Antibody drug conjugates with linkers comprising hydrophilic groups

Abstract

Antibody-drug conjugates comprising a linker, a linker-drug group, and a hydrophilic group are provided.SOLUTION: A linker for use in improving the solubility of a linker-drug conjugate, wherein the conjugate comprises one or more hydrophobic drug compounds and the linker comprises one or more hydrophilic groups. Also provided is a linker for use in improving the solubility of an antibody drug conjugate (ADC), wherein the ADC comprises one or more hydrophobic drug compounds and the linker comprises one or more hydrophilic groups.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application was filed on May 20, 2019, the entire contents of which are incorporated herein by reference. The present application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 850,094. To stretch.

[0002] The present invention provides antibody drug conjugates (ADCs) containing one or more hydrophobic drug compounds. A linker is provided to improve solubility. [Background technology]

[0003] One aspect in the design of antibody drug conjugates (ADCs) is the coupling of the drug moiety with the targeting moiety. The design of a chemical linker that connects the drug to the molecule is crucial. Generally, ADCs use a hydrophobic drug moiety. However, when these drug moieties are used in combination with relatively hydrophobic linkers, AD Solubility issues may arise that may affect the biocompatibility and pharmaceutical efficacy of C. Summary of the Invention [Problem to be solved by the invention]

[0004] To overcome these challenges, hydrophilic phosphorus-containing polymers, especially those incorporating polyethylene glycol, have been developed. Car (RP Lyon, TD Bovee, SO Doronina, PJB urke, JHHunter, HDNeff-LaFord, M. Jonas, MEAnderson,JRSetter,PDSenter,Nat.B iotechnol., 2015, 33, 733-735 and International Publication No. 2015057 699), sulfonate-incorporated linkers (RY Zhao, SD Wilhelm, C. Audette, G. Jones, BAL eece, ACLazar, VSGoldmacher, R. Singh, Y. Kovtun,WCWiddison,JMLambert,RVJCh ari, J. Med. Chem., 2011, 54, 3606-3623) and carbohydrates Linkers with backbones (F.S.E. Kholm, H. Pynnoenen, A. Vilk man, V. Pitkaenen, J. Helin, J. Saarinen, T. Sat. omaa,ChemMedChem.,2016,11(22):2501-2505) It has been reported that linker strategies in the design of drugs have been attempted. Antibody drugs that enable targeted delivery of hydrophobic drugs with improved pharmacokinetic and pharmacodynamic properties - Patent Application 20070122999 There remains a need for conjugate formats. [Means for solving the problem]

[0005] The present invention provides a method for improving the solubility of linker-drug conjugates. and such conjugates comprise one or more hydrophobic drug compounds, The anchor contains one or more hydrophilic groups. Various embodiments of the invention are described herein. .

[0006] The present invention provides a method for improving the solubility of antibody drug conjugates (ADCs). and the ADC further comprises one or more hydrophobic drug compounds, and the linker comprises one or more hydrophilic groups. Various embodiments of the invention are described herein.

[0007] In one embodiment, a linker comprising one or more self-immolative groups is disclosed herein, Each of the above self-immolative groups is substituted with one or more hydrophilic moieties.

[0008] In one embodiment, a linker-drug group is disclosed herein, wherein the linker is attached to the drug. and one or more self-immolative groups attached to the polymer, each of the one or more self-immolative groups being one or more hydrophilic groups. is replaced by the part.

[0009] In one embodiment, an antibody drug conjugate comprising one or more linker-drug groups is described herein. and wherein the linker comprises one or more self-immolative groups attached to the drug, and one or more The self-immolative groups are each substituted with one or more hydrophilic moieties.

[0010] One embodiment is a compound of formula (I): [ka] (In the formula, R 1 is a reactive group, L1 is a bridging spacer, Lp is a divalent peptide spacer, G-L2-A is a self-immolative spacer, R 2 is the hydrophilic moiety, L2 is a bond, methylene, neopentylene, or C2-C3 alkenylene; A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(= O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where , each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl and the * in A indicates the point of attachment to D; L3 is a spacer moiety, and D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. (connected to A via a bond) or a pharmaceutically acceptable salt thereof.

[0011] One embodiment of the linker-drug group of formula (I) is represented by formula (II): [ka] (In the formula, R 1 is a reactive group, L1 is a bridging spacer, Lp is a bivalent peptide linker containing 1 to 4 amino acid residues; R 2 is the hydrophilic moiety, A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(= O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where , each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl and the * in A indicates the point of attachment to D; L3 is a spacer moiety, and D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. (connected to A via a bond) or a pharmaceutically acceptable salt thereof.

[0012] One embodiment is a compound of formula (III): [ka] (In the formula, Ab is an antibody or fragment thereof; R 100 is a coupling group, L1 is a bridging spacer, Lp is a bivalent peptide linker; G-L2-A is a self-immolative spacer, R 2 is the hydrophilic moiety, L2 is a bond, methylene, neopentylene, or C2-C3 alkenylene; A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(= O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where , each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl and the * in A indicates the point of attachment to D; L3 is a spacer moiety, D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. is connected to A via a bond, and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16) is an antibody drug conjugate of

[0013] One embodiment of the antibody drug conjugate of formula (III) is represented by formula (IV): [ka] (In the formula, Ab is an antibody or fragment thereof; R 100 is a coupling group, L1 is a bridging spacer, Lp is a bivalent peptide linker containing 1 to 4 amino acid residues; R 2 is the hydrophilic moiety, A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(= O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where , each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl and the * in A indicates the point of attachment to D; L3 is a spacer moiety, D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. is connected to A via a bond, and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16) is an antibody drug conjugate of

[0014] Another aspect of the present invention is a compound of formula (V) [ka] (In the formula, L1 is a bridging spacer, Lp is a divalent peptide spacer, G-L2-A is a self-immolative spacer, R 2 is the hydrophilic moiety, L2 is a bond, methylene, neopentylene, or C2-C3 alkenylene; A is a bond, **-OC(=O)-, [ka] , **-OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- or **-O C(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-, So, each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl selected, the ** in A indicates the point of attachment to L2, and L3 is a spacer portion) It is a linker having the structure:

[0015] One embodiment of the linker formula (V) is formula (VI): [ka] (In the formula, L1 is a bridging spacer, Lp is a divalent peptide spacer, R 2 is the hydrophilic moiety, A is a bond, -OC(=O)-, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- or -OC(=O )N(CH3)C(R a )2C(Ra )2N(CH3)C(=O)-, where each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl , and L3 is a spacer portion) It is a linker having the structure:

[0016] The linkers described herein that contain a hydrophilic moiety are useful in antibody-drug conjugates (A This contributes to the overall hydrophilicity of the ADC and improves the aqueous solubility of the ADC. The linker also unexpectedly reduces ADC aggregation, improving the pharmacokinetics and pharmacodynamics of the ADC. Furthermore, the hydrophilic linkers described herein improve the properties of the Allows for improved aqueous solubility of the linker-drug group, thereby increasing the This allows for improved antibody conjugation, which is beneficial for ADCs, especially for hydrophobic drug moieties. Improve the purification and overall synthesis yield of ADCs containing amines. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 is a line graph of the cellular activity of antibody drug conjugates titrated across selected cell lines A: HT-29 PCAD+; B: FaDu; C: HCC70; D: HT-29; and E: HCC1954. [Figure 2] FIG. 1 is a line graph of caspase-3 / 7 activity of antibody drug conjugates titrated across HCC1954 cell line after A: 24 hours and B: 48 hours. [Figure 3-1]Figure 3: Efficacy and tolerability of PCAD-ADC and huIgG1 isotype-matched control ADC in the HCC70 human TNBC xenograft model in SCID beige female mice. A) Antitumor response; B) and C) Body weight change compared to body weight at the start of treatment. Data are shown as mean ± SEM. *p<0.05 compared to the untreated group at day 20 (one-way ANOVA with post-hoc Dunnett's test). [Figure 3-2] (As mentioned above.) DETAILED DESCRIPTION OF THE INVENTION

[0018] Various embodiments of the invention are enumerated and described herein. Features may be combined with other specified features to provide further embodiments of the present invention. It will be recognized that

[0019] Throughout the text of this application, there are discrepancies between the text of the specification (e.g., Table 3) and the Sequence Listing. In such cases, the text of this specification shall take precedence.

[0020] definition As used herein, the term "alkyl" refers to an unsaturated alkyl group consisting solely of carbon and hydrogen atoms. As used herein, refers to a radical of a straight or branched hydrocarbon chain that does not contain alkyl groups. The term "C1-C6 alkyl" refers to a group consisting solely of carbon and hydrogen atoms, containing no unsaturation, A straight or branched chain carbon atom having up to 6 carbon atoms and attached to the rest of the molecule by a single bond A non-limiting example of a "C1-C6 alkyl" group is methyl. (C1 alkyl), ethyl (C2 alkyl), 1-methylethyl (C3 alkyl), n- Propyl (C3 alkyl), isopropyl (C3 alkyl), n-butyl (C4 alkyl) ), isobutyl (C4 alkyl), sec-butyl (C4 alkyl), tert-butyl (C4 alkyl), n-pentyl (C5 alkyl), isopentyl (C5 alkyl), ne Examples include pentyl (C5 alkyl) and hexyl (C6 alkyl).

[0021] As used herein, the term "alkenyl" refers to a group consisting solely of carbon and hydrogen atoms and It refers to a radical group of a straight or branched hydrocarbon chain containing at least one double bond. When used in the specification, the term "C2~C e "Alkenyl" refers to an alkyl group that is attached to the rest of the molecule by a single bond. consists of only carbon and hydrogen atoms, contains at least one double bond, and has 2 to 6 refers to a radical group of a straight or branched hydrocarbon chain having carbon atoms of 2 to 6 carbon atoms. Non-limiting examples of "alkenyl" groups include ethenyl (C2 alkenyl), prop-1-enyl, but-1-enyl (C3 alkenyl), but-1-enyl (C4 alkenyl), pent-1-enyl (C 5 alkenyl), pent-4-enyl (C5 alkenyl), penta-1,4-dienyl ( C5 alkenyl), hex-1-enyl (C6 alkenyl), hex-2-enyl (C6 alkenyl), hex-3-enyl (C6 alkenyl), hexa-1,4-dienyl (C 6 alkenyl), hexa-1,5-dienyl (C6 alkenyl), hexa-2,4-dienyl As used herein, the term "CC2-C3 alkenyl" includes C6 alkenyl. "Alkenyl" refers to a group consisting solely of carbon and hydrogen atoms attached to the rest of the molecule by single bonds. , a straight or branched chain carbon atom containing at least one double bond and having 2 to 3 carbon atoms A non-limiting example of a "C2-C3 alkenyl" group is an ethylenediamine. Thenyl (C2 alkenyl) and prop-1-enyl (C3 alkenyl).

[0022] As used herein, the term "alkylene" refers to a group consisting solely of carbon and hydrogen atoms and As used herein, refers to a divalent straight or branched hydrocarbon chain radical that contains no saturation. When the term "C1-C6 alkylene" is used, it means that the alkylene consists solely of carbon and hydrogen atoms and has no unsaturation. and a divalent linear or branched hydrocarbon chain radical having 1 to 6 carbon atoms, not including Non-limiting examples of "C1-C6 alkylene" groups include methylene (C1 alkylene ), ethylene (C2 alkylene), 1-methylethylene (C3 alkylene), -propylene propylene (C3 alkylene), isopropylene (C3 alkylene), -butylene (C4 alkylene) butylene), isobutylene (C4 alkylene), sec-butylene (C4 alkylene), ter t-butylene (C4 alkylene), -pentylene (C5 alkylene), isopentylene ( C5 alkylene), neopentylene (C5 alkylene) and hexylene (C6 alkylene) ) are mentioned.

[0023] As used herein, the term "alkenylene" refers to an alkyl group consisting solely of carbon and hydrogen atoms, refers to a divalent straight or branched hydrocarbon chain radical containing at least one double bond As used herein, the term "C2-C6 alkenylene" refers to a group containing only carbon and hydrogen atoms. and a divalent straight-chain or refers to a branched hydrocarbon chain radical group. Examples include ethenylene (C2 alkenylene), prop-1-enylene (C3 alkenylene), but-1-enylene (C4 alkenylene), pent-1-enylene (C5 alkenylene) pent-4-enylene (C5 alkenylene), penta-1,4-dienylene ( C 5 alkenylene), hex-1-enylene (C6 alkenylene), hex-2-enylene Hex-3-enylene (C6 alkenylene), hex-1,4 -Dienylene (C6 alkenylene), hexa-1,5-dienylene (C6 alkenylene) and hexa-2,4-dienylene (C6 alkenylene). When the term "C2-C6 alkenylene" is used, it means that the alkenylene is composed solely of carbon and hydrogen atoms and has at least A divalent straight or branched chain hydrocarbon having 2 to 3 carbon atoms and containing one or more double bonds. A non-limiting example of a "C2-C3 alkenylene" group is ethene. Examples include prop-1-enylene (C2 alkenylene) and prop-1-enylene (C3 alkenylene). do.

[0024] As used herein, the term "cycloalkyl" or "C3-C8 cycloalkyl" refers to a saturated, monocyclic, fused bicyclic, fused tricyclic or bridged polycyclic ring system. Non-limiting examples of bridged polycyclic ring systems include bicyclo[1.1.1]pentane, bicyclo[1.1.1]pentane, [2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane butane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane and adamantane Non-limiting examples of monocyclic C3-C8 cycloalkyl groups include cintanyl. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclohexyl An example is a chlorooctyl group.

[0025] As used herein, the term "polyethylene glycol" or "PEG" refers to a polyethylene glycol (OC In certain embodiments, the term "polyethylene glycol" refers to a linear, branched, or star-shaped configuration of polyethylene glycol (H2CH2) groups. The ethylene or PEG group is -(OCH2CH2) t *-, where t is 4 to 40 where "-" indicates the end pointing towards the self-immolative spacer and "*-" indicates the end group R R' indicates the point of attachment to OH, OCH3, or OCH2CH2C(=O)OH. In other embodiments, the polyethylene or PEG group is —(CH2CH2O) t *-in where t is 4 to 40, and "-" is the terminal end pointing to the self-immolative spacer. The "*-" indicates the point of attachment to the terminal group R", where R" is H, CH3 or CH2CH2C(=O)OH.

[0026] As used herein, the term "polyalkylene glycol" refers to a group consisting of (O(CH) m ) t In certain embodiments, polyethylene or The PEG group is -(O(CH2) m ) t *-, where m is 1 to 10, and t is , 4 to 40, where "-" indicates the end toward the self-immolative spacer, and "*-" indicates the point of attachment to the terminal group R', where R' is OH, OCH3 or OCH2CH2C( In other embodiments, the polyethylene or PEG group is —((CH) m O) t *-, where m is 1 to 10, t is 4 to 40, and "-" is refers to the end pointing towards the self-immolative spacer, and "*-" indicates the bond to the terminal group R'' where R'' is H, CH3 or CH2CH2C(=O)OH.

[0027] As used herein, the term "drug moiety," "D," or "drug" refers to a compound that possesses a desired biological activity. and having a reactive functional group that can be used to incorporate a drug into the linker-drug group of the invention. The term "biological activity" refers to any compound that has a desired biological activity, such as diagnosing disease in humans or other animals. The reactive functional group is a group represented by the formula (I) and the formula (II): Compounds and conjugates of formula (III) and formula (IV) that form a bond to "A" In some embodiments, the drug moiety contains a nitrogen atom capable of forming a bond with "A." In other embodiments, the drug moiety has a hydroxyl group capable of forming a bond with "A." In other embodiments, the drug moiety has a carboxylic acid capable of forming a bond with "A." In other embodiments, the drug moiety has a carbonyl group capable of forming a bond with "A." In yet other embodiments, the drug moiety contains a sulfhydryl group capable of forming a bond with "A." Has.

[0028] If the requisite reactive functional group is present, the term "drug moiety," "D," or "drug" is used in the formula United States Pharmacopeia, Official Homeopath ic Pharmacopeia of the United States or Recognized as a drug in the official National Formulary or any of its supplements Representative drugs include Physician's Desk R Reference (PDR) and Oran maintained by the U.S. Food and Drug Administration (FDA) It is described in the ge Book.

[0029] In one embodiment, the drug moiety (D) is a cytotoxic, cytostatic, or immunosuppressive drug. Such cytotoxic or immunosuppressive drugs include, for example, antitubulin agents, Tubulin inhibitors, DNA minor groove binders, DNA replication inhibitors, alkylating antibiotics, antibacterial Folic acid agents, antimetabolites, chemotherapy sensitizers, topoisomerase inhibitors, vinca alkaloids, etc. Examples of such cytotoxic drugs include auristatins, camptothecins, and the like. toxin, duocarmycin, etoposide, maytansine and maytansinoids, tachycardia benzodiazepines or benzodiazepine-containing drugs (e.g., pyrrolo[1,4]benzyl) Benzodiazepines (PBDs), indolinobenzodiazepines and oxazolidinobenzodiazepines zepines) and vinca alkaloids.

[0030] The effects of the present invention are more pronounced in embodiments in which the drug moiety is hydrophobic. Thus, the drug moieties of the present invention have an SlogP value of 1.5 or greater, 2.0 or greater, or 2.5 or greater. In some embodiments, the drug used in the present invention is (a) about 1.5, about 2, or 2.5 to about 7, (b) about 1.5, about 2, or 2.5 to about 6, (c) about 1.5, about 2, or about 2.5 to about 5, (d) about 1.5, about 2, or 2. or (e) an SlogP value of about 1.5, about 2, or about 2.5 to about 3.

[0031] Hydrophobicity can be measured using SlogP, which is the octanol / water partition coefficient. It is defined as the logarithm of the number (including implicit hydrogens) and is used in Chemical Computing. The SlogP value can be calculated using the program MOE™ from the Sigma-Aldrich Group. Wildman,25 SA,Crippen,GM;Prediction of Physiochemical Parameters by Atomic C ontributions;J.Chern.lnf Comput.Sci.39 N o.5(1999)868-873).

[0032] As used herein, the term "reactive group" refers to a group that can be covalently bonded to a functional group on an antibody or antibody fragment. Non-limiting examples of such functional groups include those described herein. Examples of reactive groups include those listed in Table 1 provided herein.

[0033] As used herein, the term "coupling group" refers to a group that connects a cross-linking spacer to an antibody or its A coupling group refers to a bivalent moiety that links a reactive group on an antibody or fragment thereof to a functional group. Non-limiting examples of such divalent moieties include: Examples include the divalent chemical moieties shown in Tables 1 and 2 provided herein.

[0034] As used herein, the term "bridge spacer" refers to a group of molecules that covalently link together a divalent moiety. and this divalent moiety links the divalent peptide spacer to the reactive group, or Refers to one or more linker components that connect the peptide space to the coupling group. In embodiments, a "bridging spacer" is a linker that connects the N-terminus of a divalent peptide spacer via an amide bond. It contains a carboxyl group attached to the end.

[0035] As used herein, the term "spacer moiety" refers to a group of molecules that are covalently linked together and self-immolating. refers to one or more linker components that form the moiety connecting the moiety spacer to the hydrophilic moiety.

[0036] As used herein, the term "bivalent peptide spacer" refers to a peptide spacer that is covalently linked together , one or more amino acids that form the moiety connecting the bridging spacer to the self-immolative spacer The term "bivalent linker" refers to a bivalent linker containing one or more amino acid residues, such as alanine (Ala), cysteine ​​(C1), methylamino acid (M1), methylamino acid (M2), methylamino acid (M3), methylamino acid (M4), methylamino acid (M5), methylamino acid (M6), methylamino acid (M7), methylamino acid (M8), methylamino acid (M9), methylamino acid (M10), methylamino acid ( Cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine Phe, glycine (Gly), histidine (His), isoleucine (Ile) ), lysine (Lys), leucine (Leu), methionine (Met), asparagine (A sn), proline (Pro), glutamine (Gln), arginine (Arg), serine ( Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine Tyr, Citrulline (Cit), Norvaline (Nva), Norleucine (Nle ), selenocysteine ​​(Sec), pyrrolysine (Pyl), homoserine, homocysteine and desmethylpyrrolysine.

[0037] In certain embodiments, a "bivalent peptide spacer" is a peptide in which each residue is an alanine (Ala ), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine ( Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagi Ascending nucleotides (Asn), proline (Pro), glutamine (Gln), arginine (Arg), cerebrospinal fluid (CF), Phosphorus (Ser), Threonine (Thr), Valine (Val), Tryptophan (Trp) , tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucine ( Nle), selenocysteine ​​(Sec), pyrrolidine (Pyl), homoserine, homocysteine and independently selected from residues of an amino acid selected from desmethylpyrrolysine and desmethylpyrrolysine. Combinations of 2 to 4 amino acid residues, e.g., -ValCit*;-CitVal*;- AlaAla*;-AlaCit*;-CitAla*;-AsnCit*;-CitA sn*;-CitCit*;-ValGlu*;-GluVal*;-SerCit*; -CitSer*;-LysCit*;-CitLys*;-AspCit*;-Cit Asp*;-AlaVal*;-ValAla*;-PheAla*;-AlaPhe* ;-PheLys*;-LysPhe*;-ValLys*;-LysVal*;-Al aLys*;-LysAla*;-PheCit*;-CitPhe*;-LeuCit *;-CitLeu*;-IleCit*;-CitIle*;-PheArg*;-A rgPhe*;-CitTrp*;-TrpCit*;-PhePheLys*;-Ly sPhePhe*;-DPhePheLys*;-DLysPhePhe*;-GlyP heLys*;-LysPheGly*;-GlyPheLeuGly-[SEQ ID NO: 16 0];-GlyLeuPheGly-[SEQ ID NO: 161];-AlaLeuAlaLeu -[SEQ ID NO: 162], -GlyGlyGly*; -GlyGlyGlyGly-[SEQ ID NO: SEQ ID NO: 163]; -GlyPheValGly- [SEQ ID NO: 164]; and -GlyVal PheGly-[SEQ ID NO: 165], where "-" is the bridging spacer The points of attachment are indicated, where "*" indicates the point of attachment to the self-immolative spacer.

[0038] As used herein, the term "linker moiety" refers to: a) Alkylene group: —(CH) n - which can be either linear or branched (in this example, n is 1 to 18); b) an alkenylene group; c) an alkynylene group; d) an alkenyl group; e) an alkynyl group; f) ethylene glycol unit: -OCH2CH2 or -CH2CH2O; g) Polyethylene glycol unit: (-CH2CH2O-) x (In this example, x is 2 ~20); h)-O; i)-S; j) Carbonyl: -C(=O); k) Esters: -C(=O)-O- or -OC(=O); l) Carbonate: -OC(=O)O; m) Amine: -NH; n) tertiary amine o) Amide: -C(=O)-NH-, -NH-C(=O)- or -C(=O)N(C 1~ 6 alkyl); p) Carbamates: -OC(=O)NH- or -NHC(=O)O; q) Urea:-NHC(=O)NH; r) sulfonamide: -S(O)2NH- or -NHS(O)2; s) Ether: -CH2O- or -OCH2; t) Carboxy, sulfonate, hydroxyl, amine, amino acid, saccharide, phosphonate alkylene substituted with one or more groups independently selected from phosphate and phosphonate; ; u) Carboxy, sulfonate, hydroxyl, amine, amino acid, saccharide, phosphonate alkenyl substituted with one or more groups independently selected from phosphate and phosphonate; hmm; v) Carboxylic, sulfonate, hydroxyl, amine, amino acid, saccharide, phosphonic acid Alkynylene substituted with one or more groups independently selected from phosphate and phosphonate hmm; w) one or more methylene groups are replaced by one or more -S-, -NH- or -O- moieties; C1~C 10 Alkylene; x) Phenyl (including 1,2-, 1,3- and 1,4-disubstituted phenyl), C5-C6 Heteroaryl, C3-C8 cycloalkyl (1,1-disubstituted cyclopropyl, cyclobutyl) cyclohexyl, cyclopentyl or cyclohexyl and 1,4-disubstituted cyclohexyl) and two available points of attachment, such as a bivalent ring selected from C4-C8 heterocycloalkyl A ring system having y) Alanine (Ala), Cysteine ​​(Cys), Aspartic acid (Asp), Glutamate Glu, phenylalanine (Phe), glycine (Gly), histidine (Hi s), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine ( Met), asparagine (Asn), proline (Pro), glutamine (Gln), Arginine (Arg), serine (Ser), threonine (Thr), valine (Val), triglyceride Pyrophosphate (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nv a), norleucine (Nle), selenocysteine ​​(Sec), pyrrolysine (Pyl), a residue of an amino acid selected from homoserine, homocysteine, and desmethylpyrrolysine; Each residue is alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine Methamine (Met), Asparagine (Asn), Proline (Pro), Glutamine (Gln) , arginine (Arg), serine (Ser), threonine (Thr), valine (Val) , tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucine (Nle), selenocysteine ​​(Sec), pyrrolysine (Py l) of an amino acid selected from homoserine, homocysteine ​​and desmethylpyrrolysine A combination of two or more amino acid residues, independently selected from residues, e.g., Val-C it;Cit-Val;Ala-Ala;Ala-Cit;Cit-Ala;Asn-C it;Cit-Asn;Cit-Cit;Val-Glu;Glu-Val;Ser-C it;Cit-Ser;Lys-Cit;Cit-Lys;Asp-Cit;Cit-A sp;Ala-Val;Val-Ala;Phe-Lys;Lys-Phe;Val-L ys;Lys-Val;Ala-Lys;Lys-Ala;Phe-Cit;Cit-P he;Leu-Cit;Cit-Leu;Ile-Cit;Cit-Ile;Phe-A rg; Arg-Phe; Cit-Trp; and Trp-Cit; and z) Acid-induced cleavage, peptide-induced cleavage, esterase-induced cleavage, glycosidase-induced cleavage induced cleavage, phosphodiesterase-induced cleavage, phosphatase-induced cleavage, protease-induced cleavage one or more protected ( A self-immolative spacer containing a (inducing) group.

[0039] Non-limiting examples of such self-immolative spacers include: [ka] where: PG is a protecting group, X a is O, NH or S, X b is O, NH, NCH3 or S, X c is O or NH, Y a is CH2, CH2O or CH2NH, Y b is CH, O or NH, Y c is a bond, CH, O or NH, LG is a leaving group, such as the drug moiety (D) of a linker-drug group of the invention.

[0040] Further non-limiting examples of such self-immolative spacers can be found in Angew. Chem. In It is described in t.Ed.2015,54,7492-7509.

[0041] Additionally, the linker component is a chemical moiety that is readily formed by a reaction between two reactive groups. Non-limiting examples of such chemical moieties are provided in Table 1.

[0042] [Table 1]

[0043] [Table 2]

[0044] [Table 3]

[0045] [Table 4]

[0046] [Table 5]

[0047] [Table 6]

[0048] R in Table 1 32 is H, C 1~4 alkyl, phenyl, pyrimidine or pyridine Yes; R in Table 1 35 is H, C 1~6 Alkyl, phenyl or 1 to 3 -OH groups C replaced with 1~4 alkyl; each R in Table 1 7 is H, C 1~6 Alkyl, Fluoro, benzyloxy substituted with -C(=O)OH, benzyl, C(=O)OH-substituted 1~4 Alkoxy and -C(=O)OH Substituted C 1~4 R in Table 1 is independently selected from alkyl; 37 H, Feni q in Table 1 is 0, 1, 2 or 3; R in 1 8 or R 13 is H or methyl; R in Table 1 9 or R 14 is H , -CH3 or phenyl; R in Table 1 is H or a suitable substituent, such as alkyl. It is.

[0049] Additionally, the linker moiety can be a group provided in Table 2 below.

[0050] [Table 7]

[0051] [Table 8]

[0052] [Table 9]

[0053] [Table 10]

[0054] As used herein, when a substructure of a compound is depicted with a wavy line:

number

[0055] As used herein, the term "self-immolative spacer" refers to a group consisting of one or more triggering groups (T G), which induces acid-induced cleavage, peptide-induced cleavage, esterification, Glycosidase-induced cleavage, phosphodiesterase-induced cleavage, phosphatase-induced cleavage tase-induced cleavage, protease-induced cleavage, lipase-induced cleavage or disulfide bond After activation, the protecting groups are removed, which initiates a cascade of decomposition reactions. This cascade of reactions leads to the sequential release of leaving groups. The reaction may be, but is not limited to, 1,6-, or 1,8-elimination reactions.

[0056] Non-limiting examples of such self-immolative spacers include: [ka] and such groups can be optionally substituted, where: TG is the inducing group, X a is O, NH or S, X b is O, NH, NCH3 or S, X c is O or NH, Y a is CH2, CH2O or CH2NH, Y b is CH, O or NH, Y c is a bond, CH, O or NH, LG is a leaving group, such as the drug moiety (D) of a linker-drug group of the invention.

[0057] Further non-limiting examples of such self-immolative spacers can be found in Angew. Chem. In It is described in t.Ed.2015,54,7492-7509.

[0058] In certain embodiments, the self-immolative spacer has the structure [ka] where Lp is an enzymatically cleavable bivalent peptide spacer. Yes, A, D, L3 and R 2 is as defined herein.

[0059] In a preferred embodiment, the self-immolative spacer has the structure [ka] where Lp is an enzymatically cleavable bivalent peptide spacer. Yes, D, L3 and R 2is as defined herein.

[0060] In another preferred embodiment, the self-immolative spacer has the structure [ka] where Lp is an enzymatically cleavable bivalent peptide spacer. Yes, D, L3 and R 2 is as defined herein. In some embodiments D is a quaternized tertiary amine-containing drug moiety, wherein the ammonium cation The ions are optionally present in zwitterionic form or have a monovalent anionic counterion. Has.

[0061] As used herein, the term "hydrophilic moiety" refers to a hydrophilic moiety that is present in the drug moiety (D) of the present invention. refers to a moiety that has hydrophilic properties that, when attached to a group, increases the aqueous solubility of the drug moiety (D) Examples of such hydrophilic groups include polyethylene glycol and polyalkylene glycol. , sugars, oligosaccharides, polypeptides, 1-3 [ka] C2-C6 alkyl substituted with a group, and [ka] (wherein n is an integer of 2 to 25, and R is -CH or -CHCHC(=O )OH) and polysarcosines such as those having the formula:

[0062] In some embodiments, the hydrophilic moiety has the formula [ka] where R is H, -CH3, -CH2CH2NHC (=O)OR a , -CH2CH2NHC(=O)R a or -CH2CH2C(=O)OR a and R' is OH, -OCH3, -CH2CH2NHC(=O)OR a , -CH2 CH2NHC(=O)R a or -OCH2CH2C(=O)OR a where R a is H or optionally OH or C 1~4 C1 substituted with either alkoxyl ~4 alkyl, and m and n are each an integer of 2 to 25 (e.g., 3 to 25). In some embodiments, the hydrophilic moiety is [ka] Includes.

[0063] As used herein, the term "antibody" refers to an immunoglobulin molecule that specifically binds to an antigen. Antibodies are proteins or polypeptide sequences derived from a human. may be clonal, multi-chain or single-chain or intact immunoglobulins, and may be of natural origin Naturally occurring "antibodies" can be derived from human or recombinant sources. A glycoprotein containing at least two interconnected heavy (H) chains and two light (L) chains. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is composed of three domains: CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is composed of one domain, CL. The VH and VL regions are composed of a frame. The complementarity-determining regions (CDRs) are inserted with more conserved regions called network regions (FRs). Each VH and VL can be further subdivided into hypervariable regions called CDRs. From the three CDRs and four FRs arranged from the amino terminus to the carboxyl terminus in the following order: Composed of: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Heavy chain and The variable regions of the light and dark chains contain a binding domain that interacts with an antigen. Binding of immunoglobulins to host tissues or to various cells of the immune system (e.g., effector cells) and the first component of the classical complement system (C1q). The antibody may be a clonal antibody, a human antibody, a humanized antibody, a camelized antibody or a chimeric antibody. can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA, and IgY). ), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2 ) or a subclass.

[0064] The term "antibody fragment", or "antigen-binding fragment", or "functional fragment" refers to an antibody fragment that binds to an epitope of an antigen. specifically interact with (e.g., by binding, steric hindrance, stabilization / destabilization, spatial distribution) An antibody fragment refers to at least a portion of an antibody that retains the ability to bind to an antibody. Examples of antibody fragments include, but are not limited to, However, Fab, Fab', F(ab')2, Fv fragments, scFv antibody fragments, disulfide Fvs (sdFv), Fd fragments consisting of VH and CH1 domains, linear antibodies, sd Single domain antibodies (either VL or VH) such as Ab, camelid VHH domains, Antibody fragments such as bivalent fragments containing two Fab fragments linked by a disulfide bridge at the Fab region Multispecific antibodies formed from antibody fragments and isolated CDRs or other epitopes of antibodies Antigen-binding fragments include single domain antibodies, maxibodies, minibodies, etc. , nanobody, intrabody, bispecific antibody, trispecific antibody, tetraspecific antibody, vN AR and bis-scFv (see, e.g., Hollinger and H udson,Nature Biotechnology 23:1126-1136, 2005). Antigen-binding fragments include those derived from fibronectin type III (Fn3), Scaffolds based on other polypeptides may also be implanted (fibronectin polypeptide minibodies). (See U.S. Patent No. 6,703,199, which describes the technology.) "scFv" refers to an antibody fragment that contains at least one light chain variable region and one heavy chain variable region. and at least one antibody fragment containing a light chain variable region and a heavy chain variable region. The domains may be linked, for example, via a synthetic linker, such as a short, flexible polypeptide linker. are contiguously linked and can be expressed as a single polypeptide chain, The antibodies described herein retain the specificity of the intact antibody from which they are derived. When used in the present invention, scFvs are prepared by combining the VL and VH variable regions in one of the following orders: For example, the scFv may be VL-linker- It may comprise a VH, or it may comprise a VH-linker-VL.

[0065] As used herein, the term "complementarity determining region" or "CDR" refers to a region that is responsible for antigen specificity and It refers to the amino acid sequence within the antibody variable region that confers binding affinity. For example, typically, three in each heavy chain variable region (e.g., HCDR1, HCDR2, and HCDR3), and There are three CDRs in each light chain variable region (LCDR1, LCDR2 and LCDR3). The exact amino acid sequence boundaries of a given CDR can be determined by Kabat et al. (1991), Sequences of Proteins of Immunological I nterest,”5th Ed.Public Health Service,Na tional Institutes of Health, Bethesda, MD ( "Kabat" numbering scheme), Al-Lazikani et al.,(1 997) JMB 273,927-948 ("Chothia" numbering scheme) or a combination thereof and ImMunoGenTics (IMGT) numbering (L efranc, M.-P., The Immunologist, 7, 132-136( 1999);Lefranc,M.-P.et al.,Dev.Comp.Immun ol.,27,55-77(2003)("IMGT" numbering scheme) It can be determined using any of a number of well-known schemes, including those described . A given CDR region (e.g. HC CDR1, HC CDR2, HC CDR3, LC Kabat and Chothi et al. In some embodiments, in a combination of numbering schemes, the CDRs are The Kabat CDR along with the amino acid residues defined as part of the hothia CDR As used herein, "Choice" corresponds to an amino acid residue defined as being part of a The CDRs defined according to the "Ia" numbering scheme are referred to as "hypervariable loops." This sometimes happens.

[0066] For example, under Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are , 31-35 (HCDR1) (e.g., insertion after position 35), 50-65 (HCDR2 ) and 95 to 102 (HCDR3); and light chain variable domain (VL) The CDR amino acid residues in They are numbered as follows: 50-56 (LCDR1), 89-97 (LCDR2), and 89-97 (LCDR3). As another example, under Chothia, the CDR amino acids in VH are 26 to 32 (H CDR1) (e.g., insertion after position 31), 52-56 (HCDR2) and 95-10 2 (HCDR3); and the amino acid residues in VL are numbered 26 to 32 ( LCDR1) (e.g., insertion after position 30), 50-52 (LCDR2) and 91-9 6 (LCDR3). Both Kabat and Chothia CDRs Combining the definitions, a CDR may be, for example, a CDR consisting of amino acid residue 26 in a human VH. ~35 (HCDR1), 50-65 (HCDR2) and 95-102 (HCDR3) amino acid residues 24-34 (LCDR1) and 50-56 (LCDR2) in human VL and 89-97 (LCDR3). The CDR amino acid residues are approximately 26 to 35 (CDR1), 51 to 57 (CDR2), and The CDR amino acid residues in VL are numbered 93 to 102 (CDR3). 27-32 (CDR1), 50-52 (CDR2) and 89-97 (CDR3) ( Under IMGT, the CD of an antibody is numbered according to the "Kabat" numbering system. Determine the R region using the program IMGT / DomainGap Align. can be done.

[0067] The term "epitope" refers to a molecule capable of specific binding to an immunoglobulin or other target molecule. An epitopic determinant includes any protein determinant capable of interacting with a molecule in a manner consistent with the present invention. Generally, they consist of chemically active surface groups of molecules such as amino acids or carbohydrate or sugar side chains. An epitope can have specific three-dimensional structural characteristics and specific charge characteristics. Conformational and linear epitopes can be either "linear" or "conformational." The former is distinguished from the latter in that its binding to the latter is lost in the presence of denaturing solvents, while the latter is not.

[0068] As used herein, the phrase "monoclonal antibody" or "monoclonal antibody composition" refers to a "Antibodies" include antibodies, double antibodies, and antibodies having substantially identical amino acid sequences or derived from the same genetic source. The term refers to a polypeptide comprising a specific antibody or the like. The term also refers to a preparation of antibody molecules of single molecular composition. Monoclonal antibody compositions have a single binding specificity for a particular epitope and Shows affinity.

[0069] As used herein, the term "human antibody" refers to a human antibody having a humanized framework and CDR regions. It also includes antibodies having variable regions derived from sequences of human origin. If included, the constant regions may also contain such human sequences, e.g., human germline sequences or human biotin sequences. Variants of the germline sequence or, for example, Knappik, et al. (2000. J Mol The sequences are derived from the analysis of human framework sequences described in Biol 296, 57-86. It is derived from an antibody containing a consensus framework sequence. The structures and locations of CDRs are determined according to well-known numbering schemes, e.g., Kabat numbering scheme, Chothia numbering scheme or Kabat and Cho The combination of thia and ImMunoGenTics (IMGT) numbering (e.g. For example, Sequences of Proteins of Immunologica l Interest,USDepartment of Health and Human Services(1991), eds.Kabat et al.;Al Lazikani et al.,(1997)J.Mol.Bio.273:927 948);Kabat et al.,(1991)Sequences of Pr oteins of Immunological Interest,5th edi t.,NIH Publication no.91-3242 USDepart ment of Health and Human Services;Chothi a et al.,(1987)J.Mol.Biol.196:901-917;Ch othia et al.,(1989)Nature 342:877-883;Al -Lazikani et al.,(1997)J.Mal.Biol.273:92 7-948; and Lefranc, M.-P., The Immunologist, 7 ,132-136(1999);Lefranc,M.-P.et al.,Dev.C omp. Immunol., 27, 55-77 (2003) It can be defined.

[0070] Human antibodies of the invention may contain amino acid residues that are not encoded by human sequences (e.g., in vitro). Derived by random or site-specific mutagenesis in vitro or by somatic mutation in vivo However, the present invention may contain mutations introduced into the nucleotide sequence or conservative substitutions to enhance stability or production. As used herein, the term "human antibody" refers to an antibody derived from a human antibody derived from the germline of another mammalian species, such as a mouse. It is intended to include antibodies in which CDR sequences derived from the sequences have been grafted onto human framework sequences. It has not been done.

[0071] The phrase "recombinant human antibody" as used herein refers to an antibody prepared, expressed by recombinant means. , all human antibodies produced or isolated, e.g., human immunoglobulin genes Transgenic or transchromosomal animals (e.g., mice) or hybrids prepared therefrom. Antibodies isolated from human dendritic cells, host cells transformed to express human antibodies, e.g. Antibodies isolated from transfectomas, antibodies isolated from recombinants, combined antibodies Other DNA sequences of human antibody libraries and all or part of human immunoglobulin gene sequences Antibodies prepared, expressed, produced or isolated by any other means involving splicing into Such recombinant human antibodies include those in which the framework and CDR regions are derived from human germline clones. However, in certain embodiments, Such recombinant human antibodies can be produced by in vitro mutagenesis (or gene recombination for human Ig sequences). If transgenic animals are used, they may be subject to in vivo somatic mutagenesis, and therefore the recombinant The amino acid sequences of the VH and VL regions of the antibody are derived from human germline VH and VL sequences. In this regard, it is also possible to identify sequences that do not naturally exist in vivo within the human antibody germline repertoire. It is a column.

[0072] As used herein, the term "Fc region" refers to the CH3, CH2 and constant domains of an antibody. Optionally, the term "hinge region" refers to a polypeptide comprising at least a portion of the hinge region. The Fc region may contain a CH4 domain, which is present in some antibody classes. In one embodiment, the present invention provides a method for determining the Fc region of an antibody, comprising administering to the patient a method for determining whether or not a particular antibody is Fc-dependent. and CH1 region. In one embodiment, the invention comprises the Fc region CH3 region of an antibody. In another embodiment, the present invention provides a method for the production of a polypeptide comprising an Fc region, a CH1 region, and a Ckappa region from the constant region of an antibody. In one embodiment, a binding molecule of the invention comprises a constant region, e.g., a heavy chain constant region. In one embodiment, such a constant region is modified compared to the wild-type constant region. That is, the polypeptides of the present invention disclosed herein contain three heavy chain constant regions. (CH1, CH2, or CH3) and / or one or more light chain constant region domains (CL) Examples of modifications include alterations or modifications to one or more of the domains. These changes may include addition, deletion, or substitution of amino acids. These changes may affect effector function, half-life, and other functions. It may be included to optimize the period, etc.

[0073] As used herein, the term "binding specificity" refers to the ability of an antibody to react with one antigenic determinant and bind to another. The ability of an individual antibody combining site to react with an antigenic determinant of the molecule. The Fab portion is composed of the hypervariable regions of the heavy and light chains. The binding affinity of an antibody is is the strength of the reaction between a single antigenic determinant and a single binding site on an antibody. It is the sum of the attractive and repulsive forces acting between a determinant and the binding site of an antibody.

[0074] As used herein, the term "affinity" refers to the affinity of an antibody to an antigen at a single antigenic site. Within each antigenic site, the variable regions of the antibody "arms" interact with multiple It interacts with the antigen through weak non-covalent forces at the site of The affinity becomes stronger.

[0075] The term "conservative sequence modifications" refers to amino acid sequences that are modified to improve the binding characteristics of an antibody or antibody fragment containing the amino acid sequence. These conservative modifications refer to amino acid modifications that do not substantially affect or alter the Modifications include amino acid substitutions, additions, and deletions. Modifications can be made by any method known in the art. Mutagenesis of the present invention can be achieved by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are those in which the amino acid residues have similar side chains. A family of amino acid residues with similar side chains is used. These families include those with basic side chains. amino acids with acidic side chains (e.g., lysine, arginine, histidine), aspartic acid, glutamic acid), amino acids with uncharged polar side chains (e.g., Glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, threonine tryptophan), amino acids with nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), amino acids with β-branched side chains amino acids (e.g., threonine, valine, isoleucine) and amino acids with aromatic side chains (e.g., For example, tyrosine, phenylalanine, tryptophan, and histidine. Thus, one or more amino acid residues in an antibody may be more closely related to other amino acids from the same side chain family. The modified antibodies can be substituted with the amino acid residues described herein. It can be tested using the

[0076] The terms "homology" or "identity" refer to the degree of similarity between two polymer molecules, e.g., two DNA molecules or The term "synaptic cleavage" refers to the cleavage of two nucleic acid molecules, such as two RNA molecules, or two polypeptide molecules. The sequence identity of the subunits in both molecules is the same. For example, if the DNA is occupied by monomeric subunits, If a position is occupied by an adenine, then they are homologous or identical at that position. The homology between two sequences is a direct function of the number of matched or homologous positions, e.g. For example, half of the positions in the two sequences (e.g., if the polymer length is 5 subunits out of 10 subunits) positions) are homologous, two sequences are 50% homologous, and 90% of the positions (e.g. 9 out of 10) match or are homologous, the two sequences are 90% The percentage of "sequence identity" is calculated by comparing the two best matches over the comparison window. The sequence of interest can be determined by comparing the aligned sequences, where the The amino acid sequence fragments are used as reference sequences (additional or additions or deletions (e.g., gaps or overhangs) compared to the The percentages are the positions where identical amino acid residues occur in both sequences. Determine the number of matched positions to get the number of matched positions in the comparison window. Divide by the total number of positions in the sequence and multiply the result by 100 to get the percentage of sequence identity. The result is the percent identity of the subject sequence to the query sequence. The percent identity between two sequences is the result of optimal alignment of the two sequences. These arrangements take into account the number of gaps that need to be introduced and the length of each gap. It is a function of the number of identical positions shared by the columns.

[0077] The comparison of sequences and determination of percent identity between two sequences may be accomplished using a mathematical algorithm. In a preferred embodiment, the percent identity between two amino acid sequences can be achieved by The materials used were Blossum62 matrix or PAM250 matrix and 16, 14 , 12, 10, 8, 6 or 4 gap weight and 1, 2, 3, 4, 5 or 6 length weight The GAP program in the GCG software package (www.gc Needleman and Wunsch (1977) incorporated in the paper "The Journal of Clinical Nutrition and Life Sciences," available at www.clinicalnutrition.org.uk / 0) J. Mol. Biol. 48:444-453) algorithm. In yet another preferred embodiment, the percent identity between two nucleotide sequences is SgapDNA.CMP matrix and gap weights of 40, 50, 60, 70 or 80 In the GCG software package, using the weight of the quantity and length of 1, 2, 3, 4, 5 or 6 The GAP program of the GCG (available at www.gcg.com) is particularly preferred. The preferred set of parameters (and the one that should be used unless otherwise specified) is 12 gap penalty of 4, gap extension penalty of 4 and frameshift gap penalty of 5 This is the Blossum62 scoring matrix with the

[0078] The percent identity between two amino acid or nucleotide sequences is determined based on the PAM120 sequence. A weighted residue table, a gap length penalty of 12, and a gap penalty of 4 were used. E. Meyers and W. Mil incorporated into the IGN program (version 2.0) It was also determined using the algorithm of ler ((1989) CABIOS, 4:11-17). It is possible.

[0079] The nucleic acid and protein sequences described herein can be used as a "query sequence" to Searches are performed against databases to identify, for example, other family members or related sequences. Such searches can be performed as described by Altschul, et al. (1990) J. Mol. Biol. 215:403-10 NBLAST and XBLAST programs ( Nucleotide searches can be performed using BLAST (version 2.0). was performed using the NBLAST program, score=100, word length=12, Nucleotide sequences homologous to the specified nucleic acid molecule can be obtained. A quality search was performed using the XBLAST program, score=50, word length=3. Amino acid sequences homologous to the protein molecules of the invention can be obtained. Gapped sequences are available for comparison purposes. To obtain the alignment, Altschul et al. (1997) Nucl Gapped B as described in eic Acids Res.25:3389-3402 BLAST and Gapped BLAST programs can be used. When using the program, the default parameters of each program (e.g., XBLAST and NBLA) ST) can be used. See www.ncbi.nlm.nih.gov stomach.

[0080] As used herein, the term "composition" or "pharmaceutical composition" refers to a pharmaceutical composition containing a compound of the present invention and at least one carrier, stabilizer, diluent, dispersant, suspending agent, thickener and / or excipient, , optionally in admixture with two or more other pharmaceutically acceptable chemical components.

[0081] As used herein, the term "optical isomer" or "stereoisomer" refers to a given optical isomer of the present invention. It refers to any of the various stereoisomeric configurations that may exist for a compound, and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. refers to a molecule that has the property of not being superimposable on its mirror image partner, "Chiral" refers to a molecule that can be superimposed on its mirror image partner. The present invention includes enantiomers, diastereomers or racemates of the compounds. "Omers" are pairs of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. This term may be used interchangeably where appropriate. and is used to describe a racemic mixture. "Diastereoisomer" means a mixture of at least two Stereoisomers that have asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is determined by Cahn - Designated according to the Ingold-Prelog RS system. When they are antipodes, the stereochemistry at each chiral carbon is determined by either R or S. Resolved compounds of unknown absolute configuration can be assigned average values ​​at the wavelength of the sodium D line. It can be designated as (+) or (-) depending on the direction (right-handed or left-handed) that it rotates the plane polarized light. Certain compounds described herein contain one or more asymmetric centers or axes, however Regarding enantiomers, diastereomers and absolute stereochemistry, (R)- or (S)- Other stereoisomeric forms may occur which may be defined as:

[0082] As used herein, the term "pharmaceutically acceptable carrier" refers to a compound that is suitable for use in a pharmaceutical composition, as known to those skilled in the art. any solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g. , antibacterial agents, antifungal agents), isotonicity agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders , excipients, disintegrants, lubricants, sweeteners, flavoring agents, colorants, etc., and combinations thereof. (e.g., Remington's Pharmaceutical Sciences ,18th Ed.Mack Printing Company,1990,pp.1 289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, are contemplated for use in therapeutic or pharmaceutical compositions.

[0083] As used herein, the term "pharmaceutically acceptable salt" refers to a compound of the present invention that retains the biological activity of the compound. It refers to a salt that does not interfere with the properties and characteristics of the substance and does not cause significant irritation to the subject to which it is administered. vinegar.

[0084] As used herein, the term "subject" includes mammals and non-mammals. Examples of animals include, but are not limited to, humans, chimpanzees, apes, monkeys, cows, and horses. , sheep, goats, pigs; rabbits, dogs, cats, rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds and fish. In the case of, the subject is a human.

[0085] The term "subject in need of such treatment" refers to a person who is suffering from any biological, medical or physiological condition that may result from such treatment. refers to those who will benefit in terms of quality of life.

[0086] As used herein, the terms "treat" and "treat" refer to any disease or disorder. "Treating" or "treating" in one embodiment refers to ameliorating a disease or disorder (i.e., or delay, prevent, or reduce the development of at least one of its clinical symptoms. In another embodiment, "treat," "treating," or "treatment" refers to the treatment of a patient. At least one physical parameter, including those that may not be discernible by the individual, is considered In yet another embodiment, "treat," "treating," or "improving" refers to reducing or ameliorating "Treatment" can be physical (e.g., stabilization of discernible symptoms) or physiological (e.g., physical This refers to modulating a disease or disorder through either or both of the following: (a) stabilization of physiological parameters; (b) stabilization of physiological parameters;

[0087] As used herein, the terms "prevent" and "prevent" refer to any disease or disorder. "Preventing" or "preventing" means the prophylactic treatment of a disease or disorder or the early prevention or treatment of the onset of a disease or disorder. It refers to slowing down the progression of a disease.

[0088] The terms "therapeutically effective amount" or "therapeutically effective dose" refer interchangeably to the amount of a compound that produces a desired result (i.e., an enzyme or is a compound that reduces or inhibits protein activity, improves symptoms, alleviates symptoms or pathology, delays disease progression, Reduction of tumor size, inhibition of tumor growth, prevention of metastasis, viral, bacterial, fungal or parasitic infection In some embodiments, a therapeutically effective amount refers to an amount sufficient to produce a therapeutically effective effect (inhibition or prevention of a disease or injury). The amount does not induce or cause undesirable side effects. A therapeutically effective amount is an amount that does not induce or cause side effects, but is acceptable to medical professionals considering the patient's condition. A therapeutically effective amount is an amount that is tolerated by the patient. A therapeutically effective amount is achieved by administering a low dose initially, followed by increasing the desired dose. This can be determined by gradually increasing the dose until an effect is achieved. A "prophylactically effective dose" or "prophylactically effective amount" of a molecule of the invention is intended to be used to treat a disease, including conditions associated with cancer. The onset of symptoms can be prevented. " can result in a reduction in the severity of disease symptoms, including symptoms associated with cancer.

[0089] The compound names provided herein are based on ChemBioDraw Ultra ve This was obtained using version 14.0.

[0090] As used herein, the terms "a," "an," and "the" The term and similar terms used in connection with this invention (particularly in connection with the claims) are Unless otherwise indicated herein or clearly contradicted by context, the singular and plural It should be interpreted as including both.

[0091] Any formula given herein represents unlabeled forms as well as isotopically labeled forms of the compounds. It is also intended that isotopically labeled compounds have one or more atoms with a selected atomic mass. or mass numbers, except as substituted by atoms having the formulas depicted herein. The isotopes that can be incorporated into the compounds of the present invention include, for example, hydrogen Examples include elemental isotopes.

[0092] Linker-drug group The linker-drug groups of the present invention have the formula (I): [ka] (In the formula, R 1 is a reactive group, L1 is a bridging spacer, Lp is a divalent peptide spacer, G-L2-A is a self-immolative spacer, R 2 is the hydrophilic moiety, L2 is a bond, methylene, neopentylene, or C2-C3 alkenylene; A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(= O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where , each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl and the * in A indicates the point of attachment to D; L3 is a spacer moiety, and D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. (connected to A via a bond) or a pharmaceutically acceptable salt thereof.

[0093] Specific aspects and examples of linker-drug groups of the present invention are listed in the list of embodiments below. The features specified in each embodiment may be combined with other specified features to achieve the present invention. It will be appreciated that further embodiments of the invention may be provided.

[0094] Embodiment 1.R 1 is a reactive group, L1 is a bridging spacer, Lp is a divalent peptide spacer containing 1 to 4 amino acid residues; G-L2-A is a self-immolative spacer, R 2 is the hydrophilic moiety, L2 is a bond, methylene, neopentylene, or C2-C3 alkenylene; A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(= O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where , each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl and the * in A indicates the point of attachment to D; L3 is a spacer moiety, and D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A is bonded to A via a covalent bond.

[0095] Embodiment 2.R 1 is a reactive group, L1 is a bridging spacer, Lp is a divalent peptide spacer containing 1 to 4 amino acid residues; [ka] The base is [ka] is selected from, where: [ka] * indicates the point of attachment to the N or O of the drug moiety; [ka] *** indicates the attachment point to Lp, R 2 is the hydrophilic moiety, L2 is a bond, methylene, neopentylene, or C2-C3 alkenylene; A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(= O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where , each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl and the * in A indicates the point of attachment to D; L3 is a spacer moiety, and D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A is bonded to A via a covalent bond.

[0096] Embodiment 3. Formula (II): [ka] (In the formula, R1 is a reactive group, L1 is a bridging spacer, Lp is a divalent peptide spacer containing 1 to 4 amino acid residues; R 2 is the hydrophilic moiety, A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(= O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where , each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl and the * in A indicates the point of attachment to D; L3 is a spacer moiety, and D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. (connected to A via a bond) or a pharmaceutically acceptable salt thereof.

[0097] Embodiment 4.R 1 teeth, [ka] [ka] and L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C(=O)((CH2 ) m O) t (CH2) n -**;*-C(=O)(CH2) m-**;*-C(=O)N H((CH2) m O) t (CH2) n -**;*-C(=O)O(CH2) m SSC(R 3 )2(CH2) m C(=O)NR 3 (CH2) m ARN 3 C(=O)(CH2) m -** ;*-C(=O)O(CH2) m C(=O)NH(CH2) m -**;*-C(=O)( CH2) m NH(CH2) m -**;*-C(=O)(CH2) m NH(CH2) n C( =O)-**;*-C(=O)(CH2) m X1(CH2) m -**;*-C(=O)( (CH2) m O) t (CH2) n X1(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH 2) n X1(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n NH C(=O)(CH2) n X1(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n C(=O)NH(CH2) m -**;*-C(=O)(CH2) m C(R 3 )2-** or *-C(=O)(CH2) m C(=O)NH(CH2) m -** and where * in L1 indicates the point of attachment to Lp, and ** in L1 indicates the point of attachment to R1. Indicate the point, R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido or 1 to 3 [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group, Each R 3 is independently selected from H and C1-C6 alkyl; R 4 is 2-pyridyl or 4-pyridyl, Each R 5 are independently selected from H, C1-C6 alkyl, F, Cl, and —OH; Each R 6 are independently H, C1-C6 alkyl, F, Cl, -NH2, -OCH3, -O selected from CH2CH3, —N(CH3)2, —CN, —NO2 and —OH; Each R 7 are independently H, C 1~6 Alkyl, fluoro, -C(=O)OH substituted Benzyloxy, benzyl substituted with -C(=O)OH, benzyl substituted with -C(=O)OH TaC 1~4 C substituted with alkoxy and -C(=O)OH 1~4 alkyl , X1 is [ka] and each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 1 4, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 , 28, 29 and 30; Lp is composed of glycine, valine, citrulline, lysine, isoleucine, phenylalanine, Thionine, asparagine, proline, alanine, leucine, tryptophan and tyrosine is a bivalent peptide spacer comprising an amino acid residue selected from A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(= O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where , each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl and the * in A indicates the point of attachment to D; L3 is the structure [ka] (In the formula, (i) W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(= O)C(R b )2NHC(=O)O-**, -NHC(=O)C(R b )2NH-**, NHC(=O)C(R b )2NHC(=O)-**, -CH2N(XR 2 )C(=O) O-**, -C(=O)N(XR 2 )-**, -CH2N(XR 2 )C(=O)-* *, -C(=O)NR b -**, -C(=O)NH-**, -CH2NR b C(=O)- **, -CH2NR b C(=O)NH-**, -CH2NR b C(=O)NR b -**, -NHC(=O)-**, -NHC(=O)O-**, -NHC(=O)NH-**, - OC(=O)NH-**, -S(O)2NH-**, -NHS(O)2-**, -C(= O)-, -C(=O)O-**, -NH- or -CHN(R b )C(=O)CH2-* *, where each R b are independently H, C1-C6 alkyl or C3-C8 cyclo alkyl, and the ** in W indicates the point of attachment to X; X is a bond, triazolyl, or ***-CH2-triazolyl-*, where X *** indicates the point of attachment to W, and * of X indicates the point of attachment to R 2 indicates the point of attachment to (ii) W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC( =O)C(R b )2NHC(=O)O-**, -NHC(=O)C(R b )2NH-** , NHC(=O)C(R b )2NHC(=O)-**, -CH2N(XR 2 )C(=O )O-**, -C(=O)N(XR 2 )-**, -CH2N(XR 2)C(=O)- **, -C(=O)NR b -**, -C(=O)NH-**, -CH2NR b C(=O) -**, -CH2NR b C(=O)NH-**, -CH2NR b C(=O)NR b -** , -NHC(=O)-**, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-**, -S(O)2NH-**, -NHS(O)2-**, -C( ═O)—, —C(═O)O—, or —NH—, where each R b are independently H , C1-C6 alkyl, or C3-C8 cycloalkyl; and ** of W is indicates the point of attachment, X is ***-CH2-triazolyl-C 1~4 Alkylene-OC(O)NHS(O)2 NH-*, ***-C 4~6 Cycloalkylene-OC(O)NHS(O)2NH-*, * **-(CH2CH2O) n -C(O)NHS(O)2NH-*, ***-(CH2CH 2O) n -C(O)NHS(O)2NH-(CH2CH2O) n -* or ***-CH2 -Triazolyl-C 1~4 Alkylene-OC(O)NHS(O)2NH-(CH2CH2 O) n -*, where each n is independently 1, 2, or 3; and *** of X is W indicates the point of attachment to X, and the * indicates R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to and D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. of formula (I) or any one of embodiments 1-3, which is connected to A via a covalent bond. The compound or a pharmaceutically acceptable salt thereof.

[0098] Embodiment 5.R 1 teeth, [ka] and L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C(=O)((CH2 ) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; or *-C(=O )NH((CH2) m O) t (CH2) n -, where * in L1 is the indicates the point of attachment, and ** in L1 indicates R 1 indicates the point of attachment to each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is [ka] where * in Lp is a bond to L1. and ** in Lp indicates the point of attachment to the —NH— group of G; L3 is the structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-**, -C(=O )N(XR 2 )-**, -CH2N(XR 2 )C(=O)-**, -C(=O)NR b -**, -C(=O)NH-**, -CH2NR b C(=O)-**, -CH2NR b C(=O)NH-**, -CH2NR b C(=O)NR b -**, -NHC(=O)-* *, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-* *, -S(O)2NH-**, -NHS(O)2-**, -C(=O)-, -C(=O) -O-** or -NH-, where each R b are independently H, C1-C6 alkyl or is selected from C3-C8 cycloalkyl, and the ** in W indicates the point of attachment to X; X is a bond, triazolyl, or ***-CH2-triazolyl-*, where X *** indicates the point of attachment to W, and * of X indicates the point of attachment to R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to a spacer moiety having the formula: R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido or 1 to 3 [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group, A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(= O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where , each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl and the * in A indicates the point of attachment to D, and D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. of formula (I) or any one of embodiments 1-4, which is connected to A via a covalent bond. The compound or a pharmaceutically acceptable salt thereof.

[0099] Embodiment 6.R 1 teeth, [ka] and L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C(=O)((CH2 ) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; or *-C(=O )NH((CH2) m O) t (CH2) n -, where * in L1 is the indicates the point of attachment, and ** in L1 indicates R 1 indicates the point of attachment to each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is [ka] where * in Lp is a bond to L1. and ** in Lp indicates the point of attachment to the —NH— group of G; L3 is the structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-**, -C(=O )N(XR 2 )-**, -CH2N(XR 2 )C(=O)-**, -C(=O)NR b -**, -C(=O)NH-**, -CH2NR b C(=O)-**, -CH2NR b C(=O)NH-**, -CH2NR b C(=O)NR b -**, -NHC(=O)-* *, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-* *, -S(O)2NH-**, -NHS(O)2-**, -C(=O)-, -C(=O) -O-** or -NH-, where each R b are independently H, C1-C6 alkyl or is selected from C3-C8 cycloalkyl, and the ** in W indicates the point of attachment to X; X is a bond, triazolyl, or ***-CH2-triazolyl-*, where X *** indicates the point of attachment to W, and * of X indicates the point of attachment to R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to a spacer moiety having the formula: R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido or 1 to 3 [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group, A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(= O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where , each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl and the * in A indicates the point of attachment to D, and D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. of formula (I) or any one of embodiments 1-5, which is connected to A via a covalent bond. The compound or a pharmaceutically acceptable salt thereof.

[0100] Embodiment 7.R 1 teeth, [ka] and L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C(=O)((CH2 ) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; or *-C(=O )NH((CH2) m O) t (CH2) n -, where * in L1 is the indicates the point of attachment, and ** in L1 indicates R 1 indicates the point of attachment to each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is [ka] where * in Lp is a bond to L1. and ** in Lp indicates the point of attachment to the —NH— group of G; L3 is the structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b)C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-**, -C(=O )N(XR 2 )-**, -C(=O)NR b -**, -C(=O)NH-**, -CH 2NR b C(=O)-**, -CH2NR b C(=O)NH-**, -CH2NR b C( =O)NR b -**, -NHC(=O)-**, -NHC(=O)O-** or -NHC (=O)NH-**, where each R b are independently H, C1-C6 alkyl or C3-C8 cycloalkyl, and the ** in W indicates the point of attachment to X; X is a bond, triazolyl, or ***-CH2-triazolyl-*, where X *** indicates the point of attachment to W, and * of X indicates the point of attachment to R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to a spacer moiety having the formula: R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido or 1 to 3 [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group, A is a bond or -OC(=O)*, where * indicates the point of attachment to D, and D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. of formula (I) or any one of embodiments 1-6, which is connected to A via a covalent bond. The compound or a pharmaceutically acceptable salt thereof.

[0101] Embodiment 8.R 1 teeth, [ka] and L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C(=O)((CH2 ) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; or *-C(=O )NH((CH2) m O) t (CH2) n -, where * in L1 is the indicates the point of attachment, and ** in L1 indicates R 1 indicates the point of attachment to each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is [ka] where * in Lp is a bond to L1. and ** in Lp indicates the point of attachment to the —NH— group of G; L3 is the structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-** or -C(= O)N(XR 2 )-**, where each R b are independently H, C1-C6 alkyl and ** in W indicates the point of attachment to X; X is ***-CH2-triazolyl-*, where the *** of X is the bond to W. * indicates the point, and * indicates the R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to a spacer moiety having the formula: R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido or 1 to 3 [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group, A is a bond or -OC(=O)*, where * indicates the point of attachment to D, and D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. of formula (I) or any one of embodiments 1-7, which is connected to A via a covalent bond. The compound or a pharmaceutically acceptable salt thereof.

[0102] Embodiment 9.R 1 is a reactive group selected from Table 1 or Table 2, The compound of any one of embodiments 1 to 8, or a pharmaceutically acceptable salt thereof.

[0103] Embodiment 10.R 1 teeth, [ka] [ka] or a pharmaceutically acceptable salt thereof. Salt to be used.

[0104] Embodiment 11.R 1 teeth, [ka] or a pharmaceutically acceptable salt thereof. Salt to be used.

[0105] Embodiment 12.R 1 teeth, [ka] or a pharmaceutically acceptable salt thereof. Salt to be used.

[0106] Embodiment 13.R 1 teeth, [ka] or a pharmaceutically acceptable salt thereof. Salt to be used.

[0107] Embodiment 14.R1 is [ka] or a pharmaceutically acceptable salt thereof. Salt to be used.

[0108] Embodiment 15.R 1 is —ONH2, or one of the compounds or a pharmaceutically acceptable salt thereof.

[0109] Embodiment 16.R 1 teeth, [ka] or a pharmaceutically acceptable salt thereof. Salt to be used.

[0110] Embodiment 17.R 1 teeth, [ka] or a pharmaceutically acceptable salt thereof. Salt to be used.

[0111] Embodiment 18. Structure: [ka] wherein R is H, —CH or —CHCHC(═O)OH. or a pharmaceutically acceptable salt thereof of the compound of formula (I) or any one of embodiments 1-8, Acceptable salt.

[0112] Embodiment 19. Structure: [ka] wherein R is H, —CH or —CHCHC(═O)OH. or a pharmaceutically acceptable salt thereof of the compound of formula (I) or any one of embodiments 1-8, Acceptable salt.

[0113] Embodiment 20. Structure: [ka] wherein R is H, —CH or —CHCHC(═O)OH. or a pharmaceutically acceptable salt thereof of the compound of formula (I) or any one of embodiments 1-8, Acceptable salt.

[0114] Embodiment 21. Structure: [ka] wherein each R is independently selected from H, —CH, or —CHCHC(═O)OH. can be) or a pharmaceutically acceptable salt thereof of the compound of formula (I) or any one of embodiments 1-8, Acceptable salt.

[0115] Embodiment 22. Structure: [ka] wherein each R is independently selected from H, —CH, or —CHCHC(═O)OH. can be) or a pharmaceutically acceptable salt thereof of the compound of formula (I) or any one of embodiments 1-8, Acceptable salt.

[0116] Embodiment 23. Structure: [ka] (Wherein, Xa is —CH—, —OCH—, —NHCH—, or —NRCH—. and each R is independently H, —CH, or —CHCHC(═O)OH. or a pharmaceutically acceptable salt thereof of the compound of formula (I) or any one of embodiments 1-8, Acceptable salt.

[0117] Embodiment 24. Structure: [ka] wherein R is H, —CH or —CHCHC(═O)OH. or a pharmaceutically acceptable salt thereof of the compound of formula (I) or any one of embodiments 1-8, Acceptable salt.

[0118] Embodiment 25. Structure: [ka] (Wherein, Xb is —CH—, —OCH—, —NHCH—, or —NRCH—. and each R is independently H, —CH, or —CHCHC(═O)OH. or a pharmaceutically acceptable salt thereof of the compound of formula (I) or any one of embodiments 1-8, Acceptable salt.

[0119] Embodiment 26. Structure: [ka] or a pharmaceutically acceptable salt thereof of the compound of formula (I) or any one of embodiments 1-8, Acceptable salt.

[0120] Embodiment 27. Structure: [ka] or a pharmaceutically acceptable salt thereof of the compound of formula (I) or any one of embodiments 1-8, Acceptable salt.

[0121] Embodiment 28. Structure: [ka] or a pharmaceutically acceptable salt thereof of the compound of formula (I) or any one of embodiments 1-8, Acceptable salt.

[0122] Embodiment 29. Structure: [ka] or a pharmaceutically acceptable salt thereof of the compound of formula (I) or any one of embodiments 1-8, Acceptable salt.

[0123] Embodiment 30. Structure: [ka] or a pharmaceutically acceptable salt thereof of the compound of formula (I) or any one of embodiments 1-8, Acceptable salt.

[0124] Embodiment 31. Structure of a compound in any one of Tables 4A-4C contained herein or a pharmaceutically acceptable salt thereof of the compound of formula (I) or any one of embodiments 1-8, Acceptable salt.

[0125] Embodiment 32. Formula (V) [ka] (In the formula, L1 is a bridging spacer, Lp is a divalent peptide spacer, G-L2-A is a self-immolative spacer, R 2is the hydrophilic moiety, L2 is a bond, methylene, neopentylene, or C2-C3 alkenylene; A is a bond, **-OC(=O)-, [ka] , **-OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- or **-O C(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-, So, each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl selected, the ** in A indicates the point of attachment to L2, and L3 is a spacer portion) A linker-drug group linker of formula (I) having the structure:

[0126] Embodiment 33. L1 is a bridging spacer, Lp is a divalent peptide spacer containing 1 to 4 amino acid residues; G-L2-A is a self-immolative spacer, R 2 is the hydrophilic moiety, L2 is a bond, methylene, neopentylene, or C2-C3 alkenylene; A is a bond, **-OC(=O)-, [ka] , **-OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- or **-O C(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-, So, each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl selected, the ** in A indicates the point of attachment to L2, and 33. The linker of embodiment 32, wherein L3 is a spacer moiety.

[0127] Embodiment 34. L1 is a bridging spacer, Lp is a divalent peptide spacer containing 1 to 4 amino acid residues; [ka] The base is [ka] is selected from, where: [ka] * indicates the point of attachment to the N or O of the drug moiety; [ka] *** indicates the attachment point to Lp, R 2 is the hydrophilic moiety, L2 is a bond, methylene, neopentylene, or C2-C3 alkenylene; A is a bond, **-OC(=O)-, [ka] , **-OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- or **-O C(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-, So, each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl selected, the ** in A indicates the point of attachment to L2, and 34. The linker of embodiment 32 or 33, wherein L3 is a spacer moiety.

[0128] Embodiment 35. L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C( =O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; *-C(=O)NH((CH2) m O) t (CH2) n -**;*-C(=O)O(CH 2) m SSC(R 3 )2(CH2) m C(=O)NR 3 (CH2) m NR 3 C(=O)( CH2) m -**;*-C(=O)O(CH2) m C(=O)NH(CH2) m -**; *-C(=O)(CH2) m NH(CH2) m -**;*-C(=O)(CH2) m NH (CH2) n C(=O)-**;*-C(=O)(CH2) m X1(CH2) m -**; *-C(=O)((CH2) m O) t (CH2) n X1(CH2) n -**;*-C(= O)(CH2) m NHC(=O)(CH2) n -**;*-C(=O)((CH2) m O ) t (CH2) n NHC(=O)(CH2) n -**;*-C(=O)(CH2)m NH C(=O)(CH2) n X1(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n X1(CH2) n -**;*-C(=O)(( CH2) m O) t (CH2) n C(=O)NH(CH2) m -**;*-C(=O)(C H2) m C(R 3 )2-** or *-C(=O)(CH2) m C(=O)NH(CH2) m -**, where * of L1 indicates the point of attachment to Lp, R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido or 1 to 3 [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group, Each R 3 is independently selected from H and C1-C6 alkyl; X1 is [ka] and each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is composed of glycine, valine, citrulline, lysine, isoleucine, phenylalanine, Thionine, asparagine, proline, alanine, leucine, tryptophan and tyrosine is a bivalent peptide spacer comprising an amino acid residue selected from A is a bond, **-OC(=O)-, [ka] , **-OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- or **-O C(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-, So, each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl The ** in A indicates the attachment point to L2, L3 is the structure [ka] (In the formula, (i) W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(= O)C(R b )2NHC(=O)O-**, -NHC(=O)C(R b )2NH-**, NHC(=O)C(R b )2NHC(=O)-**, -CH2N(XR 2 )C(=O) O-**, -C(=O)N(XR 2 )-**, -CH2N(XR 2 )C(=O)-* *, -C(=O)NR b -**, -C(=O)NH-**, -CH2NRb C(=O)- **, -CH2NR b C(=O)NH-**, -CH2NR b C(=O)NR b -**, -NHC(=O)-**, -NHC(=O)O-**, -NHC(=O)NH-**, - OC(=O)NH-**, -S(O)2NH-**, -NHS(O)2-**, -C(= O)-, -C(=O)O-**, -NH- or -CHN(R b )C(=O)CH2-* *, where each R b are independently H, C1-C6 alkyl or C3-C8 cyclo alkyl, and the ** in W indicates the point of attachment to X; X is a bond, triazolyl, or ***-CH2-triazolyl-*, where X *** indicates the point of attachment to W, and * of X indicates the point of attachment to R 2 indicates the point of attachment to (ii) W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC( =O)C(R b )2NHC(=O)O-**, -NHC(=O)C(R b )2NH-** , NHC(=O)C(R b )2NHC(=O)-**, -CH2N(XR 2 )C(=O )O-**, -C(=O)N(XR 2 )-**, -CH2N(XR 2 )C(=O)- **, -C(=O)NR b -**, -C(=O)NH-**, -CH2NR b C(=O) -**, -CH2NR b C(=O)NH-**, -CH2NR b C(=O)NR b -** , -NHC(=O)-**, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-**, -S(O)2NH-**, -NHS(O)2-**, -C( ═O)—, —C(═O)O—, or —NH—, where each R b are independently H , C1-C6 alkyl, or C3-C8 cycloalkyl; and ** of W is indicates the point of attachment, X is ***-CH2-triazolyl-C 1~4 Alkylene-OC(O)NHS(O)2 NH-*, ***-C 4~6 Cycloalkylene-OC(O)NHS(O)2NH-*, * **-(CH2CH2O) n -C(O)NHS(O)2NH-*, ***-(CH2CH 2O) n -C(O)NHS(O)2NH-(CH2CH2O) n -* or ***-CH2 -Triazolyl-C 1~4 Alkylene-OC(O)NHS(O)2NH-(CH2CH2 O) n -*, where each n is independently 1, 2, or 3; and *** of X is W indicates the point of attachment to X, and the * indicates R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to 35. The linker of any one of embodiments 32-34, which is a spacer moiety having the following structure:

[0129] Embodiment 36. L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C( =O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; or -C(=O)NH((CH2) m ) t (CH2) n -, where * in L1 is , indicating the point of attachment to Lp, each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is [ka] where * in Lp is a bond to L1. and ** in Lp indicates the point of attachment to the —NH— group of G; L3 is the structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-**, -C(=O )N(XR 2 )-**, -CH2N(XR 2 )C(=O)-**, -C(=O)NR b -**, -C(=O)NH-**, -CH2NR b C(=O)-**, -CH2NR b C(=O)NH-**, -CH2NR b C(=O)NR b -**, -NHC(=O)-* *, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-* *, -S(O)2NH-**, -NHS(O)2-**, -C(=O)-, -C(=O) -O-** or -NH-, where each R b are independently H, C1-C6 alkyl or is selected from C3-C8 cycloalkyl, and the ** in W indicates the point of attachment to X; X is a bond, triazolyl, or ***-CH2-triazolyl-*, where X *** indicates the point of attachment to W, and * of X indicates the point of attachment to R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to a spacer moiety having the formula: R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido or 1 to 3 [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group, and A is a bond, **-OC(=O)-, [ka] , **-OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- or **-O C(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-, So, each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl Any one of embodiments 32 to 35, wherein ** in A indicates the point of attachment to L2. Linker.

[0130] Embodiment 37. L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C( =O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; or -C(=O)NH((CH2) m ) t (CH2) n -, where * in L1 is , indicating the point of attachment to Lp, each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is [ka] where * in Lp is a bond to L1. and ** in Lp indicates the point of attachment to the —NH— group of G; L3 is the structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-**, -C(=O )N(XR 2 )-**, -CH2N(XR 2)C(=O)-**, -C(=O)NR b -**, -C(=O)NH-**, -CH2NR b C(=O)-**, -CH2NR b C(=O)NH-**, -CH2NR b C(=O)NR b -**, -NHC(=O)-* *, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-* *, -S(O)2NH-**, -NHS(O)2-**, -C(=O)-, -C(=O) -O-** or -NH-, where each R b are independently H, C1-C6 alkyl or is selected from C3-C8 cycloalkyl, and the ** in W indicates the point of attachment to X; X is a bond, triazolyl, or ***-CH2-triazolyl-*, where X *** indicates the point of attachment to W, and * of X indicates the point of attachment to R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to a spacer moiety having the formula: R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido or 1 to 3 [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group, and A is a bond, **-OC(=O)-, [ka] , **-OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- or **-O C(=O)N(CH3)C(R a )2C(Ra )2N(CH3)C(=O)-, So, each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl Any one of embodiments 32-36, wherein ** in A indicates the point of attachment to L2. Linker.

[0131] Embodiment 38. L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C( =O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; or -C(=O)NH((CH2) m ) t (CH2) n -, where * in L1 is , indicating the point of attachment to Lp, each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is [ka] where * in Lp is a bond to L1. and ** in Lp indicates the point of attachment to the —NH— group of G; L3 is the structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-**, -C(=O )N(XR 2 )-**, -C(=O)NR b -**, -C(=O)NH-**, -CH 2NR b C(=O)-**, -CH2NR b C(=O)NH-**, -CH2NR b C( =O)NR b -**, -NHC(=O)-**, -NHC(=O)O-** or -NHC (=O)NH-**, where each R b are independently H, C1-C6 alkyl or C3-C8 cycloalkyl, and the ** in W indicates the point of attachment to X; X is a bond, triazolyl, or ***-CH2-triazolyl-*, where X *** indicates the point of attachment to W, and * of X indicates the point of attachment to R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to a spacer moiety having the formula: R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido or 1 to 3 [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group, and A is a bond or **-OC(=O)-, where ** of A is the point of attachment to L2. 38. The linker of any one of embodiments 32 to 37, wherein:

[0132] Embodiment 39. L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C( =O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; or -C(=O)NH((CH2) m ) t (CH2) n -, where * in L1 is , indicating the point of attachment to Lp, each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is [ka] where * in Lp is a bond to L1. and ** in Lp indicates the point of attachment to the —NH— group of G; L3 is the structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-** or -C(= O)N(XR 2 )-**, where each R b are independently H, C1-C6 alkyl and ** in W indicates the point of attachment to X; X is ***-CH2-triazolyl-*, where the *** of X is the bond to W. * indicates the point, and * indicates the R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to a spacer moiety having the formula: R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido or 1 to 3 [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group, and A is a bond or **-OC(=O)-, where ** of A is the point of attachment to L2. 39. The linker of any one of embodiments 32 to 38, wherein:

[0133] Embodiment 40. Formula (VI) [ka] (In the formula, L1 is a bridging spacer, Lp is a divalent peptide spacer, R 2 is the hydrophilic moiety, A is a bond, -OC(=O)-, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- or -OC(=O )N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-, where each Ra are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl , and L3 is a spacer portion) A linker of formula (V) having a structure having the structure:

[0134] Embodiment 41. L1 is a bridging spacer, Lp is a divalent peptide spacer containing 1 to 4 amino acid residues; R 2 is the hydrophilic moiety, A is a bond, -OC(=O)-, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- or -OC(=O )N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-, where each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl , and 41. The linker of embodiment 40, wherein L3 is a spacer moiety.

[0135] Embodiment 42. L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C( =O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; *-C(=O)NH((CH2) m O) t (CH2) n -**;*-C(=O)O(CH 2) m SSC(R 3 )2(CH2) m C(=O)NR 3(CH2) m NR 3 C(=O)( CH2) m -**;*-C(=O)O(CH2) m C(=O)NH(CH2) m -**; *-C(=O)(CH2) m NH(CH2) m -**;*-C(=O)(CH2) m NH (CH2) n C(=O)-**;*-C(=O)(CH2) m X1(CH2) m -**; *-C(=O)((CH2) m Or) t (CH2) n X1(CH2) n -**;*-C(= O)(CH2) m NHC(=O)(CH2) n -**;*-C(=O)((CH2) m Or ) t (CH2) n NHC(=O)(CH2) n -**;*-C(=O)(CH2) m NH C(=O)(CH2) n X1(CH2) n -**;*-C(=O)((CH2) m Or) t (CH2) n NHC(=O)(CH2) n X1(CH2) n -**;*-C(=O)(( CH2) m Or) t (CH2) n C(=O)NH(CH2) m -**;*-C(=O)(C H2) m C(R 3 )2-**or*-C(=O)(CH2) m C(=O)NH(CH2) m-**, where * of L1 indicates the point of attachment to Lp, R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido, 1 to 3 pieces [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group or polysarcosine; , Each R 3 is independently selected from H and C1-C6 alkyl; X1 is [ka] and each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is composed of glycine, valine, citrulline, lysine, isoleucine, phenylalanine, Thionine, asparagine, proline, alanine, leucine, tryptophan and tyrosine is a bivalent peptide spacer comprising an amino acid residue selected from A is a bond, -OC(=O)-, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- or -OC(=O )N(CH3)C(R a )2C(R a)2N(CH3)C(=O)-, where each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl , L3 is the structure [ka] (In the formula, (i) W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(= O)CH2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-**, -C (=O)N(XR 2 )-**, -CH2N(XR 2 )C(=O)-**, -C(=O )NR b -**, -C(=O)NH-**, -CH2NR b C(=O)-**, -CH2 NR b C(=O)NH-**, -CH2NR b C(=O)NR b -**, -NHC(=O )-**, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)N H-**, -S(O)2NH-**, -NHS(O)2-**, -C(=O)-, -C( =O)O-**, -NH- or -CH2N(R b )C(=O)CH2-**, where So, each R b are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl. The ** in W indicates the point of attachment to X, X is a bond, triazolyl, or ***-CH2-triazolyl-*, where X *** indicates the point of attachment to W, and * of X indicates the point of attachment to R 2 indicates the point of attachment to (ii) W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC( =O)C(R b )2NHC(=O)O-**, -NHC(=O)C(R b )2NH-** , NHC(=O)C(R b )2NHC(=O)-**, -CH2N(XR 2 )C(=O )O-**, -C(=O)N(XR 2 )-**, -CH2N(XR 2 )C(=O)- **, -C(=O)NR b -**, -C(=O)NH-**, -CH2NR b C(=O) -**, -CH2NR b C(=O)NH-**, -CH2NR b C(=O)NR b -** , -NHC(=O)-**, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-**, -S(O)2NH-**, -NHS(O)2-**, -C( ═O)—, —C(═O)O—, or —NH—, where each R b are independently H , C1-C6 alkyl, or C3-C8 cycloalkyl; and ** of W is indicates the point of attachment, X is ***-CH2-triazolyl-C 1~4 Alkylene-OC(O)NHS(O)2 NH-*, ***-C 4~6 Cycloalkylene-OC(O)NHS(O)2NH-*, * **-(CH2CH2O) n -C(O)NHS(O)2NH-*, ***-(CH2CH 2O) n -C(O)NHS(O)2NH-(CH2CH2O) n -* or ***-CH2 -Triazolyl-C 1~4Alkylene-OC(O)NHS(O)2NH-(CH2CH2 O) n -*, where each n is independently 1, 2, or 3; and *** of X is W indicates the point of attachment to X, and the * indicates R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to 42. The linker of embodiment 40 or 41, wherein the linker is a spacer moiety having the following structure:

[0136] Embodiment 43. L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C( =O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; or -C(=O)NH((CH2) m ) t (CH2) n -, where * in L1 is , indicating the point of attachment to Lp, each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is [ka] where * in Lp is a bond to L1. and ** in Lp indicates the point of attachment to the -NH- group; L3 is the structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-**, -C(=O )N(XR 2 )-**, -CH2N(XR 2 )C(=O)-**, -C(=O)NR b -**, -C(=O)NH-**, -CH2NR b C(=O)-**, -CH2NR b C(=O)NH-**, -CH2NR b C(=O)NR b -**, -NHC(=O)-* *, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-* *, -S(O)2NH-**, -NHS(O)2-**, -C(=O)-, -C(=O) -O-** or -NH-, where each R b are independently H, C1-C6 alkyl or is selected from C3-C8 cycloalkyl, and the ** in W indicates the point of attachment to X; X is a bond, triazolyl, or ***-CH2-triazolyl-*, where X *** indicates the point of attachment to W, and * of X indicates the point of attachment to R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to a spacer moiety having the formula: R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido, 1 to 3 pieces [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group or polysarcosine; , and A is a bond, -OC(=O)-, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- or -OC(=O )N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-, where each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl The linker of any one of embodiments 40 to 42.

[0137] Embodiment 44. L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C( =O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; or -C(=O)NH((CH2) m ) t (CH2) n -, where * in L1 is , indicating the point of attachment to Lp, each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is [ka] where * in Lp is a bond to L1. and ** in Lp indicates the point of attachment to the -NH- group; L3 is the structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-**, -C(=O )N(XR 2 )-**, -CH2N(XR 2 )C(=O)-**, -C(=O)NR b -**, -C(=O)NH-**, -CH2NR b C(=O)-**, -CH2NR b C(=O)NH-**, -CH2NR b C(=O)NR b -**, -NHC(=O)-* *, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-* *, -S(O)2NH-**, -NHS(O)2-**, -C(=O)-, -C(=O) -O-** or -NH-, where each R b are independently H, C1-C6 alkyl or is selected from C3-C8 cycloalkyl, and the ** in W indicates the point of attachment to X; X is a bond, triazolyl, or ***-CH2-triazolyl-*, where X *** indicates the point of attachment to W, and * of X indicates the point of attachment to R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to a spacer moiety having the formula: R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido, 1 to 3 pieces [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group or polysarcosine; , and A is a bond, -OC(=O)-, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- or -OC(=O )N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-, where each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl The linker of any one of embodiments 40 to 43.

[0138] Embodiment 45.L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C( =O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; or -C(=O)NH((CH2) m ) t (CH2) n -, where * in L1 is , indicating the point of attachment to Lp, each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is [ka] where * in Lp is a bond to L1. and ** in Lp indicates the point of attachment to the -NH- group; L3 is the structure [ka] (In the formula, W is -CH2O-**, CH2N(R b )C(=O)O-**, -NHC(=O)CH 2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-**, -C(=O) N(XR 2 )-**, -C(=O)NR b -**, -C(=O)NH-**, -CH2 NR b C(=O)-**, -CH2NR b C(=O)NH-**, -CH2NR b C(= O)NR b -**, -NHC(=O)-**, -NHC(=O)O-** or -NHC( =O)NH-**, where each R b are independently H, C1-C6 alkyl or C 3-C8 cycloalkyl, and the ** in W indicates the point of attachment to X; X is a bond, triazolyl, or ***-CH2-triazolyl-*, where X *** indicates the point of attachment to W, and * of X indicates the point of attachment to R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to a spacer moiety having the formula: R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido, 1 to 3 pieces [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group or polysarcosine; , and The linker of any one of embodiments 40 to 44, wherein A is a bond or -OC(=O)-. .

[0139] Embodiment 46.L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C( =O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; or -C(=O)NH((CH2) m ) t (CH2) n -, where * in L1 is , indicating the point of attachment to Lp, each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is [ka] where * in Lp is a bond to L1. and ** in Lp indicates the point of attachment to the -NH- group; L3 is the structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-** or -C(= O)N(XR 2 )-**, where each R b are independently H, C1-C6 alkyl and ** in W indicates the point of attachment to X; X is ***-CH2-triazolyl-*, where the *** of X is the bond to W. * indicates the point, and * indicates the R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to a spacer moiety having the formula: R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido, 1 to 3 pieces [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group or polysarcosine; , and The linker of any one of embodiments 40 to 45, wherein A is a bond or -OC(=O)-. .

[0140] Embodiment 47. Structure: [ka] wherein R is H, —CH or —CHCHC(═O)OH. 47. The linker of any one of embodiments 32 to 46, having the following structure:

[0141] Embodiment 48. Structure: [ka] wherein R is H, —CH or —CHCHC(═O)OH. 47. The linker of any one of embodiments 32 to 46, having the following structure:

[0142] Embodiment 49. Structure: [ka] wherein R is H, —CH or —CHCHC(═O)OH. 47. The linker of any one of embodiments 32 to 46, having the following structure:

[0143] Embodiment 50. Structure: [ka] wherein each R is independently selected from H, —CH, or —CHCHC(═O)OH. can be) 47. The linker of any one of embodiments 32 to 46, having the following structure:

[0144] Embodiment 51. Structure: [ka] wherein each R is independently selected from H, —CH, or —CHCHC(═O)OH. can be) 47. The linker of any one of embodiments 32 to 46, having the following structure:

[0145] Embodiment 52. Structure: [ka] (Wherein, Xa is —CH—, —OCH—, —NHCH—, or —NRCH—. and each R is independently H, —CH, or —CHCHC(═O)OH. 47. The linker of any one of embodiments 32 to 46, having the following structure:

[0146] Embodiment 53. Structure: [ka] wherein R is H, —CH or —CHCHC(═O)OH. 47. The linker of any one of embodiments 32 to 46, having the following structure:

[0147] Embodiment 54. Structure: [ka] (Wherein, Xb is —CH—, —OCH—, —NHCH—, or —NRCH—. and each R is independently H, —CH, or —CHCHC(═O)OH. 47. The linker of any one of embodiments 32 to 46, having the following structure:

[0148] Embodiment 55. Structure: [ka] 47. The linker of any one of embodiments 32 to 46, having the following structure:

[0149] Embodiment 56. Structure: [ka] 47. The linker of any one of embodiments 32 to 46, having the following structure:

[0150] Embodiment 57. Structure: [ka] 47. The linker of any one of embodiments 32 to 46, having the following structure:

[0151] Embodiment 58. Structure: [ka] 47. The linker of any one of embodiments 32 to 46, having the following structure:

[0152] Embodiment 59. Structure: [ka] 47. The linker of any one of embodiments 32 to 46, having the following structure:

[0153] For illustrative purposes, the general reaction schemes shown herein are for the preparation of compounds of the present invention and polymers. This provides a promising route for the synthesis of key intermediates. A more detailed description of the individual reaction steps is provided in See the Examples section below. Specific starting materials and reagents are shown in the schemes below. Although the present invention is illustrated and described, other starting materials and reagents can be easily substituted to produce a variety of derivatives and / or can provide the reaction conditions. Furthermore, compounds prepared by the methods described below Many of these can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art. It can also be done as follows.

[0154] By way of example, a general synthesis of compounds of formula (II) is shown below in Scheme 1. [ka]

[0155] Antibody-drug conjugates of the present invention The present invention relates to immunoconjugates herein that comprise a linker that includes one or more hydrophilic moieties. The present invention provides antibody-drug conjugates, also referred to as antibody-drug conjugates.

[0156] The antibody drug conjugate of the present invention has the formula (III): [ka] (In the formula, Ab is an antibody or fragment thereof; R 100 is a coupling group, L1 is a bridging spacer, Lp is a divalent peptide spacer, G-L2-A is a self-immolative spacer, R 2 is the hydrophilic moiety, L2 is a bond, methylene, neopentylene, or C2-C3 alkenylene; A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(= O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where , each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl and the * in A indicates the point of attachment to D; L3 is a spacer moiety, D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. is connected to A via a bond, and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16) It has the following structure.

[0157] Particular aspects and examples of antibody drug conjugates of the invention are listed below in the embodiments. The features specified in each embodiment may be combined with other specified features. It will be appreciated that further embodiments of the present invention may be provided.

[0158] Embodiment 60. Ab is an antibody or a fragment thereof, R 100 is a coupling group, L1 is a bridging spacer, Lp is a divalent peptide spacer containing 1 to 4 amino acid residues; G-L2-A is a self-immolative spacer, R 2 is the hydrophilic moiety, L2 is a bond, methylene, neopentylene, or C2-C3 alkenylene; A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(= O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where , each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl and the * in A indicates the point of attachment to D; L3 is a spacer moiety, D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. is connected to A via a bond, and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16. An immunoconjugate of formula (III):

[0159] Embodiment 61. Ab is an antibody or a fragment thereof, R 100 is a coupling group, L1 is a bridging spacer, Lp is a divalent peptide spacer containing 1 to 4 amino acid residues; [ka] The base is [ka] is selected from, where: [ka] * indicates the point of attachment to the N or O of the drug moiety; [ka] *** indicates the attachment point to Lp, R 2 is the hydrophilic moiety, L2 is a bond, methylene, neopentylene, or C2-C3 alkenylene; A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(= O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where , each R aare independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl and the * in A indicates the point of attachment to D; L3 is a spacer moiety, D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. is connected to A via a bond, and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16. The immunoconjugate of formula (III) or embodiment 60, wherein

[0160] Embodiment 62. Formula (IV) [ka] (In the formula, Ab is an antibody or fragment thereof; R 100 is a coupling group, L1 is a bridging spacer, Lp is a divalent peptide spacer containing 1 to 4 amino acid residues; R 2 is the hydrophilic moiety, A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(= O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where , each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl and the * in A indicates the point of attachment to D; L3 is a spacer moiety, D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. is connected to A via a bond, and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16) The immunoconjugate of formula (III) or any one of embodiments 60-61, having the structure Route.

[0161] Embodiment 63. Ab is an antibody or a fragment thereof, R 100 teeth, [ka] [ka] where R 100 *** indicates the attachment point for Ab, L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C(=O)((CH2 ) m O) t (CH2) n -**;*-C(=O)(CH2) m -**;*-C(=O)N H((CH2) m O) t (CH2) n -**;*-C(=O)O(CH2) m SSC(R 3 )2(CH2) m C(=O)NR 3 (CH2) m NR 3 C(=O)(CH2) m -** ;*-C(=O)O(CH2) m C(=O)NH(CH2) m -**;*-C(=O)( CH2)m NH(CH2) m -**;*-C(=O)(CH2) m NH(CH2) n C( =O)-**;*-C(=O)(CH2) m X1(CH2) m -**;*-C(=O)( (CH2) m O) t (CH2) n X1(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH 2) n X1(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n NH C(=O)(CH2) n X1(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n C(=O)NH(CH2) m -**;*-C(=O)(CH2) m C(R 3 )2-** or *-C(=O)(CH2) m C(=O)NH(CH2) m -** and where * in L1 indicates the point of attachment to Lp, and ** in L1 indicates the point of attachment to R 100 against indicates the point of attachment, R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido, 1 to 3 pieces [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group and polysarcosine; , Each R 3 is independently selected from H and C1-C6 alkyl; R 4 is 2-pyridyl or 4-pyridyl, Each R 5 are independently selected from H, C1-C6 alkyl, F, Cl, and —OH; Each R 6 are independently H, C1-C6 alkyl, F, Cl, -NH2, -OCH3, -O selected from CH2CH3, —N(CH3)2, —CN, —NO2 and —OH; Each R 7 are independently H, C 1~6 Alkyl, fluoro, -C(=O)OH substituted Benzyloxy, benzyl substituted with -C(=O)OH, benzyl substituted with -C(=O)OH TaC 1~4 C substituted with alkoxy and -C(=O)OH 1~4 alkyl , X1 is [ka] and each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp contains valine, citrulline, lysine, isoleucine, phenylalanine, methionine, selected from asparagine, proline, alanine, leucine, tryptophan and tyrosine a divalent peptide spacer comprising an amino acid residue A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(= O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where , each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl and the * in A indicates the point of attachment to D; L3 is the structure [ka] (In the formula, (i) W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(= O)C(R b )2NHC(=O)O-**, -NHC(=O)C(R b )2NH-**, NHC(=O)C(R b )2NHC(=O)-**, -CH2N(XR 2 )C(=O) O-**, -C(=O)N(XR 2 )-**, -CH2N(XR 2 )C(=O)-* *, -C(=O)NR b -**, -C(=O)NH-**, -CH2NR b C(=O)- **, -CH2NR b C(=O)NH-**, -CH2NR bC(=O)NR b -**, -NHC(=O)-**, -NHC(=O)O-**, -NHC(=O)NH-**, - OC(=O)NH-**, -S(O)2NH-**, -NHS(O)2-**, -C(= O)-, -C(=O)O-**, -NH- or -CHN(R b )C(=O)CH2-* *, where each R b are independently H, C1-C6 alkyl or C3-C8 cyclo alkyl, and the ** in W indicates the point of attachment to X; X is a bond, triazolyl, or ***-CH2-triazolyl-*, where X *** indicates the point of attachment to W, and * of X indicates the point of attachment to R 2 indicates the point of attachment to (ii) W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC( =O)C(R b )2NHC(=O)O-**, -NHC(=O)C(R b )2NH-** , NHC(=O)C(R b )2NHC(=O)-**, -CH2N(XR 2 )C(=O )O-**, -C(=O)N(XR 2 )-**, -CH2N(XR 2 )C(=O)- **, -C(=O)NR b -**, -C(=O)NH-**, -CH2NR b C(=O) -**, -CH2NR b C(=O)NH-**, -CH2NR b C(=O)NR b -** , -NHC(=O)-**, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-**, -S(O)2NH-**, -NHS(O)2-**, -C( ═O)—, —C(═O)O—, or —NH—, where each R b are independently H , C1-C6 alkyl, or C3-C8 cycloalkyl; and ** of W is indicates the point of attachment, X is ***-CH2-triazolyl-C 1~4 Alkylene-OC(O)NHS(O)2 NH-*, ***-C 4~6 Cycloalkylene-OC(O)NHS(O)2NH-*, * **-(CH2CH2O) n -C(O)NHS(O)2NH-*, ***-(CH2CH 2O) n -C(O)NHS(O)2NH-(CH2CH2O) n -* or ***-CH2 -Triazolyl-C 1~4 Alkylene-OC(O)NHS(O)2NH-(CH2CH2 O) n -*, where each n is independently 1, 2, or 3; and *** of X is W indicates the point of attachment to X, and the * indicates R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to a spacer moiety having the formula: D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. is connected to A via a bond, and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16. The immunoconjugate of formula (III) or any one of embodiments 60-62, .

[0162] Embodiment 64. Ab is an antibody or a fragment thereof, R 100 teeth, [ka] where R 100 *** indicates the attachment point for Ab, L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C(=O)((CH2 ) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; or *-C(=O )NH((CH2) m O) t (CH2) n -, where * in L1 is the indicates the point of attachment, and ** in L1 indicates R 100 indicates the point of attachment to each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is [ka] where * in Lp is a bond to L1. and ** in Lp indicates the point of attachment to the —NH— group of G; L3 is the structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-**, -C(=O )N(XR 2 )-**, -CH2N(XR 2 )C(=O)-**, -C(=O)NR b -**, -C(=O)NH-**, -CH2NR b C(=O)-**, -CH2NR b C(=O)NH-**, -CH2NR b C(=O)NR b -**, -NHC(=O)-* *, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-* *, -S(O)2NH-**, -NHS(O)2-**, -C(=O)-, -C(=O) -O-** or -NH-, where each R b are independently H, C1-C6 alkyl or is selected from C3-C8 cycloalkyl, and the ** in W indicates the point of attachment to X; X is a bond, triazolyl, or ***-CH2-triazolyl-*, where X *** indicates the point of attachment to W, and * of X indicates the point of attachment to R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to a spacer moiety having the formula: R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido, 1 to 3 pieces [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group and polysarcosine; , A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(= O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where , each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl and the * in A indicates the point of attachment to D; D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. is connected to A via a bond, and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16. The immunoconjugate of formula (III) or any one of embodiments 60-63, .

[0163] Embodiment 65. Ab is an antibody or a fragment thereof, R 100 teeth, [ka] where R 100 *** indicates the attachment point for Ab, L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C(=O)((CH2 ) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; or *-C(=O )NH((CH2) m O) t (CH2) n -, where * in L1 is the indicates the point of attachment, and ** in L1 indicates R 100 indicates the point of attachment to each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is [ka] where * in Lp is a bond to L1. and ** in Lp indicates the point of attachment to the —NH— group of G; L3 is the structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-**, -C(=O )N(XR 2 )-**, -CH2N(XR 2 )C(=O)-**, -C(=O)NR b -**, -C(=O)NH-**, -CH2NR b C(=O)-**, -CH2NR b C(=O)NH-**, -CH2NR b C(=O)NR b -**, -NHC(=O)-* *, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-* *, -S(O)2NH-**, -NHS(O)2-**, -C(=O)-, -C(=O) -O-** or -NH-, where each R b are independently H, C1-C6 alkyl or is selected from C3-C8 cycloalkyl, and the ** in W indicates the point of attachment to X; X is a bond, triazolyl, or ***-CH2-triazolyl-*, where X *** indicates the point of attachment to W, and * of X indicates the point of attachment to R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to a spacer moiety having the formula: R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido or 1 to 3 [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group and polysarcosine; , A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(= O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where , each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl and the * in A indicates the point of attachment to D; D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. is connected to A via a bond, and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16. The immunoconjugate of formula (III) or any one of embodiments 60-64, .

[0164] Embodiment 66. Ab is an antibody or a fragment thereof, R 100 teeth, [ka] where R 100 *** indicates the attachment point for Ab, L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C(=O)((CH2 ) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; or *-C(=O )NH((CH2) m O) t (CH2) n -, where * in L1 is the indicates the point of attachment, and ** in L1 indicates R 100 indicates the point of attachment to each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is [ka] where * in Lp is a bond to L1. and ** in Lp indicates the point of attachment to the —NH— group of G; L3 is the structure [ka] (In the formula, W is -CH2O-**, CH2N(R b )C(=O)O-**, -NHC(=O)CH 2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-**, -C(=O) N(XR 2 )-**, -C(=O)NR b -**, -C(=O)NH-**, -CH2 NR b C(=O)-**, -CH2NR b C(=O)NH-**, -CH2NR b C(= O)NR b -**, -NHC(=O)-**, -NHC(=O)O-** or -NHC( =O)NH-**, where each R b are independently H, C1-C6 alkyl or C 3-C8 cycloalkyl, and the ** in W indicates the point of attachment to X; X is a bond, triazolyl, or ***-CH2-triazolyl-*, where X *** indicates the point of attachment to W, and * of X indicates the point of attachment to R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to a spacer moiety having the formula: R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido, 1 to 3 pieces [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group and polysarcosine; , A is a bond or -OC(=O)*, where * indicates the point of attachment to D; D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. is connected to A via a bond, and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16. The immunoconjugate of formula (III) or any one of embodiments 60-65, .

[0165] Embodiment 67. Ab is an antibody or a fragment thereof, R 100 teeth, [ka] where R 100 *** indicates the attachment point for Ab, L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C(=O)((CH2 ) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; or *-C(=O )NH((CH2) m O) t (CH2) n -, where * in L1 is the indicates the point of attachment, and ** in L1 indicates R 100 indicates the point of attachment to each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is [ka] where * in Lp is a bond to L1. and ** in Lp indicates the point of attachment to the —NH— group of G; L3 is the structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-** or -C(= O)N(XR 2 )-**, where each R b are independently H, C1-C6 alkyl and ** in W indicates the point of attachment to X; X is ***-CH2-triazolyl-*, where the *** of X is the bond to W. * indicates the point, and * indicates the R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to a spacer moiety having the formula: R 2 Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Chido, 1 to 3 pieces [ka] a hydrophilic moiety selected from C2-C6 alkyl substituted with a group and polysarcosine; , A is a bond or -OC(=O)*, where * indicates the point of attachment to D; D is a drug moiety containing N or O, where D is a direct link from A to the N or O of the drug moiety. is connected to A via a bond, and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16. The immunoconjugate of formula (III) or any one of embodiments 60-66, .

[0166] Embodiment 68.R 100 is a coupling group, Formula (III) or embodiment 60 to Any one of 62 immunoconjugates.

[0167] Embodiment 69.R 100 teeth, [ka] [ka] where R 100 The *** indicates the point of attachment to Ab. The immunoconjugate of any one of embodiments 60 to 63.

[0168] Embodiment 70.R 100 teeth, [ka] where R 100 The *** indicates the point of attachment to Ab. The immunoconjugate of any one of embodiments 60 to 63.

[0169] Embodiment 71.R 100 teeth, [ka] where R 100 The *** indicates the point of attachment to Ab. The immunoconjugate of any one of embodiments 60 to 63.

[0170] Embodiment 72.R 100 teeth, [ka] where R 100 The *** indicates the point of attachment to Ab. The immunoconjugate of any one of embodiments 60 to 63.

[0171] Embodiment 73. Structure: [ka] wherein R is H, —CH or —CHCHC(═O)OH, and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ) The immunoconjugate of formula (III) or any one of embodiments 60-72, having the formula:

[0172] Embodiment 74. Structure: [ka] wherein R is H, —CH or —CHCHC(═O)OH, and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ) The immunoconjugate of formula (III) or any one of embodiments 60-72, having the formula:

[0173] Embodiment 75. Structure: [ka] wherein R is H, —CH or —CHCHC(═O)OH, and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ) The immunoconjugate of formula (III) or any one of embodiments 60-72, having the formula:

[0174] Embodiment 76. Structure: [ka] wherein each R is independently selected from H, —CH, or —CHCHC(═O)OH. and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16) The immunoconjugate of formula (III) or any one of embodiments 60-72, having the formula:

[0175] Embodiment 77. Structure: [ka] wherein each R is independently selected from H, —CH, or —CHCHC(═O)OH. and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16) The immunoconjugate of formula (III) or any one of embodiments 60-72, having the formula:

[0176] Embodiment 78. Structure: [ka] (Wherein, Xa is —CH—, —OCH—, —NHCH—, or —NRCH—. and each R is independently H, —CH, or —CHCHC(═O)OH; and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16) The immunoconjugate of formula (III) or any one of embodiments 60-72, having the formula:

[0177] Embodiment 79. Structure: [ka] wherein R is H, —CH or —CHCHC(═O)OH, and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ) The immunoconjugate of formula (III) or any one of embodiments 60-72, having the formula:

[0178] Embodiment 80. Structure: [ka] (Wherein, Xb is —CH—, —OCH—, —NHCH—, or —NRCH—. and each R is independently H, —CH, or —CHCHC(═O)OH; and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16) The immunoconjugate of formula (III) or any one of embodiments 60-72, having the formula:

[0179] Embodiment 81. Structure: [ka] (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16) The immunoconjugate of formula (III) or any one of embodiments 60-72, having the formula:

[0180] Embodiment 82. Structure: [ka] (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16) The immunoconjugate of formula (III) or any one of embodiments 60-72, having the formula:

[0181] Embodiment 83. Structure: [ka] (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16) The immunoconjugate of formula (III) or any one of embodiments 60-72, having the formula:

[0182] Embodiment 84. Structure: [ka] (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16) The immunoconjugate of formula (III) or any one of embodiments 60-72, having the formula:

[0183] Embodiment 85. Structure: [ka] (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16) The immunoconjugate of formula (III) or any one of embodiments 60-72, having the formula:

[0184] Specific Embodiments and Examples of Linker-Drug Groups, Linkers, and Antibody Drug Conjugates of the Invention are provided in the list of additional embodiments listed below. The features described may be combined with other specified features to provide further embodiments of the present invention. It will be recognized that.

[0185] Embodiment 86.G is [ka] where * in G indicates the point of attachment to L2 and ** in G indicates the point of attachment to L3. and *** in G indicates the point of attachment to Lp. or a pharmaceutically acceptable salt thereof, formula (V) or any one of embodiments 32-3 9 and a linker of formula (III) or any one of embodiments 60 to 61. Immunoconjugates.

[0186] Embodiment 87.G is [ka] where * in G indicates the point of attachment to L2 and ** in G indicates the point of attachment to L3. and *** in G indicates the point of attachment to Lp. or a pharmaceutically acceptable salt thereof, formula (V) or any one of embodiments 32-3 9 and a linker of formula (III) or any one of embodiments 60 to 61. Immunoconjugates.

[0187] embodiment88.L1は、*-C(=O)(CH2) m O(CH2) m -**;*-C( =O)((CH2) m Or) t (CH2) n -**;*-C(=O)(CH2) m -**; *-C(=O)NH((CH2) m Or) t (CH2) n -**;*-C(=O)O(CH 2) m SSC(R) 3 )2(CH2) m C(=O)NR 3 (CH2) m NR 3 C(=O)( CH2) m -**;*-C(=O)O(CH2) m C(=O)NH(CH2) m -**; *-C(=O)(CH2) m NH(CH2) m -**;*-C(=O)(CH2) m NH (CH2) n C(=O)-**;*-C(=O)(CH2) m X1(CH2) m -**; *-C(=O)((CH2) m Or) t (CH2) n X1(CH2) n -**;*-C(= O)(CH2) m NHC(=O)(CH2) n -**;*-C(=O)((CH2) m Or ) t (CH2) n NHC(=O)(CH2) n -**;*-C(=O)(CH2) m NH C(=O)(CH2) n X1(CH2) n-**;*-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n X1(CH2) n -**;*-C(=O)(( CH2) m O) t (CH2) n C(=O)NH(CH2) m -**;*-C(=O)(C H2) m C(R 3 )2-** or *-C(=O)(CH2) m C(=O)NH(CH2) m -**, where * in L1 indicates the point of attachment to Lp, and ** in L1 If present, R 1 or ** in L1, if present, indicates the point of attachment to R 10 0 a compound of formula (I) or any one of embodiments 1-17, showing the point of attachment to or a pharmaceutically acceptable salt thereof, a linker of formula (V) or any one of embodiments 32 to 46. and an immunoconjugate of formula (III) or any one of embodiments 60 to 72.

[0188] Embodiment 89.L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C( =O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; *-C(=O)NH((CH2) m O) t (CH2) n -**;*-C(=O)(CH2 ) m NH(CH2) m -**;*-C(=O)(CH2) mNH(CH2) n C(=O) -**;*-C(=O)(CH2) m NHC(=O)(CH2) n -**;*-C(=O )((CH2) m O) t (CH2) n NHC(=O)(CH2) n -**;*-C(=O )((CH2) m O) t (CH2) n C(=O)NH(CH2) m -**;*-C(=O )(CH2) m C(R 3 )2-** or *-C(=O)(CH2) m C(=O)NH(C H2) m -**, where * in L1 indicates the point of attachment to Lp, and * in L1 * indicates R if present 1 or ** in L1, if present, indicates the point of attachment to R 100 The compound of formula (I) or any one of embodiments 1 to 17, showing the point of attachment to or a pharmaceutically acceptable salt thereof, formula (V) or any one of embodiments 32 to 46. a linker and an immunoconjugate of formula (III) or any one of embodiments 60 to 72 .

[0189] Embodiment 90.L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C( =O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; *-C(=O)NH((CH2) m O) t (CH2) n -**;*-C(=O)(CH2 ) m NH(CH2) m -**;*-C(=O)(CH2) m NH(CH2) n C(=O) -**; or *-C(=O)(CH2) m NHC(=O)(CH2) n -** and this where * in L1 indicates the point of attachment to Lp, and ** in L1, if present, indicates the point of attachment to R 1 or ** in L1, if present, indicates the point of attachment to R 100 The connection point for 16. A compound of formula (I) or any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, a salt of formula (V) or a linker of any one of embodiments 32 to 46 and formula (III) Or the immunoconjugate of any one of embodiments 60 to 72.

[0190] Embodiment 91.L1 is *-C(=O)(CH2) m O(CH2) m -**;*-C( =O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; or -C(=O)NH((CH2) m O) t (CH2) n -**, where L1 * in L indicates the point of attachment to Lp, and ** in L indicates the point of attachment to R, if present. 1 Conclusion Indicates the match or L1 **, if present, R 100 The formula ( I) or any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof; a linker of formula (V) or any one of embodiments 32 to 46 and a linker of formula (III) or any one of embodiments 32 to 46 1. An immunoconjugate of any one of forms 60 to 72.

[0191] Embodiment 92.L1 is *-C(=O)(CH2) m O(CH2) m -** and this where * in L1 indicates the point of attachment to Lp, and ** in L1, if present, indicates the point of attachment to R 1 or ** in L1, if present, indicates the point of attachment to R 100 The connection point for 16. A compound of formula (I) or any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, a salt of formula (V) or a linker of any one of embodiments 32 to 46 and formula (III) Or the immunoconjugate of any one of embodiments 60 to 72.

[0192] Embodiment 93.L1 is *-C(=O)((CH2) m O) t (CH2) n -** where * in L1 indicates the point of attachment to Lp, and ** in L1, if present , R 1 or ** in L1, if present, indicates the point of attachment to R 100 Conclusion A compound of formula (I) or any one of embodiments 1 to 17 or a pharmaceutical composition thereof, an acceptable salt of formula (V) or a linker of any one of embodiments 32 to 46 and formula (I II) or the immunoconjugate of any one of embodiments 60 to 72.

[0193] Embodiment 94. L1 is *-C(=O)(CH2) m -**, where L1* indicates the point of attachment to Lp, and ** in L1, if present, indicates the point of attachment to R 1 Attachment point for or L1 ** indicates R, if present 100Formula (I) showing the point of attachment to or a compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, of the formula V) or any one of embodiments 32 to 46 and a linker of formula (III) or embodiment 6 Any one of immunoconjugates 0 to 72.

[0194] Embodiment 95.L1 is -C(=O)NH((CH2) m O) t (CH2) n -** where * in L1 indicates the point of attachment to Lp, and ** in L1 indicates the point of attachment to Lp, In this case, R 1 or ** in L1, if present, indicates the point of attachment to R 100 against 18. A compound of formula (I) or any one of embodiments 1-17, or a pharmaceutical composition thereof, showing the point of attachment. a physiologically acceptable salt, a linker of formula (V) or any one of embodiments 32 to 46 and a compound of formula (III) Or the immunoconjugate of any one of embodiments 60 to 72.

[0195] Embodiment 96. Lp is a bivalent peptide spacer, such as an enzymatically cleavable spacer. A compound of formula (I) or any one of embodiments 1 to 17, or a pharmaceutical composition thereof, an acceptable salt of formula (V) or a linker of any one of embodiments 32 to 46 and formula (I II) or any one of embodiments 60 to 72 or any one of embodiments 86 to 95 Two immunoconjugates.

[0196] Embodiment 97. Lp is selected from the group consisting of glycine, valine, citrulline, lysine, isoleucine, phenylalan ... Aminopropyl, thiamin ... a bivalent peptide spacer comprising an amino acid residue selected from guanine and tyrosine; A compound of formula (I) or any one of embodiments 1 to 17 or a pharmaceutically acceptable salt thereof a salt, a linker of formula (V) or any one of embodiments 32 to 46 and a compound of formula (III) or The immunoconjugate of any one of embodiments 60 to 72 or any one of embodiments 86 to 95. Jugate.

[0197] Embodiment 98. Lp contains 1 to 4 amino acid residues, for example 2 to 4 amino acid residues. Formula (I) or any one of embodiments 1 to 17, wherein the bivalent peptide spacer or a pharmaceutically acceptable salt thereof, a compound of formula (V) or any one of embodiments 32 to 46 a linker and formula (III) or any one of embodiments 60 to 72 or embodiment Any one of 86 to 95 immunoconjugates.

[0198] Embodiment 99. Lp is each independently selected from glycine, valine, citrulline, lysine, iodopropyl methylcellulose, methylcellulose, methylcellulose, methylcellulose-1, methylcellulose-2, methylcellulose-3, methylcellulose-4, methylcellulose-5, methylcellulose-6, methylcellulose-7, methylcellulose-8, methylcellulose-9, methylcellulose-10, methylcellulose-11, methylcellulose-12, methylcellulose-13 Soleucine, phenylalanine, methionine, asparagine, proline, alanine, leucine A bivalent amino acid comprising 1 to 4 amino acid residues selected from sucrose, tryptophan, and tyrosine. A compound of formula (I) or any one of embodiments 1 to 17, which is a peptide spacer or a pharmaceutically acceptable salt thereof, the phosphorus of formula (V) or any one of embodiments 32 to 46. Car and formula (III) or any one of embodiments 60 to 72 or embodiments 86 to 9 5. Any one of the immunoconjugates.

[0199] Embodiment 100.Lp is [ka] where * in Lp is a bond to L1. and ** in Lp indicates the point of attachment to the -NH- group in formula (II), or The ** in Lp indicates the point of attachment to G in formula (I). or a pharmaceutically acceptable salt thereof, formula (V) or any one of embodiments 32 to 4 6 and a linker of formula (III) or any one of embodiments 60 to 72. or the immunoconjugate of any one of embodiments 86 to 95.

[0200] Embodiment 101.Lp is [ka] wherein * in Lp indicates the point of attachment to L1, and ** in Lp indicates the group of formula (II ) or the ** in Lp indicates the point of attachment to G in formula (I). The compound of formula (I) or any one of embodiments 1 to 17 or a pharmaceutically acceptable salt thereof, An acceptable salt, a linker of formula (V) or any one of embodiments 32 to 46 and a compound of formula (II I) or any one of embodiments 60 to 72 or any one of embodiments 86 to 95 Immunoconjugates of.

[0201] Embodiment 102.Lp is [ka] wherein * in Lp indicates the point of attachment to L1, and ** in Lp indicates the group of formula (II ) or the ** in Lp indicates the point of attachment to G in formula (I). The compound of formula (I) or any one of embodiments 1 to 17 or a pharmaceutically acceptable salt thereof, An acceptable salt, a linker of formula (V) or any one of embodiments 32 to 46 and a compound of formula (II I) or any one of embodiments 60 to 72 or any one of embodiments 86 to 95 Immunoconjugates of.

[0202] Embodiment 103.Lp is [ka] wherein * in Lp indicates the point of attachment to L1, and ** in Lp indicates the group of formula (II ) or the ** in Lp indicates the point of attachment to G in formula (I). The compound of formula (I) or any one of embodiments 1 to 17 or a pharmaceutically acceptable salt thereof, An acceptable salt, a linker of formula (V) or any one of embodiments 32 to 46 and a compound of formula (II I) or any one of embodiments 60 to 72 or any one of embodiments 86 to 95 Immunoconjugates of.

[0203] Embodiment 104.Lp is [ka] wherein * in Lp indicates the point of attachment to L1, and ** in Lp indicates the group of formula (II ) or the ** in Lp indicates the point of attachment to G in formula (I). The compound of formula (I) or any one of embodiments 1 to 17 or a pharmaceutically acceptable salt thereof, An acceptable salt, a linker of formula (V) or any one of embodiments 32 to 46 and a compound of formula (II I) or any one of embodiments 60 to 72 or any one of embodiments 86 to 95 Immunoconjugates of.

[0204] Embodiment 105.Lp is [ka] wherein * in Lp indicates the point of attachment to L1, and ** in Lp indicates the group of formula (II ) or the ** in Lp indicates the point of attachment to G in formula (I). The compound of formula (I) or any one of embodiments 1 to 17 or a pharmaceutically acceptable salt thereof, An acceptable salt, a linker of formula (V) or any one of embodiments 32 to 46 and a compound of formula (II I) or any one of embodiments 60 to 72 or any one of embodiments 86 to 95 Immunoconjugates of.

[0205] Embodiment 106. L2 is a bond, methylene, neopentylene or C2-C3 alkenyl. 16. The compound of formula (I) or any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, An acceptable salt, a linker of formula (V) or any one of embodiments 32 to 46 and a compound of formula (II I) or any one of embodiments 60 to 72 or any one of embodiments 86 to 105 Two immunoconjugates.

[0206] Embodiment 107. L2 is a bond or methylene, Formula (I) or Embodiments 1-1 7, or a pharmaceutically acceptable salt thereof, Formula (V) or any one of embodiments 32 to 7 46 and a linker of formula (III) or any one of embodiments 60 to 72. Or the immunoconjugate of any one of embodiments 86 to 105.

[0207] Embodiment 108. A compound of Formula (I) or any of Embodiments 1-17, wherein L2 is a bond. A compound or a pharmaceutically acceptable salt thereof, of formula (V) or any of embodiments 32 to 46 or one linker and formula (III) or any one of embodiments 60 to 72 or The immunoconjugate of any one of Forms 86 to 105.

[0208] Embodiment 109. L2 is methylene, Any one of the compounds or pharmaceutically acceptable salts thereof, formula (V) or any of embodiments 32 to 46 any one of the linkers and formula (III) or any one of embodiments 60 to 72 or The immunoconjugate of any one of embodiments 86 to 105.

[0209] Embodiment 110.A is a bond, -OC(=O)-, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- or -OC(=O )N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-, where each R a are independently selected from H, C1-C6 alkyl, or C3-C8 cycloalkyl a compound of formula (I) or any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, a salt of formula (V) or a linker of any one of embodiments 32 to 46 and formula (III) or or any one of embodiments 60 to 72 or any one of embodiments 86 to 109. Epidemic conjugate.

[0210] Embodiment 111. A is a bond or -OC(=O), 17. Any one of the compounds of formula (V) or embodiment 3, or a pharmaceutically acceptable salt thereof. 2 to 46 and a linker of formula (III) or any of embodiments 60 to 72 The immunoconjugate of one or any one of embodiments 86 to 109.

[0211] Embodiment 112. A is a compound of formula (I) or any one of embodiments 1 to 17, which is a bond. a compound or a pharmaceutically acceptable salt thereof, of formula (V) or any of embodiments 32 to 46 one linker and formula (III) or any one or embodiment of embodiments 60 to 72 86-109.

[0212] Embodiment 113.A is a compound of formula (I) or any of embodiments 1 to 17, wherein -OC(=O). Any one of the compounds or pharmaceutically acceptable salts thereof, formula (V) or embodiments 32 to 46 and a linker according to any one of formula (III) or any one of embodiments 60 to 72 or the immunoconjugate of any one of embodiments 86 to 109.

[0213] Embodiment 114.A is [ka] 18. A compound of formula (I) or any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, an acceptable salt thereof, a linker of formula (V) or any one of embodiments 32 to 46 and a linker of formula (III ) or any one of embodiments 60 to 72 or any one of embodiments 86 to 109 Immunoconjugates of.

[0214] Embodiment 115.A is -OC(=O)N(CH3)CH2CH2N(CH3)C(= O)- or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O )-, where each R a are independently H, C1-C6 alkyl or C3-C8 cyclo A compound of Formula (I) or any one of Embodiments 1-17, wherein or a pharmaceutically acceptable salt thereof, the phosphorus of formula (V) or any one of embodiments 32 to 46. Car and formula (III) or any one of embodiments 60 to 72 or embodiments 86 to 1 Any one of the immunoconjugates of 09.

[0215] Embodiment 116. L3 is a spacer moiety, Formula (I) or any of embodiments 1-17. or a pharmaceutically acceptable salt thereof, formula (V) or any one of embodiments 32 to 4 6 and a linker of formula (III) or any one of embodiments 60 to 72. or the immunoconjugate of any one of embodiments 86 to 115.

[0216] Embodiment 117.L3 is a structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -NHC(=O)C(R b )2NH-**, NHC(=O )C(R b )2NHC(=O)-**, -CH2N(XR 2 )C(=O)O-**, - C(=O)N(XR 2 )-**, -CH2N(XR 2 )C(=O)-**, -C(= O)NR b -**, -C(=O)NH-**, -CH2NR b C(=O)-**, -CH 2NR b C(=O)NH-**, -CH2NR b C(=O)NR b -**, -NHC(= O)-**, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O) NH-**, -S(O)2NH-**, -NHS(O)2-**, -C(=O)-, -C (=O)O-** or -NH-, where each R b are independently H, C1 to C6 alkyl and C3-C8 cycloalkyl, wherein the ** of W is the bond to X. Showing the point, X is a bond, triazolyl, or ***-CH2-triazolyl-*, where X *** indicates the point of attachment to W, and * of X indicates the point of attachment to R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to The compound of formula (I) or any one of embodiments 1 to 17, wherein the compound is a spacer moiety having the formula: or a pharmaceutically acceptable salt thereof, formula (V) or any one of embodiments 32 to 46. a linker and formula (III) or any one of embodiments 60 to 72 or embodiment 86 Any one of ~115 immunoconjugates.

[0217] Embodiment 118.L3 is a structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -NHC(=O)CH2NH-**, NHC(=O)CH 2NHC(=O)-**, -CH2N(XR 2 )C(=O)O-**, -C(=O)N (XR 2 )-**, -CH2N(XR 2 )C(=O)-**, -C(=O)NRb - **, -C(=O)NH-**, -CH2NR b C(=O)-**, -CH2NR b C( =O)NH-**, -CH2NR b C(=O)NR b -**, -NHC(=O)-**, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-**, -S(O)2NH-**, -NHS(O)2-**, -C(=O)-, -C(=O)O- ** or -NH-, where each R b are independently H, C1-C6 alkyl or C 3-C8 cycloalkyl, where ** of W indicates the point of attachment to X; X is a bond, and L3 *R 2 (indicating the attachment point to The compound of formula (I) or any one of embodiments 1 to 17, wherein the compound is a spacer moiety having the formula: or a pharmaceutically acceptable salt thereof, formula (V) or any one of embodiments 32 to 46. a linker and formula (III) or any one of embodiments 60 to 72 or embodiment 86 Any one of ~115 immunoconjugates.

[0218] Embodiment 119.L3 is a structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-**, -C(=O )N(XR 2 )-**, -CH2N(XR 2 )C(=O)-**, -C(=O)NR b -**, -C(=O)NH-**, -CH2NR b C(=O)-**, -CH2NR b C(=O)NH-**, -CH2NR b C(=O)NR b -**, -NHC(=O)-* *, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-* *, -S(O)2NH-**, -NHS(O)2-**, -C(=O)-, -C(=O) -O-** or -NH-, where each R b are independently H, C1-C6 alkyl or is selected from C3-C8 cycloalkyl, and the ** in W indicates the point of attachment to X; X is triazolyl, where *** of X indicates the point of attachment to W, and * of X is R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to The compound of formula (I) or any one of embodiments 1 to 17, wherein the compound is a spacer moiety having the formula: or a pharmaceutically acceptable salt thereof, formula (V) or any one of embodiments 32 to 46. a linker and formula (III) or any one of embodiments 60 to 72 or embodiment 86 Any one of ~115 immunoconjugates.

[0219] Embodiment 120.L3 is a structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-**, -C(=O )N(XR 2 )-**, -CH2N(XR 2 )C(=O)-**, -C(=O)NR b -**, -C(=O)NH-**, -CH2NR b C(=O)-**, -CH2NR b C(=O)NH-**, -CH2NR b C(=O)NR b -**, -NHC(=O)-* *, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-* *, -S(O)2NH-**, -NHS(O)2-**, -C(=O)-, -C(=O) -O-** or -NH-, where each R b are independently H, C1-C6 alkyl or is selected from C3-C8 cycloalkyl, and the ** in W indicates the point of attachment to X; X is ***-CH2-triazolyl-*, where the *** of X is the bond to W. * indicates the point, and * indicates the R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to The compound of formula (I) or any one of embodiments 1 to 17, wherein the compound is a spacer moiety having the formula: or a pharmaceutically acceptable salt thereof, formula (V) or any one of embodiments 32 to 46. a linker and formula (III) or any one of embodiments 60 to 72 or embodiment 86 Any one of ~115 immunoconjugates.

[0220] Embodiment 121.L3 is a structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-**, -C(=O )N(XR 2 )-**, where each R b are independently H, C1-C6 alkyl or C3-C8 cycloalkyl, where ** in W indicates the point of attachment to X. Show, X is a bond, triazolyl, or ***-CH2-triazolyl-*, where X *** indicates the point of attachment to W, and * of X indicates the point of attachment to R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to The compound of formula (I) or any one of embodiments 1 to 17, wherein the compound is a spacer moiety having the formula: or a pharmaceutically acceptable salt thereof, formula (V) or any one of embodiments 32 to 46. a linker and formula (III) or any one of embodiments 60 to 72 or embodiment 86 Any one of ~115 immunoconjugates.

[0221] Embodiment 122.L3 is a structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-**, -C(=O )N(XR 2 )-**, where each R b are independently H, C1-C6 alkyl or C3-C8 cycloalkyl, where ** in W indicates the point of attachment to X. Show, X is a bond, and L3 *R 2 (indicating the attachment point to The compound of formula (I) or any one of embodiments 1 to 17, wherein the compound is a spacer moiety having the formula: or a pharmaceutically acceptable salt thereof, formula (V) or any one of embodiments 32 to 46. a linker and formula (III) or any one of embodiments 60 to 72 or embodiment 86 Any one of ~115 immunoconjugates.

[0222] Embodiment 123.L3 is a structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-**, -C(=O )N(XR 2 )-**, where each R b are independently H, C1-C6 alkyl or C3-C8 cycloalkyl, where ** in W indicates the point of attachment to X. Show, X is triazolyl, where *** of X indicates the point of attachment to W, and * of X is R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to The compound of formula (I) or any one of embodiments 1 to 17, wherein the compound is a spacer moiety having the formula: or a pharmaceutically acceptable salt thereof, formula (V) or any one of embodiments 32 to 46. a linker and formula (III) or any one of embodiments 60 to 72 or embodiment 86 Any one of ~115 immunoconjugates.

[0223] Embodiment 124.L3 is a structure [ka] (In the formula, W is -CH2O-**, -CH2N(R b )C(=O)O-**, -NHC(=O)C H2NHC(=O)O-**, -CH2N(XR 2 )C(=O)O-**, -C(=O )N(XR 2 )-**, where each R b are independently H, C1-C6 alkyl or C3-C8 cycloalkyl, where ** in W indicates the point of attachment to X. Show, X is ***-CH2-triazolyl-*, where the *** of X is the bond to W. * indicates the point, and * indicates the R 2 indicates the point of attachment to L3 *R 2 (indicating the attachment point to The compound of formula (I) or any one of embodiments 1 to 17, wherein the compound is a spacer moiety having the formula: or a pharmaceutically acceptable salt thereof, formula (V) or any one of embodiments 32 to 46. a linker and formula (III) or any one of embodiments 60 to 72 or embodiment 86 Any one of ~115 immunoconjugates.

[0224] Embodiment 125.R 2 is a hydrophilic moiety, Any one of the compounds or pharmaceutically acceptable salts thereof, formula (V) or embodiments 32 to 46 Any one of the linkers and formula (III) or any one of embodiments 60 to 72 or the immunoconjugate of any one of embodiments 86 to 124.

[0225] Embodiment 126.R 2 polyethylene glycol, polyalkylene glycol, sugar, Oligosaccharides, polypeptides, 1-3 [ka] The hydrophilic moiety is selected from C2-C6 alkyl substituted with a group and polysarcosine. a compound of formula (I) or any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof; a salt of formula (V) or a linker according to any one of embodiments 32 to 46 and formula (III) or The immunization method according to any one of embodiments 60 to 72 or any one of embodiments 86 to 124. Conjugates.

[0226] Embodiment 127.R 2 is a sugar, a compound or a pharmaceutically acceptable salt thereof, of formula (V) or any of embodiments 32 to 46 one linker and formula (III) or any one or embodiment of embodiments 60 to 72 1. The immunoconjugate of any one of forms 86 to 124.

[0227] Embodiment 128.R 2 is an oligosaccharide, Any one of the compounds or pharmaceutically acceptable salts thereof, formula (V) or any of embodiments 32 to 46 any one of the linkers and formula (III) or any one of embodiments 60 to 72 or The immunoconjugate of any one of embodiments 86 to 124.

[0228] Embodiment 129.R 2 is a polypeptide of formula (I) or of embodiments 1 to 17. Any one of the compounds or pharmaceutically acceptable salts thereof, formula (V) or embodiments 32 to 46 and a linker according to any one of formula (III) or any one of embodiments 60 to 72 or the immunoconjugate of any one of embodiments 86 to 124.

[0229] Embodiment 130.R 2 is a polyalkylene glycol, A compound of any one of Forms 1 to 17 or a pharmaceutically acceptable salt thereof, Formula (V) or embodiment A linker according to any one of embodiments 32 to 46 and a linker according to formula (III) or any one of embodiments 60 to 72 125. The immunoconjugate of any one of embodiments 86 to 124.

[0230] Embodiment 131.R 2 is the structure -(O(CH2) m ) t Polyalkylene having R' where R' is OH, OCH3 or OCH2CH2C(=O)OH. wherein m is 1 to 10 and t is 4 to 40. 17. Any one of the compounds of formula (V) or embodiment 3, or a pharmaceutically acceptable salt thereof. 2 to 46 and a linker of formula (III) or any of embodiments 60 to 72 The immunoconjugate of one or any one of embodiments 86 to 124.

[0231] Embodiment 132.R 2 has the structure -((CH2) m O) t Polyalkylene having R''- glycol, where R'' is CH3 or CH2CH2C(=O)OH , m is 1 to 10, and t is 4 to 40, 7, or a pharmaceutically acceptable salt thereof, Formula (V) or any one of embodiments 32 to 7 46 and a linker of formula (III) or any one of embodiments 60 to 72. Or the immunoconjugate of any one of embodiments 86 to 124.

[0232] Embodiment 133.R 2 is polyethylene glycol, 1 to 17, or a pharmaceutically acceptable salt thereof, of formula (V) or embodiment 32 to 46 and a linker of formula (III) or any of embodiments 60 to 72 or the immunoconjugate of any one of embodiments 86 to 124.

[0233] Embodiment 134.R 2 The structure is -(OCH2CH2) t Polyethylene glycol having R' where R' is OH, OCH3 or OCH2CH2C(=O)OH. and t is 4 to 40. or a pharmaceutically acceptable salt thereof, formula (V) or any one of embodiments 32 to 46. a linker and formula (III) or any one of embodiments 60 to 72 or embodiment 86 Any one of ~124 immunoconjugates.

[0234] Embodiment 135.R 2 The structure is -(CH2CH2O) t Polyethylene with R''- glycol, where R'' is H, CH3, or CH2CH2C(=O)OH. and t is 4 to 40. or a pharmaceutically acceptable salt thereof, formula (V) or any one of embodiments 32 to 46. a linker and formula (III) or any one of embodiments 60 to 72 or embodiment 86 Any one of ~124 immunoconjugates.

[0235] Embodiment 136.R 2 teeth, [ka] where R 2 The * or wavy line indicates the point of attachment to X or L3. or a compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, of formula (V): or a linker according to any one of embodiments 32 to 46 and formula (III) or embodiments 60 to 68 72 or the immunoconjugate of any one of embodiments 86 to 124. .

[0236] Embodiment 137.R 2 teeth, [ka] where R 2 * indicates the point of attachment to X or L3. A compound of any one of Forms 1 to 17 or a pharmaceutically acceptable salt thereof, Formula (V) or A linker according to any one of embodiments 32 to 46 and formula (III) or any one of embodiments 60 to 72 The immunoconjugate of any one of embodiments 86 to 124.

[0237] Embodiment 138.R 2 teeth, [ka] where R 2* indicates the point of attachment to X or L3. A compound of any one of Forms 1 to 17 or a pharmaceutically acceptable salt thereof, Formula (V) or A linker according to any one of embodiments 32 to 46 and formula (III) or any one of embodiments 60 to 72 The immunoconjugate of any one of embodiments 86 to 124.

[0238] Embodiment 139.R 2 teeth, [ka] where R 2 * indicates the point of attachment to X or L3. A compound of any one of Forms 1 to 17 or a pharmaceutically acceptable salt thereof, Formula (V) or A linker according to any one of embodiments 32 to 46 and formula (III) or any one of embodiments 60 to 72 The immunoconjugate of any one of embodiments 86 to 124.

[0239] Embodiment 140. Each R 3 are independently selected from H and C1-C6 alkyl, (I) or a compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof. , a linker of formula (V) or any one of embodiments 32 to 46 and a linker of formula (III) or The immunoconjugate of any one of embodiments 60 to 72 or any one of embodiments 86 to 139. Jugate.

[0240] Embodiment 141. Each R 3 is H, A compound or a pharmaceutically acceptable salt thereof, of formula (V) or any of embodiments 32 to 46 or one linker and formula (III) or any one of embodiments 60 to 72 or The immunoconjugate of any one of Forms 86 to 139.

[0241] Embodiment 142. Each R 3 are independently selected from C1 to C6 alkyl, or a compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, of the formula V) or any one of embodiments 32 to 46 and a linker of formula (III) or embodiment 6 The immunoconjugate of any one of embodiments 0 to 72 or any one of embodiments 86 to 139. Route.

[0242] Embodiment 143.X1 is [ka] 18. A compound of formula (I) or any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, an acceptable salt thereof, a linker of formula (V) or any one of embodiments 32 to 46 and a linker of formula (III ) or any one of embodiments 60 to 72 or any one of embodiments 86 to 142 Immunoconjugates of.

[0243] Embodiment 144.X1 is [ka] 18. A compound of formula (I) or any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, an acceptable salt thereof, a linker of formula (V) or any one of embodiments 32 to 46 and a linker of formula (III ) or any one of embodiments 60 to 72 or any one of embodiments 86 to 142 Immunoconjugates of.

[0244] Embodiment 145. Each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. A compound of formula (I) or any one of embodiments 1 to 17, or a pharmaceutical composition thereof, selected from a compound represented by the formula (V) or any one of embodiments 32 to 46, III) or any one of embodiments 60 to 72 or any one of embodiments 86 to 144 or one immunoconjugate.

[0245] Embodiment 146. A compound of Formula (I), wherein each m is independently selected from 1, 2, 3, 4, and 5. or a compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, of the formula V) or any one of embodiments 32 to 46 and a linker of formula (III) or embodiment 6 The immunoconjugate of any one of embodiments 0 to 72 or any one of embodiments 86 to 144. Route.

[0246] Embodiment 147. A compound of Formula (I) or The compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, of formula (V) or The linker of any one of embodiments 32 to 46 and formula (III) or embodiments 60 to 72 or the immunoconjugate of any one of embodiments 86 to 144.

[0247] Embodiment 148. Each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. A compound of formula (I) or any one of embodiments 1 to 17, or a pharmaceutical composition thereof, selected from a compound represented by the formula (V) or any one of embodiments 32 to 46, III) or any one of embodiments 60 to 72 or any one of embodiments 86 to 147 or one immunoconjugate.

[0248] Embodiment 149. A compound of Formula (I), wherein each n is independently selected from 1, 2, 3, 4, and 5. or a compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, of the formula V) or any one of embodiments 32 to 46 and a linker of formula (III) or embodiment 6 The immunoconjugate of any one of embodiments 0 to 72 or any one of embodiments 86 to 147. Route.

[0249] Embodiment 150. A compound of Formula (I) or The compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, of formula (V) or The linker of any one of embodiments 32 to 46 and formula (III) or embodiments 60 to 72 or the immunoconjugate of any one of embodiments 86 to 147.

[0250] Embodiment 151. Each t is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 25, 26, 27, 28, 29 and 30. 17. Any one of the compounds of formula (V) or embodiment 3, or a pharmaceutically acceptable salt thereof. 2 to 46 and a linker of formula (III) or any of embodiments 60 to 72 The immunoconjugate of one or any one of embodiments 86 to 150.

[0251] Embodiment 152. Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30. or a pharmaceutically acceptable salt thereof, a compound of formula (V) or any one of embodiments 32 to 46 a linker and formula (III) or any one of embodiments 60 to 72 or embodiment Any one of 86 to 150 immunoconjugates.

[0252] Embodiment 153. Each t is independently 4, 5, 6, 7, 8, 9, 10, 11, 12, 1 From 3, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 A compound of formula (I) or any one of embodiments 1 to 17, or a pharmaceutical composition thereof, an acceptable salt of formula (V) or a linker of any one of embodiments 32 to 46 and formula (I II) or any one of embodiments 60 to 72 or any one of embodiments 86 to 150 One immunoconjugate.

[0253] Embodiment 154. Each t is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17 and 18, A compound of any one of embodiments 1 to 17 or a pharmaceutically acceptable salt thereof, The linker of any one of embodiments 32 to 46 and formula (III) or of embodiments 60 to 72 The immunoconjugate of any one or any one of embodiments 86 to 150.

[0254] Embodiment 155.y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 1 3, 14, 15 or 16 of formula (III) or any one of embodiments 60 to 72. or the immunoconjugate of any one of embodiments 86 to 154.

[0255] Embodiment 156.y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 1 3 or 14. 86-154. An immunoconjugate according to any one of claims 86 to 154.

[0256] Embodiment 157.y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 Formula (III) or any one of embodiments 60 to 72 or embodiments 86 to 15 Any one of the four immunoconjugates.

[0257] Embodiment 158.y is a compound of formula (I) II) or any one of embodiments 60 to 72 or any one of embodiments 86 to 154 One immunoconjugate.

[0258] Embodiment 159.y is 1, 2, 3, 4, 5, 6, 7 or 8 of formula (III) or The immunization method according to any one of embodiments 60 to 72 or any one of embodiments 86 to 154. Conjugates.

[0259] Embodiment 160. y is 1, 2, 3, 4, 5 or 6, Formula (III) or embodiment The immunoconjugate of any one of embodiments 60 to 72 or any one of embodiments 86 to 154. gate.

[0260] Embodiment 161.y is 1, 2, 3 or 4, Formula (III) or embodiments 60 to 7 155. The immunoconjugate of any one of embodiments 2 or any one of embodiments 86 to 154.

[0261] In embodiment 162, y is 1 or 2, and y is 1 or 2. 155. The immunoconjugate of any one of embodiments 86 to 154.

[0262] Embodiment 163. The compound of formula (III) or any one of embodiments 60 to 72, wherein y is 2. or the immunoconjugate of any one of embodiments 86 to 154.

[0263] Embodiment 164. The compound of formula (III) or any one of embodiments 60 to 72, wherein y is 4. or the immunoconjugate of any one of embodiments 86 to 154.

[0264] Embodiment 165. The compound of formula (III) or any one of embodiments 60 to 72, wherein y is 6. or the immunoconjugate of any one of embodiments 86 to 154.

[0265] Embodiment 166. The compound of formula (III) or any one of embodiments 60 to 72, wherein y is 8. or the immunoconjugate of any one of embodiments 86 to 154.

[0266] Embodiment 167.D is a compound of Formula (I) or any of Embodiments 1-17, which is a drug moiety. or one of the compounds or pharmaceutically acceptable salts thereof or Formula (III) or embodiments 60 to 7 167. The immunoconjugate of any one of embodiments 2 or any one of embodiments 86 to 166.

[0267] Embodiment 168. D is a drug moiety containing N or O, wherein D is a drug moiety selected from A and and a group according to formula (I) or embodiment 1-10, wherein the group is attached to A through a direct bond to N or O of the group. 17 or a pharmaceutically acceptable salt thereof or a compound of formula (III) or The immunoconjugate of any one of embodiments 60 to 72 or any one of embodiments 86 to 166. Jugate.

[0268] Embodiment 169.D is a compound of Formula (I) or any of embodiments 1-17, which is a hydrophobic drug moiety. Any one of the compounds or pharmaceutically acceptable salts thereof or Formula (III) or Embodiment 6 The immunoconjugate of any one of embodiments 0 to 72 or any one of embodiments 86 to 166. Route.

[0269] Embodiment 170. D is a hydrophobic drug moiety containing N or O, where D is any one of A to is attached to A via a direct bond to an N or O of the drug moiety (e.g., D is attached to A ammonium nitrite when added), Formula (I) or any of Embodiments 1 to 17 or one of the compounds or pharmaceutically acceptable salts thereof or Formula (III) or embodiments 60 to 7 167. The immunoconjugate of any one of embodiments 2 or any one of embodiments 86 to 166.

[0270] Embodiment 171.D is a hydrophobic drug moiety of the formula having an SlogP value of 1.5 to 7. (I) or a compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof. or formula (III) or any one of embodiments 60 to 72 or embodiments 86 to 16 6. Any one of the immunoconjugates.

[0271] Embodiment 172.D is a hydrophobic drug moiety of the formula having an SlogP value of 1.5 to 6. (I) or a compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof. or formula (III) or any one of embodiments 60 to 72 or embodiments 86 to 16 6. Any one of the immunoconjugates.

[0272] Embodiment 173.D is a hydrophobic drug moiety of the formula having an SlogP value of 1.5 to 5. (I) or a compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof. or formula (III) or any one of embodiments 60 to 72 or embodiments 86 to 16 6. Any one of the immunoconjugates.

[0273] Embodiment 174.D is a hydrophobic drug moiety of the formula having an SlogP value of 1.5 to 4. (I) or a compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof. or formula (III) or any one of embodiments 60 to 72 or embodiments 86 to 16 6. Any one of the immunoconjugates.

[0274] Embodiment 175.D is a hydrophobic drug moiety of the formula having an SlogP value of 1.5 to 3. (I) or a compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof. or formula (III) or any one of embodiments 60 to 72 or embodiments 86 to 16 6. Any one of the immunoconjugates.

[0275] Embodiment 176.D is a hydrophobic drug moiety of the formula having an SlogP value of 1.5 to 2. (I) or a compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof. or formula (III) or any one of embodiments 60 to 72 or embodiments 86 to 16 6. Any one of the immunoconjugates.

[0276] Embodiment 177.D relates to a hydrophobic drug moiety of formula (I) having an SlogP value of 2 to 7. ) or a compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, or is of formula (III) or any one of embodiments 60 to 72 or embodiments 86 to 166 Any one immunoconjugate.

[0277] Embodiment 178.D relates to a hydrophobic drug moiety of formula (I) having an SlogP value of 2 to 6. ) or a compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, or is of formula (III) or any one of embodiments 60 to 72 or embodiments 86 to 166 Any one immunoconjugate.

[0278] Embodiment 179.D relates to a hydrophobic drug moiety of formula (I) having an SlogP value of 2 to 5. ) or a compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, or is of formula (III) or any one of embodiments 60 to 72 or embodiments 86 to 166 Any one immunoconjugate.

[0279] Embodiment 180.D relates to a hydrophobic drug moiety of formula (I) having an SlogP value of 2 to 4. ) or a compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, or is of formula (III) or any one of embodiments 60 to 72 or embodiments 86 to 166 Any one immunoconjugate.

[0280] Embodiment 181.D relates to a hydrophobic drug moiety of formula (I) having an SlogP value of 2 to 3. ) or a compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, or is of formula (III) or any one of embodiments 60 to 72 or embodiments 86 to 166 Any one immunoconjugate.

[0281] Embodiment 182.D is a compound of formula (I) or of embodiments 1 to 17 which is an auristatin. Any one of the compounds or pharmaceutically acceptable salts thereof or Formula (III) or Embodiment 6 The immunoconjugate of any one of embodiments 0 to 72 or any one of embodiments 86 to 166. Route.

[0282] Embodiment 183.D is [ka] 18. A compound of formula (I) or any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, or any one of the formula (III) or any one of the embodiments 60 to 72 or any one of the embodiments Any one of 86 to 166 immunoconjugates.

[0283] Embodiment 184.D is a compound of Formula (I) or Embodiments 1-1 which is not an MCL-1 inhibitor. 7 or a pharmaceutically acceptable salt thereof or a compound of formula (III) or an embodiment thereof The immunoconjugate of any one of embodiments 60 to 72 or any one of embodiments 86 to 166. ugate.

[0284] Embodiment 185.D is a compound of Formula (I) or Embodiments 1-1 that is not a BCL-2 inhibitor. 7 or a pharmaceutically acceptable salt thereof or a compound of formula (III) or an embodiment thereof The immunoconjugate of any one of embodiments 60 to 72 or any one of embodiments 86 to 166. ugate.

[0285] Embodiment 186.D relates to a compound of formula (I) or embodiment 1 to 6 which is not a BCL-XL inhibitor. 17 or a pharmaceutically acceptable salt thereof or a compound of formula (III) or The immunoconjugate of any one of embodiments 60 to 72 or any one of embodiments 86 to 166. Jugate.

[0286] Embodiment 187. A linker of formula (I) (i.e., the portion not including D) or formula (III) The linker (i.e., the portion connecting Ab and D) may be any of the linkers shown in Tables 4A to 4C herein, for example. A linker selected from the disclosed L2 to L208, for example: [ka] wherein the wavy line indicates the point of attachment to D. or a pharmaceutically acceptable salt thereof or a compound of formula (III) or an embodiment thereof The immunoconjugate of any one of embodiments 60 to 72 or any one of embodiments 86 to 166. gate.

[0287] Embodiment 188. Any linker selected from L2 to L208 described herein. ,for example, [ka] etc., where the wavy line indicates the point of attachment to D, and * indicates an antibody or fragment thereof a linker-drug group or a compound of formula (I) having the structure of formula (V) 47. The linker of any one of forms 32 to 46.

[0288] Conjugation Methods The present invention provides a method for conjugating a linker-drug group of the invention to an antibody or antibody fragment to form a single Various methods for producing antibody drug conjugates containing linkers with the above hydrophilic moieties to provide.

[0289] A general reaction scheme for forming an antibody drug conjugate of formula (III) is shown below: Scheme 2: [ka] where RG2 is the R of compatibility.1 reacts with the corresponding R 100 Base (such The D, R groups are reactive groups that form a 1 , L1, Lp, Ab, y and BiR 100 is as defined herein.

[0290] Scheme 3 shows the R 1 group (as defined herein) to form R 100 Groups (as used herein) a reactive group (RG2) that covalently attaches the linker-drug group to the antibody via a linker-drug group (defined as This general method for forming an antibody drug conjugate of formula (III) further comprises: For illustrative purposes only, Scheme 3 shows an antibody with four RG2 groups. [ka]

[0291] In one embodiment, the linker-drug group is attached to the antibody via a modified cysteine ​​residue in the antibody. conjugated (see, e.g., WO 2014 / 124316 Scheme 4 shows the free cysteine ​​generated from engineered cysteine ​​residues in antibodies. The ol group is R 1 group (where R 1 is a maleimide) to form a linker-drug The group R 100 group (where R 100 is a succinimide ring) This approach is illustrated for forming antibody-drug conjugates of formula (III). For demonstration purposes only, Scheme 4 shows an antibody with four free thiol groups. [ka]

[0292] In another embodiment, the linker-drug group is conjugated to the antibody via a lysine residue in the antibody. Scheme 5 shows how free amine groups from lysine residues in antibodies can be converted to R 1 Group (where: R 1 is an NHS ester, pentafluorophenyl, or tetrafluorophenyl) to react with the linker-drug group, R 100 group (where R 100 is an amide) to form an antibody-drug conjugate of formula (III) which is covalently attached to the antibody via For illustrative purposes only, Scheme 5 shows an antibody with four amine groups. vinegar. [ka]

[0293] In another embodiment, the linker-drug group is an oxidase at the naturally occurring disulfide bridges of the antibody. It is conjugated to the antibody via the formation of an oxime bridge. Reduction of the inter-disulfide bridge to generate a ketone bridge and the reaction with 1,3-dihaloacetone (e.g. , 1,3-dichloroacetone). Reaction of the linker-drug group with a hydroxylamine-containing linker-drug group to attach the linker-drug group to the antibody An oxime bond (oxime bridge) is formed (see, for example, WO 2014 / 083 (See, for example, US Pat. No. 5,055,505.) Scheme 6 illustrates the antibody drug conjugate of formula (III): This technique is shown for forming a conjugate. [ka]

[0294] A general reaction scheme for forming an antibody drug conjugate of formula (IV) is shown below: Scheme 7: [ka] where RG2 is the R of compatibility. 1 reacts with the corresponding R 100 Base (such The groups are reactive groups that form a hydroxyl group (as shown in Table 1). 1 , L1, Lp, Ab, y and BiR 100 is as defined herein.

[0295] Scheme 8 shows the R 1 group (as defined herein) to form R 100 Groups (as used herein) a reactive group (RG2) that covalently attaches the linker-drug group to the antibody via a linker-drug group (defined as This general approach for forming antibody drug conjugates of formula (IV) is further illustrated, comprising: For illustrative purposes only, Scheme 8 shows an antibody with four RG2 groups. [ka]

[0296] In one embodiment, the linker-drug group is attached to the antibody via a modified cysteine ​​residue in the antibody. conjugated (see, for example, WO 2014 / 124316 Scheme 9 shows the free cysteine ​​generated from engineered cysteine ​​residues in antibodies. The ol group is R 1 group (where R 1 is a maleimide) to form a linker-drug The group R 100 group (where R 100 is a succinimide ring) This approach is shown for forming antibody drug conjugates of formula (IV). For purposes only, Scheme 9 shows an antibody with four free thiol groups. [ka]

[0297] In another embodiment, the linker-drug group is conjugated to the antibody via a lysine residue in the antibody. Scheme 10 shows that free amine groups from lysine residues in antibodies are converted to R 1 Group (where: R 1 is an NHS ester, pentafluorophenyl, or tetrafluorophenyl) to react with the linker-drug group, R 100 group (where R 100 is an amide) to form an antibody drug conjugate of formula (IV) which is covalently attached to the antibody via For illustrative purposes only, Scheme 10 shows an antibody with four amine groups. vinegar. [ka]

[0298] In another embodiment, the linker-drug group is an oxidase at the naturally occurring disulfide bridges of the antibody. It is conjugated to the antibody via the formation of an oxime bridge. Reduction of the inter-disulfide bridge to generate a ketone bridge and the reaction with 1,3-dihaloacetone (e.g. , 1,3-dichloroacetone). Reaction of the linker-drug group with a hydroxylamine-containing linker-drug group to attach the linker-drug group to the antibody An oxime bond (oxime bridge) is formed (see, for example, WO 2014 / 083 (See, for example, US Pat. No. 5,055,505.) Scheme 11 illustrates the antibody drug conjugate of formula (IV): This technique is shown for forming a conjugate. [ka]

[0299] For some embodiments of the analytical methodology for evaluating the antibody conjugates of the present invention Protocols are also provided. These analytical methodologies and results demonstrate that the conjugates are advantageous properties, such as making them easier to manufacture, easier to administer to patients, more effective, and / or can be demonstrated to have properties that make them potentially safe for patients. One example is , the determination of molecular size by size exclusion chromatography (SEC), which determines the molecular size of the molecules present in a sample. Present high molecular weight contaminants (e.g., dimers, multimers, or aggregated antibodies) or low molecular weight contaminants the amount of the desired antibody species in the sample relative to the amount of (e.g., antibody fragments, degradation products, or individual antibody chains) Generally, for example, the aggregates are analyzed based on, but not limited to, clearance rate, The use of larger amounts of monomers and It is desirable to have less, for example, aggregated antibodies. Determination of hydrophobicity by hydrophobicity chromatography (HIC), which compares the hydrophobicity of a sample with a series of known properties. The hydrophobicity is evaluated by comparing it with a standard antibody. In general, hydrophobicity is a measure of, but not limited to, aggregation, time course, antibody samples, such as aggregation due to steroids, adhesion to surfaces, hepatotoxicity, clearance rate and pharmacokinetic exposure It is desirable to have low hydrophobicity because it affects other properties of the material. Damle, N. K.,Nat Biotechnol.2008;26(8):884-885;Sin See gh,SK,Pharm Res.2015;32(11):3541-71 Hydrophobicity Index Score as measured by hydrophobic interaction chromatography The higher the pH (i.e., the faster it elutes from the HIC column), the more hydrophobic the conjugate. As shown in the examples below, most of the antibody conjugates tested The hydrophobicity index of the hydroxyl group was greater than 0.8. Antibody conjugates with a hydrophobicity index of 0.8 or greater as determined by chromatography A guide is provided.

[0300] antibody The present invention provides antibodies or antibody fragments (e.g., antibodies) that specifically bind to antigens, e.g., tumor antigens. The present invention provides an antibody conjugate comprising an antibody or antibody fragment (e.g., a nucleotide-binding fragment) of the present invention. Antigen-binding fragments include human monoclonal antibodies isolated as described in the Examples. or fragments thereof, but are not limited to these.

[0301] In certain embodiments, the present invention provides an antibody or antibody fragment that specifically binds to P-cadherin. an antibody conjugate comprising a fragment (e.g., an antigen-binding fragment) of the antibody or antibody fragment; (e.g., antigen-binding fragment) is SEQ ID NO: 7, 27, 47, 67, 87, 107 or 154 The present invention provides an antibody conjugate comprising a VH domain having an amino acid sequence of In embodiments, the present invention provides antibodies or antibody fragments (e.g., , antigen-binding fragment), wherein the antibody or antibody fragment (e.g., The antigen-binding fragment (Ag) comprises the amino acid sequence of any one of the VH CDRs listed in Table 3 below. Also provided are antibody conjugates comprising a VH CDR having the following structure: The invention provides antibodies or antibody fragments (e.g., antigen-binding fragments) that specifically bind to P-cadherin. wherein the antibody comprises a VH CDR listed in Table 3 below. one, two, three, four, five or more VH CDRs having any of the amino acid sequences The present invention provides an antibody conjugate comprising (or alternatively consisting of):

[0302] The present invention relates to antibodies or antibody fragments (e.g., antigen-binding fragments) that specifically bind to P-cadherin. an antibody conjugate comprising the antibody or antibody fragment (e.g., an antigen-binding fragment), ) has the amino acid sequence of SEQ ID NO: 17, 37, 57, 77, 97, 117 or 166 The present invention provides an antibody conjugate comprising a VL domain specific to P-cadherin. antibody conjugates comprising a heterologous antibody or antibody fragment (e.g., an antigen-binding fragment) wherein the antibody or antibody fragment (e.g., antigen-binding fragment) is selected from the group consisting of V, VL ... and an antibody conjugate comprising a VL CDR having the amino acid sequence of any one of the L CDRs. Specifically, the present invention provides an antibody or antibody that specifically binds to P-cadherin. an antibody conjugate comprising an antibody fragment (e.g., an antigen-binding fragment) of the antibody or antibody complex; Fragments (e.g., antigen-binding fragments) may comprise any of the VL CDRs listed in Table 3 below. and / or a VL CDR having one, two, three or more VL CDRs with the amino acid sequence and (c) providing an antibody conjugate comprising:

[0303] Other antibodies or antibody fragments (e.g., antigen-binding fragments) of the invention include those that are mutated but In the CDR region, a sequence having at least 60, 70 or 80% CDR region shown in the sequence in Table 3 is Some examples include amino acids with percent identity of at least 80, 90, or 95%. In embodiments, the antibody has one, two, three or more CDR regions as compared to the sequences set forth in Table 3. , including variant amino acid sequences in which no more than four or five amino acids are mutated in the CDR regions.

[0304] The present invention relates to antibodies or Also provided are antibody conjugates comprising antigen-binding fragments thereof, wherein specific amino acid residues are substituted with serotype. and is also referred to herein as a "CysMab" or "Cys" antibody. As discussed above, the drug moieties can be site-specifically and with controlled numbers of drug moieties (" The immunoconjugates can be conjugated to cysteine ​​residues on the antibody. Cysteine ​​modifications to antibodies for site-specific control of ligation can be performed, for example, by Disclosed in WO 2014 / 124316, which is incorporated herein by reference.

[0305] In some embodiments, the antibody is modified at positions 152 and 375 of the heavy chain, The positions are defined according to the EU numbering system, i.e., the modifications are E152 In other embodiments, the antibody has a nucleotide sequence at position 360 of the heavy chain and a nucleotide sequence at position 375 of the kappa light chain. Modified at position 107, which is defined according to the EU numbering system That is, the modifications are K360C and K107C. The positions of these mutations are, for example, Regarding the human IgG1 heavy chain and kappa light chain constant regions in SEQ ID NOs: 148 to 150 in Table 3, Throughout Table 3, cysteine ​​modifications from the wild-type sequence are underlined. do.

[0306] The present invention relates to VH, VL, full-length heavy chain and full-length light chain of an antibody that specifically binds to P-cadherin. Nucleic acid sequences encoding the chains are also provided. Such nucleic acid sequences are suitable for expression in mammalian cells. can be optimized for

[0307] [Table 11]

[0308] [Table 12]

[0309] [Table 13]

[0310] [Table 14]

[0311] [Table 15]

[0312] [Table 16]

[0313] [Table 17]

[0314] [Table 18]

[0315] [Table 19]

[0316] Table 20

[0317] Table 21

[0318] Table 22

[0319] Table 23

[0320] Table 24

[0321] Table 25

[0322] Table 26

[0323] Table 27

[0324] Table 28

[0325] Table 29

[0326] [Table 30]

[0327] [Table 31]

[0328] [Table 32]

[0329] [Table 33]

[0330] [Table 34]

[0331] [Table 35]

[0332] Other antibodies of the present invention may have amino acid or nucleic acid mutations but may have the same sequence as those listed in Table 3. Amino acids with at least 60, 70, 80, 90 or 95 percent identity are coded. In some embodiments, the variable regions shown in the sequences in Table 3 are 1, 2, 3, 4, or 5 amino acids are mutated in the variable region compared to the These antibodies retain substantially the same therapeutic activity as the antibodies listed above.

[0333] In some embodiments, antibodies or antibody fragments (e.g., antibodies) useful in the immunoconjugates of the invention The fragments (e.g., antigen-binding fragments) may contain one or more functional groups as sites for conjugation to a drug moiety. and antibodies that have been modified or engineered, such as antibodies modified to introduce cysteine ​​residues such as (Junutula JR, et al.:Nat Biotechnol 2008 , 26:925-932). In one embodiment, the present invention provides a method for producing a medicament for the treatment of ... A modified antibody or antibody fragment thereof comprising one or more amino acid substitutions with cysteine. The sites for cysteine ​​substitution are in the constant region of the antibody and therefore can be used in a variety of applicable to antibodies, and the sites are selected to provide stable and uniform conjugates. The modified antibody or fragment may have two or more cysteine ​​substitutions, which These substitutions may be combined with other antibody modification and conjugation methods described herein. Methods for inserting cysteines at specific positions in antibodies are well known in the art. and is known in, for example, Lyons et al. (1990) Protein Eng. ,3:703-708, International Publication No. 2011 / 005481, International Publication No. See US Pat. No. 2014 / 124316. In certain embodiments, modified The antibody or antibody fragment may have 117, 119, 121, 124, 126, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 39, 152, 153, 155, 157, 164, 169, 171, 174, 189, 2 05, 207, 246, 258, 269, 274, 286, 288, 290, 292, 2 93, 320, 322, 326, 333, 334, 335, 337, 344, 355, 3 60, 375, 382, ​​390, 392, 398, 400 and 422 and a substitution of one or more amino acids in the constant region of the nucleotide sequence ... In some embodiments, the modified antibody or antibody The fragment may comprise a fragment having a sequence corresponding to positions 107, 108, 109, 114, 129, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 2, 143, 145, 152, 154, 156, 159, 161, 165, 168, 16 9, 170, 182, 183, 197, 199, and 203 with cysteine, the positions being and the light chain is a human kappa light chain. In certain embodiments, the modified antibody The antibody or antibody fragment thereof may have two or more amino acids in its constant region replaced by cysteine. The combination includes a substitution combination of a nucleotide at position 375 of the antibody heavy chain, a nucleotide at position 152 of the antibody heavy chain, The substitution may be at position 360 of the antibody heavy chain or at position 107 of the antibody light chain, the positions being in accordance with the EU system. In certain embodiments, the modified antibody or antibody fragment thereof is numbered as follows: The antibody comprises a substitution of one amino acid in the constant region of the antibody with a cysteine, the substitution being Position 375 of the antibody heavy chain, position 152 of the antibody heavy chain, position 360 of the antibody heavy chain, position 107 of the antibody light chain, position 165 of the antibody light chain or position 159 of the antibody light chain, positions numbered according to the EU system and the light chain is a kappa chain. In certain embodiments, the modified antibody or antibody fragment thereof The fragment contains a combination of two amino acid substitutions with cysteine ​​in its constant region, The combination comprises a substitution at position 375 of the antibody heavy chain and at position 152 of the antibody heavy chain, the positions being , numbered according to the EU system. In certain embodiments, the modified antibody or The antibody fragment comprises a substitution of one amino acid by cysteine ​​at position 360 of the antibody heavy chain. , positions are numbered according to the EU system. The antibody or antibody fragment thereof has one amino acid residue due to a cysteine ​​at position 107 of the antibody light chain. The positions are numbered according to the EU system, and the light chain is a kappa chain. Exemplary embodiments of these positions are disclosed in SEQ ID NOs: 148, 149 and 150. Specific embodiments of these positions are shown in SEQ ID NO: 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, Anti-P-cadherin antibody sequences 141, 142, 143, 144, 145, 146, and 147 Disclosed with respect to columns.

[0334] These antibodies can bind to P-cadherin, and are available in VH, VL, full-length light chain, and The full-length heavy chain sequence (amino acid sequence and nucleotide sequence encoding the amino acid sequence) is and "mixing and matching" to generate other P-cadherin binding antibodies of the invention. Such "mixed and matched" P-cadherin binding antibodies are known in the art. Binding assays known in the art (e.g., ELISA and other assays described in the Examples section) ) can be used to test. When these strands are mixed and matched, The VH sequence from the VH / VL pair should be replaced with a structurally similar VH sequence. Similarly, the full-length heavy chain sequence from a particular full-length heavy chain / full-length light chain pair can be compared with structurally similar full-length heavy chains. Similarly, the VL sequence from a particular VH / VL pairing should be replaced with a long heavy chain sequence. A structurally similar VL sequence should be substituted. Similarly, a particular full-length heavy chain / full-length light chain pair The full-length light chain sequence derived from the IL-11A gene should be replaced with a structurally similar full-length light chain sequence. Thus, in one aspect, the present invention provides a method for the production of a nucleic acid sequence comprising SEQ ID NOs: 7, 27, 47, 67, 87 and 107. a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 37, 57, 7 and a light chain variable region comprising an amino acid sequence selected from the group consisting of: 7, 97, and 117. and an antibody conjugate comprising an isolated monoclonal antibody or an antigen-binding region thereof. The antibody specifically binds to P-cadherin.

[0335] In another aspect, the present invention provides a method for the preparation of a nucleic acid sequence comprising: (i) a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 9, 29, 49, 69, 89, and 109; The amino acid sequence is optimized for expression in cells of a mammalian expression system selected from the group consisting of a full-length heavy chain comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 19, 39, 59, 79, 99 and 119; and a single antibody having a full-length light chain containing an amino acid sequence optimized for expression in mammalian cells. or (ii) a functional protein containing an antigen-binding portion thereof. The present invention provides antibody conjugates containing the antibody.

[0336] In another aspect, the present invention provides heavy and light chain CDR1, CDR2 and CDR3 sequences as set forth in Table 3. R3 or a combination thereof. The amino acid sequences of the VH CDR1 of the antibodies are shown in SEQ ID NOs: 1, 21, 41, 61, 8 The amino acid sequences of the VH CDR2 of the antibodies are shown in SEQ ID NOs: 2, 22, The amino acid sequences of the VH CDR3 of the antibodies are shown in the sequences: The amino acids of the VL CDR1 of the antibody are shown as numbers 3, 23, 43, 63, 83 and 103. The VL sequences of the antibodies are shown in SEQ ID NOs: 11, 31, 51, 71, 91 and 111. The amino acid sequences of CDR2 are shown in SEQ ID NOs: 12, 32, 52, 72, 92 and 112. The amino acid sequences of the VL CDR3 of the antibody are shown in SEQ ID NOs: 13, 33, 53, 73, 93 and and 113.

[0337] Each of these antibodies can bind to P-cadherin, and their antigen-binding specificity is mainly If VH is provided by CDR1, CDR2 and CDR3 regions, The VL CDR1, CDR2 and CDR3 sequences and the VL CDR1, CDR2 and CDR3 sequences are "mixed and matched" CDRs from different antibodies can be mixed and matched. Such "mixed and matched" P-cadherin binding antibodies are known in the art. and can be tested using the binding assays (e.g., ELISA) described in the Examples. When mixing and matching VH CDR sequences, the CDRs from a particular VH sequence The R1, CDR2 and / or CDR3 sequences should be replaced with structurally similar CDR sequences. Similarly, when VL CDR sequences are mixed and matched, Replacing the original CDR1, CDR2 and / or CDR3 sequences with structurally similar CDR sequences The novel VH and VL sequences should be selected from one or more VH and / or VL CDR regions. The CDR sequences are derived from the CDR sequences shown herein for the monoclonal antibodies of the invention. It will be readily apparent to those skilled in the art that the structure of the nucleotide sequence can be generated by substituting a structurally similar sequence. It will be possible.

[0338] Thus, the present invention provides a method for the preparation of a nucleic acid sequence comprising the group consisting of SEQ ID NOs: 1, 21, 41, 61, 81 and 101. heavy chain CDR1 comprising an amino acid sequence selected from SEQ ID NOs: 2, 22, 42, 62, 82 and heavy chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 23 and 102; , 43, 63, 83 and 103 3, an amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 31, 51, 71, 91 and 111 light chain CDR1 comprising the amino acid sequences of SEQ ID NOs: 12, 32, 52, 72, 92 and 112 A light chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 33, 53, 73 a light chain CDR3 comprising an amino acid sequence selected from the group consisting of: and an isolated monoclonal antibody or antigen-binding region thereof, wherein the antibody binds to P-cadherin. Specific binding.

[0339] In certain embodiments, an antibody or antibody fragment that specifically binds to P-cadherin (e.g., The antigen-binding fragment comprises a heavy chain CDR1 of SEQ ID NO: 1, a heavy chain CDR2 of SEQ ID NO: 2, a heavy chain CDR3 of SEQ ID NO: 3, a heavy chain CDR4 of SEQ ID NO: 4, a heavy chain CDR5 of SEQ ID NO: 5, a heavy chain CDR6 of SEQ ID NO: 6, a heavy chain CDR7 of SEQ ID NO: 7, a heavy chain CDR8 of SEQ ID NO: 8, a heavy chain CDR3 of SEQ ID NO: 11, light chain CDR2 of SEQ ID NO: 12 and No. 13 light chain CDR3.

[0340] In another particular embodiment, an antibody or antibody fragment (e.g., For example, the antigen-binding fragment comprises a heavy chain CDR1 of SEQ ID NO: 21, a heavy chain CDR2 of SEQ ID NO: 22, Heavy chain CDR3 of sequence number 23, light chain CDR1 of sequence number 31, light chain CDR2 of sequence number 32 and the light chain CDR3 of SEQ ID NO: 33.

[0341] In yet another embodiment, an antibody or antibody fragment that specifically binds to P-cadherin (e.g., , antigen-binding fragment) comprises a heavy chain CDR1 of SEQ ID NO: 41, a heavy chain CDR2 of SEQ ID NO: 42, and a CDR3 of SEQ ID NO: 43. heavy chain CDR3 of SEQ ID NO: 43, light chain CDR1 of SEQ ID NO: 51, light chain CDR2 of SEQ ID NO: 52, and and a light chain CDR3 of SEQ ID NO: 53.

[0342] In further embodiments, an antibody or antibody fragment that specifically binds to P-cadherin (e.g., The antigen-binding fragment comprises a heavy chain CDR1 of SEQ ID NO: 61, a heavy chain CDR2 of SEQ ID NO: 62, a heavy chain CDR3 of SEQ ID NO: 63, a heavy chain CDR4 of SEQ ID NO: 64, a heavy chain CDR5 of SEQ ID NO: 65, a heavy chain CDR6 of SEQ ID NO: 66, a heavy chain CDR7 of SEQ ID NO: 67, a heavy chain CDR8 of SEQ No. 63, a heavy chain CDR1 of SEQ ID NO: 71, a light chain CDR2 of SEQ ID NO: 72, and Contains the light chain CDR3 of SEQ ID NO: 73.

[0343] In another particular embodiment, an antibody or antibody fragment (e.g., For example, the antigen-binding fragment comprises a heavy chain CDR1 of SEQ ID NO: 81, a heavy chain CDR2 of SEQ ID NO: 82, Heavy chain CDR3 of sequence number 83, light chain CDR1 of sequence number 91, light chain CDR2 of sequence number 92 and the light chain CDR3 of SEQ ID NO: 93.

[0344] In further particular embodiments, an antibody or antibody fragment (e.g., a nucleotide sequence) that specifically binds to P-cadherin is provided. For example, the antigen-binding fragment comprises a heavy chain CDR1 of SEQ ID NO: 101, a heavy chain CDR2 of SEQ ID NO: 102, a 2, heavy chain CDR3 of SEQ ID NO: 103, light chain CDR1 of SEQ ID NO: 111, light chain CDR2 and light chain CDR3 of SEQ ID NO: 113.

[0345] In certain embodiments, the antibody that specifically binds to P-cadherin is an antibody listed in Table 3. The antibody may be an antibody or antibody fragment (e.g., an antigen-binding fragment).

[0346] 2. Further Modifications of the Framework or Fc Region The immunoconjugates of the invention may, for example, be modified in VH and / or VH sequences to improve antibody properties. The modified antibody or its antigen-binding domain further comprises modifications to framework residues within the VL. In some embodiments, framework modifications may be made to enhance the immunogenicity of the antibody. For example, one approach is to replace one or more framework residues with the corresponding germline residues. More specifically, antibodies that have undergone somatic mutation are It may contain framework residues that differ from the germline sequence from which the antibody is derived. The basis for this is to compare the antibody framework sequences to the germline sequences from which the antibody is derived. Somatic mutations can be performed to restore the framework region sequences to their germline configuration. can be "backmutated" to the germline sequence by, for example, site-directed mutagenesis. Such "backmutated" antibodies are also intended to be encompassed by the present invention.

[0347] Another mode of framework modification is to modify the amino acid sequence within the framework region or additionally within one or more CDR regions. Mutating one or more residues within the region to remove T cell epitopes, thereby reducing antibody latency This approach involves reducing the specific immunogenicity of a given antigen. This approach is also called "deimmunization" and is This is further described in U.S. Patent Application Publication No. 20030153043 by S. et al.

[0348] In addition to or instead of modifications made within the framework or CDR regions, Within the Fc region, antibodies typically contain one or more functional properties of the antibody, such as serum half-life, complementation, etc. The antibodies may be engineered to include modifications that alter antibody binding, Fc receptor binding, and / or antigen-dependent cytotoxicity. Additionally, the antibodies of the present invention may be chemically modified (e.g., by one or more chemical the glycosylation of the antibody, and further modify one or more of the antibody's Each of these embodiments is described in more detail below. It is stated.

[0349] In one embodiment, the hinge region of CH1 is modified by altering the number of cysteine ​​residues in the hinge region. This technique is based on the US method by Bodmer et al. The hinge region of CH1 is further described in US Pat. No. 5,677,425. The number of cysteine ​​residues in the ribonucleotides may be altered to, for example, facilitate assembly of the light and heavy chains. Or the stability of the antibody is increased or decreased.

[0350] In another embodiment, the mutation in the Fc hinge region of the antibody reduces the biological half-life of the antibody. More specifically, the antibody Staphylococcus aureus protein A ( SpA) is reduced compared to the SpA binding of the native Fc hinge domain. One or more amino acid mutations are introduced into the CH2-CH3 domain interface region of the Fc hinge fragment. This technique is further described in U.S. Pat. No. 6,165,745 to Ward et al. It is being done.

[0351] In yet another embodiment, the Fc region is modified with at least one amino acid residue replaced by a different amino acid. The antibody effector functions are modified by replacing the amino acid residues with amino acid residues. The antibody has an altered affinity for the effector ligand but retains the antigen-binding ability of the parent antibody. One or more amino acids can be replaced with different amino acid residues, such as The effector ligand with altered properties is, for example, an Fc receptor or the C1 component of complement. This technique is described, for example, in U.S. Pat. No. 5,624,822, both to Winter et al. No. 1 and No. 5,648,260.

[0352] In another embodiment, the antibody has modified C1q binding and / or reduced or eliminated C1q binding. One or more amino acid residues selected from the group consisting of α- and β-glucan-1, ... The amino acids in the nucleotide sequence can be replaced with different amino acid residues. No. 6,194,551 to Ogie et al.

[0353] In another embodiment, one or more amino acid residues are modified to enhance the ability of the antibody to fix complement. This technique is described, for example, in WO 94 / 2935 by Bodmer et al. In certain embodiments, the antibodies or antigen-binding fragments thereof of the present invention are described in pamphlet No. 1. One or more amino acids of the fragment are replaced by one or more allotypic amino acid residues. The amino acid residues of the allotypes are as follows: Jefferis et al., MAbs.1: IgG1, IgG2 and IgG3 subclasses, as described in J. Immunol. 1999, 332-338 (2009) The constant region of the heavy chain of the kappa isotype and the constant region of the light chain of the kappa isotype are also included. Not limited.

[0354] In yet another embodiment, the Fc region is modified by one or more amino acids to provide a Increase the ability of the antibody to mediate ADCC and / or Fcγ receptors The antibody is modified to increase its affinity for the antibody. This technique is described, for example, in Pres. Furthermore, human IgG 1, which matches the binding sites for FcγRI, FcγRII, FcγRIII, and FcRn. Shield has been tested and mutants with improved binding have been described (Shield s et al., J. Biol. Chem. 276:6591-6604, 2001. See the reference.

[0355] In yet another embodiment, the glycosylation of the antibody is modified. For example, an aglycosylated antibody Glycosylation can be altered to produce antibodies that lack glycosylation, e.g. For example, carbohydrate modifications can increase the affinity of an antibody for an "antigen." This can be achieved, for example, by modifying one or more glycosylation sites within the antibody sequence. For example, one or more amino acid substitutions may be made to modify one or more variable region framework sequences. The glycosylation site of the target protein may be abolished, thereby abolishing glycosylation at that site. Such aglycosylation may increase the affinity of the antibody for the antigen. Techniques are described, for example, in U.S. Pat. Nos. 5,714,350 and 6,355,235 by Co et al. This is described in specification 0,861.

[0356] Additionally or alternatively, antibodies with altered glycosylation patterns, e.g., the amount of fucosyl residues Hypofucosylated antibodies with reduced or increased bisecting GlcNac structures Such alterations in glycosylation patterns can improve the ADCC ability of antibodies. These carbohydrate modifications have been demonstrated to increase the glycosylation machinery, for example. This can be achieved by expressing the antibody in a host cell where the glycosylation machinery has been modified. The modified cells have been described in the art and are capable of expressing and carrying out the recombinant antibodies of the invention. The host cells can be used to produce antibodies with modified glycosylation. Ang et al., European Patent No. 1,176,195, discloses a method for producing fucosyltransferases. described a cell line with a functionally disrupted FUT8 gene that encodes Antibodies expressed in the cell lines shown in this publication exhibit low fucosylation. No. 03 / 035835 pamphlet describes a carbohydrate derivative with fucose linked to Asn(297). They described a mutant CHO cell line, Lecl3, that has a reduced ability to bind to ATP. , they also result in hypofucosylation of antibodies expressed in their host cells (Shie lds.et al.,(2002)J.Biol.Chem.277:26733-2 (See also WO 99 / 54342 by Umana et al.) The results show that antibodies expressed in engineered cell lines result in increased ADCC activity of the antibody. Glycoproteins were modified with glycosyltransferases, showing an increase in bisecting GlcNac structures. transferases (e.g., β(1,4)-N-acetylglucosaminyltransferases) describes a cell line engineered to express globin-transferase III (GnTIII). (Umana et al., Nat.Biotech.17:176-180,199 See also 9).

[0357] In another embodiment, the antibody is modified to increase its biological half-life. For example, one or more of the following mutations can be introduced: T252L, T254S, and T256F as described in 6,277,375. In addition, U.S. Patent Nos. 5,869,046 and 6,121, As described in US Pat. No. 5,822,222, antibodies may be modified with a CH1 Or, in the CL region, there is a salve obtained from two loops of the CH2 domain of the Fc region of IgG. The polypeptide may be modified to contain a polypeptide receptor binding epitope.

[0358] 3. Antibody Generation Antibodies and antibody fragments thereof (e.g., antigen-binding fragments) can be produced by recombinant expression, chemical synthesis, and antibody cloning. any means known in the art, including, but not limited to, enzymatic digestion of dimers Although full length monoclonal antibodies can be produced by, for example, hybridoma or recombinant Recombinant expression can be achieved by any suitable method known in the art. host cells, such as mammalian host cells, bacterial host cells, yeast host cells, insect host cells, etc. It can be derived from.

[0359] The present invention also provides polynucleotides encoding the antibodies described herein, such as those described herein. A fragment encoding a heavy or light chain variable region or segment containing a complementarity determining region as set forth in In some embodiments, a polynucleotide encoding a heavy chain variable region is further provided. The oligonucleotide is selected from the group consisting of SEQ ID NOs: 8, 28, 48, 68, 88, 108 and 151. and at least 85%, 89%, 90%, 91%, 92% , 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% nucleic acid sequence identity In some embodiments, the polynucleotide encoding the light chain variable region has , SEQ ID NOs: 18, 38, 58, 78, 98, 118 and 153 Polynucleotides and at least 85%, 89%, 90%, 91%, 92%, 93%, 94 %, 95%, 96%, 97%, 98%, 99% or 100% nucleic acid sequence identity.

[0360] In some embodiments, the polynucleotide encoding the heavy chain is SEQ ID NO: 10, 30 , 50, 70, 90, 110 or 152 polynucleotides and at least 85%, 89% , 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% nucleic acid sequence identity. In some embodiments, the polypeptide encoding the light chain The oligonucleotide is a polynucleotide of SEQ ID NO: 20, 40, 60, 80, 100, 120 or 154. Nucleotides and at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, having 95%, 96%, 97%, 98%, 99% or 100% nucleic acid sequence identity.

[0361] The polynucleotides of the present invention may encode only the variable region sequences of the antibodies. The polynucleotide sequence may encode both the variable and constant regions of the polypeptide. Some contain both the heavy and light chain variable regions of one of the exemplified anti-P-cadherin antibodies. Several other polynucleotides encode polypeptides containing the heavy chains of antibodies. and two polypeptide segments that are substantially identical to the variable region of the light chain.

[0362] The polynucleotide sequences may be prepared by de novo solid-phase DNA synthesis or by the synthesis of antibodies or their binding fragments. PCR mutagenesis of existing sequences encoding fragments (e.g., sequences described in the Examples below) Direct chemical synthesis of nucleic acids can be performed by the method of Narang et al., Me phosphotriester method of Enzymol. 68:90, 1979; Brown et al. phosphodiester method of T. et al., Meth. Enzymol. 68:109, 1979 ;Beaucage et al.,Tetra.Lett.,22:1859,198 1 diethyl phosphoramidite method; and the solid-state method of U.S. Pat. No. 4,458,066. This can be achieved by methods known in the art, such as support methods. Mutations can be introduced into the nucleotide sequence using, for example, PCR Technology: ciples and Applications for DNA Amplific ation, H.A. Erlich (Ed.), Freeman Press, NY, N. Y,1992;PCR Protocols: A Guide to Methods and Applications, Innis et al. (Ed.), Acade mic Press, San Diego, CA, 1990;Mattila et a I., Nucleic Acids Res. 19:967, 1991; and Ecker t et al., PCR Methods and Applications 1: 17, 1991.

[0363] Expression vectors and host cells for producing the antibodies described herein are also provided herein. A variety of expression vectors can be used to express polynucleotides encoding antibody chains or binding fragments. Viral-based and non-viral expression vectors can be used to express the peptide. Any of the non-viral vectors can be used to produce antibodies in mammalian host cells. Viral vectors and non-viral systems use plasmids, typically expressing proteins or RNA. These include episomal vectors and human artificial chromosomes with expression cassettes for , Harrington et al., Nat Genet 15:345,1997 For example, anti-P-cadherin antibodies in mammalian (e.g., human) cells Non-viral vectors useful for expressing oligonucleotides and polypeptides include pTh ioHis A, B and C, pcDNA™3.1 / His, pEBVHis A, B and C (Invitrogen, San Diego, CA), MPSV vectors and Many other vectors known in the art are available for expressing other proteins. Useful viral vectors include retroviruses, adenoviruses, and adeno-associated viruses. virus, herpesvirus-based vectors, SV40, papillomavirus, HBP Stein-Barr virus, vaccinia virus vectors and Semliki Forest virus (S Examples of vectors based on FV include Brent et al. (supra); Smith , Annu. Rev. Microbiol. 49:807, 1995; and Rosenf See Eld et al., Cell 68:143, 1992.

[0364] The choice of expression vector will depend on the intended host cell in which the vector will be expressed. Typically, the expression vector contains a polynucleotide encoding an anti-P-cadherin antibody chain or fragment. A promoter and other control sequences (e.g., enhancers) operably linked to the In some embodiments, the expression of the inserted sequence is prevented except under inducing conditions. An inducible promoter is used to induce the expression of the α-amyloid β-glucan. promoters such as lacZ, metallothionein promoter, or heat shock promoters. Cultures of transformed organisms are grown to ensure that their expression products are well tolerated by the host cells. It can be grown under non-inducing conditions without biasing the population of coding sequences. In addition to the promoter, other regulatory elements are required for efficient expression of the antibody chain or fragment. These elements may be present or required. Typically, the expression efficiency depends on the cell type used. It can also be enhanced by incorporating enhancers suitable for the cell system (e.g., Sc harf et al.,Results Probl.Cell Differ.20 :125, 1994; and Bittner et al., Meth. Enzymol. , 153:516, 1987). For example, the SV40 enhancer or CM The V enhancer can be used to increase expression in mammalian host cells.

[0365] The expression vector contains a fusion protein with the polypeptide encoded by the inserted antibody sequence. It may also provide a secretory signal sequence for forming a protein. The antibody sequence is linked to a signal sequence before inclusion in the vector. The vectors used to receive the sequences encoding the heavy and low chain variable domains are stationary. Such vectors may encode a fusion protein with a constant region or a portion thereof. This allows for the expression of variable regions as proteins, thereby producing intact antibodies or fragments thereof. Typically, such constant regions are human constant regions.

[0366] Host cells for harboring and expressing antibody chains can be either prokaryotic or eukaryotic. E. coli has been used to clone and express the polynucleotides of the present invention. Other microbial hosts suitable for use include Bacillus subtilis. Bacillus such as Bacillus subtilis and Salmonella monella species, Serratia species and various Pseudomonas ( These prokaryotic hosts include other Enterobacteriaceae, such as Pseudomonas species. The host cell typically contains expression control sequences compatible with the host cell (e.g., an origin of replication). In addition, expression vectors using the lactose promoter system, tryptophan, Fan (trp) promoter system, beta-lactamase promoter system or Phagilla There are also any number of different known promoters, such as promoter systems derived from Muda. The promoter typically controls expression, optionally with an operator sequence, and initiates transcription. and a ribosome binding site sequence for initiating and terminating translation. Other microbes, such as yeast, may also be used to express antibody polypeptides. Insect cells in combination with vectors can also be used.

[0367] In some preferred embodiments, mammalian host cells are used to produce antibody polypeptides of the invention. For example, they are produced by expressing peptides that express endogenous immunoglobulin genes. hybridoma cell lines (e.g., myeloma hybridoma clones described in the Examples) or mammalian cell lines carrying exogenous expression vectors (e.g., SP2 / These can be any normal non-immortal or normal young myeloma cells. or abnormal immortal animal or human cells. For example, CHO cell lines, various Co including s cell lines, HeLa cells, myeloma cell lines, transformed B cells and hybridomas. Several suitable host cell lines capable of secreting intact immunoglobulins have been developed. The use of mammalian tissue cell cultures to express polypeptides is described, e.g. For example, Winnacker, From Genes to Clones, VCH Pu Blishers, NY, NY, 1987. Mammalian host cells The expression vector for the present invention contains expression control sequences such as an origin of replication, a promoter, and an enhancer. (See, e.g., Queen, et al., Immunol. Rev. 89:49-68, 1 986) as well as ribosome binding sites, RNA splice sites, polyadenylation sites, It may contain necessary processing information sites, such as nucleotide sequences and transcription terminator sequences. These expression vectors usually contain promoters derived from mammalian genes or mammalian Suitable promoters include constitutive promoters. , cell type-specific promoters, developmental stage-specific promoters and / or modulatable promoters Useful promoters include promoters such as Tarothionein promoter, constitutive adenovirus major late promoter, dexamethasone Zone-inducible MMTV promoter, SV40 promoter, MRP pol III promoter promoter, constitutive MPSV promoter, tetracycline-inducible CMV promoter (human constitutive CMV promoters and those known in the art, such as the immediate early CMV promoter Examples include, but are not limited to, promoter-enhancer combinations.

[0368] Methods for introducing expression vectors containing polynucleotide sequences of interest include the introduction of vectors into cell host species. For example, calcium chloride transfection is used in prokaryotic cells. While commonly used for erythropoietin, calcium phosphate treatment or elec- trolysis is used for other cellular hosts. Microporation can be used (see generally Sambrook et al., 2012 ,MOLECULAR CLONING:A LABORATORY MANUAL,v See volumes 1-4, Cold Spring Harbor Press, NY. Other methods include electroporation, calcium phosphate Processing, liposome-mediated transformation, injection and microinjection, ballistics method, virosomes, immunoliposomes, polycation:nucleic acid conjugates, naked DNA, human virions, fusion with the herpesvirus structural protein VP22 (Elliot and O'Hare, Cell 88:223, 1997), drug-enhanced uptake of DNA These include ex vivo transduction and ex vivo transduction. For example, stable expression of antibody chains or binding fragments is often desirable. The cell line contains a viral origin of replication or endogenous expression elements and a selectable marker gene. After the vector is introduced, the cells are cultured in a rich medium. After 1-2 days of growth in the medium, they can be switched to selective media. The purpose of the present invention is to confer resistance to selection for the introduced sequence in selective media. Allows for the growth of cells that express the gene without problems. Resistant and stably transfected cells can be grown using tissue culture methods appropriate to the cell type.

[0369] Therapeutic Uses and Methods of Treatment The provided antibody conjugates are useful in a variety of applications, including, but not limited to, the treatment of cancer. In certain embodiments, the antibody conjugates provided herein are useful for , are useful for inhibiting tumor growth, reducing tumor volume, inducing differentiation and / or reducing tumorigenicity. The method of use may be an in vitro, ex vivo or in vivo method.

[0370] In some embodiments, any of the antibody conjugates described herein is directed to to treat a disease, e.g., a disorder, in a subject in need thereof, e.g., a human patient, by administering Methods for treating, preventing, or ameliorating cancer are provided herein. Also provided is the use of an antibody conjugate of the invention to treat or prevent a disease in Also provided is the use of the antibody conjugate in treating or preventing disease in a subject. In some embodiments, the compound is used in the manufacture of a medicament for treating or preventing a disease in a subject. In certain embodiments, antibody conjugates for The disease to be treated is cancer.

[0371] In one aspect, the immunoconjugates described herein are used to treat solid tumors. Examples of solid tumors include malignant tumors, such as those of the liver, lung, breast, lymphatic system, and gallbladder. intestinal tract (e.g., colon), genitourinary tract (e.g., kidney, urothelial cells), prostate, and pharynx These include sarcomas, adenocarcinomas, blastomas, and carcinomas of various organ systems, including those affecting the liver. Colon cancer, rectal cancer, renal cell carcinoma, liver cancer, small cell lung cancer, non-small cell lung cancer, small intestine cancer, and esophageal cancer In one embodiment, the cancer is melanoma, for example, advanced stage melanoma. Examples of other cancers that may be treated include bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignancies. Melanoma, uterine cancer, ovarian cancer, rectal cancer, colorectal cancer, cancer of the anal region, cancer of the peritoneum, stomach cancer, esophageal cancer , salivary gland cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, and carcinoma of the cervix , vaginal carcinoma, vulvar carcinoma, penile cancer, glioblastoma, neuroblastoma, cervical cancer, Hodgkin's disease , non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, Soft tissue sarcoma, urethral cancer, penile cancer, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia Leukemia, chronic or acute leukemia including chronic lymphoblastic leukemia, childhood solid tumors, lymphoma lymphoma, bladder cancer, kidney or ureter cancer, renal pelvis cancer, neoplasms of the central nervous system (CNS), genotype Primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brainstem glioma, pituitary adenoma, Kaposi's tumor tumors, neuroendocrine tumors (including carcinoid tumors, gastrinomas, and pancreatic islet cell carcinomas), Mesothelioma, Schwannoma (including acoustic neuroma), meningioma, epidermoid carcinoma, squamous cell carcinoma, T-cell Lymphoma, environmentally induced cancers including those induced by asbestos and combinations of such cancers Examples include combinations of

[0372] In another aspect, the immunoconjugates described herein are used to treat hematological cancers. Blood cancers include leukemia, lymphoma, and other cancers that affect the blood, bone marrow, and lymphatic system. Malignant lymphoproliferative conditions include:

[0373] Leukemia can be classified as acute leukemia and chronic leukemia. Acute leukemia is classified as acute myeloid leukemia. It can be further classified as acute lymphoblastic leukemia (AML) and acute lymphoblastic leukemia (ALL). Diseases include chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Other associated pathologies include the failure of bone marrow blood cell production (or dysplasia) and progression to AML. Myelodysplastic syndromes (MDS), a diverse collection of hematological conditions united by the risk of transformation MDS, formerly known as "preleukemia").

[0374] Lymphomas are a group of blood cell tumors that arise from lymphocytes. Exemplary lymphomas include: These include non-Hodgkin's lymphoma and Hodgkin's lymphoma.

[0375] In some embodiments, the cancer is, for example, but not limited to, B-cell acute lymphoblastic leukemia. (“BALL”), T-cell acute lymphoblastic leukemia (“TALL”), acute lymphoblastic leukemia ( ALL), including, but not limited to, acute leukemia; one or more of the following, including but not limited to: chronic lymphocytic leukemia (CML), chronic lymphocytic leukemia (CLL), Chronic leukemia; e.g., B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm , Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy lymphoma leukemia, small cell or large cell follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and bone marrow Dysplastic syndromes, non-Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia and bone marrow blood cell production failure (or dysplasia) This includes "preleukemia," a diverse collection of hematological conditions grouped together by Further examples of hematological cancers or conditions include, but are not limited to, tumor antigen expression. Diseases associated with the disease include those described herein, such as atypical and / or non-classical cancers, malignancies, These include, but are not limited to, cancers, precancerous conditions, or proliferative disorders that express tumor antigens. Metastatic lesions of the aforementioned cancers may also be treated or prevented using the methods and compositions of the present invention. .

[0376] In certain embodiments, the cancer is treated with an antibody or antibody fragment (e.g., an antigen) of an antibody conjugate. They are characterized by cells expressing target tumor antigens to which the target antigen (binding fragment) binds. In embodiments, the immunoconjugates described herein are directed to tumor antigens (e.g., and an antigen-binding domain (e.g., an antibody or antibody fragment) that binds to a tumor antigen (e.g., a tumor antigen described in the document). Methods for detecting the presence or overexpression of such tumor antigens are known to those skilled in the art. These include immunohistocompatibility (IHC) assays that use antibodies that specifically bind to tumor antigens. (i) Methods include detecting the RNA expression level of tumor antigens.

[0377] In some embodiments, the tumor antigen is selected from one or more of the following targets: receptors Tyrosine-protein kinase ERBB2 (Her2 / neu); receptor tyrosine-protein kinase Protein kinase ERBB3 (Her3); receptor tyrosine-protein kinase ERBB 4 (Her4); epidermal growth factor receptor (EGFR); E-cadherin; P-cadherin; Cadherin 6; Cathepsin D; Estrogen receptor; Progesterone receptor; CA125 ;CA15-3;CA19-9;P-glycoprotein (CD243);CD2;CD19; CD20;CD22;CD24;CD27;CD30;CD37;CD38;CD40; CD44v6;CD45;CD47;CD52;CD56;CD70;CD71;CD7 9a;CD79b;CD72;CD97;CD179a;CD123;CD137;CD 171; CS-1 (CD2 subset 1, CRACC, SLAMF7, CD319 and 1 C-type lectin-like molecule-1 (CLL-1 or CLECL1); also called 9A24 Epidermal growth factor receptor variant III (EGFRvIII); ganglioside G2 (GD2); Ganglioside GD3(aNeu5Ac(2-8)aNeu5Ac(2-3)bDGal p(1-4)bDGlcp(1-1)Cer; TNF receptor family member B cell Mature (BCMA); Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr) ); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 ( ROR1); Fms-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (T AG72); carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD 276);KIT (CD117);Interleukin-13 receptor subunit alpha -2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor Interleukin-11Ra alpha (IL-11Ra); Prostate stem cell antigen (PSCA); Protease serine 2 1 (Testisin or PRSS21); Vascular endothelial growth factor receptor 2 (VEGFR2); Y antigen; platelet-derived growth factor receptor beta (PDGFR-beta); developmental stage specific Subtype specific embryonic antigen-4 (SSEA-4); folate receptor alpha; neural cell adhesion molecule (NCAM) prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutant (ELF2M) ;ephrin B2;fibroblast activation protein alpha (FAP);insulin-like growth factor IGF-I receptor (IGF-I receptor), carbonic anhydrase IX (CAIX); proteasome (proteasome) LMP2 (LMP2) glycoprotein 10 (LMP2) 0 (gp100); breakpoint cluster region (BCR) and Abelson mouse white Oncogene fusion protein consisting of hemolytic viral oncogene homolog 1 (Abl) (bcr-abl) Protein; Tyrosinase; Ephrin type A receptor 2 (EphA2); Fucosyl GM1; Cya Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bD Galp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TG S5); high molecular weight melanoma-associated antigen (HMWMAA); o-acetyl-GD2 ganglioside folate receptor beta; tumor endothelial marker 1 (TEM1 / CD248) );Tumor endothelial marker 7-related (TEM7R);Thyroid-stimulating hormone receptor (TSHR) ;G protein-coupled receptor class C group 5, member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); anaplastic lymphoma kinase (A LK); polysialic acid; placenta-specific 1 (PLAC1); globoH glycoceramide (G Hexasaccharide portion of loboH; mammary differentiation antigen (NY-BR-1); adrenergic receptor beta 3 (ADRB3); pannexin 3 (PANX3); G protein-coupled receptor 20 (GP R20); olfactory receptor 51E2 (OR51E2); TCR gamma alternative reading frame tumor protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (N Y-ESO-1; Cancer / Testis Antigen 2 (LAGE-1a); Melanoma-Associated Antigen 1 (MAGE- A1); ETS translocation-mutant gene 6 (ETV6-AML) located on chromosome 12p; Subunit protein 17 (SPA17); X antigen family, member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer testis antigen-1 (MAD-C) T-1); melanoma cancer testis antigen-2 (MAD-CT-2); Fos-related antigen 1; tumor protein Protein p53 (p53); p53 mutant; prostein; survival; telomerase; prostate carcinoma PCTA-1 or galectin-8, a melanoma antigen recognized by T cells 1 (MelanA or MART1); Rat sarcoma (Ras) mutant; Human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoint; melanoma inhibitor of apoptosis (M L-IAP; ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene) gene); N-acetylglucosaminyltransferase V (NA17); paired Pax-3 (PAX3); androgen receptor; cyclin B1; v- myc Avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (MYCN); Ra s homolog family member C (RhoC); tyrosinase-related protein 2 (TRP -2);Cytochrome P450 1B1 (CYP1B1);CCCTC binding factor finger protein)-like (related to BORIS or regulator of imprinted sites), Squamous cell carcinoma antigen recognized by T cells 3 (SART3); paired box tag Protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TE) S1); lymphocyte-specific protein tyrosine kinase (LCK); A kinase anchor AKAP-4; synovial sarcoma, X breakpoint 2 (SSX2); advanced glycation end Receptor for AGE-1 (RAGE-1); Renal Ubiquitous 1 (RU1); Renal Ubiquitous 2 (RU2 );Legumain;Human papillomavirus E6 (HPV E6);Human papillomavirus HPV E7; intestinal carboxylesterase; mutant heat shock protein 7 0-2 (mut hsp70-2); leukocyte-associated immunoglobulin-like receptor 1 (LAIR1 ); Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor Subfamily A member 2 (LILRA2); CD300-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A ); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor lymphocyte antigen 75 (LY75); glypican-3 (GPC3); and Immunoglobulin lambda-like polypeptide 1 (IGLL1); CD184; LGR5; AXL ;RON;CD352 / SLAMf6;KAAG-1;5T4;c-Met;ITGA3 ;Endosialin;CD166;SAIL(c15orf54);NaPi2b;DLL 3;CD133;FZD7;dysadherin;PD-L1;SLITRK6;Nectin -4;FGFR2;FGFR3;FGFR4;CEACAM1;CEACAM5;CD7 4;STEAP-1;PMEL17;Muc16;FcRH5;TENB2;Ly6E; ETBR;158P1D7;161P2F10B;191p4d12;162p1e6; Notch3; PTK7; and EFNA4.

[0378] Tumor-supporting antigens In some embodiments, the immunoconjugates described herein are directed to a tumor-supporting antigen. an antigen-binding domain (e.g., a nucleotide sequence that binds to a target antigen) (e.g., a tumor-supporting antigen described herein); The antibody may comprise an antibody or antibody fragment.

[0379] In some embodiments, the tumor-supporting antigen is a stromal cell, an antigen-presenting cell, or a myeloid-derived antigen. This antigen is present on MDSCs. Stromal cells secrete growth factors and MDSC cells can promote cell division in the microenvironment. In some embodiments, the stromal cell antigen is a bone marrow stromal cell antigen. fibroblast activation protein (FAP) and tenascin-1 (TNF-α) In an embodiment, the MDSC antigen is selected from CD33, CD11b, C14, C D15 and CD66b. Thus, in some embodiments, Tumor-supporting antigens include bone marrow stromal cell antigen 2 (BST2), fibroblast activation protein (F AP) or one of tenascin, CD33, CD11b, C14, CD15, and CD66b It is selected from the above.

[0380] The antibody conjugates described herein are useful in treating inflammatory bowel disease (IBD), gastrointestinal ulcers, Menetrier's disease, hepatitis B, hepatitis C, secretory adenoma or protein-losing syndrome, nephropathy, Vasculogenic disorders, age-related macular degeneration, suspected ocular histoplasmosis syndrome, or age-related macular degeneration Eye diseases, bone-related conditions such as osteoarthritis, rickets and osteoporosis, systemic hyperviscosity syndrome, Laer-Weber-Rendu disease, chronic pulmonary obstructive disease, or post-burn edema, trauma, radiation, brain Stroke, hypoxia or ischemia, diabetic nephropathy, Paget's disease, (e.g. UV irradiation of human skin) Photoaging, benign prostatic hyperplasia, adenovirus, hantavirus, borrelia Borrelia burgdorferi, Yersinia species (Y ersinia spp. and Bordetella pertussis certain microbial infections, including microbial pathogens selected from the group consisting of: uterine thrombosis, endometriosis, ovarian hyperstimulation syndrome, preeclampsia, dysfunctional uterine bleeding or dysfunctional uterine ejaculation reproductive conditions such as haematological conditions, acute and chronic nephropathy (including proliferative glomerulonephritis), hypertrophic scar formation, Endotoxic shock and fungal infections, familial adenomatous polyposis, myelodysplastic syndrome, regeneration Aplastic anemia, ischemic injury, pulmonary, renal or hepatic fibrosis, infantile hypertrophic pyloric stenosis, urinary tract obstruction It can be used to treat a variety of non-malignant diseases or disorders, such as pulmonary embolism, psoriatic arthritis, and the like. It is also considered that

[0381] Methods of administration of such antibody conjugates include parenteral (e.g., intravenous) administration; injection over a period of time, e.g., as a bolus or continuous infusion, oral administration, intramuscular administration , intratumoral administration, intramuscular administration, intraperitoneal administration, intracerebrospinal administration, subcutaneous administration, intraarticular administration, intrasynovial administration These include, but are not limited to, intrathecal administration, injection into lymph nodes, or intrathecal administration.

[0382] For the treatment of a disease, the appropriate dosage of the antibody conjugate of the invention will depend on the disease being treated. The type of disease, severity and course of the disease, response to the disease, treatment history, and patient history are all factors that affect the outcome. Antibody conjugates can be administered either once or over a series of treatments lasting from several days to several months. or until a cure or diminution of the disease state (e.g., a decrease in tumor size) is achieved. The optimal dosing schedule can be determined by measuring drug accumulation in the patient's body. values ​​and may vary depending on the relative potency of a particular antibody conjugate. In some embodiments, the dosage is between 0.01 mg / kg and 20 mg / kg of body weight. g (e.g., 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg , 0.06mg, 0.07mg, 0.08mg, 0.09mg, 0.1mg, 0.2mg , 0.3mg, 0.4mg, 0.5mg, 0.6mg, 0.7mg, 0.8mg, 0.9 mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 1 0mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 1 8 mg, 19 mg, or 20 mg) and administered at least once a day, at least once a week, at least once a month, or In certain embodiments, the antibody conjugates of the invention may be administered one or more times per year. In certain embodiments, the antibody compositions of the invention are administered once every two weeks or once every three weeks. The conjugate is administered only once. The treating physician may wish to measure the drug in body fluids or tissues. Based on the established residence time and concentration, the repetition rate of administration can be estimated.

[0383] Pharmaceutical Composition Preparing a pharmaceutical or sterile composition comprising one or more antibody conjugates described herein To achieve this, the provided antibody conjugates may be mixed with a pharmaceutically acceptable carrier or excipient. can be combined.

[0384] Therapeutic and diagnostic formulations may be, for example, lyophilized powders, slurries, aqueous solutions, lotions, or by mixing with a physiologically acceptable carrier, excipient or stabilizer in the form of a suspension. can be prepared (e.g., Hardman et al., Goodman and Gi lman's The Pharmacological Basis of Ther apeutics, McGraw-Hill, New York, NY, 2001; Gennaro, Remington: The Science and Practice ce of Pharmacy, Lippincott, Williams, and W. ilkins, New York, NY, 2000; Avis, et al. (ed. s.),Pharmaceutical Dosage Forms:Parenter al Medications,Marcel Dekker,NY,1993;Lie berman, et al. (eds.), Pharmaceutical Dosag. e Forms:Tablets,Marcel Dekker,NY,1990;Li eberman,et al.(eds.)Pharmaceutical Dosag e Forms:Disperse Systems,Marcel Dekker,N Y,1990;Weiner and Kotkoskie,Excipient To xicity and Safety,Marcel Dekker,Inc.,New (See, e.g., New York, NY, 2000).

[0385] In some embodiments, pharmaceutical compositions comprising the antibody conjugates of the present invention are lyophilized. In certain embodiments, the pharmaceutical composition comprising the antibody conjugate is a formulation. Freezing in vials containing sucrose, histidine, sucrose, and polysorbate 20 In certain embodiments, the pharmaceutical composition comprising the antibody conjugate is Lyophilized in vials containing adjugate, sodium succinate and polysorbate 20 In certain embodiments, the pharmaceutical composition comprising the antibody conjugate is Freezing in vials containing dextrose, trehalose, citrate, and polysorbate 8 The lyophilized product can be reconstituted with, for example, water for injection, saline solution. In certain embodiments, the solution contains an antibody conjugate, histidine, and a pH of about 5.0. In another particular embodiment, the solution comprises an antibody coagulant, sucrose, and polysorbate 20. Conjugate, sodium succinate and polysorbate 20. In this example, the solution contains antibody conjugate, trehalose anhydrous, and citrate-free at a pH of approximately 6.6. Water, citric acid, and polysorbate 8. For intravenous administration, the resulting solution is usually is further diluted with the carrier solution.

[0386] The choice of dosage regimen for a therapeutic agent depends on the serum or tissue turnover rate of the entity, the level of symptoms, the efficacy of the agent, and the It depends on several factors, including the immunogenicity of the body and the accessibility of target cells in the biological matrix. In certain embodiments, the dosage regimen is delivered to the patient consistent with an acceptable level of side effects. Therefore, the amount of biologic delivered is determined, in part, by the amount of the biologic delivered. The appropriateness of antibodies, cytokines, and small molecules will depend on the specific entity and the severity of the condition being treated. Guidance for selecting the appropriate dose is available (e.g., Wawrzynczak ,Antibody Therapy,Bios Scientific Pub.Lt d,Oxfordshire,UK,1996;Kresina(ed.),Monoc lonal Antibodies,Cytokines and Arthritis ,Marcel Dekker,New York,NY,1991;Bach(e d.), Monoclonal Antibodies and Peptide Th erapy in Autoimmune Diseases,Marcel Dekk er,New York,NY,1993;Baert et al.,New E ngl.J.Med.348:601-608,2003;Milgrom et al .,New Engl.J.Med.341:1966-1973,1999;Slam on et al.,New Engl.J.Med.344:783-792,200 1;Beniaminovitz et al.,New Engl.J.Med.34 2:613-619,2000;Ghosh et al.,New Engl.JM ed.348:24-32,2003;Lipsky et al.,New Engl. (See J. Med. 343:1594-1602, 2000).

[0387] Determining the appropriate dose can be, for example, a therapeutically effective dose that affects or is expected to affect treatment. to the clinician using parameters or factors known or suspected in the art. Generally, the dose is started at a level somewhat lower than the optimum dose, and then increased to Increased in small increments until the desired or optimal effect is achieved relative to any negative side effects Important diagnostic measures include, for example, the presence or absence of symptoms of inflammation or the level of inflammatory cytokines produced. Includes things.

[0388] The actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be adjusted to avoid causing toxicity to the patient. effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration. The dosage level selected may vary depending on the composition of the invention being used. The activity of the particular composition or its esters, salts or amides, the route of administration of the compound used the time of administration, the rate of excretion, the treatments used in combination with the particular composition used, other drugs the duration of the agent, compound and / or material, the age, sex, weight, condition of the patient to be treated, including general health and past medical history, as well as factors known in the medical arts It will depend on a variety of pharmacokinetic factors.

[0389] Compositions comprising the antibody conjugates of the invention can be administered by continuous infusion or by, for example, daily, weekly, or semi-daily infusion. or 1 to 7 times a week, once every other week, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks The dose may be administered at intervals of once every 7 weeks, once every 8 weeks, or once every 10 weeks. administered intravenously, subcutaneously, topically, orally, intranasally, rectally, intramuscularly, intracerebrally or by inhalation. A particular administration protocol may be used to determine the maximum dose or dosage that avoids significant undesirable side effects. This includes the frequency of delivery.

[0390] For the antibody conjugates of the present invention, the dosage administered to a patient is 0.0001 mg The dosage may be 0.001 mg / kg to 50 mg / kg of patient body weight. mg / kg, 0.005mg / kg~20mg / kg, 0.01mg / kg~20mg / kg, 0.02mg / kg~10mg / kg, 0.05~5mg / kg, 0.1mg / k g~10mg / kg, 0.1mg / kg~8mg / kg, 0.1mg / kg~5mg / k g, 0.1mg / kg~2mg / kg, 0.1mg / kg~1mg / kg patient body weight The dose of antibody conjugate is calculated based on the patient's body weight in kilograms (kg) in mg / kg. It can be calculated using the unit dose multiplied by the dose.

[0391] The administration of the antibody conjugate of the present invention may be repeated, with the administration occurring for less than one day, at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, The intervals may be 4 months, 5 months, or at least 6 months apart. The antibody conjugates of the present invention may be administered twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks. In certain embodiments, the antibody conjugates of the invention are administered once a week or less frequently. The administration of Dugate is repeated every two weeks.

[0392] The effective amount for a particular patient will depend on the condition being treated, the patient's overall health, the method of administration, and the patient's overall health. The dose may vary depending on factors such as route and dose, and the severity of side effects (e.g., Mayna rd et al., A Handbook of SOPs for Good Cl inical Practice,Interpharm Press,Boca Ra ton,Fla.,1996;Dent,Good Laboratory and G ood Clinical Practice, Urch Publ., London, (See UK, 2001).

[0393] Routes of administration include, for example, topical or cutaneous application, subcutaneous, intravenous, intraperitoneal, intracerebral, and intramuscular. , intraocular, intra-arterial, intracerebrospinal, intralesional injection or infusion, or sustained release system or It can be by embedding (e.g., Sidman et al., Biopoly mers 22:547-556,1983;Langer et al., J.Bio med.Mater.Res.15:167-277,1981;Langer,Che m.Tech.12:98-105,1982;Epstein et al.,Pro c.Natl.Acad.Sci.USA 82:3688-3692,1985;Hw ang et al.,Proc.Natl.Acad.Sci.USA 77:403 0-4034, 1980; U.S. Pat. Nos. 6,350,466 and 6,316, (See US Pat. No. 5,624,114.) Optionally, the composition may contain a solubilizing agent or a steroid at the injection site. A local anesthetic such as lidocaine to reduce pain during the procedure may also be included, or both. Pulmonary administration may also be employed, for example, by use of an inhaler or nebulizer and a formulation containing an aerosolizing agent. See, for example, U.S. Patent Nos. 6, 749, 752, 6, 760, 6, 770, 6, 780, 6, 790, 6, 800, 6, 810, 6, 820, 6, 830, 6, 840, 6, 850, 6, 860, 6, 870, 6, 8 Specification No. 019,968, Specification No. 5,985,320, No. 5,985,309 Specification, Specification No. 5,934,272, Specification No. 5,874,064, No. 5, Nos. 855,913, 5,290,540 and 4,880,078 and International Publication No. 92 / 19244, International Publication No. 97 / 3257 Pamphlet No. 2, International Publication No. 97 / 44013, Pamphlet No. 98 / 31 See, for example, WO 99 / 66903 and WO 99 / 66903.

[0394] Examples of such additional ingredients are well known to those skilled in the art.

[0395] a second therapeutic agent, such as a cytokine, steroid, chemotherapeutic agent, antibiotic, or radiation; Methods for co-administration or treatment of dman et al.,(eds.)(2001)Goodman and Gilm an's The Pharmacological Basis of Therap eutics,10.sup.th ed.,McGraw-Hill,New Yor. k, NY; Poole and Peterson (eds.) (2001) Pha rmacotherapeutics for Advanced Practice: A Practical Approach, Lippincott, Williams &Wilkins,Phila.,Pa.;Chabner and Longo(ed. s.)(2001) Cancer Chemotherapy and Biother apy, Lippincott, Williams & Wilkins, Phila.,P (See a.) An effective amount of a therapeutic agent is one that alleviates symptoms by at least 10%, at least 20%, , may be reduced by at least about 30%, at least 40%, or at least 50%.

[0396] Additional therapies (e.g., prophylactic agents) that may be administered in combination with the antibody conjugates of the invention or a therapeutic agent) is administered less than 5 minutes apart from the antibody conjugate of the present invention, and less than 30 minutes apart. Leave 1 hour apart, leave about 1 hour apart, leave about 1 to 2 hours apart, leave about 2 to 3 hours apart, about Leave between 3 and 4 hours, between 4 and 5 hours, between 5 and 6 hours, and between 6 and 7 hours. 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours apart Leave between about 10 hours, between about 10 hours and about 11 hours, between about 11 hours and about 12 hours , about 12 to 18 hours apart, 18 to 24 hours apart, 24 to 36 hours apart , 36 to 48 hours apart, 48 to 52 hours apart, 52 to 60 hours apart, 60 to 72 hours apart, 72 to 84 hours apart, 84 to 96 hours apart, or Two or more therapies may be administered within the same patient visit, with the administration being 96 to 120 hours apart. It can be applied.

[0397] In certain embodiments, the antibody conjugates of the invention are capable of ensuring proper distribution in vivo. Exemplary targeting moieties include folic acid or biotin (e.g., See U.S. Patent No. 5,416,016 to Low et al.; Manno Sid (Umezawa et al., (1988)Biochem.Biophys. Res.Commun.153:1038);Antibodies(Bloeman et al.,( 1995)FEBS Lett.357:140;Owais et al.,(199 5)Antimicrob.Agents Chemother.39:180);Interface Activator protein A receptor (Briscoe et al., (1995) Am. JP hysiol.1233:134);p120(Schreier et al.,(1 994) J. Biol. Chem. 269:9090); K. Keinane n;MLLaukkanen(1994)FEBS Lett.346:123;J .J.Killion;IJFidler(1994)Immunomethods See also 4:273.

[0398] The present invention relates to pharmaceutical compositions comprising the antibody conjugates of the invention, alone or in combination with other therapies. Protocols are provided for administering the pharmaceutical compositions to subjects in need thereof. The therapies (e.g., prophylactic or therapeutic agents) of the combination therapy can be administered simultaneously or sequentially to a subject. The therapies (e.g., prophylactic or therapeutic agents) of the combination therapies of the present invention may also be administered cyclically. Cycling therapy may be used to reduce the development of resistance to one of the therapies (e.g., drugs). , to avoid or reduce the side effects of one of the therapies (e.g., a drug), and / or To improve efficacy, the first therapy (e.g., the first prophylactic or therapeutic agent) may be administered for a predetermined period of time. ), followed by administration of a second therapy (e.g., a second prophylactic or therapeutic agent) for a predetermined period of time. This includes administration and repetition of this successive administration, i.e., cycles.

[0399] The therapies (e.g., prophylactic or therapeutic agents) of the combination therapies of the invention are administered simultaneously to a subject. It is possible.

[0400] The term "concurrently" does not limit the administration of therapies (e.g., prophylactic or therapeutic agents) at exactly the same time. It is not intended to be a pharmaceutical composition containing the antibody of the present invention or a fragment thereof, but rather to be a pharmaceutical composition containing the antibody of the present invention, which is The antibody or antibody conjugate may work in conjunction with other therapies to prevent the development of other therapeutic agents that are not otherwise administered. This means that the drug is administered to a subject at time intervals that may provide increased benefit compared to when the drug is administered alone. For example, each therapy may be administered to a subject simultaneously or sequentially in any order at different times. if not administered simultaneously, they must be administered in sufficient amounts to provide the desired therapeutic or prophylactic effect. Each therapy should be administered in any suitable form and in any suitable manner. They may be administered to a subject separately by a suitable route. In various embodiments, therapies (e.g., , preventive or therapeutic agent) should be taken at intervals of less than 5 minutes, less than 15 minutes, less than 30 minutes, or 1 hour. Less than an hour apart, about 1 hour apart, about 1 to 2 hours apart, about 2 to 3 hours apart , about 3 to 4 hours apart, about 4 to 5 hours apart, about 5 to 6 hours apart, About 6 to 7 hours apart, about 7 to 8 hours apart, about 8 to 9 hours apart, about Leave between 9 and 10 hours, between 10 and 11 hours, and between 11 and 12 hours and administered to the subject 24 hours apart, 48 hours apart, 72 hours apart, or 1 week apart. In other embodiments, two or more therapies (e.g., prophylactic or therapeutic agents) are administered to the same patient. It is administered during observation.

[0401] The prophylactic or therapeutic agents of the combination therapies can be administered to a subject in the same pharmaceutical composition. Alternatively, the prophylactic or therapeutic agents of the combination therapies are administered concurrently to a subject in separate pharmaceutical compositions. The prophylactic or therapeutic agents may be administered to a subject by the same or different routes of administration. obtain. [Example]

[0402] The invention is further described in the following examples, which are set forth in the claims. It is not intended to limit the scope of the invention.

[0403] Temperatures are given in degrees Celsius (°C). Unless otherwise noted, all evaporations were performed under reduced pressure. It is usually carried out at about 15 mmHg to 100 mmHg (= 20 to 133 mbar). The structure of the products, intermediates and starting materials may be confirmed by standard analytical methods, e.g., microanalysis or spectroscopic characterization, e.g., For example, confirmation is made by MS, IR or NMR. Abbreviations used are those conventional in the art. be.

[0404] All starting materials, building blocks, reagents, acids, salts utilized to synthesize the compounds of the present invention. The groups, dehydrating agents, solvents and catalysts are commercially available or can be prepared by organic synthesis methods known to those skilled in the art. and by the organic synthesis methods described herein. can.

[0405] Abbreviation Abbreviations used are those conventional in the art or are as follows:

[0406] [Table 36]

[0407] Analysis method

[0408] [Table 37]

[0409] The method used to generate the LC / MS data is as follows.

[0410] [Table 38]

[0411] [Table 39]

[0412] [Table 40]

[0413] [Table 41]

[0414] HRMS data of linker / payload and the methods used to generate synthetic intermediates The law was as follows:

[0415] [Table 42]

[0416] [Table 43]

[0417] [Table 44]

[0418] Example 1: Synthesis of linker intermediate Example 1-1: tert-butyl ((S)-1-(((S)-1-((4-(hydroxy Methyl)-3-((prop-2-yn-1-yloxy)methyl)phenyl)amino)- 1-Oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutanol Synthesis of phenyl-2-yl carbamate (LI-1) [ka] Step 1: Synthesis of 2-(bromomethyl)-4-nitrobenzoic acid [ka] 2-Methyl-4-nitrobenzoic acid (300 g, 1.53 mL) in CCl4 (3000 mL) To a stirred solution of 71 mol of NBS (300.93 g, 1.6908 mol) and A was added at rt. IBN (37.86 g, 0.2305 mol) was added, and the reaction mixture was heated at 80° C. for 16 hours. The reaction mixture was monitored by TLC analysis. The reaction mixture was diluted with saturated NaHC1 The mixture was diluted with O3 solution (2 L) and extracted with ethyl acetate (2 x 2 L). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was obtained as the eluent. Column chromatography on silica gel using 2-3% ethyl acetate in petroleum ether. The resulting mixture was purified by 9%). 1 H NMR(400MHz,CDCl3):δ 8.35(d,J=2.0H z,1H),8.20(q,J=8.8,2.4Hz,1H),8.12(d,J=8. 8Hz,1H),4.97(s,2H),4.00(s,3H).

[0419] Step 2: 4-nitro-2-((prop-2-yn-1-yloxy)methyl)benzoic acid synthesis [ka] 2-(Bromomethyl)-4-nitrobenzoic acid (250 g, 0 A mixture of prop-2-yn-1-ol (255.68 g, 265.50 mL, 4.5609 mol, d = 0.963 g / mL) and Cs2CO3 ( The resulting mixture was stirred for 16 hours. The reaction mixture was heated to 0° C. After filtering the reaction mixture through a pad of Celite, ethyl acetate (2 L) was added. The filtrate was concentrated under reduced pressure. The crude compound was dissolved in saturated NaHCO3 solution. (1 L) and the aqueous layer (aq) was extracted with 2N HCl (2 L). The layer was acidified to pH 2. After filtration and vacuum drying, 4-nitro-2-((propanol) 2-yn-1-yloxy)methyl)benzoic acid was obtained (130 g, 60.6%). 1 H NMR(400MHz,DMSO):δ 13.61(brs,1H),8.37(d, J=2.4Hz,1H),8.23(dd,J=2.4,8.4Hz,1H),8.10 (d,J=8.8Hz,1H),4.95(s,2H),4.37(d,J=2.4Hz ,2H),3.52(t,J=2.4Hz,1H)

[0420] Step 3: Methyl 4-nitro-2-((prop-2-yn-1-yloxy)methyl)benzoate Synthesis of zoate [ka] 4-nitro-2-((prop-2-yn-1-yl)oxy)-2-oxo-2-nitropropanol in MeOH (1300 mL) To a stirred solution of methylbenzoic acid (130 g, 0.5527 mol) at 0°C, add SOCl2 (526.08g, 320.78mL, 4.4219mol, d=1.64g / mL) The reaction was stirred for 4 hours at 70° C. The reaction solvent was evaporated under reduced pressure. The resulting residue was dissolved in ethyl acetate (1000 mL) and saturated NaHCO3 (600 mL) The separated organic layer was washed with water (500 mL) and brine solution (500 mL). Dried over sodium, filtered, and evaporated under reduced pressure to give methyl 4-nitro-2-((propanol) Pa-2-yn-1-yloxymethyl)benzoate was obtained (110 g, 80% yield) . 1 H NMR(400MHz,CDCl3):δ 8.56(t,J=0.8Hz,1 H),8.18-8.09(m,2H),5.03(s,2H),4.35(d,J=2 .4Hz,2H),3.96(s,3H),2.49(t,J=2.4Hz,1H).

[0421] Step 4: Methyl 4-amino-2-((prop-2-yn-1-yloxy)methyl)benzoate Synthesis of zoate [ka] Methyl 4-nitro- in a mixture of EtOH (1100 mL) and HO (550 mL) 2-((prop-2-yn-1-yloxy)methyl)benzoate (110g, 0.4 A solution of Fe powder (197.21 g, 3.5310 mol) and N HCl (188.88 g, 3.5310 mol) was added. The resulting mixture was stirred for 16 h. The reaction mixture was cooled to rt, filtered through Celite, and ethyl acetate was added. The filtrate was concentrated under reduced pressure to half its volume. Ethyl acetate (1.5 L) was added, the two layers were separated, and the aqueous layer was diluted with ethyl acetate (2 L). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude The product was obtained by SiO2 column chromatography (15-20% acetic acid in petroleum ether). ethyl) to give methyl 4-amino-2-((prop-2-yn-1-yl) The resulting hydroxymethyl benzoate was obtained (70 g, 72% yield). 1 H NMR (400MH z, CDCl3):δ 7.67(d,J=8.8Hz,1H),6.78(t,J=1 .6Hz,1H),6.48(q,J=8.4,2.4Hz,1H),4.79(s,2 H),4.25(d,J=2.4Hz,2H),3.70(d,J=4.0Hz,3H) ,3.42(t,J=2.4Hz,1H).

[0422] Step 5: (4-amino-2-((prop-2-yn-1-yloxy)methyl)phenyl ) Synthesis of methanol [ka] A stirred solution of THF (1000 mL) was added at 0 °C with LiAlH4 (1 M in THF) (21.2 3g, 798.2mmol, 798.2mL) was slowly added. THF (800m L) Methyl 4-amino-2-((prop-2-yn-1-yloxy)methyl)benzoate A solution of tetrahydrofuran (70 g, 319.3 mmol) was added slowly at 0° C. The reaction was heated at rt The reaction mixture was stirred at rt for 4 h. The reaction mixture was cooled to 0° C., and then water (22 mL) was added very slowly. The reaction mixture was added, followed by the addition of 20% NaOH (22 mL) and water (66 mL). The mixture was stirred at 0°C for 30 minutes. Anhydrous sodium sulfate was added to absorb excess water. The mixture was filtered through a filter cake with ethyl acetate (1000 mL) and 10% M The filtrate was concentrated under reduced pressure to give the crude compound The mixture was purified by SiO2 column chromatography (eluent: 35-40% acetic acid in petroleum ether). ethyl) to give (4-amino-2-((prop-2-yn-1-yloxy) )methyl)phenyl)methanol was obtained (50.6 g, yield 83%). 1 H NMR(4 00MHz, CDCl3):δ 6.98(d,J=8.0Hz,1H),6.56(d ,J=2.4Hz,1H),6.43(dd,J=2.4,8.0Hz,1H),4.9 8(s,2H),4.64(t,J=5.2Hz,1H),4.47(s,2H),4. 34(d,J=5.6Hz,2H),4.15(d,J=2.4Hz,2H),3.46 (t,J=2.4Hz,1H).

[0423] Step 6: (9H-fluoren-9-yl)methyl (S)-(1-((4-(hydroxymethyl) ... methyl)-3-((prop-2-yn-1-yloxy)methyl)phenyl)amino)-1 Synthesis of (oxo-5-ureidopentan-2-yl)carbamate [ka] (4-amino-2-((prop-2-yn-1-yloxy) (methyl)phenyl)methanol (1.92 g, 10.04 mmol, 1.0 equiv.) and ( 9H-Fluoren-9-yl)methyl (S)-(1-amino-1-oxo-5-ureido pentan-2-yl)carbamate (3.99 g, 10.04 mmol, 1.0 equiv.) , (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5 -b]pyridinium 3-oxide hexafluorophosphate (4.20 g, 11.04 To a solution of N,N-diisopropylethylamine (2.62 mL) , 15.06 mmol, 1.5 equivalents) was added. After stirring at ambient temperature for 1 hour, the mixture was The mixture was poured into water (200 mL), and the resulting solid was filtered, rinsed with water, and dried under vacuum. (9H-fluoren-9-yl)methyl(S)-(1-((4-(hydroxymethyl)methyl)methyl)methyl)methyl methyl)-3-((prop-2-yn-1-yloxy)methyl)phenyl)amino)-1 -oxo-5-ureidopentan-2-yl) carbamate (6.08g, 99% LCMS: MH+ = 571.5; Rt = 0.93 min (2 min acidic method - Method A).

[0424] Step 7: (S)-2-amino-N-(4-(hydroxymethyl)-3-((propan-2-yl)methyl)-2-methylpropan-2-yl) Synthesis of (1-yn-1-yloxy)methyl)phenyl)-5-ureidopentanamide [ka] (9H-Fluoren-9-yl)methyl(S)-(1-((4-(hydroxymethyl) -3-((prop-2-yn-1-yloxy)methyl)phenyl)amino)-1-oxo so-5-ureidopentan-2-yl)carbamate (6.08g, 10.65mmol , 1.0 equiv.) to dimethylamine (2 M in THF, 21.31 mL, 42.62 mmol After stirring at ambient temperature for 1.5 hours, the gummy residue formed was dissolved in 100 ml of ethanol. The supernatant was decanted from the residue, triturated with ether (3 x 50 mL), and the resulting solid was filtered. The resulting mixture was filtered, washed with ether, and dried under vacuum. ((prop-2-yn-1-yloxy)methyl)phenyl)-5 -Ureidopentanamide was obtained (3.50 g, 10.04 mmol, 94%). CMS: MH+ 349.3; Rt=0.42 min (2 min acid method - Method A).

[0425] Step 8: tert-Butyl ((S)-1-(((S)-1-((4-(hydroxymethyl )-3-((prop-2-yn-1-yloxy)methyl)phenyl)amino)-1-o 2-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutane-2 Synthesis of (-yl)carbamate (LI-1) [ka] (S)-2-amino-N-(4-(hydroxymethyl)-3- ((prop-2-yn-1-yloxy)methyl)phenyl)-5-ureidopenta amide (3.50 g, 10.04 mmol, 1.0 equiv.) and (tert-butoxycarbonyl (1-[bis(2-methyl-1-methyl-2-phenyl-1-yl)-L-valine (2.62 g, 12.05 mmol, 1.2 equiv.) (Dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridin ammonium 3-oxide hexafluorophosphate (4.58 g, 12.05 mmol, 1. 2 equivalents) to a solution of N,N-diisopropylethylamine (3.50 mL, 20.08 m mol, 2.0 equiv.) was added. After stirring at ambient temperature for 2 hours, the mixture was diluted with water (200 The resulting suspension was extracted with EtOAc (3 x 100 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. After purification by chromatography (0-20% methanol / dichloromethane), ((S)-1-(((S)-1-((4-(hydroxymethyl)-3-((propa-2- (1-ynyloxy)methyl)phenyl)amino)-1-oxo-5-ureidopenta (L-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate I-1) was obtained (2.49 g, 4.55 mmol, 45%). z,DMSO-d6)δ 10.00(s,1H),7.96(d,J=7.7Hz,1 H), 7.55 (dq, J = 4.9, 2.2 Hz, 2H, aryl), 7.32 (d, J = 8.9Hz, 1H, aryl), 6.76(d, J = 8.9Hz, 1H), 5.95( t,J=5.8Hz,1H),5.38(s,2H),5.01(t,J=5.5Hz, 1H),4.54(s,2H),4.45(dd,J=25.2,5.3Hz,3H), 4.20(d,J=2.4Hz,2H),3.83(dd,J=8.9,6.7Hz,1 H),3.49(t,J=2.4Hz,1H),2.97(dh,J=26.0,6.5 Hz,2H),1.96(h,J=6.6Hz,1H),1.74-1.50(m,2H ),1.39(m,11H),0.84(dd,J=16.2,6.7Hz,6H).L CMS: MNa+ 570.5; Rt=0.79 min (2 min acid method - Method A).

[0426] Example 1-2: Prop-2-yn-1-yl (5-((S)-2-((S)-2-((t ert-Butoxycarbonyl)amino)-3-methylbutanamido)-5-ureidopentene Tanamido)-2-(hydroxymethyl)benzyl)(prop-2-yn-1-yl)ca Synthesis of rubamate (LI-2) [ka] Step 1: 2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-nitro Synthesis of benzoic acid [ka] 6-Nitroisobenzofuran-1(3H)-one (90 g) in MeOH (1000 mL) To a solution of 28 HCl (502.43 mmol, 1.00 equiv.) in HO (150 mL) The brown mixture was stirred at 25°C for 1 hour. The brown mixture was concentrated under reduced pressure to give a residue that was dissolved in DCM (2000 mL). The mixture was dissolved in TBDPSCl (296.91 g, 1.08 mol, 277.49 m L, 2.15 equiv.) and imidazole (171.03 g, 2.51 mol, 5.00 equiv. ) was added and stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0, 1 / 1) Purify and obtain 2-(((tert-butyldiphenylsilyl)oxy)methyl silane as a white solid. )-5-nitrobenzoic acid (34 g, 74.16 mmol, 14.76% yield). 1 H NMR (400 MHz, methanol-d4) δ ppm 1.13 (s, 9H) 5. 26(s,2H)7.34-7.48(m,6H)7.68(br d,J=8Hz,4 H)8.24(br d,J=8Hz,1H)8.46(br d,J=8Hz,1H) 8.74(s,1H)

[0427] Step 2: (2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-nitrile Synthesis of (triphenyl)methanol [ka] 2-(((tert-butyldiphenylsilyl)oxy)methyl) in THF (205 mL) A mixture of BH3· THF (1M, 470.68 mL, 5 equiv.) was added and the yellow mixture was stirred at 60°C for 2 h. The mixture was added with MeOH (400 mL) and concentrated under reduced pressure to give a residue, followed by H2O (200 mL) and DCM (300 mL) were added and extracted with DCM (3 x 200 mL). mL), brine (300 mL), dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate). The compound was purified by ethanol (1 / 0, 1 / 1) to give a white solid (2-(((tert-butyl 2-methyl-2-propanol). Diphenylsilyl)oxy)methyl)-5-nitrophenyl)methanol (34g, 80 0.65 mmol, yield 85.7%. 1H NMR (400MHz, methanol-d4) δ ppm 1.10 (s, 9H) .58(s,2H)4.89(s,2H)7.32-7.51(m,6H)7.68(d d,J=8,1.38Hz,4H)7.76(d,J=8Hz,1H)8.15(dd, J=82.26Hz,1H)8.30(d,J=2Hz,1H).

[0428] Step 3: 2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-nitro Benzaldehyde synthesis [ka] (2-(((tert-butyldiphenylsilyl)oxy) (methyl)-5-nitrophenyl)methanol (34 g, 80.65 mmol, 1 equiv.) To the solution was added MnO2 (56.09 g, 645.22 mmol, 8 equiv.). The mixture was stirred at 25° C. for 36 hours. MeOH (400 mL) was added to the mixture and concentrated under reduced pressure. The residue was concentrated, followed by the addition of H2O (200 mL) and DCM (300 mL). Extract with MgSO4 (3 x 200 mL), wash with brine (300 mL), and dry over anhydrous MgSO4. The residue was purified by silica gel chromatography ( Purification was performed with CH2Cl2 = 100%. 2-(((tert-butyl))- ... (Diphenylsilyl)oxy)methyl)-5-nitrobenzaldehyde (30g, 71. 51 mmol, 88.7% yield was obtained. 1H NMR (400 MHz, chloroform-d) δ ppm 1.14 (s, 9H) .26(s,2H)7.34-7.53(m,6H)7.60-7.73(m,4H)8 .13(d,J=8Hz,1H)8.48(dd,J=8,2.51Hz,1H)8.6 7(d,J=2Hz,1H)10.16(s,1H)

[0429] Step 4: N-(2-(((tert-butyldiphenylsilyl)oxy)methyl)-5- Synthesis of nitrobenzylprop-2-yn-1-amine [ka] 2-(((tert-butyldiphenylsilyl)oxy)methyl)methylsilane in DCM (130 mL) (ethyl)-5-nitrobenzaldehyde (12.6 g, 30.03 mmol, 1 equiv.) The solution was treated with propane-2-yn-1-amine (4.14 g, 75.08 mmol, 4.81 mL, 2 0.5 equiv.) and MgSO4 (36.15 g, 300.33 mmol, 10 equiv.) were added. The suspension mixture was then stirred at 25°C for 24 hours. A small amount of the reaction solution was taken and NaBH4 Upon treatment with HCl, TLC showed the formation of one new spot. The reaction mixture was filtered and The residue was concentrated under reduced pressure to give (E)-N-[[2-[[tert- Butyl(diphenyl)silyl]oxymethyl]-5-nitro-phenyl]methyl]propan To this was obtained 12 g of 1-2-yn-1-imine (crude). 1 H NMR (400 MHz, chloro Holm-d)δ ppm 1.11(s,9H)2.48(t,J=2.38Hz,1H )4.52(t,J=2.13Hz,2H)5.09(s,2H)7.35-7.49( m,6H)7.63-7.72(m,4H)7.79(d,J=8.53Hz,1H)8 .25(dd,J=8.53,2.51Hz,1H)8.68(d,J=2.26Hz, 1H)8.84(t,J=1.88Hz,1H).

[0430] (E)-N-[[2-[[tert-butyl(diphenyl)silyl]oxymethyl]- 5-Nitro-phenyl]methyl]prop-2-yn-1-imine (12g, 26.28m mol, 1 equiv) in MeOH (100 mL) and THF (50 mL), followed by N aBH4 (1.49 g, 39.42 mmol, 1.5 equiv.) was added and the yellow mixture was cooled to -2 The reaction mixture was stirred at 0° C. for 2 hours. LCMS showed that the desired compound was detected. Quench the reaction mixture by adding 200 mL of MeOH at -20 °C. The residue was dissolved in 500 mL of EtOAc and 15 0 mL of brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue The residue was purified by flash silica gel chromatography (0 to 10% ethyl acetate / The product was purified by petroleum ether gradient elution. N-(2-(((te) rt-Butyldiphenylsilyl)oxy)methyl)-5-nitrobenzyl)prop-2- Yne-1-amine (9 g, 18.45 mmol, 70% yield) was obtained. 1 H NMR(4 00MHz, chloroform-d) δ ppm 1.12(s,9H) 2.13(t,J= 2.38Hz,1H)3.33(d,J=2.51Hz,2H)3.80(s,2H)4 .93(s,2H)7.36-7.49(m,6H)7.69(dd,J=7.91,1 .38Hz,4H)7.77(d,J=8.53Hz,1H)8.16(dd,J=8. 41,2.38Hz,1H)8.24(d,J=2.26Hz,1H).

[0431] Step 5: (9H-Fluoren-9-yl)methyl (2-(((tert-butyldiphenyl) (( ... Synthesis of rubamate [ka] N-(2-(((tert-butyldiphenylsilyl)isopropyl)methyl)-2-(((tert-butyldiphenylsilyl)methyl ... (5-nitrobenzyl)prop-2-yn-1-amine (9g, 19.6 2 mmol, 1 eq) and Fmoc-OSU (7.28 g, 21.59 mmol, 1.1 To a solution of 100 equivalents of NaHCO3 (90 mL) was added saturated NaHCO3 (90 mL), and the white suspension was stirred at 20 °C for 12 h. The reaction mixture was diluted with 150 mL of H2O and extracted with EtOAc (1 portion each time). 50 mL). The combined organic layers were washed with 200 mL of brine and dried over anhydrous Na2SO4. The mixture was evaporated, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography. The product was purified by filtration (eluent: 0-30% ethyl acetate / petroleum ether). (9H-fluoren-9-yl)methyl(2-(((tert-butyldiphenyl) Silyl)oxy)methyl)-5-nitrobenzyl)(prop-2-yn-1-yl)carboxamide Bamate (7.7 g, 11.08 mmol, 56.48% yield, 98% purity) was obtained. 1H NMR (400MHz, chloroform-d) δ ppm 1.12 (s, 9H) .17(br d,J=14.31Hz,1H)3.87-4.97(m,9H)6.9 8-8.28(m,21H).

[0432] Step 6: (9H-Fluoren-9-yl)methyl (5-amino-2-(((tert-butyl) (ethyldiphenylsilyl)oxy)methyl)benzyl)(prop-2-yn-1-yl)ca Synthesis of rubamate [ka] (9H-Fluoren-9-yl)methyl in 10% AcOH / CH2Cl2 (100 mL) thyl(2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-nitrobenzyl (prop-2-yn-1-yl)carbamate (5.0 g, 7.34 mmol, Zn (7.20 g, 110 mmol, 15 equiv.) was added to an ice-bath cooled solution of Zn (1.0 equiv.). The ice bath was removed and the resulting mixture was stirred for 2 hours, at which time it was passed through a pad of Celite. The volatiles were removed in vacuo and the residue was dissolved in EtOAc and added NaHCO3 (sat. ), washed with NaCl (sat), dried over MgSO4, filtered, concentrated and purified by ISCO After silica gel chromatography (0-75% EtOAc / heptane), (9H-fluoro phenyl-9-yl)methyl(5-amino-2-(((tert-butyldiphenylsilyl) (oxy)methyl)benzyl)(prop-2-yn-1-yl)carbamate was obtained (2. 99g, 62%). LCMS: MH+ = 651.6; Rt = 3.77 min (5 min acid method) - Method C).

[0433] Step 7: (9H-fluoren-9-yl)methyl (5-((S)-2-((S)-2-( (tert-Butoxycarbonyl)amino)-3-methylbutanamido)-5-ureide Pentanamido)-2-(((tert-butyldiphenylsilyl)oxy)methyl)benzyl Synthesis of (2-in-1-yl)(prop-2-yn-1-yl)carbamate [ka] (9H-Fluoren-9-yl)methyl(5-amino-) in CH2Cl2 (40 mL) 2-(((tert-butyldiphenylsilyl)oxy)methyl)benzyl)(propan- 2-yn-1-yl)carbamate (2.99 g, 4.59 mmol, 1.0 equiv.) and (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-methyl butanamido)-5-ureidopentanoic acid (1.72 g, 4.59 mmol, 1.0 equiv. ) to ethyl 2-ethoxyquinoline-1(2H)-carboxylate (2.27g, 9.1 After stirring for 10 minutes, MeOH (1 mL) was added. The solution then became homogenous. The reaction was stirred for 16 hours, the volatiles were removed in vacuo, and the reaction mixture was purified by ISCO Si After purification by O2 chromatography (0-15% MeOH / CH2Cl2), (9H- Fluoren-9-yl)methyl (5-((S)-2-((S)-2-((tert-butanoyl)methyl) (oxycarbonyl)amino)-3-methylbutanamido)-5-ureidopentanamido -2-(((tert-butyldiphenylsilyl)oxy)methyl)benzyl)(propanol) (2.78 g, 60%). LCMS: MH+ = 1008.8; Rt = 3.77 min (5 min acid method - Method C).

[0434] Step 8: Prop-2-yn-1-yl (5-((S)-2-((S)-2-((tert -butoxycarbonyl)amino)-3-methylbutanamido)-5-ureidopentaenoic acid 2-(((tert-butyldiphenylsilyl)oxy)methyl)benzyl)( Synthesis of prop-2-yn-1-yl carbamate [ka] (9H-fluoren-9-yl)methyl(5-((S)-2-((S)-2-((te rt-Butoxycarbonyl)amino)-3-methylbutanamido)-5-ureidopenta 2-(((tert-butyldiphenylsilyl)oxy)methyl)benzyl )(prop-2-yn-1-yl)carbamate (1.60 g, 1.588 mmol, 1 0.0 equiv) in MeOH (30 mL, 60 mmol, 37 equiv) and THF (10 mL) of 2M dimethylamine was added. After standing for 3 hours, the volatiles were removed in vacuo and the residue was dissolved in Et The Fmoc deprotection by-product was removed by trituration with HCl. The resulting solid was added with CH2Cl2 (1 6 mL) and pyridine (4 mL) were added, and the heterogeneous solution was dissolved in propargyl chloroformate (1 After stirring for 30 minutes, additional Propargyl chloroformate (155 μL, 1.588 mmol, 1.0 equiv) was added. After stirring for an additional 20 min, MeOH (1 mL) was added to quench the remaining chloroformate. The mixture was quenched and the volatiles were removed in vacuo. ISCO SiO2 chromatography (0-15% MeOH / CH2Cl2) to give prop-2-yn-1-yl (5-((S )-2-((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanol (( ... (aryl)oxy)methyl)benzyl)(prop-2-yn-1-yl)carbamate (984 mg, 71%). LCMS: MH+ = 867.8; Rt = 3.40 min (5 min Interacid method - method C).

[0435] Step 9: Prop-2-yn-1-yl (5-((S)-2-((S)-2-((tert -butoxycarbonyl)amino)-3-methylbutanamido)-5-ureidopentaenoic acid (2-hydroxymethyl)benzyl)(prop-2-yn-1-yl)carbamate Synthesis of LI-2 [ka] Propionyl-2-yn-1-yl (5-((S)-2-((S) -2-((tert-butoxycarbonyl)amino)-3-methylbutanamide)-5- Ureidopentanamido)-2-(((tert-butyldiphenylsilyl)oxy)methyl (ethyl)benzyl)(prop-2-yn-1-yl)carbamate (984 mg, 1.13 5 mmol, 1.0 equiv) in THF (2.27 mL, 2.27 mmol, 2.0 equiv) 1.0 M tetrabutylammonium fluoride in 100 ml of water was added. After leaving the mixture to stand for 6 hours, The material was removed in vacuo and the residue was purified by ISCO SiO2 chromatography (0-40% MeOH / CHCl), and purified as propionyl-2-yn-1-yl (5-((S)-2-((S )-2-((tert-butoxycarbonyl)amino)-3-methylbutanamide)-5 -ureidopentanamido)-2-(hydroxymethyl)benzyl)(prop-2-yne (629 mg, 88%). LCMS: MH+=629. 6; Rt=1.74 min (5 min acid method - Method C).

[0436] Example 1-3: Prop-2-yn-1-yl (5-((S)-2-((S)-2-((t ert-Butoxycarbonyl)amino)-3-methylbutanamido)-5-ureidopentene Tanamido)-2-(hydroxymethyl)benzyl)(methyl)carbamate (LI-3 ) synthesis [ka] Step 1: Synthesis of 2-(hydroxymethyl)-N-methyl-5-nitrobenzamide [ka] 6-Nitroisobenzofuran-1(3H)-one (50 mL) in MeOH (1500 mL) To a stirred suspension of MeNH2 (3.00 kg, 29.94 mol) was added MeNH2 (3.00 kg, 29.94 mol) at 25 °C. 600 mL of 1,000 mol (purity 31.0%) was added and stirred for 1 hour. The solid was filtered and The residue was washed twice with HCl (600 mL) and dried under high vacuum to give the product as a white solid. 2-(hydroxymethyl)-N-methyl-5-nitrobenzamide (560 g, crude) Got it. LCMS: RT=0.537 min, MS m / z=193.2.1H NMR:40 0MHz DMSO δ 8.57(br d,J=4.4Hz,1H),8.31(d d,J=2.4,8.6Hz,1H),8.21(d,J=2.4Hz,1H),7.8 6(d,J=8.8Hz,1H),5.54(t,J=5.6Hz,1H),4.72( d,J=5.5Hz,2H),2.78(d,J=4.4Hz,3H).

[0437] Step 2: Synthesis of (2-((methylamino)methyl)-4-nitrophenyl)methanol [ka] 2-(hydroxymethyl)-N-methyl-5-nitrobenz in THF (5000 mL) A solution of the amide (560 g, 2.66 mol) was cooled to 0 °C, followed by BH3-Me2S( 506 g, 6.66 mol) (2.0 M in THF) was added dropwise over 60 minutes, and the mixture was The mixture was heated to 70° C. for 1 hour. LCMS showed that the starting material had been consumed. Then, 4M HCl in methanol (1200 mL) was added to the reaction mixture at 0°C, and the mixture was stirred for 8 hours. The mixture was heated to 65° C. The reaction mixture was cooled to 0° C., the solids were filtered, and the mixture was concentrated under reduced pressure. (2-((methylamino)methyl)-4-nitrophenyl)methanol as a white solid Obtained (520g). LCMS: RT=0.742 min, MS m / z=197.1[M+H ]+. 1 H NMR:400MHz DMSO δ 9.25(br s,2H),8. 37(d,J=2.4Hz,1H),8.14(dd,J=2.4,8.5Hz,1H) ,7.63(d,J=8.4Hz,1H),5.72(br s,1H),4.65(s ,2H),4.15(br s,2H),2.55-2.45(m,3H)

[0438] Step 3: 1-(2-(((tert-butyldiphenylsilyl)oxy)methyl)-5- Synthesis of (nitrophenyl)-N-methylmethanamine [ka] (2-((methylamino)methyl)-4-nitrophenyl) in DCM (2600 mL) Methanol (520 g, 2.65 mol) and imidazole (721 g, 10.6 mol ) was cooled to 0 °C and TBDPS-Cl (1.09 kg, 3.98 mol, 1.02 L) was added dropwise and the mixture was stirred for 2 hours. The mixture was poured into ice-cold water (1000 mL) and acetic acid The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The crude product was purified by distillation under vacuum using ethyl acetate:petroleum ether (10 The residue was purified by chromatography on silica gel eluted with 100 mL of 1000 M NaOH / 1000 M NaOH to give 1-(2-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methyl-2-propanol as a yellow liquid )-5-nitrophenyl)-N-methylmethanamine (600 g) was obtained. LCMS: Composition: RT=0.910 min, MS m / z=435.2[M+H]+ 1H NMR:400MHz CDCl3 δ 8.23(d,J=2.4Hz,1H) ,8.15(dd,J=2.4,8.4Hz,1H),7.76(d,J=8.4Hz, 1H),7.71-7.66(m,4H),7.50-7.37(m,6H),4.88 (s,2H),3.65(s,2H),2.39(s,3H),1.12(s,9H)

[0439] Step 4: (9H-Fluoren-9-yl)methyl (2-(((tert-butyldiphenyl) Synthesis of (( ... [ka] 1-(2-(((tert-butyldiphenylsilyl)oxy)- ... (Ci)methyl)-5-nitrophenyl)-N-methylmethanamine (400g, 920.3 A solution of Fmoc-OSU (341.5 g, 1.01 mol) and EtN( 186.2 g, 1.84 mol, 256.2 mL) was added and the mixture was stirred at 25°C for 1 hour. The mixture was poured into water (1600 mL) and extracted twice with ethyl acetate (1000 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was extracted with petroleum ether:ethyl acetate (1 / 0 to 1 / 1) and Purification by chromatography on silica gel eluting with 9H-fluorenone was carried out as a white solid. fluoren-9-yl)methyl(2-(((tert-butyldiphenylsilyl)oxy) Methyl)-5-nitrobenzyl)(methyl)carbamate was obtained (405g). LCMS :RT=0.931 min, MS m / z=657.2[M+H]+. 1H NMR:400MHz CDCl3 δ 8.21-7.96(m,1H),7. 87-7.68(m,3H),7.68-7.62(m,4H),7.62-7.47( m,2H),7.47-7.28(m,9H),7.26-7.05(m,2H),4. 81(br s,1H),4.62-4.37(m,4H),4.31-4.19(m, 1H),4.08-3.95(m,1H),2.87(br d,J=5.2Hz,3H ),1.12(s,9H).

[0440] Step 5: (9H-Fluoren-9-yl)methyl (5-amino-2-(((tert-butyl) Synthesis of (diphenylsilyl)oxy)methyl)benzyl)methyl)carbamate [ka] (9H-Fluoren-9-yl) in MeOH (90 mL) and EtOAc (30 mL) )methyl(2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-nitrilo (benzyl)(methyl)carbamate (3.0 g, 4.57 mmole, 1.0 equiv.) The solution was degassed and purged with a balloon of N2 via a three-way stopcock. The degassing / N2 purging was repeated for 2 After repeating this process several times, 10% Pd / C deGussa type (0.486 g, 0.457 The resulting mixture was degassed and cooled via a three-way stopcock for 2 h. After repeating the degassing / H2 purging twice, the reaction was stopped at the balloon pressure of Stirred under H2 for 4 h. The reaction was degassed, purged with N2, and filtered through a pad of Celite. Further elution was performed with MeOH. After removing the volatiles in vacuo and pumping at high pressure, (9H-fluoro phenyl-9-yl)methyl(5-amino-2-(((tert-butyldiphenylsilyl) (oxy)methyl)benzyl)(methyl)carbamate was obtained (2.78 g, 97%). CMS: MH+ = 627.7; Rt = 1.59 min (2 min acid method - Method A). 1 H NMR:400MHz CDCl3 δ 7.80(br d,J=7.2Hz,1H) ,7.74-7.67(m,5H),7.64(br d,J=6.8Hz,1H),7 .49-7.30(m,10H),7.23-7.06(m,2H),6.61-6.4 1(m,2H),4.66(br d,J=7.2Hz,2H),4.55(s,2H) ,4.51-4.34(m,2H),4.32-4.10(m,1H),3.66(br s,2H),2.96-2.78(m,3H),,1.07(s,9H).

[0441] Step 6: (9H-fluoren-9-yl)methyl (5-((S)-2-((S)-2-( (tert-Butoxycarbonyl)amino)-3-methylbutanamido)-5-ureide Pentanamido)-2-(((tert-butyldiphenylsilyl)oxy)methyl)benzyl Synthesis of benzyl(methyl)carbamate [ka] (9H-Fluoren-9-yl)methyl in 2:1 CH2Cl2 / MeOH (60 mL) ethyl(5-amino-2-(((tert-butyldiphenylsilyl)oxy)methyl)benzyl (2.86 g, 4.56 mmol, 1.0 equiv.) and ( S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutoxycarbonyl Tanamido)-5-ureidopentanoic acid (1.71 g, 4.56 mmol, 1.0 equiv.) Ethyl 2-ethoxyquinoline-1(2H)-carboxylate (2.256g, 9.1 2 mmol, 2.0 equiv.) was added. The homogeneous solution was stirred for 16 h, at which point additional (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-methyl butanamido)-5-ureidopentanoic acid (0.340 g, 0.2 equivalents) and ethyl 2- Add ethoxyquinoline-1(2H)-carboxylate (0.452 g, 0.4 eq.) After stirring for an additional 5 hours, the volatiles were removed in vacuo and the mixture was eluted with ISCO Si After purification by O2 chromatography (0-5% MeOH / CH2Cl2), (9H- Fluoren-9-yl)methyl (5-((S)-2-(((S)-2-((tert-butoxy) Dicarbonylamino-3-methylbutanamido-5-ureidopentanamido 2-(((tert-butyldiphenylsilyl)oxy)methyl)benzyl)(methyl) Carbamate was obtained (2.95 g, 65%). LCMS: MH+=984.1; Rt=1 .54 minutes (2 minute acid method - Method A).

[0442] Step 7: Prop-2-yn-1-yl (5-((S)-2-((S)-2-((tert -butoxycarbonyl)amino)-3-methylbutanamido)-5-ureidopentaenoic acid 2-(((tert-butyldiphenylsilyl)oxy)methyl)benzyl)( Synthesis of methyl carbamates [ka] 9H-Fluoren-9-yl)methyl (5-((S)-2-( (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanamide -5-ureidopentanamido)-2-(((tert-butyldiphenylsilyl)oxy) (Ci)methyl)benzyl)(methyl)carbamate (2.05g, 2.085mmol, 1 0.0 equiv) in 2.0 M dichloromethane (10.42 mL, 20.85 mmol, 10 equiv) in MeOH (10.42 mL, 20.85 mmol, 10 equiv). Methylamine was added. After stirring for 16 hours, the volatiles were removed in vacuo. The residue was dissolved in CH2C Dissolved in l2 (20 mL) and DIEA (0.533 mL, 4.17 mmol, 2 equiv.) , and propargyl chloroformate (0.264 mL, 2.71 mmol, 1.3 equiv.) was added. After stirring at rt for 16 h, the reaction was diluted with CH2Cl2 (20 mL) and 3 (sat), washed with NaCl (sat), dried over MgSO4, filtered, concentrated, and Purification was performed by SCO SiO2 chromatography (0-15% MeOH / CH2Cl2). Propionyl-2-yn-1-yl (5-((S)-2-(((S)-2-((tert -butoxycarbonyl)amino)-3-methylbutanamido)-5-ureidopentaenoic acid 2-(((tert-butyldiphenylsilyl)oxy)methyl)benzyl)( Methyl)carbamate (1.04 grams, 59%) was obtained. LCMS: MH+ = 843. 8; Rt=1.35 min (2 min acid method - Method A).

[0443] Step 8: Prop-2-yn-1-yl (5-((S)-2-((S)-2-((tert -butoxycarbonyl)amino)-3-methylbutanamido)-5-ureidopentaenoic acid Synthesis of (2-(hydroxymethyl)benzyl)(methyl)carbamate (LI-3) Growth [ka] Propionyl-2-yn-1-yl (5-((S)-2-((S )-2-((tert-butoxycarbonyl)amino)-3-methylbutanamide)-5 -ureidopentanamido)-2-(((tert-butyldiphenylsilyl)oxy) (methyl)benzyl)(methyl)carbamate (1.6 g, 1.90 mmol, 1.0 equiv. To a 0 °C solution of 1.0 M fluoride in THF (3.80 mL, 3.80 mmol, 2.0 equiv.) Tetrabutylammonium fluoride was added. After warming to rt and stirring for 16 h, the volatiles were removed. The residue was dissolved in EtOAc and washed with NaHCO3 (sat.), NaCl (sat.). Wash, dry over MgSO4, filter, concentrate, and the residue is purified by ISCO SiO2 chromatography. The product was purified by chromatography (0-30% MeOH / CH2Cl2) to give prop-2-yn- 1-yl(5-((S)-2-((S)-2-((tert-butoxycarbonyl)amido) (3-methylbutanamido)-5-ureidopentanamido)-2-(hydroxymethyl (methyl)benzyl)(methyl)carbamate (LI-3) (1.0 g, 87%) was obtained. CMS: MH+ = 605.7; Rt = 0.81 min (2 min acid method - Method A).

[0444] Example 1-4: tert-butyl ((S)-1-(((S)-1-((4-(hydroxy methyl)-3-(2-(((prop-2-yn-1-yloxy)carbonyl)amino) Acetamido)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)a Synthesis of (amino)-3-methyl-1-oxobutan-2-yl)carbamate (LI-4) [ka] Step 1: (9H-fluoren-9-yl)methyl (S)-(1-((4-(hydroxymethyl) ... (ethyl)-3-nitrophenyl)amino)-1-oxo-5-ureidopentan-2-yl ) Synthesis of carbamates [ka] (4-amino-2-nitrophenyl)methanol (10 g, 5 mL) in DMF (50 mL) 9.5 mmol, 1.0 equiv.) and (9H-fluoren-9-yl)methyl(S)-(1 -amino-1-oxo-5-ureidopentan-2-yl) carbamate (23.64g , 59.5 mmol, 1.0 equivalent) and 1-hydroxy-7-azabenzotriazole ( 8.50 g, 62.4 mmol, 1.05 equiv.) with 1-(3-dimethylaminopropanediol) (propyl)-3-ethylcarbodiimide (11.97 g, 62.4 mmol, 1.05 equiv. After stirring at ambient temperature for 16 hours, the mixture was poured into water (4 L) and The resulting solid was filtered, rinsed with water, and dried under vacuum. Oren-9-yl)methyl (S)-(1-((4-(hydroxymethyl)-3-nitrophenyl)-4-[(4-hydroxymethyl)-2-[(4-[(4-hydroxymethyl)-3-nitrophenyl)-4-[(4-hydroxymethyl)-2 ... (phenylamino)-1-oxo-5-ureidopentan-2-yl)carbamate was obtained. (31.49g, 57.5mmol, 97%). LCMS:MH+=548;Rt=2. 02 min (5 min acid method - Method C).

[0445] Step 2: (S)-2-amino-N-(4-(hydroxymethyl)-3-nitrophenyl) Synthesis of 5-ureidopentanamide [ka] (9H-Fluoren-9-yl)methyl (S)-(1-((4- (Hydroxymethyl)-3-nitrophenyl)amino)-1-oxo-5-ureidopentene Solution of tan-2-yl)carbamate (31.49 g, 57.5 mmol, 1.0 equiv.) Dimethylamine (2 M in MeOH, 331 mL, 661 mmol, 11.5 equiv.) was added to After stirring at ambient temperature for 24 hours, the volatiles were removed in vacuo and the resulting residue was The residue was dried under vacuum to give (S)- 2-amino-N-(4-(hydroxymethyl)-3-nitrophenyl)-5-ureidopeptide 21.85 g (57.5 mmol, 99%) of methyl methyl amine was obtained. LCMS: MH+= 326.4; Rt=0.35 min (2 min acid method - Method A).

[0446] Step 3: tert-Butyl ((S)-1-(((S)-1-((4-(hydroxymethyl )-3-nitrophenyl)amino)-1-oxo-5-ureidopentan-2-yl)a Synthesis of (amino)-3-methyl-1-oxobutan-2-yl)carbamate [ka] (S)-2-amino-N-(4-(hydroxymethyl)-3- Nitrophenyl)-5-ureidopentanamide (10.89 g, 28.8 mmol, 1 0.0 equivalents) and (tert-butoxycarbonyl)-L-valine (6.25 g, 28.8 mmol, 1.0 equivalent) and 1-hydroxy-7-azabenzotriazole (3.92 g , 28.8 mmol, 1.0 equiv) and 1-(3-dimethylaminopropyl)-3 -ethylcarbodiimide (5.52 g, 28.8 mmol, 1.0 equiv.) was added. After stirring at ambient temperature for 24 hours, the mixture was added dropwise to water (2 L), stirred for 30 minutes, and then overnight. The mixture was saturated with NaCl and the resulting solid was filtered off and dried under vacuum. tert-Butyl ((S)-1-(((S)-1-((4-(hydroxymethyl) (3-nitrophenyl)amino)-1-oxo-5-ureidopentan-2-yl (amino)-3-methyl-1-oxobutan-2-yl)carbamate (11.96 g, 22.8 mmol, 79%). LCMS: MH+ = 525.4; Rt = 0.79 min ( 2 minute acid method - Method A).

[0447] Step 4: tert-Butyl ((S)-1-(((S)-1-((4-(((tert-butyl) (dimethylsilyl)oxy)methyl)-3-nitrophenyl)amino)-1-oxo- 5-Ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl ) Synthesis of carbamates [ka] tert-Butyl ((S)-1-(((S)-1-((4-( Hydroxymethyl)-3-nitrophenyl)amino)-1-oxo-5-ureidopenta (1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate 1.96 g, 22.8 mmol, 1.0 equiv.) and imidazole (15.52 g, 228 m mol, 10 equiv.) to a suspension of tert-butyldimethylchlorosilane (13.68 g The resulting mixture was stirred at ambient temperature for 48 hours. The mixture was stirred for 96 hours, followed by heating at 45° C. for 4 hours. The mixture was poured into water and stirred for 96 hours. The solid was filtered, washed with water (2 x 100 mL) and dried under vacuum. After purification by chromatography (0-30% methanol / dichloromethane), tert -butyl((S)-1-(((S)-1-((4-(((tert-butyldimethylsilyl (N-(2-amino-1-oxo-5-ureidopentyl)oxy)methyl)-3-nitrophenyl)amino)-1-oxo-5-ureidopentyl (3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate Obtained (8.02 g, 12.56 mmol, 55%). LCMS: MH+ = 639.6; R t = 1.22 min (2 min acid method - Method A).

[0448] Step 5: tert-butyl ((S)-1-(((S)-1-((3-amino-4-((( tert-Butyldimethylsilyl)oxy)methyl)phenyl)amino)-1-oxo- 5-Ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl ) Synthesis of carbamates [ka] Under a nitrogen atmosphere, tert-butyl ((S)-1- (((S)-1-((4-(((tert-butyldimethylsilyl)oxy)methyl)- 3-Nitrophenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino )-3-methyl-1-oxobutan-2-yl)carbamate (8.02 g, 12 A solution of palladium on carbon (10 wt%, 2.00 g, 1. The mixture was placed under 1 atmosphere of dihydrogen and the atmosphere The mixture was stirred at room temperature for 18 hours. The mixture was filtered through Celite and dried under vacuum. After purification by ISCO chromatography (0–40% methanol / dichloromethane), tert-Butyl ((S)-1-(((S)-1-((3-amino-4-(((tert -butyldimethylsilyl)oxy)methyl)phenyl)amino)-1-oxo-5-urea (Idopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carba The mate was obtained (4.82 g, 7.92 mmol, 63%). LCMS: MH+=609. 6; Rt=2.65 min (5 min acid method - Method C).

[0449] Step 6: tert-Butyl ((S)-1-(((S)-1-((4-(hydroxymethyl )-3-(2-(((prop-2-yn-1-yloxy)carbonyl)amino)aceto Amido)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino) Synthesis of 1-(3-methyl-1-oxobutan-2-yl)carbamate (LI-4) [ka] Step 6a): 2M aqueous sodium hydroxide solution (63.3mL, 127mmol, NaOH, 3.0eq. To a solution of glycine (3.19 g, 42.5 mmol, 1.0 equiv.) in HCl was added prochloroformate. Pargyl (5.0 g, 42.5 mmol, 1.0 equiv.) was added. The resulting mixture was stirred at rt. The mixture was stirred at ambient temperature for 3 hours. The mixture was extracted with ethyl acetate (3 x 250 mL). The organic layer was dried over magnesium sulfate, filtered, and the volatiles were removed in vacuo. (prop-2-yn-1-yloxy)carbonyl)glycine, [ka] (3.97 g, 25.3 mmol, 59%) 1 H NMR (400 MHz, DM SO-d6)δ ppm 3.48(t,J=2.40Hz,1H)3.66(d,J= 6.19Hz,2H)4.63(d,J=2.40Hz,2H)7.63(t,J=6. 13Hz,1H)12.57(br s,1H).

[0450] Step 6b): tert-Butyl ((S)-1-(((S)-1-((3-amino)methyl)-3-azabicyclo[3.2.1.2 ...1.2.1.2.2.1.2.1 4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino) -1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl To a solution of (tan-2-yl)carbamate (2.7 g, 4.43 mmol, 1.0 equiv.) (Prop-2-yn-1-yloxy)carbonyl)glycine (0.732g, 4.66 mmol, 1.05 equiv.) and 1-hydroxy-7-azabenzotriazole (0.66 4g, 4.88mmol, 1.1eq) and 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride (0.935 g, 4.88 mmol, 1.1 equiv.) was added. The resulting mixture was stirred at ambient temperature for 1 hour and then added dropwise to water (500 mL). The resulting precipitate was filtered, washed with water, and dried under vacuum. SiO2 ISCO chromatography (0-50% methanol / dichloromethane) After purification, tert-butyl ((S)-1-(((S)-1-((4-(hydroxymethyl )-3-(2-(((prop-2-yn-1-yloxy)carbonyl)amino)aceto Amido)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino) 1.5-(3-methyl-1-oxobutan-2-yl)carbamate (LI-4) was obtained. 2g, 2.40mmol, 54%). LCMS:MH+=634.6;Rt=1.97min (5 minute acid method - Method C). 1 H NMR (400 MHz, DMSO-d6) δ p pm 0.76-0.91(m,6H)1.30-1.47(m,11H)1.51-1 .73(m,2H)1.87-2.00(m,1H)2.89-3.07(m,2H)3 .50(t,J=2.32Hz,1H)3.73-3.87(m,3H)4.37-4. 47(m,3H)4.65(d,J=2.45Hz,2H)5.30(t,J=5.44 Hz,1H)5.38(s,2H)5.96(t,J=5.81Hz,1H)6.72( br d,J=8.93Hz,1H)7.25(d,J=8.44Hz,1H)7.45 (dd,J=8.25,2.02Hz,1H)7.78(br t,J=5.87Hz, 1H)7.87-8.00(m,2H)9.51(s,1H)10.04(s,1H).

[0451] Example 1-5: tert-butyl ((S)-1-(((S)-1-((3-(di(propanol) -2-yn-1-yl)carbamoyl)-4-(hydroxymethyl)phenyl)amino -1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl Synthesis of Tan-2-yl)carbamate (LI-5) [ka] Step 1: 2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-nitro Synthesis of N,N-di(prop-2-yn-1-yl)benzamide [ka] 2-(((tert-butyldiphenylsilyl)oxy) in dichloromethane (6 ml) (methyl)-5-nitrobenzoic acid (1.00 g, 2.30 mmol, 1.0 equiv....

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, R １ is a reactive group, L １ is a bridging spacer, Lp is a divalent peptide spacer; G-L ２ -A is a self-immolative spacer, R ２ is the hydrophilic moiety, L ２ is a bond, methylene, neopentylene or C ２ ~C ３ is alkenylene, A is a bond, —OC(═O)—*, 【Chemistry 2】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)- * or -OC(= O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ )C(=O)-*, where , each R ａ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ Select from cycloalkyl and * in A indicates the point of attachment to D; L ３ is a spacer moiety, and D is a drug moiety containing N or O, where D is the N or O moiety of the drug moiety from A. and is connected to A via a direct bond to said O. or a pharmaceutically acceptable salt thereof.

2. R １ is a reactive group, L １ is a bridging spacer, Lp is a divalent peptide spacer containing 1 to 4 amino acid residues; 【Transformation 3】 The base is 【Chemistry 4】 is selected from, where: 【Transformation 5】 * indicates the point of attachment to the N or O of the drug moiety; 【Transformation 6】 *** indicates the point of attachment to Lp, R ２ is the hydrophilic moiety, L ２ is a bond, methylene, neopentylene or C ２ ~C ３ is alkenylene, A is a bond, —OC(═O)—*, 【Transformation 7】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(= O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ )C(=O)-*, where , each R ａ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ Select from cycloalkyl and * in A indicates the point of attachment to D; L ３ is a spacer moiety, and D is a drug moiety containing N or O, where D is the N or O moiety of the drug moiety from A. A compound of formula (I) according to claim 1, wherein A is bonded to O via a direct bond. is a pharmaceutically acceptable salt thereof.

3. The compound of formula (II) or a pharmaceutically acceptable salt thereof is a compound of formula (II) 【Transformation 8】 (In the formula, R １ is a reactive group, L １ is a bridging spacer, Lp is a divalent peptide spacer containing 1 to 4 amino acid residues; R ２ is the hydrophilic moiety, A is a bond, —OC(═O)—*, 【Chemistry 9】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)- * or -OC(= O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ )C(=O)-*, where , each R ａ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ Select from cycloalkyl and * in A indicates the point of attachment to D; L ３ is a spacer moiety, and D is a drug moiety containing N or O, where D is the N or O moiety of the drug moiety from A. and is connected to A via a direct bond to said O. or a pharmaceutically acceptable salt thereof.

4. R １ teeth, 【Chemistry 10】 【Chemistry 11】 and L １ は、*-C(=O)(CH ２ ) ｍ O(CH ２ ) ｍ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ -**;*-C(=O)N H((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -**;*-C(=O)O(CH ２ ) ｍ SSC(R ３ ) ２ (CH ２ ) ｍ C(=O)NR ３ (CH ２ ) ｍ NR ３ C(=O)(CH ２ ) ｍ -** ;*-C(=O)O(CH ２ ) ｍ C(=0)NH(CH ２ ) ｍ -**;*-C(=O)( CH ２ ) ｍ NH(CH) ２ ) ｍ -**;*-C(=O)(CH ２ ) ｍ NH(CH) ２ ) ｎ C( =O)-**;*-C(=O)(CH ２ ) ｍ X １ (CH ２ ) ｍ -**;*-C(=O)( (CH ２ ) ｍ O) ｔ (CH ２ ) ｎ X １ (CH ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ NHC(=0)(CH ２ ) ｎ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH) ２ ) ｎ NHC(=0)(CH ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ NHC(=0)(CH ２ ) ｎ X １ (CH) ２ ) ｎ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH) ２ ) ｎ NH C(=O)(CH ２ ) ｎ X １ (CH ２ ) ｎ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ C(=O)NH(CH ２ ) ｍ -**;*-C(=O)(CH ２ ) ｍ C(R ３ ) ２ -** or *-C(=O)(CH ２ ) ｍ C(=O)NH(CH ２ ) ｍ -**, Here, L １ * indicates the point of attachment to Lp, and L １ ** is R １ Binding to Indicate the point, R ２ Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide Tide, polysarcosine or 1 to 3 【Chemistry 12】 C substituted with a group ２ ~C ６ a hydrophilic moiety selected from alkyl; Each R ３ are independently H and C １ ~C ６ alkyl, R ４ is 2-pyridyl or 4-pyridyl, Each R ５ are independently H, C １ ~C ６ selected from alkyl, F, Cl and —OH; Each R ６ are independently H, C １ ~C ６ Alkyl, F, Cl, —NH ２ , -OCH ３ , -O CH ２ CH ３ , -N(CH ３ ) ２ , -CN, -NO ２ and —OH; Each R ７ are independently H, C １ ~ ６ Alkyl, fluoro, -C(=O)OH substituted benzyloxy, benzyl substituted with -C(=O)OH, TaC １～４ C substituted with alkoxy and —C(═O)OH １～４ alkyl 、 X １ teeth, 【Chemistry 13】 and each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is composed of glycine, valine, citrulline, lysine, isoleucine, phenylalanine, Thionine, asparagine, proline, alanine, leucine, tryptophan and tyrosine and a bivalent peptide spacer comprising 1 to 4 amino acid residues independently selected from 、 A is a bond, —OC(═O)—*, 【Chemistry 14】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(= O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ )C(=O)-*, where , each R ａ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ Select from cycloalkyl and * in A indicates the point of attachment to D; L ３ is the structure 【Chemistry 15】 (In the formula, (i)Wは、-CH ２ O-**、-CH ２ N(R ｂ )C(=O)O-**、-NHC(= O)C(R) ｂ ) ２ NHC(=O)O-**、-NHC(=O)C(R ｂ ) ２ NH-***, -NHC(=O)C(R ｂ ) ２ NHC(=O)-**、-CH ２ N (X-R ２ )C(=O )O-**、-C(=O)N(X-R ２ )-**、-CH ２ N(X-R ２ )C(=O)- **、-C(=O)NR ｂ -**、-C(=O)NH-**、-CH ２ NR ｂ C(=O) -**、-CH ２ NR ｂ C(=0)NH-***,-CH ２ NR ｂ C(=0)NR ｂ -** , -NHC(=O)-**, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-**、-S(O) ２ NH-**、-NHS(O) ２ -**、-C( =O)-, -C(=O)O-**, -NH- or -CH ２ N(R ｂ )C(=O)CH ２ - **, where each R ｂ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ Shik ** in W indicates the point of attachment to X; X is a bond, triazolyl or ***-CH ２ -triazolyl-*, where X is *** indicates the point of attachment to W, and * in X indicates the point of attachment to R ２ indicates the point of attachment to (ii)Wは、-CH ２ O-**、-CH ２ N(R ｂ )C(=O)O-**、-NHC( =O)C(R ｂ ) ２ NHC(=O)O-**、-NHC(=O)C(R ｂ ) ２ NH-*** 、NHC(=O)C(R ｂ ) ２ NHC(=O)-**、-CH ２ N (X-R ２ )C(=O )O-**、-C(=O)N(X-R ２ )-**、-CH ２ N(X-R ２ )C(=O)- **、-C(=O)NR ｂ -**、-C(=O)NH-**、-CH ２ NR ｂ C(=O) -**、-CH ２ NR ｂ C(=0)NH-***,-CH ２ NR ｂ C(=0)NR ｂ -** , -NHC(=O)-**, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-**、-S(O) ２ NH-**、-NHS(O) ２ -**、-C( ═O)—, —C(═O)O—**, or —NH—, where each R ｂ are independently H , C １ ~C ６ Alkyl or C ３ ~C ８ cycloalkyl, and ** of W is selected from the group consisting of cycloalkyl and cycloalkyl. indicates the point of attachment, X is ***-CH ２ -Triazolyl-C １～４ Alkylene-OC(O)NHS(O) ２ NH-*, ****-C ４～６ Cycloalkylene-OC(O)NHS(O) ２ NH-*, * **-(CH ２ CH ２ O) ｎ -C(O)NHS(O) ２ NH-*, ******-(CH) ２ CH ２ O) ｎ -C(O)NHS(O) ２ NH-(CH ２ CH ２ O) ｎ -* or ***-CH ２ -Triazolyl-C １～４ Alkylene-OC(O)NHS(O) ２ NH-(CH ２ CH ２ O) ｎ -*, where each n is independently 1, 2, or 3, and *** of X is W and * in X indicates the point of attachment to R ２ indicates the point of attachment to L ３ The * is R ２ (indicating the point of attachment to and D is a drug moiety containing N or O, where D is the N or O moiety of the drug moiety from A.

4. The compound according to claim 1, wherein the O is bonded to A via a direct bond to the O. The compound or a pharmaceutically acceptable salt thereof.

5. R １ teeth, 【Chemistry 16】 and L １ は、*-C(=O)(CH ２ ) ｍ O(CH ２ ) ｍ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ -**; or *-C(=O )NH((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -, where L １ * indicates the ratio of Lp indicates the point of attachment, and L １ ** is R １ indicates the point of attachment to each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is 【Chemistry 17】 wherein * in Lp is a divalent peptide spacer selected from L １ Conclusion indicates the point of attachment to the —NH— group of G; and ** in Lp indicates the point of attachment to the —NH— group of G; L ３ is the structure [Chemistry 18] (In the formula, Wは、-CH ２ O-**、-CH ２ N(R ｂ )C(=O)O-**、-NHC(=O)C H ２ NHC(=0)O-***,-CH ２ N(X-R) ２ )C(=O)O-**、-C(=O )N(X-R ２ )-**、-CH ２ N(X-R ２ )C(=O)-**、-C(=O)NR ｂ -**、-C(=O)NH-**、-CH ２ NR ｂ C(=O)-**、-CH ２ NR ｂ C(=0)NH-***,-CH ２ NR ｂ C(=0)NR ｂ -**、-NHC(=O)-* *, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-* *、-S(O) ２ NH-**、-NHS(O) ２ -**、-C(=O)-、-C(=O) O-** or -NH-, where each R ｂ are independently H, C １ ~C ６ Alkyl or is C ３ ~C ８ cycloalkyl, wherein ** in W indicates the point of attachment to X; X is a bond, triazolyl or ***-CH ２ -triazolyl-*, where X is *** indicates the point of attachment to W, and * in X indicates the point of attachment to R ２ indicates the point of attachment to L ３ The * is R ２ (indicating the point of attachment to a spacer moiety having the formula: R ２ Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polysulfone Cosine, polypeptide or 1 to 3 【Chemistry 19】 C substituted with a group ２ ~C ６ a hydrophilic moiety selected from alkyl; A is a bond, —OC(═O)—*, 【Chemistry 20】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(= O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ )C(=O)-*, where , each R ａ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ Select from cycloalkyl and * in A indicates the point of attachment to D, and D is a drug moiety containing N or O, where D is the N or O moiety of the drug moiety from A.

5. The compound according to claim 1, wherein the O is bonded to A via a direct bond to the O. The compound or a pharmaceutically acceptable salt thereof.

6. R １ teeth, 【Chemistry 21】 and L １ は、*-C(=O)(CH ２ ) ｍ O(CH ２ ) ｍ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ -**; or *-C(=O )NH((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -, where L １ * indicates the ratio of Lp indicates the point of attachment, and L １ ** is R １ indicates the point of attachment to each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is 【Chemistry 22】 wherein * in Lp is a divalent peptide spacer selected from L １ Conclusion indicates the point of attachment to the —NH— group of G; and ** in Lp indicates the point of attachment to the —NH— group of G; L ３ is the structure 【Chemistry 23】 (In the formula, Wは、-CH ２ O-**、-CH ２ N(R ｂ )C(=O)O-**、-NHC(=O)C H ２ NHC(=0)O-***,-CH ２ N(X-R) ２ )C(=O)O-**、-C(=O )N(X-R ２ )-**、-CH ２ N(X-R ２ )C(=O)-**、-C(=O)NR ｂ -**、-C(=O)NH-**、-CH ２ NR ｂ C(=O)-**、-CH ２ NR ｂ C(=0)NH-***,-CH ２ NR ｂ C(=0)NR ｂ -**、-NHC(=O)-* *, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-* *、-S(O) ２ NH-**、-NHS(O) ２ -**、-C(=O)-、-C(=O) O-** or -NH-, where each R ｂ are independently H, C １ ~C ６ Alkyl or is C ３ ~C ８ cycloalkyl, wherein ** in W indicates the point of attachment to X; X is a bond, triazolyl or ***-CH ２ -triazolyl-*, where X is *** indicates the point of attachment to W, and * in X indicates the point of attachment to R ２ indicates the point of attachment to L ３ The * is R ２ (indicating the point of attachment to a spacer moiety having the formula: R ２ Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polysulfone Cosine, polypeptide or 1 to 3 【Chemistry 24】 C substituted with a group ２ ~C ６ a hydrophilic moiety selected from alkyl; A is a bond, —OC(═O)—*, 【Chemistry 25】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(= O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ )C(=O)-*, where , each R ａ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ Select from cycloalkyl and * in A indicates the point of attachment to D, and D is a drug moiety containing N or O, where D is the N or O moiety of the drug moiety from A.

6. The compound according to claim 1, wherein the O is bonded to A via a direct bond to the O. The compound or a pharmaceutically acceptable salt thereof.

7. R １ teeth, 【Chemistry 26】 and L １ は、*-C(=O)(CH ２ ) ｍ O(CH ２ ) ｍ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ -**; or *-C(=O )NH((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -, where L １ * indicates the ratio of Lp indicates the point of attachment, and L １ ** is R １ indicates the point of attachment to each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is 【Chemistry 27】 wherein * in Lp is a divalent peptide spacer selected from L １ Conclusion indicates the point of attachment to the —NH— group of G; and ** in Lp indicates the point of attachment to the —NH— group of G; L ３ is the structure 【Chemistry 28】 (In the formula, Wは、-CH ２ O-**、-CH ２ N(R ｂ )C(=O)O-**、-NHC(=O)C H ２ NHC(=0)O-***,-CH ２ N(X-R) ２ )C(=O)O-**、-C(=O )N(X-R ２ )-**、-C(=O)NR ｂ -**、-C(=O)NH-**、-CH ２ NR ｂ C(=O)-**、-CH ２ NR ｂ C(=O)NH-**、-CH ２ NR ｂ C( =O)NR ｂ -**, -NHC(=O)-**, -NHC(=O)O-** or -NHC (=O)NH-**, where each R ｂ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ cycloalkyl, wherein ** in W indicates the point of attachment to X; X is a bond, triazolyl or ***-CH ２ -triazolyl-*, where X is *** indicates the point of attachment to W, and * in X indicates the point of attachment to R ２ indicates the point of attachment to L ３ The * is R ２ (indicating the point of attachment to a spacer moiety having the formula: R ２ Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polysulfone Cosine, polypeptide or 1 to 3 【Chemistry 29】 C substituted with a group ２ ~C ６ a hydrophilic moiety selected from alkyl; A is a bond or —OC(═O)*, where * indicates the point of attachment to D, and D is a drug moiety containing N or O, where D is the N or O moiety of the drug moiety from A.

7. The compound according to claim 1, wherein the O is bonded to A via a direct bond to the O. The compound or a pharmaceutically acceptable salt thereof.

8. R １ teeth, 【Transformation 30】 and L １ は、*-C(=O)(CH ２ ) ｍ O(CH ２ ) ｍ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ -**; or *-C(=O )NH((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -, where L １ * indicates the ratio of Lp indicates the point of attachment, and L １ ** is R １ indicates the point of attachment to each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is 【Chemistry 31】 wherein * in Lp is a divalent peptide spacer selected from L １ Conclusion indicates the point of attachment to the —NH— group of G; and ** in Lp indicates the point of attachment to the —NH— group of G; L ３ is the structure 【Chemistry 32】 (In the formula, Wは、-CH ２ O-**、-CH ２ N(R ｂ )C(=O)O-**、-NHC(=O)C H ２ NH C(=O)O-**, -CH ２ N(X-R ２ ), C(=O)O-** or -C(= O)N(X-R ２ )-**, where each R ｂ are independently H, C １ ~C ６ Archi Lu or C ３ ~C ８ cycloalkyl, wherein ** in W indicates the point of attachment to X; X is ***-CH ２ -triazolyl-*, where *** of X is the bond to W. indicates the match, and * of X indicates R ２ indicates the point of attachment to L ３ The * is R ２ (indicating the point of attachment to a spacer moiety having the formula: R ２ Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polysulfone Cosine, polypeptide or 1 to 3 【Transformation 33】 C substituted with a group ２ ~C ６ a hydrophilic moiety selected from alkyl; A is a bond or —OC(═O)*, where * indicates the point of attachment to D, and D is a drug moiety containing N or O, where D is the N or O moiety of the drug moiety from A.

8. The compound according to claim 1, wherein the O is bonded to A via a direct bond to the O. The compound or a pharmaceutically acceptable salt thereof.

9. R １ teeth, 【Transformation 34】 and L １ は、*-C(=O)(CH ２ ) ｍ O(CH ２ ) ｍ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ -**; or *-C(=O )NH((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -, where L １ * indicates the ratio of Lp indicates the point of attachment, and L １ ** is R １ indicates the point of attachment to each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is 【Chemistry 35】 wherein * in Lp is a divalent peptide spacer selected from L １ Conclusion indicates the point of attachment to the —NH— group of G; and ** in Lp indicates the point of attachment to the —NH— group of G; L ３ is the structure 【Transformation 36】 (In the formula, Wは、-CH ２ O-**、-CH ２ N(R ｂ )C(=O)O-**、-NHC(=O)C H ２ NH C(=O)O-**, -CH ２ N(X-R ２ ), C(=O)O-** or -C(= O)N(X-R ２ )-**, where each R ｂ are independently H, C １ ~C ６ Archi Lu or C ３ ~C ８ cycloalkyl, wherein ** in W indicates the point of attachment to X; X is ***-CH ２ -triazolyl-*, where *** of X is the bond to W. indicates the match, and * of X indicates R ２ indicates the point of attachment to L ３ The * is R ２ (indicating the point of attachment to a spacer moiety having the formula: R ２ is polyethylene glycol, A is a bond or —OC(═O)*, where * indicates the point of attachment to D, and D is a drug moiety containing N or O, where D is the N or O moiety of the drug moiety from A.

9. The compound according to claim 1, wherein the O is bonded to A via a direct bond to the O. The compound or a pharmaceutically acceptable salt thereof.

10. structure: 【Chemistry 37】 (Wherein, R is H, —CH ３ or -CH ２ CH ２ C(=O)OH) The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having the formula:

11. structure: 【Transformation 38】 (Wherein, R is H, —CH ３ or -CH ２ CH ２ C(=O)OH) The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having the formula:

12. structure: 【Chemistry 39】 (Wherein, R is H, —CH ３ or -CH ２ CH ２ C(=O)OH) or a pharmaceutically acceptable salt thereof.

13. structure: 【Chemistry 40】 wherein each R is independently H, —CH ３ or -CH ２ CH ２ C(=O)OH can be) or a pharmaceutically acceptable salt thereof.

14. structure: 【Chemistry 41】 wherein each R is independently H, —CH ３ or -CH ２ CH ２ C(=O)OH can be) or a pharmaceutically acceptable salt thereof.

15. structure: 【Chemistry 42】 (Wherein, Xa is —CH ２ -, -OCH ２ --NHCH ２ -or-NRCH ２ - and and each R is independently H, —CH ３ or -CH ２ CH ２ C(=O)OH) or a pharmaceutically acceptable salt thereof.

16. structure: 【Chemistry 43】 (Wherein, R is H, —CH ３ or -CH ２ CH ２ C(=O)OH) or a pharmaceutically acceptable salt thereof.

17. structure: 【Chemistry 44】 (Wherein, Xb is —CH ２ -, -OCH ２ --NHCH ２ -or-NRCH ２ - and and each R is independently H, —CH ３ or -CH ２ CH ２ C(=O)OH) or a pharmaceutically acceptable salt thereof.

18. structure: 【Chemistry 45】 or a pharmaceutically acceptable salt thereof.

19. structure: 【Chemistry 46】 or a pharmaceutically acceptable salt thereof.

20. structure: 【Chemistry 47】 or a pharmaceutically acceptable salt thereof.

21. structure: 【Chemistry 48】 or a pharmaceutically acceptable salt thereof.

22. structure: 【Chemistry 49】 or a pharmaceutically acceptable salt thereof.

23. Formula (V) [Transformation 50] (In the formula, L １ is a bridging spacer, Lp is a divalent peptide spacer; G-L ２ -A is a self-immolative spacer, R ２ is the hydrophilic moiety, L ２ is a bond, methylene, neopentylene or C ２ ~C ３ is alkenylene, A is a bond, **-OC(=O)-, 【Chemistry 51】 , **-OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)- or **-O C(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ )C(=O)-, So, each R ａ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ From cycloalkyl is selected, and A's ** is L ２ indicates the point of attachment to L ３ is the spacer moiety) A linker having the structure:

24. L １ is a bridging spacer, Lp is a divalent peptide spacer containing 1 to 4 amino acid residues; G-L ２ -A is a self-immolative spacer, R ２ is the hydrophilic moiety, L ２ is a bond, methylene, neopentylene or C ２ ~C ３ is alkenylene, A is a bond, **-OC(=O)-, 【Chemistry 52】 , **-OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)- or **-O C(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ )C(=O)-, So, each R ａ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ From cycloalkyl is selected, and A's ** is L ２ indicates the point of attachment to L ３ is a spacer moiety.

25. L １ is a bridging spacer, Lp is a divalent peptide spacer containing 1 to 4 amino acid residues; 【Chemistry 53】 The base is 【Chemistry 54】 is selected from, where: 【Transformation 55】 * indicates the point of attachment to the N or O of the drug moiety; 【Transformation 56】 *** indicates the point of attachment to Lp, R ２ is the hydrophilic moiety, L ２ is a bond, methylene, neopentylene or C ２ ~C ３ is alkenylene, A is a bond, **-OC(=O)-, 【Chemistry 57】 , **-OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)- or **-O C(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ )C(=O)-, So, each R ａ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ From cycloalkyl is selected, and A's ** is L ２ indicates the point of attachment to L ３ is a spacer moiety.

26. Formula (VI) 【Transformation 58】 (In the formula, L １ is a bridging spacer, Lp is a divalent peptide spacer; R ２ is the hydrophilic moiety, A is a bond, —OC(═O)—, 【Chemistry 59】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)- or -OC(=O ) N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ )C(=O)-, where each R ａ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ cycloalkyl , and L ３ is the spacer moiety) The linker according to any one of claims 23 to 25, having the structure:

27. L １ is a bridging spacer, Lp is a divalent peptide spacer containing 1 to 4 amino acid residues; R ２ is the hydrophilic moiety, A is a bond, —OC(═O)—, 【Transformation 60】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)- or -OC(=O ) N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ )C(=O)-, where each R ａ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ cycloalkyl , and L ３ is a spacer moiety.

28. L １ は、*-C(=O)(CH ２ ) ｍ O(CH ２ ) ｍ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ -**;*-C(=O) NH((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -**;*-C(=O)O(CH ２ ) ｍ SSC( R ３ ) ２ (CH ２ ) ｍ C(=O)NR ３ (CH ２ ) ｍ NR ３ C(=O)(CH ２ ) ｍ -* *;*-C(=O)O(CH ２ ) ｍ C(=0)NH(CH ２ ) ｍ -**;*-C(=O) (CH) ２ ) ｍ NH(CH) ２ ) ｍ -**;*-C(=O)(CH ２ ) ｍ NH(CH) ２ ) ｎ C (=O)-**;*-C(=O)(CH ２ ) ｍ X １ (CH ２ ) ｍ -**;*-C(=O) ((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ X １ (CH ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ NHC(=0)(CH ２ ) ｎ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH) ２ ) ｎ NHC(=0)(CH ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ NHC(=0)(C) H ２ ) ｎ X １ (CH ２ ) ｎ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ N HC(=O)(CH ２ ) ｎ X １ (CH ２ ) ｎ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ C(=O)NH(CH ２ ) ｍ -**;*-C(=O)(CH ２ ) ｍ C(R ３ ) ２ -** or *-C(=O)(CH ２ ) ｍ C(=O)NH(CH ２ ) ｍ -** is , where L １ * indicates the point of attachment to Lp, R ２ Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polysulfone Cosine, polypeptide or 1 to 3 【Chemistry 61】 C substituted with a group ２ ~C ６ a hydrophilic moiety selected from alkyl; Each R ３ are independently H and C １ ~C ６ alkyl, X １ teeth, 【Transformation 62】 and each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is composed of glycine, valine, citrulline, lysine, isoleucine, phenylalanine, Thionine, asparagine, proline, alanine, leucine, tryptophan and tyrosine and a bivalent peptide spacer comprising 1 to 4 amino acid residues independently selected from 、 A is a bond, —OC(═O)—, 【Transformation 63】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)- or -OC(=O ) N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ )C(=O)-, where each R ａ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ cycloalkyl 、 L ３ is the structure 【Chemistry 64】 (In the formula, (i)Wは、-CH ２ O-**、-CH ２ N(R ｂ )C(=O)O-**、-NHC(= O)C(R) ｂ ) ２ NHC(=O)O-**、-NHC(=O)C(R ｂ ) ２ NH-***, -NHC(=O)C(R ｂ ) ２ NHC(=O)-**、-CH ２ N (X-R ２ )C(=O )O-**、-C(=O)N(X-R ２ )-**、-CH ２ N(X-R ２ )C(=O)- **、-C(=O)NR ｂ -**、-C(=O)NH-**、-CH ２ NR ｂ C(=O) -**、-CH ２ NR ｂ C(=0)NH-***,-CH ２ NR ｂ C(=0)NR ｂ -** , -NHC(=O)-**, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-**、-S(O) ２ NH-**、-NHS(O) ２ -**、-C( =O)-, -C(=O)O-**, -NH- or -CH ２ N(R ｂ )(=O)CH ２ - **, where each R ｂ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ Shik ** in W indicates the point of attachment to X; X is a bond or ***-CH ２ -triazolyl-*, where *** of X is and * in X indicates the point of attachment to R ２ indicates the point of attachment to (ii)Wは、-CH ２ O-**、-CH ２ N(R ｂ )C(=O)O-**、-NHC( =O)C(R ｂ ) ２ NHC(=O)O-**、-NHC(=O)C(R ｂ ) ２ NH-*** 、NHC(=O)C(R ｂ ) ２ NHC(=O)-**、-CH ２ N (X-R ２ )C(=O )O-**、-C(=O)N(X-R ２ )-**、-CH ２ N(X-R ２ )C(=O)- **、-C(=O)NR ｂ -**、-C(=O)NH-**、-CH ２ NR ｂ C(=O) -**、-CH ２ NR ｂ C(=0)NH-***,-CH ２ NR ｂ C(=0)NR ｂ -** , -NHC(=O)-**, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-**、-S(O) ２ NH-**、-NHS(O) ２ -**、-C( ═O)—, —C(═O)O—**, or —NH—, where each R ｂ are independently H , C １ ~C ６ Alkyl or C ３ ~C ８ cycloalkyl, and ** of W is selected from the group consisting of cycloalkyl and cycloalkyl. indicates the point of attachment, X is ***-CH ２ -Triazolyl-C １～４ Alkylene-OC(O)NHS(O) ２ NH-*, ****-C ４～６ Cycloalkylene-OC(O)NHS(O) ２ NH-*, * **-(CH ２ CH ２ O) ｎ -C(O)NHS(O) ２ NH-*, ******-(CH) ２ CH ２ O) ｎ -C(O)NHS(O) ２ NH-(CH ２ CH ２ O) ｎ -*or***-CH ２ -Triazolyl-C １～４ Alkylene-OC(O)NHS(O) ２ NH-(CH ２ CH ２ O) ｎ -*, where each n is independently 1, 2, or 3, and *** of X is W and * in X indicates the point of attachment to R ２ indicates the point of attachment to L ３ The * is R ２ (indicating the point of attachment to The linker of any one of claims 23 to 27, which is a spacer moiety having the formula:

29. L １ は、*-C(=O)(CH ２ ) ｍ O(CH ２ ) ｍ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ -**; or *-C (= O)NH((CH ２ ) ｍ ) ｔ (CH ２ ) ｎ -, where L １ * indicates the ratio of Lp indicates the point of attachment, each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is 【Transformation 65】 wherein * in Lp is a divalent peptide spacer selected from L １ Conclusion indicates the point of attachment to the —NH— group, and ** in Lp indicates the point of attachment to the —NH— group; L ３ is the structure 【Chemical Formula 66】 (In the formula, Wは、-CH ２ O-**、-CH ２ N(R ｂ )C(=O)O-**、-NHC(=O)C H ２ NHC(=0)O-***,-CH ２ N(X-R) ２ )C(=O)O-**、-C(=O )N(X-R ２ )-**、-CH ２ N(X-R ２ )C(=O)-**、-C(=O)NR ｂ -**、-C(=O)NH-**、-CH ２ NR ｂ C(=O)-**、-CH ２ NR ｂ C(=0)NH-***,-CH ２ NR ｂ C(=0)NR ｂ -**、-NHC(=O)-* *, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-* *、-S(O) ２ NH-**、-NHS(O) ２ -**、-C(=O)-、-C(=O) O-** or -NH-, where each R ｂ are independently H, C １ ~C ６ Alkyl or is C ３ ~C ８ cycloalkyl, wherein ** in W indicates the point of attachment to X; X is a bond, triazolyl or ***-CH ２ -triazolyl-*, where X is *** indicates the point of attachment to W, and * in X indicates the point of attachment to R ２ indicates the point of attachment to L ３ The * is R ２ (indicating the point of attachment to a spacer moiety having the formula: R ２ Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polysulfone Cosine, polypeptide or 1 to 3 【Transformation 67】 C substituted with a group ２ ~C ６ alkyl, and A is a bond, —OC(═O)—, 【Transformation 68】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)- or -OC(=O ) N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ )C(=O)-, where each R ａ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ cycloalkyl The linker according to any one of claims 23 to 28.

30. L １ は、*-C(=O)(CH ２ ) ｍ O(CH ２ ) ｍ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ -**; or *-C (= O)NH((CH ２ ) ｍ ) ｔ (CH ２ ) ｎ -, where L １ * indicates the ratio of Lp indicates the point of attachment, each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is 【Transformation 69】 wherein * in Lp is a divalent peptide spacer selected from L １ Conclusion indicates the point of attachment to the —NH— group, and ** in Lp indicates the point of attachment to the —NH— group; L ３ is the structure 【Transformation 70】 (In the formula, Wは、-CH ２ O-**、-CH ２ N(R ｂ )C(=O)O-**、-NHC(=O)C H ２ NHC(=0)O-***,-CH ２ N(X-R) ２ )C(=O)O-**、-C(=O )N(X-R ２ )-**、-CH ２ N(X-R ２ )C(=O)-**、-C(=O)NR ｂ -**、-C(=O)NH-**、-CH ２ NR ｂ C(=O)-**、-CH ２ NR ｂ C(=0)NH-***,-CH ２ NR ｂ C(=0)NR ｂ -**、-NHC(=O)-* *, -NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-* *、-S(O) ２ NH-**、-NHS(O) ２ -**、-C(=O)-、-C(=O) O-** or -NH-, where each R ｂ are independently H, C １ ~C ６ Alkyl or is C ３ ~C ８ cycloalkyl, wherein ** in W indicates the point of attachment to X; X is a bond, triazolyl or ***-CH ２ -triazolyl-*, where X is *** indicates the point of attachment to W, and * in X indicates the point of attachment to R ２ indicates the point of attachment to L ３ The * is R ２ (indicating the point of attachment to a spacer moiety having the formula: R ２ Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polysulfone Cosine, polypeptide or 1 to 3 【Chemistry 71】 C substituted with a group ２ ~C ６ alkyl, and A is a bond, —OC(═O)—, 【Chemistry 72】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)- or -OC(=O ) N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ )C(=O)-, where each R ａ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ cycloalkyl The linker according to any one of claims 23 to 29.

31. L １ は、*-C(=O)(CH ２ ) ｍ O(CH ２ ) ｍ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ -**; or *-C (= O)NH((CH ２ ) ｍ ) ｔ (CH ２ ) ｎ -, where L １ * indicates the ratio of Lp indicates the point of attachment, each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is 【Transformation 73】 wherein * in Lp is a divalent peptide spacer selected from L １ Conclusion indicates the point of attachment to the —NH— group, and ** in Lp indicates the point of attachment to the —NH— group; L ３ is the structure 【Chemistry 74】 (In the formula, Wは、-CH ２ O-**、CH ２ N(R ｂ )C(=O)O-**、-NHC(=O)CH ２ NHC(=0)O-***,-CH ２ N(X-R) ２ )C(=O)O-**、-C(=O) N(X-R ２ )-**、-C(=O)NR ｂ -**、-C(=O)NH-**、-CH ２ NR ｂ C(=O)-**、-CH ２ NR ｂ C(=O)NH-**、-CH ２ NR ｂ C(= O)NR ｂ -**, -NHC(=O)-**, -NHC(=O)O-** or -NHC( ═O)NH-**, where each R ｂ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ cycloalkyl, wherein ** in W indicates the point of attachment to X; X is a bond or ***-CH ２ -triazolyl-*, where *** of X is and * in X indicates the point of attachment to R ２ indicates the point of attachment to L ３ The * is R ２ (indicating the point of attachment to a spacer moiety having the formula: R ２ Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polysulfone Cosine, polypeptide or 1 to 3 【Chemistry 75】 C substituted with a group ２ ~C ６ alkyl, and A phosphorus compound according to any one of claims 23 to 30, wherein A is a bond or -OC(=O)-. car.

32. L １ は、*-C(=O)(CH ２ ) ｍ O(CH ２ ) ｍ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ -**; or *-C (= O)NH((CH ２ ) ｍ ) ｔ (CH ２ ) ｎ -, where L １ * indicates the ratio of Lp indicates the point of attachment, each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is 【Transformation 76】 wherein * in Lp is a divalent peptide spacer selected from L １ Conclusion indicates the point of attachment to the —NH— group, and ** in Lp indicates the point of attachment to the —NH— group; L ３ is the structure 【Chemical 77】 (In the formula, Wは、-CH ２ O-**、-CH ２ N(R ｂ )C(=O)O-**、-NHC(=O)C H ２ NH C(=O)O-**, -CH ２ N(X-R ２ ), C(=O)O-** or -C(= O)N(X-R ２ )-**, where each R ｂ are independently H, C １ ~C ６ Archi Lu or C ３ ~C ８ cycloalkyl, wherein ** in W indicates the point of attachment to X; X is ***-CH ２ -triazolyl-*, where *** of X is the bond to W. indicates the match, and * of X indicates R ２ indicates the point of attachment to L ３ The * is R ２ (indicating the point of attachment to a spacer moiety having the formula: R ２ Polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polysulfone Cosine, polypeptide or 1 to 3 【Transformation 78】 C substituted with a group ２ ~C ６ alkyl, and A phosphorus compound according to any one of claims 23 to 31, wherein A is a bond or -OC(=O)-. car.

33. L １ は、*-C(=O)(CH ２ ) ｍ O(CH ２ ) ｍ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ -**; or *-C (= O)NH((CH ２ ) ｍ ) ｔ (CH ２ ) ｎ -, where L １ * indicates the ratio of Lp indicates the point of attachment, each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 is selected from Lp is 【Transformation 79】 wherein * in Lp is a divalent peptide spacer selected from L １ Conclusion indicates the point of attachment to the —NH— group, and ** in Lp indicates the point of attachment to the —NH— group; L ３ is the structure 【Chemistry 80】 (In the formula, Wは、-CH ２ O-**、-CH ２ N(R ｂ )C(=O)O-**、-NHC(=O)C H ２ NH C(=O)O-**, -CH ２ N(X-R ２ ), C(=O)O-** or -C(= O)N(X-R ２ )-**, where each R ｂ are independently H, C １ ~C ６ Archi Lu or C ３ ~C ８ cycloalkyl, wherein ** in W indicates the point of attachment to X; X is ***-CH ２ -triazolyl-*, where *** of X is the bond to W. indicates the match, and * of X indicates R ２ indicates the point of attachment to L ３ The * is R ２ (indicating the point of attachment to a spacer moiety having the formula: R ２ is polyethylene glycol, and A phosphorus compound according to any one of claims 23 to 32, wherein A is a bond or -OC(=O)-. car.

34. structure: 【Chemistry 81】 (Wherein, R is H, —CH ３ or -CH ２ CH ２ C(=O)OH) The linker of any one of claims 23 to 33, having the following structure:

35. structure: 【Chemistry 82】 (Wherein, R is H, —CH ３ or -CH ２ CH ２ C(=O)OH) The linker of any one of claims 23 to 33, having the following structure:

36. structure: 【Chemistry 83】 (Wherein, R is H, —CH ３ or -CH ２ CH ２ C(=O)OH) The linker of any one of claims 23 to 33, having the following structure:

37. structure: 【Chemical 84】 wherein each R is independently H, —CH ３ or -CH ２ CH ２ C(=O)OH can be) The linker of any one of claims 23 to 33, having the following structure:

38. structure: 【Chemical 85】 wherein each R is independently H, —CH ３ or -CH ２ CH ２ C(=O)OH can be) The linker of any one of claims 23 to 33, having the following structure:

39. structure: 【Chemical 86】 (Wherein, Xa is —CH ２ -, -OCH ２ --NHCH ２ -or-NRCH ２ - and and each R is independently H, —CH ３ or -CH ２ CH ２ C(=O)OH) The linker of any one of claims 23 to 33, having the following structure:

40. structure: 【Chemistry 87】 (Wherein, R is H, —CH ３ or -CH ２ CH ２ C(=O)OH) The linker of any one of claims 23 to 33, having the following structure:

41. structure: 【Chemical 88】 (Wherein, Xb is —CH ２ -, -OCH ２ --NHCH ２ -or-NRCH ２ - and and each R is independently H, —CH ３ or -CH ２ CH ２ C(=O)OH) The linker of any one of claims 23 to 33, having the following structure:

42. structure: 【Chemical 89】 The linker of any one of claims 23 to 33, having the following structure:

43. structure: [Chemical 90] The linker of any one of claims 23 to 33, having the following structure:

44. structure: 【Chemistry 91】 The linker of any one of claims 23 to 33, having the following structure:

45. structure: 【Chemistry 92】 The linker of any one of claims 23 to 33, having the following structure:

46. structure: 【Chemistry 93】 The linker of any one of claims 23 to 33, having the following structure:

47. Formula (III): 【Chemical 94】 (In the formula, Ab is an antibody or fragment thereof; R １００ is a coupling group, L １ is a bridging spacer, Lp is a divalent peptide linker; G-L ２ -A is a self-immolative spacer, R ２ is the hydrophilic moiety, L ２ is a bond, methylene, neopentylene or C ２ ~C ３ is alkenylene, A is a bond, —OC(═O)—*, 【Chemical 95】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(= O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ )C(=O)-*, where , each R ａ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ Select from cycloalkyl and * in A indicates the point of attachment to D; L ３ is a spacer moiety, D is a drug moiety containing N or O, where D is the N or O moiety of the drug moiety from A. is attached to A via a direct bond to said O, and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16) Conjugate of.

48. Formula (IV): 【Chemistry 96】 (In the formula, Ab is an antibody or fragment thereof; R １００ is a coupling group, L １ is a bridging spacer, Lp is a bivalent peptide linker containing 1 to 4 amino acid residues; R ２ is the hydrophilic moiety, A is a bond, —OC(═O)—*, 【Chemistry 97】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(= O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ )C(=O)-*, where , each R ａ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ Select from cycloalkyl and * in A indicates the point of attachment to D; L ３ is a spacer moiety, D is a drug moiety containing N or O, where D is the N or O moiety of the drug moiety from A. is attached to A via a direct bond to said O, and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16) Conjugate of.

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