-961 antibody (Ab5) UC-961 is a humanized IgG1 / kappa antibody. UC-961 was transiently expressed in CHO-K1 cells and purified in a single step using protein A chromatography resin. The final buffer composition was 100 mM Tris-HCl, 85 mM acetate, 10 mM glycine, pH 7.0 (WuXi Biologics). The heavy chain and light chain sequences of the UC-961 antibody (Ab5) are shown below.

[0586] Heavy chain (SEQ ID NO: 40)

[0587] QVQLQESGPGLVKPSQTLSLTCTVSGYAFTAYNIHWVRQAPGQGLEWMGSFDPYDGGSSYNQKFKDRLTISKDTSKNQVVLTMTNMPDPVDTATYYCARGWYYFDYWGHGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0588] Heavy chain variable domain of UC-961 antibody (SEQ ID NO: 42)

[0589] QVQLQESGPGLVKPSQTLSLTCTVSGYAFTAYNIHWVRQAPGQGLEWMGSFDPYDGGSSYNQKFKDRLTISKDTSKNQVVLTMTNMPDPVDTATYYCARGWYYFDYWGHGTLVTVSS

[0590] [Table 26]

[0591] Light chain (Sequence ID 41)

[0592] DIVMTQTPLSLPVTPGEPASISCRASKSISKYLAWYQQKPGQAPRLLIYSGSTLQSGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQQHDESPYTFGEGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0593] Light chain variable domain of UC-961 antibody (SEQ ID NO: 43)

[0594] DIVMTQTPLSLPVTPGEPASISCRASKSISKYLAWYQQKPGQAPRLLIYSGSTLQSGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQQHDESPYTFGEGTKVEIK

[0595] [Table 27]

[0596] Example 32: ROR2 antibody (Ab1) The ROR2 antibody (Ab1) is a humanized IgG1 / kappa antibody. The ROR2 antibody (Ab1) was transiently expressed in CHO-K1 cells and purified in a single step using protein A chromatography resin. The final buffer composition was 20 mM histidine, 150 mM sodium chloride, pH 5.5 (WuXi Biologics). The heavy chain and light chain sequences of the ROR2 antibody (Ab1) are shown below.

[0597] Heavy chain (SEQ ID NO: 1)

[0598] EVQLVESGGGLVKPGGSLRLSCAASGFTFSTYGVSWVRQAPGKGLEWVSTISSGGGYTHYAGSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHPRDFSYALDYWGQ GTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0599] Heavy chain variable domain of ROR2 antibody (Ab1) (SEQ ID NO: 3)

[0600] EVQLVESGGGLVKPGGSLRLSCAASGFTFSTYGVSWVRQAPGKGLEWVSTISSGGGYTHYAGSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHPRDFSYALDYWGQGTTVTVSS

[0601] [Table 28]

[0602] Light chain (Sequence ID 2)

[0603] EIVMTQSPATLSVSPGERATLSCRASQDVGHYLAWYQQKPGQAPRLLIYWASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIYPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0604] Light chain variable domain of ROR2 antibody (Ab1) (SEQ ID NO: 4)

[0605] EIVMTQSPATLSVSPGERATLSCRASQDVGHYLAWYQQKPGQAPRLLIYWASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIYPWTFGQGTKVEIK

[0606] [Table 29]

[0607] Example 33: Heavy chain sequence and light chain sequence of 5T4 antibody (Ab6) The 5T4 antibody is a human IgG1 / kappa antibody. The 5T4 antibody was transiently expressed in CHO-K1 cells and purified in a single step using protein A chromatography resin. The final buffer composition was 20 mM histidine, 150 mM sodium chloride, pH 5.5 (WuXi Biologics). The heavy chain and light chain sequences of the 5T4 antibody are shown below.

[0608] Heavy chain (SEQ ID NO: 50)

[0609] QVQLQESGPGLVKPPGTLSLTCAVSGGSISSSNWWSWVRQPPGKGLEWIGEIYHGGYTNYNPSLKSRVTISIDKSKNQFSLKLSSVTAADTAVYYCTRDMGANYFGSGNYYDVG WFDPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPI EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0610] Heavy chain variable domain of 5T4 antibody (SEQ ID NO: 52)

[0611] QVQLQESGPGLVKPPGTLSLTCAVSGGSISSSNWWSWVRQPPGKGLEWIGEIYHGGYTNYNPSLKSRVTISIDKSKNQFSLKLSSVTAADTAVYYCTRDMGANYFGSGNYYDVGWFDPWGQGTLVTVSS

[0612] [Table 30]

[0613] Light chain (Sequence ID 51)

[0614] DIQLTQSPSFLSASVGDRVTITCRASQGIRSYLAWYQQKPGKAPKVLIYEASTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQLNNYPRTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0615] 5T4 antibody light chain variable domain (SEQ ID NO: 53)

[0616] DIQLTQSPSFLSASVGDRVTITCRASQGIRSYLAWYQQKPGKAPKVLIYEASTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQLNNYPRTFGQGTKVEIK

[0617] [Table 31]

[0618] Human IgG1 constant region sequence (WT) (SEQ ID NO: 60)

[0619] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0620] Human IgG1 constant region sequence (effectorless) (SEQ ID NO: 61)

[0621] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0622] Human kappa light chain constant region sequence (SEQ ID NO: 62)

[0623] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0624] Example 34: Antibody binding and immune complex binding to ROR2-positive cells The ability of various ADC constructs to bind to the non-small cell lung cancer H1155 tumor cell line was measured using an in vitro cell binding assay. Logarithmic growth phase cells were isolated at 37°C using Acutase® (Millipre Sigma), diluted in culture medium, and recovered by centrifugation at 500xg for 3 minutes. The cells were resuspended in cold 2% FBS in RPMI (binding buffer) at a concentration of 2 × 10⁶ cells / mL. Next, the cells were seeded in 96-well v-bottom plates at 50 μL / well (100,000 cells). Antibodies were sequentially diluted fourfold for binding, starting at 240 μg / mL, and 50 μL was added to each well of cells. The cells were incubated on ice for 30 minutes. The sample was washed three times with 200 μL of 2% FBS (FACS buffer) in PBS, resuspended in 100 μL of secondary antibody (goat anti-human Fc PE, Invitrogen cat.#12-4998-82), diluted 500-fold in binding buffer, and incubated on ice (in the dark) for 30 minutes. The secondary antibody solution also contained 200-fold diluted Fixable Viability Dye eFluor® 780 (Invitrogen). The cells were washed three times with 200 μL of FACS buffer and fixed with 100 μL of 2% paraformaldehyde aqueous solution (PFA) (Electron Microscopy Sciences) at 25°C (in the dark) for 10 minutes. The cells were washed twice with 200 μL of FACS buffer, resuspended in 200 μL of 2 mM EDTA in PBS, and stored at 4°C in the dark until flow cytometry analysis. Antibody binding was quantified by measuring the median PE fluorescence intensity (MFI) from 10,000 events in viable singlet cells. Intact single cells were isolated, and the MFI was subtracted from the control sample (secondary antibody only).

[0625] ADCs conjugated to H1155 cells with EC50 similar to unconjugated humanized antibodies (Ab1, ROR2 antibodies) (Figure 17) and unconjugated chimeric antibody Ab4 (Figure 18). The ADCs tested included two different payloads (exatecan derivative and duocalmycin derivative) and four different linkers, with DARs ranging from 3.2 (ADC-12) and 3.5 (ADC-11) to 7.9-8 (ADC-10, ADC-4, ADC-5).

[0626] As shown in Figure 17, the binding EC50 values ​​of linker core 4 sulfate and (Gly-Sar)5 exatecan ADCs (ADC-4, ADC-5) are similar to those of the antibody alone (Ab1) and the GGFG linker exatecan ADC (ADC-10). Binding to the native antibody is conserved for all ADCs.

[0627] Example 35: Internalization of antibodies and immune complexes on tumor cells The internalization of parental antibodies and various ADC constructs into non-small cell lung cancer H1155 tumor cell lines was evaluated. Logarithmic growth phase cells were isolated at 37°C using Acutase® (Millipre Sigma), diluted in culture medium, and recovered by centrifugation at 500xg for 3 minutes. The cells were resuspended at 2 × 10⁶ cells / mL in cold 2% FBS in RPMI (binding buffer). Next, the cells were incubated with 30 μg / mL of antibody on ice for 30 minutes. Unbound antibody was removed by washing three times with 2% ice-cold FBS in PBS (FACS buffer). After the final wash, the cells were resuspended in 1 mL of ice-cold binding buffer, and 100 μL (200,000 cells) was divided equally at each point in the internalization time. The samples were incubated in a water bath at 37°C for the specified time. To complete internalization, the cells were transferred to ice. Next, cells were collected by centrifugation at 500xg at 4°C for 3 minutes, the supernatant was aspirated, and the cells were resuspended in 100 μL of secondary antibody (goat anti-human Fc PE, Invitrogen cat.#12-4998-82) diluted 500-fold with binding buffer, and incubated on ice for 30 minutes. The secondary antibody solution also contained 200-fold diluted Fixable Viability Dye eFluor® 780 (Invitrogen). The samples were washed three times with 200 μL of ice-cold FACS buffer and fixed with 100 μL of 2% paraformaldehyde aqueous solution (PFA) (Electron Microscopy Sciences) at 25°C (in the dark) for 10 minutes. The cells were washed twice with 200 μL of FACS buffer, resuspended in 200 μL of 2 mM EDTA in PBS, and stored at 4°C in the dark until flow cytometry analysis. Antibody binding was quantified by measuring the median PE fluorescence intensity (MFI) from 10,000 events in viable singlet cells. Binding signals obtained from cells incubated on ice for the entire duration (time 0) were defined as 100% surface binding, and internalization was quantified by measuring the loss of binding signal over time (MFI) after incubation at 37°C.

[0628] The ADCs internalized at a similar rate and to a similar degree as the non-conjugate humanized antibodies (Ab1, ROR2 antibodies) (Figure 19A) and the non-conjugate chimeric antibody Ab4 (Figure 19B). The ADCs tested included two different payloads (exatecan derivative and duocalmycin derivative) and four different linkers, with DARs ranging from 3.2 (ADC-12) and 3.5 (ADC-11) to 7.9-8 (ADC-10, ADC-4, ADC-5).

[0629] Example 36: Preparation of antibody-drug conjugate (ADC)-10 using deruxtecan and ROR2 antibody ADC-10 was prepared using Example 11, deruxtecan, and ROR2 antibody (Ab1).

[0630] [ka] The DAR value determined by RP-HPLC was 7.9. The sequences of the heavy and light chain regions of the ROR2 antibody are shown in Example 32 (e.g., SEQ ID NO: 3 and SEQ ID NO: 4, respectively).

[0631] Example 37: Production of ROR2 antibody-drug conjugate (ADC) Multiple ROR2 antibody ADCs were synthesized and characterized. Two different versions of the mouse ROR2 antibody 6E6 were used: Ab4 (effectorless chimeric 6E6) and Ab1 (effectorless humanized 6E6, version 1). In addition, two different payloads (exatecan and duocalmycin derivatives) and four different linkers were used. All linkers were cleavable, and all conjugations were performed using maleimide chemistry to generate ADCs with DARs of 3–4 or 7.9–8.

[0632] [Table 32]

[0633] In the table above, the abbreviations used are valine-citrulline (VC), valine-alanine (VA), and glycine-glycine-phenylalanine-glycine (GGFG).

[0634] The following basic protocol was used for conjugation. First, the pH of 50 mg of antibody in various formulations was adjusted to a final pH of 7-8 using 0.5 M Tris, 0.025 M EDTA, pH 8.5. 0.025 M EDTA was added to the formulation buffer to prevent metal-catalyzed disulfide reoxidation. To achieve a DAR of approximately 8, 7 equivalents (eq) of tris(2-carboxyethyl)phosphine (TCEP, 10 mM) were added to the antibody and incubated at 25°C for 90 minutes. Next, 12 eq of 20 mM maleimide (MC) containing a linker payload in 10% N,N-dimethylacetamide (DMA) were added and incubated at 25°C for 60 minutes. To achieve a DAR of approximately 3-4, 2-2.5 eq of tris(2-carboxyethyl)phosphine (TCEP, 10 mM) were added to the antibody and incubated at 25°C for 90 minutes. Next, 8 eq of 20 mM linker payload in 10% N,N-dimethylacetamide (DMA) were added at 25°C for 60 minutes. Additional solvent was added to the reductive antibody before adding the linker payload (the final solvent concentration after toxin addition was 10% v / v) to maintain the solubility of the linker payload, and mixing was carried out using a stirring flask. Conjugation was terminated by adding an additional 10 mM N-acetylcysteine ​​(NAC) to quench the unreacted maleimide, and the mixture was stirred at 25°C for a further 30 minutes. Next, the ADC was incubated with activated carbon on a roller mixer at 15 rpm at 25°C for 60 minutes. Then, the carbon was pelletized by centrifugation at 4,000 x g for 10 minutes. The conjugate (yield 93-97%) was replaced with final formulation buffer (PBS containing 0.1M arginine, pH 7.4), filtered through a 0.22 μm polyethersulfone (PES) membrane, and stored at -60°C or below.

[0635] The drug-to-antibody ratio (DAR) of each ADC was determined using RP-HPLC (Table 3). The HPLC conditions used to determine the DAR were as follows: Column: Phenomenex Kinetex 100 Å, 50 × 4.6 mm, 2.6 μm, part number: PL1912-1502. MPA - 0.1% TFA / H2O, MPB - 0.1% TFA / CAN. Method: Flow rate - 1 mL / min, gradient - see Table 3. Column temperature - 50 °C. Sample temperature - room temperature. DAD 214 nm, BW 16 nm; CORPORATION 440 nm, BW 80 nm; Peak width > 0.4 min (response time 8 seconds (0.62 Hz)); Spectrum: 200~600 nm, step 1.2 nm, slit 8 nm. Sample - neat injection, approximately 5 μg.

[0636] array The sequences described in this disclosure are listed in Table S below.

[0637] [Table 33-1]

[0638] [Table 33-2]

[0639] [Table 33-3]

[0640] [Table 33-4]

[0641] [Table 33-5]

[0642] [Table 33-6]

[0643] [Table 33-7]

[0644] [Table 33-8]

[0645] Embodiment The following embodiments are not intended to be limiting in any way. 1. A conjugate of any one of the following: formula (C), formula (XX), formula (A), or formula (A-1). 2. The conjugate has the structure shown in Table H, Table HH, Table II, and Table I, and in the formula L is selected from the antibody or antigen binding moiety, one of the conjugates of formula (C), formula (XX), formula (A), or formula (A-1). 3. The antibody or antigen-binding portion, in binding to human ROR2, a) Sequence numbers 1 and 2 respectively, b) Sequence numbers 11 and 2, respectively c) Sequence numbers 15 and 16, respectively, or d) Sequence IDs 21 and 16, respectively A conjugate according to any one of claims 1 to 2, which competes with, cross-competes with, or binds to the same human ROR2 epitope as an antibody comprising a heavy chain (HC) and a light chain (LC). 4. The antibody or antigen binding portion is a) Sequence numbers 5, 6, 7, 8, 9, and 10, respectively b) Sequence numbers 13, 6, 14, 8, 9, and 10, respectively, or c) Sequence numbers 19, 6, 20, 8, 9, and 10 respectively A conjugate according to any one of claims 1 to 3, comprising the heavy chain complementarity determining region (CDR) 1-3 (HCDR1-3) amino acid sequence and the light chain CDR1-3 (LCDR1-3) amino acid sequence. 5. The antibody or antigen binding portion is HCDR1 containing amino acid sequence TY, HCDR2 containing sequence number 27, HCDR2 containing sequence number 24, LCDR1 containing the amino acid sequence GHY, LCDR2 containing sequence number 9, and LCDR3 containing sequence number 28 A conjugate according to any one of claims 1 to 4, including the conjugate described in any one of claims 1 to 4. 6. The antibody or antigen binding portion is a) Sequence numbers 3 and 4 respectively, b) Sequence IDs 12 and 4, respectively, or c) Sequence numbers 17 and 18 respectively A conjugate according to any one of claims 1 to 5, comprising a heavy chain variable domain (VH) amino acid sequence and a light chain variable domain (VL) amino acid sequence. 7. The conjugate according to any one of claims 1 to 6, wherein the antibody is an antibody of isotype IgG. 8. The conjugate according to any one of claims 1 to 7, wherein the antibody is an antibody of isotype subclass IgG1, IgG2, IgG3, or IgG4. 9. The conjugate according to any one of claims 1 to 8, wherein the Fc region of the antibody contains one or more mutations that reduce effector function. 10. Antibodies, a) Sequence numbers 1 and 2 respectively, b) Sequence numbers 11 and 2, respectively c) Sequence numbers 15 and 16, respectively, or d) Sequence IDs 21 and 16, respectively A conjugate according to any one of claims 1 to 6, comprising an HC amino acid sequence and an LC amino acid sequence, wherein optionally the HC amino acid sequence lacks a C-terminal lysine. 11. The conjugate according to any one of claims 1 to 6, wherein the antigen-binding portion is Fab, F(ab)2, or scFv. 12. A pharmaceutical composition comprising a conjugate according to any one of claims 1 to 11 and a pharmaceutically acceptable excipient. 13. The pharmaceutical composition according to claim 12, further comprising an additional therapeutic agent selected from the group consisting of immunomodulators, chemotherapeutic agents, antineoplastic agents, or anti-angiogenic agents. 14. A method for treating cancer in a human patient requiring treatment for cancer, comprising the step of administering to the patient a therapeutically effective dose of the conjugate described in any one of claims 1 to 11. 15. The method according to claim 14, wherein the cancer expresses ROR2. 16. The method according to claim 14, wherein the cancer is selected from the group consisting of head and neck cancer, non-small cell lung cancer, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, breast cancer, endometrial cancer, ovarian cancer, soft tissue sarcoma, bladder cancer, prostate cancer, kidney cancer, and melanoma. 17. The method according to claim 14 or 15, further comprising the step of administering an additional therapeutic agent to the patient. 18. The method according to claim 17, wherein the additional therapeutic agent is selected from the group consisting of immunomodulators, chemotherapeutic agents, antineoplastic agents, anti-angiogenic agents, or tumor vaccines. 19. A conjugate according to any one of claims 1 to 11, or a pharmaceutical composition according to claim 12 or 13, for use in treating cancer by the method according to any one of claims 14 to 18. 20. Use of a conjugate according to any one of claims 1 to 11, or a pharmaceutical composition according to claim 12 or 13, in the manufacture of a drug for treating cancer by the method according to any one of claims 14 to 18. 21. A method for creating a conjugate, A step to obtain an antibody or its antigen-binding moiety that specifically binds to human receptor tyrosine kinase-like orphan receptor 2 (ROR2), The process includes conjugating an antibody or antigen-binding moiety with a cytotoxic drug moiety selected from the group consisting of a tubulin-destroying agent, a topoisomerase inhibitor, a DNA minor groove binder, and a DNA alkylating agent, as well as pharmaceutically acceptable salts, esters, and analogs thereof. A method wherein the antibody or antigen-binding moiety is as defined in any one of claims 3 to 11.

Claims

1. Formula (X) 【Chemistry 1】 A drug linker or a pharmaceutically acceptable salt thereof, wherein the formula, D is a drug unit, Y １ It does not exist, or -O-T １ and -NH-T ２ Selected from, T １ This is a sugar-cleavable unit, T ２ This is a peptide-cleaving unit, S １ is (i) optionally substituted C １ -C ３０ alkylene, one or more of whose alkylene units are optionally and independently -N(R ２０ ), -N(R ２０ )C(O)-, -C(O)N(R ２０ ), -N(R<00000​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ S ２ C is replaced by an optional substitution. １ -C ３０ An alkylene in which one or more alkylene units are optionally and independently -N(R) ２０ )-,-N(R ２０ )C(O)-, -C(O)N(R ２０ )-,-N(R ２０ ) S(O) ２ -, -S(O) ２ N(R) ２０ )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O) ２ -, a 5-6 member complex ring, or -P(O)(R ２０ ) ２ C, which is replaced by -, is replaced by an optional substitution. １ -C ３０ Selected from alkylenes, S ３ It is selected from the spacers, and at this time, S ３ Does it exist or does it not exist? M １ _K １ S １ S ２ , and S ３ Each of the above optional substituents, independently, (i)ハロゲン、-OR ３０ 、-N(R ３０ ) ２ 、-SR ３０ 、-N(R ３０ ) ２ 、-C(O)R ３０ 、-C(O)N(R ３０ ) ２ 、-N(R ３０ )C(O)R ３０ 、-C(O)OR ３０ 、-OC(O)R ３０ 、-S(O)R ３０ 、-S(O) ２ R ３０ 、-O-S(O) ２ OR ３０ 、-P(O)(OR ３０ ) ２ 、-OP(O)(OR ３０ ) ２ 、-NO ２ 、=O、=S、=N(R ３０ )、および-CN、 (ii) C １－１０ alkyl, C ２－１０ alkenyl, C ２－１０ alkynyl (each of these is independently selected from halogen, -OR ３０ , -SR ３０ , -N(R ３０ ), -C(O)R ２ , -C(O)N(R ３０ ), -N(R ３０ ), -C(O)R ２ , -N(R ３０ ), -C(O)OR ３０ , -OC(O)R ３０ , -S(O)R ３０ , -S(O) ３０ R ２ , -O-S(O) ３０ , -O-S(O) ２ OR ３０ , -P(O)(OR ３０ ))<00001-03> ２ , -OP(O)(OR ３０ )) ２ ２ , -NO ２ , =O, =S, =N(R ３０ ), -CN, C ３－１０ carbocyclic ring, and optionally substituted with one or more substituents independently selected from 3- to 10-membered heterocyclic rings), and (iii) C ３－１０ Carbon rings and 3- to 10-membered heterocycles (each of these being halogens, -OR) ３０ , -SR ３０ , -N(R ３０ ) ２ , -C(O)R ３０ , -C(O)N(R ３０ ) ２ , -N(R ３０ ) C(O)R ３０ , -C(O)OR ３０ , -OC(O)R ３０ , -S(O)R ３０ , -S(O) ２ R ３０ , -P(O)(OR ３０ ) ２ , -OP(O)(OR ３０ ) ２ , -NO ２ , =O, =S, =N(R ３０ ), -CN, C １－６ Alkyl, C ２－６ Alkenyl and C ２－６ (Optionally substituted with one or more substituents independently selected from the alkynyl molecule.) Selected from, M １ This is a group that can react with a ligand to form a connector unit. K １ teeth, (i) Peptide unit, (ii) Oligosaccharides, and (iii) Polyether Selected from, R ２０ These are, independently, hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１２ Carbon rings and 3- to 12-membered heterocycles (each of which is a halogen, -OH, -CN, -NO) ２ , -NH ２ , -N(C １－６ Alkyl) ２ , C １－１０ Alkyl, -C １－１０ Haloalkyl, -O-C １－１０ Alkyl, oxo, C ３－１２ Selected from a carbon ring and one or more substituents independently selected from 3- to 12-membered heterocycles, R ３０ These are, independently, hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１２ Carbon rings and 3- to 12-membered heterocycles (each of which is a halogen, -OH, -CN, -NO) ２ , -NH ２ , -N(C １－６ Alkyl) ２ , C １－１０ Alkyl, -C １－１０ Haloalkyl, -O-C １－１０ Alkyl, oxo, C ３－１２ A drug linker, or a pharmaceutically acceptable salt thereof, selected from a carbon ring and a heterocycle of 3 to 12 members (optionally substituted with one or more substituents independently selected from these heterocycles).

2. Equation (X) is, 【Chemistry 2】 The drug linker according to claim 1, or represented by a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

3. S １ C replaced by the aforementioned optional selection １ -C ３０ A drug linker according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the alkylene is linear.

4. S １ However, (i) C replaced by arbitrary choice １ -C ３０ An alkylene in which one or more alkylene units are optionally and independently substituted with -N(H)C(O)-, an optionally substituted C １ -C ３０ A drug linker according to any one of claims 1 to 3, selected from alkylenes, or a pharmaceutically acceptable salt thereof.

5. S １ is -NH-C(O)-C １－ C ６ Alkylene-NH-C(O)-C １－ C ６ Alkylene-NH-C(O)-C １－ C ６ A drug linker according to any one of claims 1 to 4, selected from alkylenes, or a pharmaceutically acceptable salt thereof.

6. S １ is -NH-C(O)-C １－ C ６ Alkylene-NH-C(O)-C １－ C ６ Alkylene-NH-C(O)-C １－ C ６ Selected from alkylene, S ２ A drug linker according to any one of claims 1 to 5, wherein one of the alkylenes is bonded to the drug linker, or a pharmaceutically acceptable salt thereof.

7. S １ -S ２ -K １ but, 【Transformation 3】 A drug linker according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. S ２ However, C was replaced by an arbitrary choice. １ -C ３０ An alkylene in which one or more alkylene units are optionally and independently substituted with -C(O)-, an optionally substituted C １ -C ３０ A drug linker according to any one of claims 1 to 7, selected from alkylenes, or a pharmaceutically acceptable salt thereof.

9. S ２ However, C was replaced by an arbitrary choice. １ -C ６ An alkylene in which one or more alkylene units are optionally and independently substituted with -C(O)-, an optionally substituted C １ -C ６ A drug linker according to any one of claims 1 to 8, selected from alkylenes, or a pharmaceutically acceptable salt thereof.

10. S ２ but, 【Chemistry 4】 A drug linker according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. S １ -S ２ -K １ but, 【Transformation 5】 A drug linker according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. Equation (X) or Equation (I) is Equation (I-A) 【Transformation 6】 A drug linker according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, represented by a pharmaceutically acceptable salt thereof.

13. T １ A drug linker according to any one of claims 1 to 12, wherein the sugar-cleaving unit comprises a sugar, or a pharmaceutically acceptable salt thereof.

14. A drug linker according to any one of claims 1 to 13, wherein the sugar is a glucuronide, or a pharmaceutically acceptable salt thereof.

15. Y １ but, 【Transformation 7】 A drug linker according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

16. T ２ The drug linker according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein the peptide unit comprises one or more amino acids selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-alanine.

17. T ２ The drug linker according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein the peptide unit comprises a dipeptide or a tripeptide.

18. T ２ A drug linker according to any one of claims 1 to 15, wherein the peptide unit comprises a dipeptide, or a pharmaceutically acceptable salt thereof.

19. A drug linker according to any one of claims 1 to 15, wherein the dipeptide is selected from Val-Cit, Val-Ala, and Phe-Lys, or a pharmaceutically acceptable salt thereof.

20. T ２ A drug linker according to any one of claims 1 to 12 or 16 to 19, wherein the peptide unit comprises a capping portion, or a pharmaceutically acceptable salt thereof.

21. The aforementioned capping portion, 【Transformation 8】 The drug linker according to claim 20, or a pharmaceutically acceptable salt thereof.

22. Y １ but, 【Chemistry 9】 A drug linker according to any one of claims 1 to 12 or 16 to 20, or a pharmaceutically acceptable salt thereof.

23. Y １ A drug linker according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein the linker is absent.

24. K １ A drug linker according to any one of claims 1 to 23, wherein each of the units is selected from peptide units, or a pharmaceutically acceptable salt thereof.

25. The drug linker according to claim 24, or a pharmaceutically acceptable salt thereof, wherein the peptide unit has 1 to 50 amino acids.

26. K １ The drug linker according to claim 25, or a pharmaceutically acceptable salt thereof, wherein the amino acid is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-alanine.

27. K １ The drug linker according to claim 26, or a pharmaceutically acceptable salt thereof, wherein the amino acid is selected from the group consisting of glycine, sarcosine, proline, serine, alanine, and β-alanine.

28. K １ A drug linker according to any one of claims 1 to 27, wherein the peptide unit has a terminal unit, or a pharmaceutically acceptable salt thereof.

29. K １ but, 【Chemistry 10】 Selected from, where the terminal unit is R ６ A drug linker according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, represented by, where j is selected from 1 to 30.

30. R ６ However, -OR ７ and -NHR ７ Selected from, R ７ However, hydrogen, C １－１０ Alkyl, C ２－１０ Alkenil, C ２－１０ Alkinyl (each of these is a halogen, -OR ３０ , -SR ３０ , -N(R ３０ ) ２ , -C(O)R ３０ , -C(O)N(R ３０ ) ２ , -N(R ３０ ) C(O)R ３０ , -C(O)OR ３０ , -OC(O)R ３０ , -S(O)R ３０ , -S(O) ２ R ３０ , -O-S(O) ２ OR ３０ , -P(O)(OR ３０ ) ２ , -OP(O)(OR ３０ ) ２ , -NO ２ , =O, =S, =N(R ３０ ), -CN, C ３－１０ A drug linker according to claim 29, or a pharmaceutically acceptable salt thereof, selected from a carbon ring and optionally substituted with one or more substituents independently selected from a 3- to 10-membered heterocycle.

31. R ６ However, -OH, -NH ２ , and 【Chemistry 11】 A drug linker according to claim 29 or 30, or a pharmaceutically acceptable salt thereof, selected from the above.

32. K １ but, 【Chemistry 12】 【Chemistry 13】 A drug linker according to any one of claims 1 to 31, selected from the above, or a pharmaceutically acceptable salt thereof.

33. K １ A drug linker according to any one of claims 1 to 23, wherein is selected from oligosaccharides, or a pharmaceutically acceptable salt thereof.

34. K １ but, 【Chemistry 14】 A drug linker according to any one of claims 1 to 23 or 33, wherein k is selected from, in the formula, k is selected from 2 to 10, or a pharmaceutically acceptable salt thereof.

35. K １ However, each 【Chemistry 15】 A drug linker according to claim 34, or a pharmaceutically acceptable salt thereof, selected from the above.

36. M １ However, maleimide, halogen, COOH, 【Chemistry 16】 Azide, -C≡CH, activated C≡C group, 【Chemistry 17】 OH, SH, activated disulfide group, NH ２ , and -ONH ２ A drug linker according to any one of claims 1 to 35, selected from the above, or a pharmaceutically acceptable salt thereof.

37. The activated C≡C group, [Chemistry 18] A drug linker according to claim 36, or a pharmaceutically acceptable salt thereof, selected from the above.

38. The activated disulfide group is 【Chemistry 19】 A drug linker according to claim 36, or a pharmaceutically acceptable salt thereof, selected from the above.

39. A drug linker according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein the drug unit is selected from cytotoxic agents, immunomodulators, nucleic acids, growth inhibitors, PROTACs, toxins, radioisotopes, and chelating ligands.

40. The drug linker according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein the drug unit is selected from a cytotoxic agent, a camptothecin derivative, and an immunomodulator.

41. The drug linker according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein the drug unit is selected from exatecan, SN-38, and monomethyl auristatin E (MMAE).

42. A drug linker according to any one of claims 1 to 41, wherein the drug unit is exatecan, or a pharmaceutically acceptable salt thereof.

43. A conjugate comprising a drug linker according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, and a targeting unit, wherein the M of the drug linker １ A conjugate that reacts to form a covalent bond with the targeting unit.

44. The conjugate according to claim 43, wherein the targeting unit is selected from an antibody or its antigen-binding portion.

45. The conjugate according to claim 43 or 44, wherein the average ratio of drug linkers to targeting units is approximately 1 to 10.

46. A pharmaceutical composition comprising a conjugate according to any one of claims 43 to 45 and a pharmaceutically acceptable excipient.

47. A method for treating a subject suffering from cancer, comprising the step of administering to the subject requiring treatment a conjugate according to any one of claims 43 to 45 or a pharmaceutical composition according to claim 46.

48. Formula (XX) 【Chemistry 20】 A conjugate of or a pharmaceutically acceptable salt thereof, wherein the formula is D is a drug unit, Y １ It does not exist, or -O-T １ and -NH-T ２ Selected from, T １ It is a glucose-cleaving unit, T ２ This is a peptide-cleaving unit, L is the targeting unit, S １ (i) C replaced by any choice １ -C ３０ An alkylene in which one or more alkylene units are optionally and independently -N(R) ２０ )-,-N(R ２０ )C(O)-, -C(O)N(R ２０ )-,-N(R ２０ ) S(O) ２ -, -S(O) ２ N(R) ２０ )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O) ２ -, a 5-6 member complex ring, or -P(O)(R ２０ ) ２ C, which is replaced by -, is replaced by an optional substitution. １ -C ３０ Alkylene, (ii) C replaced by any choice ３ -C ３０ An alkenylene wherein one or more alkenylene units are optionally and independently -N(R) ２０ )-,-N(R ２０ )C(O)-, -C(O)N(R ２０ )-,-N(R ２０ ) S(O) ２ -, -S(O) ２ N(R) ２０ )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O) ２ -, or -P(O)(R ２０ ) ２ The optionally replaced C is replaced by ３ -C ３０ alkenylene, (iii) one or more amino acids, (iv) one or more N-substituted amino acids, (v) optionally substituted polyether, (vi) optionally substituted C ３ -C １０ Carbocyclene, (vii) Selected from 5-10 member heterocyclenes that have been optionally substituted, S ２ C is replaced by an optional substitution. １ -C ３０ An alkylene in which one or more alkylene units are optionally and independently -N(R) ２０ )-,-N(R ２０ )C(O)-, -C(O)N(R ２０ )-,-N(R ２０ ) S(O) ２ -, -S(O) ２ N(R) ２０ )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O) ２ -, a 5-6 member complex ring, or -P(O)(R ２０ ) ２ C, which is replaced by -, is replaced by an optional substitution. １ -C ３０ Selected from alkylenes, S ３ It is selected from the spacers, and at this time, S ３ Does it exist or does it not exist? M ２ _K １ S １ S ２ , and S ３ Each of the above optional substituents, independently, (i)ハロゲン、-OR ３０ 、-N(R ３０ ) ２ 、-SR ３０ 、-N(R ３０ ) ２ 、-C(O)R ３０ 、-C(O)N(R ３０ ) ２ 、-N(R ３０ )C(O)R ３０ 、-C(O)OR ３０ 、-OC(O)R ３０ 、-S(O)R ３０ 、-S(O) ２ R ３０ 、-O-S(O) ２ OR ３０ 、-P(O)(OR ３０ ) ２ 、-OP(O)(OR ３０ ) ２ 、-NO ２ 、=O、=S、=N(R ３０ )、および-CN、 (ii) C １－１０ Alkyl, C ２－１０ Alkenil, C ２－１０ Alkinyl (each of these is a halogen, -OR ３０ , -SR ３０ , -N(R ３０ ) ２ , -C(O)R ３０ , -C(O)N(R ３０ ) ２ , -N(R ３０ ) C(O)R ３０ , -C(O)OR ３０ , -OC(O)R ３０ , -S(O)R ３０ , -S(O) ２ R ３０ , -O-S(O) ２ OR ３０ , -P(O)(OR ３０ ) ２ , -OP(O)(OR ３０ ) ２ , -NO ２ , =O, =S, =N(R ３０ ), -CN, C ３－１０ (Optionally substituted with one or more substituents independently selected from a carbon ring and a 3- to 10-membered heterocycle), (iii) C ３－１０ Carbon rings and 3- to 10-membered heterocycles (each of these being halogens, -OR) ３０ , -SR ３０ , -N(R ３０ ) ２ , -C(O)R ３０ , -C(O)N(R ３０ ) ２ , -N(R ３０ ) C(O)R ３０ , -C(O)OR ３０ , -OC(O)R ３０ , -S(O)R ３０ , -S(O) ２ R ３０ , -P(O)(OR ３０ ) ２ , -OP(O)(OR ３０ ) ２ , -NO ２ , =O, =S, =N(R ３０ ), -CN, C １－６ Alkyl, C ２－６ Alkenyl and C ２－６ (Optionally substituted with one or more substituents independently selected from the alkynyl molecule.) Selected from, M ２ This is a connector unit, K １ teeth, (i) Peptide unit, (ii) Oligosaccharides, and (iii) Polyether Selected from, R ２０ These are, independently, hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１２ Carbon rings and 3- to 12-membered heterocycles (each of which is a halogen, -OH, -CN, -NO) ２ , -NH ２ , -N(C １－６ Alkyl) ２ , C １－１０ Alkyl, -C １－１０ Haloalkyl, -O-C １－１０ Alkyl, oxo, C ３－１２ Selected from a carbon ring and one or more substituents independently selected from 3- to 12-membered heterocycles, R ３０ These are, independently, hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１２ Carbon rings and 3- to 12-membered heterocycles (each of which is a halogen, -OH, -CN, -NO) ２ , -NH ２ , -N(C １－６ Alkyl) ２ , C １－１０ Alkyl, -C １－１０ Haloalkyl, -O-C １－１０ Alkyl, oxo, C ３－１２ A conjugate, or a pharmaceutically acceptable salt thereof, selected from a carbon ring and a heterocycle of 3 to 12 members (optionally substituted with one or more substituents independently selected from these).

49. The formula (XX) is, 【Chemistry 21】 The conjugate according to claim 48, or a pharmaceutically acceptable salt thereof, represented by a pharmaceutically acceptable salt thereof.

50. S １ However, (i) C replaced by arbitrary choice １ -C ３０ An alkylene in which one or more alkylene units are optionally and independently substituted with -N(H)C(O)-, an optionally substituted C １ -C ３０ A conjugate according to claim 49, selected from alkylenes, or a pharmaceutically acceptable salt thereof.

51. S １ is -NH-C(O)-C １ -C ６ Alkylene-NH-C(O)-C １ -C ６ Alkylene-NH-C(O)-C １ -C ６ A conjugate according to any one of claims 48 to 50, selected from alkylene, or a pharmaceutically acceptable salt thereof.

52. S １ is -NH-C(O)-C １ -C ６ Alkylene-NH-C(O)-C １ -C ６ Alkylene-NH-C(O)-C １ -C ６ Selected from alkylene, S ２ A conjugate according to any one of claims 48 to 51, or a pharmaceutically acceptable salt thereof, wherein one of the alkylenes is bonded.

53. S １ -S ２ -K １ but, 【Chemistry 22】 A conjugate according to any one of claims 48 to 52, selected from, or a pharmaceutically acceptable salt thereof.

54. S ２ However, C was replaced by an arbitrary choice. １ -C ３０ An alkylene in which one or more alkylene units are optionally and independently substituted with -C(O)-, an optionally substituted C １ -C ３０ A conjugate according to any one of claims 48 to 53, selected from alkylenes, or a pharmaceutically acceptable salt thereof.

55. S ２ However, C was replaced by an arbitrary choice. １ -C ６ An alkylene in which one or more alkylene units are optionally and independently substituted with -C(O)-, an optionally substituted C １ -C ６ A conjugate according to any one of claims 48 to 54, selected from alkylenes, or a pharmaceutically acceptable salt thereof.

56. S ２ but, 【Chemistry 23】 The conjugate according to any one of claims 48 to 55, or a pharmaceutically acceptable salt thereof.

57. S １ -S ２ -K １ but, 【Chemistry 24】 The conjugate according to any one of claims 48 to 56, or a pharmaceutically acceptable salt thereof.

58. Equation (A) is, 【Chemistry 25】 The conjugate according to claim 49, or a pharmaceutically acceptable salt thereof, represented by a pharmaceutically acceptable salt thereof.

59. T １ The conjugate according to any one of claims 48 to 58, wherein the sugar-cleaving unit comprises a sugar, or a pharmaceutically acceptable salt thereof.

60. A conjugate according to any one of claims 48 to 59, wherein the sugar is a glucuronide, or a pharmaceutically acceptable salt thereof.

61. Y １ but, 【Chemistry 26】 The conjugate according to any one of claims 48 to 60, or a pharmaceutically acceptable salt thereof.

62. T ２ The conjugate according to any one of claims 48 to 61, or a pharmaceutically acceptable salt thereof, wherein the peptide unit comprises one or more amino acids selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-alanine.

63. T ２ The conjugate according to any one of claims 48 to 62, or a pharmaceutically acceptable salt thereof, wherein the peptide unit comprises a dipeptide or a tripeptide.

64. T ２ The conjugate according to any one of claims 48 to 58 or 62 to 63, wherein the peptide unit comprises a dipeptide, or a pharmaceutically acceptable salt thereof.

65. A conjugate according to any one of claims 48-58 or 62-64, wherein the dipeptide is selected from Val-Cit, Val-Ala, and Phe-Lys, or a pharmaceutically acceptable salt thereof.

66. T ２ The conjugate according to any one of claims 48 to 58 or 62 to 65, wherein the peptide unit comprises a capping portion, or a pharmaceutically acceptable salt thereof.

67. The aforementioned capping portion, 【Chemistry 27】 The conjugate according to claim 66, or a pharmaceutically acceptable salt thereof.

68. Y １ but, 【Chemistry 28】 The conjugate according to any one of claims 48 to 58 or 62 to 67, or a pharmaceutically acceptable salt thereof.

69. Y １ A conjugate according to any one of claims 48 or 50-59, or a pharmaceutically acceptable salt thereof, wherein the conjugate is not present.

70. K １ A conjugate according to any one of claims 48 to 69, wherein each of the units is selected from the peptide units, or a pharmaceutically acceptable salt thereof.

71. K １ The conjugate according to claim 70, or a pharmaceutically acceptable salt thereof, wherein the peptide unit has 1 to 50 amino acids.

72. K １ The conjugate according to claim 71, or a pharmaceutically acceptable salt thereof, wherein the aforementioned amino acid is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-alanine.

73. K １ The conjugate according to claim 72, or a pharmaceutically acceptable salt thereof, wherein the aforementioned amino acid is selected from the group consisting of glycine, sarcosine, proline, serine, and β-alanine.

74. K １ The conjugate according to any one of claims 48 to 73, or a pharmaceutically acceptable salt thereof, wherein the peptide unit has a terminal unit.

75. K １ but, 【Chemistry 29】 Selected from, where the terminal unit is R ６ A conjugate according to any one of claims 48 to 74, or a pharmaceutically acceptable salt thereof, represented by, where j is selected from 1 to 30.

76. R ６ However, -OR ７ and -NHR ７ Selected from, R ７ However, hydrogen, C １－１０ Alkyl, C ２－１０ Alkenil, C ２－１０ Alkinyl (each of these is a halogen, -OR ３０ , -SR ３０ , -N(R ３０ ) ２ , -C(O)R ３０ , -C(O)N(R ３０ ) ２ , -N(R ３０ ) C(O)R ３０ , -C(O)OR ３０ , -OC(O)R ３０ , -S(O)R ３０ , -S(O) ２ R ３０ , -O-S(O) ２ OR ３０ , -P(O)(OR ３０ ) ２ , -OP(O)(OR ３０ ) ２ , -NO ２ , =O, =S, =N(R ３０ ), -CN, C ３－１０ The conjugate according to claim 75, or a pharmaceutically acceptable salt thereof, selected from a carbon ring and optionally substituted with one or more substituents independently selected from a 3- to 10-membered heterocycle.

77. R ６ However, -OH, -NH ２ , and 【Transformation 30】 A conjugate according to claim 75 or 76, or a pharmaceutically acceptable salt thereof, selected from the above.

78. K １ but, 【Chemistry 31】 【Chemistry 32】 A conjugate according to any one of claims 48 to 77, selected from, or a pharmaceutically acceptable salt thereof.

79. K １ but, 【Transformation 33】 A conjugate according to any one of claims 48 to 77, selected from, or a pharmaceutically acceptable salt thereof.

80. K １ A conjugate according to any one of claims 48 to 69, wherein each of the oligosaccharides is selected from oligosaccharides, or a pharmaceutically acceptable salt thereof.

81. K １ However, each 【Transformation 34】 A conjugate according to any one of claims 48 to 69 or 79, wherein k is selected from, in the formula, k is selected from 2 to 10, or a pharmaceutically acceptable salt thereof.

82. K １ However, each 【Chemistry 35】 A conjugate according to claim 80, or a pharmaceutically acceptable salt thereof, selected from the above.

83. M ２ but, 【Transformation 36】 A conjugate according to any one of claims 48 to 81, selected from, or a pharmaceutically acceptable salt thereof.

84. M ２ but, 【Chemistry 37】 The conjugate according to any one of claims 48 to 82, or a pharmaceutically acceptable salt thereof.

85. The aforementioned conjugate, 【Transformation 38】 Selected from, where L is the targeting unit and DAR is the ratio of the drug to the targeting unit, 【Chemistry 39】 【Chemistry 40】 The conjugate according to claim 48 or 49, or a pharmaceutically acceptable salt thereof.

86. The aforementioned conjugate, 【Chemistry 41】 A conjugate according to claim 85, or a pharmaceutically acceptable salt thereof, selected from the above.

87. The conjugate according to any one of claims 48 to 86, or a pharmaceutically acceptable salt thereof, wherein the targeting unit is selected from an antibody or its antigen-binding moiety.

88. The conjugate according to any one of claims 48 to 87, or a pharmaceutically acceptable salt thereof, wherein the targeting unit is a monoclonal antibody.

89. A conjugate according to any one of claims 48 to 88, or a pharmaceutically acceptable salt thereof, wherein the mean ratio (DAR) of drug linker to targeting unit is about 1 to about 10.

90. A conjugate according to any one of claims 48 to 88, or a pharmaceutically acceptable salt thereof, wherein the mean ratio (DAR) of drug linker to targeting unit is about 2 to about 8.

91. A conjugate according to any one of claims 48 to 88, or a pharmaceutically acceptable salt thereof, wherein the mean ratio (DAR) of drug linker to targeting unit is approximately 8.

92. A pharmaceutical composition comprising a conjugate according to any one of claims 48 to 91 and a pharmaceutically acceptable excipient.

93. A method for treating a subject suffering from a disease or disorder, comprising the step of administering to the subject requiring treatment a conjugate according to any one of claims 48 to 91 or a pharmaceutical composition according to claim 92.

94. A method for treating a subject suffering from cancer, comprising the step of administering to the subject requiring treatment a conjugate according to any one of claims 48 to 91 or a pharmaceutical composition according to claim 92.

95. A method for treating a subject suffering from a tumor, comprising the step of administering to the subject requiring treatment a conjugate according to any one of claims 48 to 91 or a pharmaceutical composition according to claim 92.

96. The method according to claim 95, wherein the tumor is associated with cancer.

97. Use of a conjugate for treating a subject suffering from a disease or disorder, comprising administering to the subject requiring treatment the conjugate according to any one of claims 48 to 91 or the pharmaceutical composition according to claim 92.

98. The use according to claim 97, wherein the disease or disorder is cancer.

99. The aforementioned cancers include head and neck cancers, including tumors of the head, neck, nasal cavity, sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, salivary glands, and paragangliomas; liver and gallbladder cancers (specifically hepatocellular carcinoma); intestinal cancers (specifically colorectal cancer); ovarian cancers; small cell lung cancers and non-small cell lung cancers (SCLC and NSCLC); breast carcinosarcomas (fibrosarcoma, malignant fibrous histiocytoma, embryonic rhabdomyosarcoma, leiomyosarcoma, neurofibrosarcoma, osteosarcoma, synovial sarcoma, liposarcoma, and alveolar soft tissue sarcoma, etc.); leukemias (acute promyelocytic leukemia, The method according to claim 94, 96, or 98, selected from APL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML), neoplasms of the central nervous system (specifically brain tumors), multiple myeloma (MM), and lymphoma (such as Hodgkin lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-series large cell lymphoma, Burkitt lymphoma, and T-cell anaplastic large cell lymphoma).

100. The aforementioned cancers include melanoma, basal cell carcinoma, glioblastoma, glioma, gliosarcoma, astrocytoma, meningioma, neuroblastoma, adrenocortical carcinoma, head and neck cancers (e.g., cancers of the head, neck, nasal cavity, sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, and / or salivary glands, as well as paragangliomas), oral cancer, salivary gland cancer, nasopharyngeal cancer, breast cancer (e.g., triple-negative breast cancer), lung cancer (e.g., non-small cell lung cancer (NSCLC), small cell lung cancer, or squamous cell lung cancer), esophageal cancer, gastroesophageal junction cancer, gastric cancer, gastrointestinal cancer, primary peritoneal cancer, liver cancer, hepatocellular carcinoma, gallbladder cancer, biliary tract cancer, bile duct cancer, colon cancer, rectal cancer, colon... Rectal cancer, ovarian cancer, fallopian tube cancer, bladder cancer, upper urinary tract cancer, urothelial carcinoma, renal cell carcinoma, kidney cancer, urogenital cancer, cervical cancer, testicular cancer, prostate cancer, fibrosarcoma, liposarcoma, rhabdomyosarcoma (e.g., embryonic rhabdomyosarcoma), leiomyosarcoma, neurofibrosarcoma, synovial sarcoma, liposarcoma, alveolar soft tissue sarcoma, osteosarcoma, histiocytoma (e.g., malignant fibrous histiocytoma), pancreatic cancer, endometrial cancer, appendiceal cancer, thyroid cancer, advanced Merkel cell carcinoma, multiple myeloma, sarcoma, choriocarcinoma, leukemia (e.g., erythroleukemia, acute lymphoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, acute myeloid leukemia, acute myeloid leukemia)A selection of cancers from leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or mast cell leukemia), lymphoma (e.g., small lymphocytic lymphoma, Burkitt lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, lymphoplasmacytoid lymphoma, mucosa-associated lymphoid lymphoma, mantle cell lymphoma, anaplastic large cell T-cell lymphoma, follicular lymphoma, monocytic lymphoma, or HTLV-associated T-cell leukemia / lymphoma), or mesothelioma, and in certain embodiments, the cancer is head and neck cancer, bone cancer (e.g., osteosarcoma) The method according to claim 94, 96, or 98, wherein the cancer is selected from Ewing's sarcoma, squamous cell carcinoma, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, cervical cancer, pancreatic cancer, breast cancer (e.g., triple-negative breast cancer), melanoma, liver cancer, bladder cancer, gastric cancer, esophageal cancer, and chronic myeloid leukemia, and in a particular embodiment, the cancer is selected from the group consisting of head and neck cancer, non-small cell lung cancer, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, breast cancer, endometrial cancer, ovarian cancer, soft tissue sarcoma, bladder cancer, prostate cancer, kidney cancer, and melanoma.

101. The method according to claim 94, 96, or 98, wherein the cancer is selected from cellular lymphoma, non-small cell lung cancer, large cell lung cancer, breast cancer, and small cell lung cancer.

102. The method according to claim 94, 96, or 98, wherein the cancer is a cellular lymphoma.

103. The method according to claim 94, 96, or 98, wherein the cancer is non-small cell lung cancer.

104. The method according to claim 94, 96, or 98, wherein the cancer is large cell lung carcinoma.

105. The method according to claim 94, 96, or 98, wherein the cancer is breast cancer.

106. The method according to claim 94, 96, or 98, wherein the cancer is small cell lung cancer.

107. Formula (XXX) 【Chemistry 42】 A linker of or a pharmaceutically acceptable salt thereof, wherein in the formula, Y １ It does not exist, or -O-T １ and -NH-T ２ Selected from, T １ It is a glucose-cleaving unit, T ２ This is a peptide-cleaving unit, S １ (i) C replaced by any choice １ -C ３０ An alkylene in which one or more alkylene units are optionally and independently -N(R) ２０ )-,-N(R ２０ )C(O)-, -C(O)N(R ２０ )-,-N(R ２０ ) S(O) ２ -, -S(O) ２ N(R) ２０ )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O) ２ -, a 5-6 member complex ring, or -P(O)(R ２０ ) ２ C, which is replaced by -, is replaced by an optional substitution. １ -C ３０ Alkylene, (ii) C replaced by any choice ３ -C ３０ An alkenylene wherein one or more alkenylene units are optionally and independently -N(R) ２０ )-,-N(R ２０ )C(O)-, -C(O)N(R ２０ )-,-N(R ２０ ) S(O) ２ -, -S(O) ２ N(R) ２０ )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O) ２ -, or -P(O)(R ２０ ) ２ The optionally replaced C is replaced by ３ -C ３０ alkenylene, (iii) one or more amino acids, (iv) one or more N-substituted amino acids, (v) optionally substituted polyether, (vi) optionally substituted C ３ -C １０ Carbocyclene, (vii) Selected from 5-10 member heterocyclenes that have been optionally substituted, S ２ C is replaced by an optional substitution. １ -C ３０ An alkylene in which one or more alkylene units are optionally and independently -N(R) ２０ )-,-N(R ２０ )C(O)-, -C(O)N(R ２０ )-,-N(R ２０ ) S(O) ２ -, -S(O) ２ N(R) ２０ )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O) ２ -, a 5-6 member complex ring, or -P(O)(R ２０ ) ２ C, which is replaced by -, is replaced by an optional substitution. １ -C ３０ Selected from alkylenes, S ３ It is selected from the spacers, and at this time, S ３ Does it exist or does it not exist? M １ _K １ S １ S ２ , and S ３ Each of the above optional substituents, independently, (i)ハロゲン、-OR ３０ 、-N(R ３０ ) ２ 、-SR ３０ 、-N(R ３０ ) ２ 、-C(O)R ３０ 、-C(O)N(R ３０ ) ２ 、-N(R ３０ )C(O)R ３０ 、-C(O)OR ３０ 、-OC(O)R ３０ 、-S(O)R ３０ 、-S(O) ２ R ３０ 、-O-S(O) ２ OR ３０ 、-P(O)(OR ３０ ) ２ 、-OP(O)(OR ３０ ) ２ 、-NO ２ 、=O、=S、=N(R ３０ )、および-CN、 (ii) C １－１０ Alkyl, C ２－１０ Alkenil, C ２－１０ Alkinyl (each of these is a halogen, -OR ３０ , -SR ３０ , -N(R ３０ ) ２ , -C(O)R ３０ , -C(O)N(R ３０ ) ２ , -N(R ３０ ) C(O)R ３０ , -C(O)OR ３０ , -OC(O)R ３０ , -S(O)R ３０ , -S(O) ２ R ３０ , -O-S(O) ２ OR ３０ , -P(O)(OR ３０ ) ２ , -OP(O)(OR ３０ ) ２ , -NO ２ , =O, =S, =N(R ３０ ), -CN, C ３－１０ (Optionally substituted with one or more substituents independently selected from a carbon ring and a 3- to 10-membered heterocycle), (iii) C ３－１０ Carbon rings and 3- to 10-membered heterocycles (each of these being halogens, -OR) ３０ , -SR ３０ , -N(R ３０ ) ２ , -C(O)R ３０ , -C(O)N(R ３０ ) ２ , -N(R ３０ ) C(O)R ３０ , -C(O)OR ３０ , -OC(O)R ３０ , -S(O)R ３０ , -S(O) ２ R ３０ , -P(O)(OR ３０ ) ２ , -OP(O)(OR ３０ ) ２ , -NO ２ , =O, =S, =N(R ３０ ), -CN, C １－６ Alkyl, C ２－６ Alkenyl and C ２－６ (Optionally substituted with one or more substituents independently selected from the alkynyl molecule.) Selected from, M １ This is a group that can react with a ligand to form a connector unit. K １ teeth, (i) Peptide unit, (ii) Oligosaccharides, and (iii) Polyether Selected from, R ２０ These are, independently, hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１２ Carbon rings and 3- to 12-membered heterocycles (each of which is a halogen, -OH, -CN, -NO) ２ , -NH ２ , -N(C １－６ Alkyl) ２ , C １－１０ Alkyl, -C １－１０ Haloalkyl, -O-C １－１０ Alkyl, oxo, C ３－１２ Selected from a carbon ring and one or more substituents independently selected from 3- to 12-membered heterocycles, R ３０ These are, independently, hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１２ Carbon rings and 3- to 12-membered heterocycles (each of which is a halogen, -OH, -CN, -NO) ２ , -NH ２ , -N(C １－６ Alkyl) ２ , C １－１０ Alkyl, -C １－１０ Haloalkyl, -O-C １－１０ Alkyl, oxo, C ３－１２ Selected from a carbon ring and one or more substituents independently selected from 3- to 12-membered heterocycles, R ５０ A linker, or a pharmaceutically acceptable salt thereof, is selected from substituents capable of reacting with a hydroxyl group or a nucleophilic group on a drug.

108. The formula (XXX) is, 【Chemistry 43】 The linker according to claim 107, or a pharmaceutically acceptable salt thereof, represented by a pharmaceutically acceptable salt thereof.

109. R ５０ but, 【Chemistry 44】 A linker according to claim 107 or 108, or a pharmaceutically acceptable salt thereof, selected from the above.

110. R ５０ but, 【Chemistry 45】 A linker according to claim 107 or 108, or a pharmaceutically acceptable salt thereof, selected from the above.

111. The nucleophilic group on the drug is -NH ２ The linker according to claim 107 or 108, or a pharmaceutically acceptable salt thereof.

112. A drug linker selected from Table A, Table AA, Table B, Table C, Table D, Table E, Table F, and Table G.

113. A drug linker selected from Table A.

114. A drug linker selected from Table AA.

115. The drug linker to be selected from Table B.

116. A drug linker selected from Table C.

117. A drug linker selected from Table D.

118. The drug linker selected from Table E.

119. Drug linker selected from Table F.

120. Drug linker selected from Table G.

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