Camptothecin antibody-drug conjugate and method of use thereof

Abstract

The present disclosure provides antibody-drug conjugate (ADC) structures, where the antibody-drug conjugate comprises a camptothecin or camptothecin derivative linked to a polypeptide (e.g., an antibody) via a linker. In addition, the present disclosure also encompasses compounds and methods for producing such conjugates, as well as methods of using the conjugates.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 237,355 filed on 26 August 2021, U.S. Provisional Patent Application No. 63 / 214,525 filed on 24 June 2021, U.S. Provisional Patent Application No. 63 / 186,489 filed on 10 May 2021, and U.S. Provisional Patent Application No. 63 / 138,182 filed on 15 January 2021, the disclosures of which are incorporated herein by reference.

[0002] Introduction The field of protein-small molecule conjugate therapy has evolved significantly and is offering many clinically beneficial drugs, with the expectation that more drugs will be available in the coming years. Protein-conjugate therapy can offer several advantages, such as specificity, functional diversity, and relatively low off-target activity, resulting in fewer side effects. [Overview of the project]

[0003] Camptothecins are a family of antitumor agents that share a common structural core i (Figure 1, Panel A). Due to their ability to inhibit the activity of DNA topoisomerase I, an intracellular enzyme essential for cell replication, several synthetic and semi-synthetic camptothecins have been used as small molecule cancer chemotherapy (e.g., topotecan and irinotecan). In contrast, more potent analogs such as SN-38(1) and exatecan(3) (Figure 1, Panel B) exhibit significant off-target toxicity that prevents their direct use to treat cancer. Targeted delivery of highly potent camptothecins to tumor tissue may offer a therapy that avoids its toxicity issues and exhibits better tolerability. This disclosure describes the preparation of antibody-drug conjugates (ADCs) containing camptothecin of general structure i (Figure 1, Panel A). In each conjugate, the selected cytotoxin is attached to an antibody (e.g., an mAb) by a cleavable linker linked to one of the common C20 alcohols, or by various chemical handles specific to a particular camptothecin analog (Figure 1).

[0004] This disclosure provides antibody-drug conjugate (ADC) structures comprising camptothecin or a camptothecin derivative linked to a polypeptide (e.g., an antibody) via a linker. In addition, this disclosure also includes compounds and methods for generating such conjugates, as well as methods for using the conjugates.

[0005] A part of this disclosure is a conjugate of formula (I), [ka] During the ceremony, Z, CR 10 or N, R 7 However, selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, R 8 and R 9 are each independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or R 8 and R 9 are optionally cyclically linked to form a 5- or 6-membered heterocyclyl, each R 10 is independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, W is a polypeptide, L is a linker connected to the compound of formula (II) via R 1 , R 2 , R 3 , R 4 , R 5 or R 6 ,

Chemical Formula

[0006] In some embodiments, the compound of formula (II) has the structure of formula (IIa). [ka] It has, in the formula, R 3 OH is, L is R 6 Connected to, or L is R 3 It is connected to R 6 Is it OH, or The compound of formula (II) has the structure of formula (IIb). [ka] It has, in the formula, R 1a The is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and L is R 6 Connected to, or L is R 1a It is connected to R 6 Is it OH, or The compound of formula (II) has the structure of formula (IIc). [ka] It has, in the formula, R 1b The is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and L is R 6 Connected to, or L is R 1b It is connected to R 6 Is it OH, or The compound of formula (II) has the structure of formula (IId). [ka] It has, in the formula, R 2a and R2b However, each is independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and L is R 6 Connected to, or L is R 2a Or R 2b It is connected to R 6 Is it OH, or The compound of formula (II) has the structure of formula (IIe). [ka] It has, in the formula, R 2c The following are selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and the connection to L is indicated by a wavy line.

[0007] In some embodiments, L is -(T 1 -V 1 ) a -(T 2 -V 2 ) b -(T 3 -V 3 ) c -(T 4 -V 4 ) d -(T 5 -V 5 ) e -(T 6 -V 6 ) f - Includes, During the ceremony, a, b, c, d, e, and f are each independently either 0 or 1. T 1 , T 2 , T 3 , T 4, T 5 , and T 6 are each independently selected from the group consisting of a covalent bond, (C1-C 12 )alkyl, substituted (C1-C 12 )alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA) w , (PEG) n , (AA) p , -(CR 13 OH) m -, 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino-benzylamino (PABA), para-amino-phenyl (PAP), para-hydroxy-phenyl (PHP), an acetal group, hydrazine, disulfide, and ester; wherein EDA is an ethylenediamine moiety, PEG is polyethylene glycol, AA is an amino acid residue or an amino acid analog, each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each m is an integer from 1 to 12, V 1 , V 2 , V 3 , V 4 , V 5 , and V 6 are each independently selected from the group consisting of a covalent bond, -CO-, -NR 15 -, -NR 15 (CH2) q -, -NR 15 (C6H4)-, -CONR 15 -, -NR 15 CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR 15 -, -NR 15 SO2-, and -P(O)OH-, and each q is an integer from 1 to 6, each R 13are each independently selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl, each R 15 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0008] In some embodiments, L is a linker, T 1 is (C1-C 12 )alkyl and substituted (C1-C 12 )alkyl, T 2 , T 3 , T 4 , T 5 , and T 6 are each independently selected from a covalent bond, (C1-C 12 )alkyl, substituted (C1-C 12 )alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA) w , (PEG) n , (AA) p , -(CR 13 OH) m -, 4-amino-piperidine (4AP), MABO, MABC, PABO, PABC, PAB, PABA, PAP, PHP, an acetal group, hydrazine, and ester, V 1 , V 2 , V 3 , V 4 , V 5 , and V 6 are each independently selected from a covalent bond, -CO-, -NR 15 -, -NR 15 (CH2) q -, -NR 15 (C6H4)-, -CONR 15 -, -NR 15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR 15 -, -NR 15 Selected from the group consisting of SO2- and -P(O)OH-, (PEG) n but, [ka] In the formula, n is an integer between 1 and 30. EDA has the following structure [ka] The ethylenediamine moiety has the following characteristics, where y is an integer from 1 to 6, and r is 0 or 1. 4-amino-piperidine (4AP) [ka] And, Each R 12 However, independently selected from hydrogen, alkyl, substituted alkyl, polyethylene glycol moiety, aryl, and substituted aryl, any two adjacent R 12 The groups may be linked in a ring to form a piperazinyl ring.

[0009] In some embodiments, T 1 , T 2 , T 3 , T 4 , T 5 , and T 6 Each of these is optionally substituted with a glycoside. In some embodiments, MABO, MABC, PABO, PABC, PAB, PABA, PAP, and PHP are each optionally substituted with a glycoside. In some embodiments, the glycoside is selected from glucuronides, galactosides, glucosides, mannosides, fucoids, O-GlcNAc, and O-GalNAc.

[0010] In some embodiments, L is a linker, T1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. T 6 However, it is EDA, V 6 However, it is either -CO- or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it does not exist, V 5 However, -NR 15 It is (C6H4)-, T 6 However, it does not exist, V 6 However, it is either -CO- or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, -NR 15 -and, T 6 However, (C1-C 12 ) is alkyl, V 6 However, it is either -CO- or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is AA, and V 2 However, it does not exist. T 3 However, it is PABC, and V 3 However, it does not exist. T 4 However, it is EDA, V 4 However, it is -CO-, e and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is AA, and V 2 However, it does not exist. T 3 However, it is PABC, and V 3 However, it does not exist. d, e, and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABA, and V 5 However, it is -CO-, T 6 However, (C1-C 12 ) is alkyl, V 6 However, it is either -SO2- or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T 2 However, (PEG) n V 2 However, it is -CO-, T 3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PABC, and V 4 However, it does not exist. e and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T 2 However, substitution (C1-C 12 ) is alkyl, V 2 However, it is -CO-, T3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PABC, and V 4 However, it does not exist. e and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T 2 However, (PEG) n V 2 However, it is -CO-, T 3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PABC, and V 4 However, it does not exist. T 5 However, (C1-C 12 ) is alkyl, V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is 4AP, V 2 However, it is -CO-, T 3 However, (C1-C 12 ) is alkyl, V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is 4AP, V 2 However, it is -CO-, T 3 However, (C1-C 12 ) is alkyl, V 3 However, it is -O-, T 4 However, (C1-C 12 ) is alkyl, V 4 However, it is -CO-, T 5 However, it is AA, and V 5 However, it does not exist. T 6 However, it is PABC, and V 6 However, it does not exist, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it does not exist. T 3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PABC, and V 4 However, it does not exist. e and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T 2 However, (PEG) n V 2 However, it is -CONH-, T 3 However, substitution (C1-C 12 ) is alkyl, V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V1 However, it is -CO-, T 2 However, it is AA, and V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABO, V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PAP, and V 5 However, he is the COO, f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T 2 However, (PEG) n V 2 However, it is -CO-, T 3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PAP, and V 4 However, he is the COO, e and f are both 0.

[0011] In some embodiments, one R 10 This is the second linker L B It is linked to the second compound of formula (II) via [a certain linkage].

[0012] In some embodiments, L B teeth, -(T 7 -V 7 ) g -(T 8 -V 8 ) h -(T 9 -V 9 ) i -(T 10 -V 10 ) j -(T 11 -V 11 ) k -(T 12 -V 12 ) l - Includes, During the ceremony, g, h, i, j, k, and l are each independently either 0 or 1. T 7 , T 8 , T 9 , T 10 , T 11 , and T 12 However, each is independent, and a covalent bond is formed, (C1-C 12) alkyl, substituted (C1-C 12 ) alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA) w (PEG) n , (AA) p ,-(CR 13 OH) m -, selected from 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino-benzylamino (PABA), para-amino-phenyl (PAP), para-hydroxyphenyl (PHP), acetal group, hydrazine, disulfide, and ester, where EDA is the ethylenediamine moiety, PEG is polyethylene glycol, AA is an amino acid residue or amino acid analog, each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each m is an integer from 1 to 12. V 7 , V 8 , V 9 , V 10 , V 11 , and V 12 However, each operates independently as a covalent bond, -CO-, -NR. 15 -, -NR 15 (CH2) q -, -NR 15 (C6H4)-, -CONR 15 -, -NR 15 CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR 15 -, -NR 15 Selected from the group consisting of SO2- and -P(O)OH-, where each q is an integer from 1 to 6. Each R 13 However, they are independently selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl. Each R 15However, these are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0013] In some embodiments, T 7 , T 8 , T 9 , T 10 , T 11 , and T 12 Each of these is optionally substituted with a glycoside. In some embodiments, MABO, MABC, PABO, PABC, PAB, PABA, PAP, and PHP are each optionally substituted with a glycoside. In some embodiments, the glycoside is selected from glucuronides, galactosides, glucosides, mannosides, fucoids, O-GlcNAc, and O-GalNAc.

[0014] In some embodiments, L B It is a linker, T 7 However, it does not exist, V 7 However, -NR 15 CO-, T 8 However, (C1-C 12 ) is alkyl, V 8 However, it is -CO-, T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PABC, and V 10 However, it does not exist. T 11 However, it is EDA, V 11 However, it is -CO-, l is 0, or T 7 However, it does not exist, V 7 However, -NR 15 CO-, T 8 However, (C1-C12 ) is alkyl, V 8 However, it is -CO-, T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PABC, and V 10 However, it does not exist. k and l are each 0, or T 7 However, it does not exist, V 7 However, it is -NHCO-, T 8 However, (C1-C 12 ) is alkyl, V 8 However, it is -CO-, T 9 However, it is an amino acid analog, V 9 However, it is -NH-, T 10 However, (PEG) n V 10 However, it is -CO-, T 11 However, it is AA, and V 11 However, it does not exist. T 12 However, it is PABC, and V 12 However, it does not exist, or T 7 However, it does not exist, V 7 However, it is -NHCO-, T 8 However, (C1-C 12 ) is alkyl, V 8 However, it is -CONH-, T 9 However, (PEG) n V 9 However, it is -CO-, T 10 However, it is AA, and V 10 However, it does not exist. T 11 However, it is PABC, and V 11 However, it does not exist. l is 0, or T 7 However, (C1-C 12 ) is alkyl, V7 However, it is -CONH-, T 8 However, substitution (C1-C 12 ) is alkyl, V 8 However, it is -CO-, T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PABC, and V 10 However, it does not exist. k and l are each 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CONH-, T 8 However, (PEG) n V 8 However, it is -CO-, T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PABC, and V 10 However, it does not exist. T 11 However, (C1-C 12 ) is alkyl, V 11 However, it does not exist. l is 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CO-, T 8 However, it is 4AP, V 8 However, it is -CO-, T 9 However, (C1-C 12 ) is alkyl, V 9 However, it is -CO-, T 10 However, it is AA, and V 10 However, it does not exist. T 11 However, it is PABC, and V 11 However, it does not exist. l is 0, or T 7However, (C1-C 12 ) is alkyl, V 7 However, it is -CO-, T 8 However, it is 4AP, V 8 However, it is -CO-, T 9 However, (C1-C 12 ) is alkyl, V 9 However, it is -O-, T 10 However, (C1-C 12 ) is alkyl, V 10 However, it is -CO-, T 11 However, it is AA, and V 11 However, it does not exist. T 12 However, it is PABC, and V 12 However, it does not exist, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CO-, T 8 However, it is an amino acid analog, V 8 However, it does not exist. T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PABC, and V 10 However, it does not exist. k and l are each 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CONH-, T 8 However, (PEG) n V 8 However, it is -CONH-, T 9 However, substitution (C1-C 12 ) is alkyl, V 9 However, it is -CO-, T 10 However, it is AA, and V 10 However, it does not exist. T 11However, it is PABC, and V 11 However, it does not exist. l is 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CO-, T 8 However, it is AA, and V 8 However, it is -NH-, T 9 However, (PEG) n V 9 However, it is -CO-, T 10 However, it is AA, and V 10 However, it does not exist. T 11 However, it is PABC, and V 11 However, it does not exist. l is 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CONH-, T 8 However, (PEG) n V 8 However, it is -CO-, T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PAP, and V 10 However, he is the COO, k and l are both 0.

[0015] In some embodiments, the conjugate is [ka] TIFF0007912544000012.tif212149 TIFF0007912544000013.tif216148 TIFF0007912544000014.tif167147TIFF0007912544000015.tif160150 TIFF0007912544000016.tif229149TIFF0007912544000017.tif208148 TIFF0007912544000018.tif209148 TIFF0007912544000019.tif208152 TIFF0007912544000020.tif178150 TIFF0007912544000021.tif178165 TIFF0007912544000022.tif206167 Selected from TIFF0007912544000023.tif187158.

[0016] Embodiments of this disclosure are compounds of formula (III), [ka] During the ceremony, Z, CR 10 or N, R 8 and R 9However, each is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or R 8 and R 9 However, they are optionally linked in a ring, forming a 5- or 6-membered heterocycline. Each R 10 However, independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, L is R 1 , R 2 , R 3 , R 4 , R 5 or R 6 This is a linker connected to the compound of formula (II), [ka] R 1 and R 2 However, each is independently selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or R 1 and R 2However, they are optionally linked cyclically to form a 5 or 6-membered cycloalkyl or heterocyclyl ring, R 3 and R 4 However, each is independently selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or R 3 and R 4 However, they are optionally linked cyclically to form a 5 or 6-membered cycloalkyl or heterocyclyl ring, R 5 However, selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, R 6 However, OH and OC(O)R 11 Selected from, R 11 However, selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, at least one R 10 However, it includes a compound of formula (III) which is optionally linked to a second compound of formula (II).

[0017] In some embodiments, the compound of formula (II) has the structure of formula (IIa). [ka] It has, in the formula, R 3 OH is, L is R 6 Connected to, or L is R3 It is connected to R 6 Is it OH, or The compound of formula (II) has the structure of formula (IIb). [ka] It has, in the formula, R 1a The is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and L is R 6 Connected to, or L is R 1a It is connected to R 6 Is it OH, or The compound of formula (II) has the structure of formula (IIc). [ka] It has, in the formula, R 1b The is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and L is R 6 Connected to, or L is R 1b It is connected to R 6 Is it OH, or The compound of formula (II) has the structure of formula (IId). [ka] It has, in the formula, R 2a and R 2b However, each is independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and L is R 6 Connected to, or L is R 2a Or R 2bIt is connected to R 6 Is it OH, or The compound of formula (II) has the structure of formula (IIe). [ka] It has, in the formula, R 2c The following are selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and the connection to L is indicated by a wavy line.

[0018] In some embodiments, L is -(T 1 -V 1 ) a -(T 2 -V 2 ) b -(T 3 -V 3 ) c -(T 4 -V 4 ) d -(T 5 -V 5 ) e -(T 6 -V 6 ) f - Includes, During the ceremony, a, b, c, d, e, and f are each independently either 0 or 1. T 1 , T 2 , T 3 , T 4 , T 5 , and T 6 However, each is independent, and a covalent bond is formed, (C1-C 12 ) alkyl, substituted (C1-C 12 ) alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA) w (PEG)n , (AA) p ,-(CR 13 OH) m -, selected from 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino-benzylamino (PABA), para-amino-phenyl (PAP), para-hydroxyphenyl (PHP), acetal group, hydrazine, disulfide, and ester, where EDA is the ethylenediamine moiety, PEG is polyethylene glycol, AA is an amino acid residue or amino acid analog, each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each m is an integer from 1 to 12. V 1 , V 2 , V 3 , V 4 , V 5 , and V 6 However, each operates independently as a covalent bond, -CO-, -NR. 15 -, -NR 15 (CH2) q -, -NR 15 (C6H4)-, -CONR 15 -, -NR 15 CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR 15 -, -NR 15 Selected from the group consisting of SO2- and -P(O)OH-, where each q is an integer from 1 to 6. Each R 13 However, they are independently selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl. Each R 15However, these are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0019] In some embodiments, L is a linker, T 1 However, (C1-C 12 )alkyl and substituted (C1-C 12 ) Selected from alkyl groups, T 2 , T 3 , T 4 , T 5 , and T 6 However, each is independent, and a covalent bond is formed, (C1-C 12 ) alkyl, substituted (C1-C 12 ) alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA) w (PEG) n , (AA) p ,-(CR 13 OH) m - Selected from 4-amino-piperidine (4AP), MABO, MABC, PABO, PABC, PAB, PABA, PAP, PHP, acetal group, hydrazine, and ester, V 1 , V 2 , V 3 , V 4 , V 5 , and V 6 However, each operates independently as a covalent bond, -CO-, -NR. 15 -, -NR 15 (CH2) q -, -NR 15 (C6H4)-, -CONR 15 -, -NR 15 CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR 15 -, -NR 15Selected from the group consisting of SO2- and -P(O)OH-, (PEG) n but, [ka] In the formula, n is an integer between 1 and 30. EDA has the following structure [ka] The ethylenediamine moiety has the following characteristics, where y is an integer from 1 to 6, and r is 0 or 1. 4-amino-piperidine (4AP) [ka] And, Each R 12 However, independently selected from hydrogen, alkyl, substituted alkyl, polyethylene glycol moiety, aryl, and substituted aryl, any two adjacent R 12 The groups may be linked in a ring to form a piperazinyl ring.

[0020] In some embodiments, T 1 , T 2 , T 3 , T 4 , T 5 , and T 6 Each of these is optionally substituted with a glycoside. In some embodiments, MABO, MABC, PABO, PABC, PAB, PABA, PAP, and PHP are each optionally substituted with a glycoside. In some embodiments, the glycoside is selected from glucuronides, galactosides, glucosides, mannosides, fucoids, O-GlcNAc, and O-GalNAc.

[0021] In some embodiments, L is a linker, T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. T 6 However, it is EDA, V 6 However, it is either -CO- or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it does not exist, V 5 However, -NR 15 It is (C6H4)-, T 6 However, it does not exist, V 6 However, it is either -CO- or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, -NR 15 -and, T 6 However, (C1-C 12 ) is alkyl, V 6 However, it is either -CO- or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is AA, and V 2 However, it does not exist. T 3 However, it is PABC, and V 3 However, it does not exist. T 4 However, it is EDA, V 4 However, it is -CO-, e and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is AA, and V 2 However, it does not exist. T 3 However, it is PABC, and V 3 However, it does not exist. d, e, and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABA, and V 5 However, it is -CO-, T 6 However, (C1-C 12 ) is alkyl, V 6 However, it is either -SO2- or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T 2 However, (PEG) n V 2 However, it is -CO-, T 3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PABC, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. e and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABA, and V 5 However, it is -CO-, T 6 However, (C1-C 12 ) is alkyl, V 6 However, it is either -SO2- or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T 2 However, (PEG) n V 2 However, it is -CO-, T 3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PABC, and V 4 However, it does not exist. e and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T 2 However, substitution (C1-C 12 ) is alkyl, V 2 However, it is -CO-, T 3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PABC, and V 4 However, it does not exist. e and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T 2 However, (PEG) n V 2 However, it is -CO-, T3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PABC, and V 4 However, it does not exist. T 5 However, (C1-C 12 ) is alkyl, V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is 4AP, V 2 However, it is -CO-, T 3 However, (C1-C 12 ) is alkyl, V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is 4AP, V 2 However, it is -CO-, T 3 However, (C1-C 12 ) is alkyl, V 3 However, it is -O-, T 4 However, (C1-C 12 ) is alkyl, V 4 However, it is -CO-, T 5 However, it is AA, and V 5 However, it does not exist. T 6 However, it is PABC, and V 6 However, it does not exist, or T 1However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it does not exist. T 3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PABC, and V 4 However, it does not exist. e and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T 2 However, (PEG) n V 2 However, it is -CONH-, T 3 However, substitution (C1-C 12 ) is alkyl, V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is AA, and V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. f is 0, or T1 is (C1-C 12 ) alkyl, and V 1 is -CO-, T 2 is an amino acid analog, and V 2 is -NH-, T 3 is (PEG) n , and V 3 is -CO-, T 4 is AA, and V 4 is absent, T 5 is PABO, and V 5 is absent, f is 0, or T 1 is (C1-C 12 ) alkyl, and V 1 is -CO-, T 2 is an amino acid analog, and V 2 is -NH-, T 3 is (PEG) n , and V 3 is -CO-, T 4 is AA, and V 4 is absent, T 5 is PAP, and V 5 is -COO-, f is 0, or T 1 is (C1-C 12 ) alkyl, and V 1 is -CONH-, T 2 is (PEG) n , and V 2 is -CO-, T 3 is AA, and V 3 is absent, T 4 is PAP, and V 4 is -COO-, e and f are each 0.

[0022] In some embodiments, one R 10 This is the second linker L B It is linked to the second compound of formula (II) via [a certain linkage].

[0023] In some embodiments, L B teeth, -(T 7 -V 7 ) g -(T 8 -V 8 ) h -(T 9 -V 9 ) i -(T 10 -V 10 ) j -(T 11 -V 11 ) k -(T 12 -V 12 ) l - Includes, During the ceremony, g, h, i, j, k, and l are each independently either 0 or 1. T 7 , T 8 , T 9 , T 10 , T 11 , and T 12 However, each is independent, and a covalent bond is formed, (C1-C 12 ) alkyl, substituted (C1-C 12 ) alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA) w (PEG) n , (AA) p ,-(CR 13 OH) m-, selected from 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino-benzylamino (PABA), para-amino-phenyl (PAP), para-hydroxyphenyl (PHP), acetal group, hydrazine, disulfide, and ester, where EDA is the ethylenediamine moiety, PEG is polyethylene glycol, AA is an amino acid residue or amino acid analog, each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each m is an integer from 1 to 12. V 7 , V 8 , V 9 , V 10 , V 11 , and V 12 However, each operates independently as a covalent bond, -CO-, -NR. 15 -, -NR 15 (CH2) q -, -NR 15 (C6H4)-, -CONR 15 -, -NR 15 CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR 15 -, -NR 15 Selected from the group consisting of SO2- and -P(O)OH-, where each q is an integer from 1 to 6. Each R 13 However, they are independently selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl. Each R 15 However, these are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0024] In some embodiments, T7 , T 8 , T 9 , T 10 , T 11 , and T 12 are each optionally substituted with a glycoside. In some embodiments, MABO, MABC, PABO, PABC, PAB, PABA, PAP, and PHP are each optionally substituted with a glycoside. In some embodiments, the glycoside is selected from glucuronide, galactoside, glucoside, mannoside, fucoside, O-GlcNAc, and O-GalNAc.

[0025] In some embodiments, L B is a linker, T 7 is absent, V 7 is -NR 15 CO-, T 8 is (C1-C 12 ) alkyl, V 8 is -CO-, T 9 is AA, V 9 is absent, T 10 is PABC, V 10 is absent, T 11 is EDA, V 11 is -CO-, l is 0, or T 7 is absent, V 7 is -NR 15 CO-, T 8 is (C1-C 12 ) alkyl, V 8 is -CO-, T 9 is AA, V 9 is absent, T 10 is PABC, V 10 is absent, k and l are each 0, or T7 However, it does not exist, V 7 However, it is -NHCO-, T 8 However, (C1-C 12 ) is alkyl, V 8 However, it is -CO-, T 9 However, it is an amino acid analog, V 9 However, it is -NH-, T 10 However, (PEG) n V 10 However, it is -CO-, T 11 However, it is AA, and V 11 However, it does not exist. T 12 However, it is PABC, and V 12 However, it does not exist, or T 7 However, it does not exist, V 7 However, it is -NHCO-, T 8 However, (C1-C 12 ) is alkyl, V 8 However, it is -CONH-, T 9 However, (PEG) n V 9 However, it is -CO-, T 10 However, it is AA, and V 10 However, it does not exist. T 11 However, it is PABC, and V 11 However, it does not exist. l is 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CONH-, T 8 However, substitution (C1-C 12 ) is alkyl, V 8 However, it is -CO-, T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PABC, and V10 However, it does not exist. k and l are each 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CONH-, T 8 However, (PEG) n V 8 However, it is -CO-, T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PABC, and V 10 However, it does not exist. T 11 However, (C1-C 12 ) is alkyl, V 11 However, it does not exist. l is 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CO-, T 8 However, it is 4AP, V 8 However, it is -CO-, T 9 However, (C1-C 12 ) is alkyl, V 9 However, it is -CO-, T 10 However, it is AA, and V 10 However, it does not exist. T 11 However, it is PABC, and V 11 However, it does not exist. l is 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CO-, T 8 However, it is 4AP, V 8 However, it is -CO-, T 9 However, (C1-C 12 ) is alkyl, V 9 However, it is -O-, T 10 However, (C1-C 12 ) is alkyl, V 10 However, it is -CO-, T 11 However, it is AA, and V 11 However, it does not exist. T 12 However, it is PABC, and V 12 However, it does not exist, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CO-, T 8 However, it is an amino acid analog, V 8 However, it does not exist. T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PABC, and V 10 However, it does not exist. k and l are each 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CONH-, T 8 However, (PEG) n V 8 However, it is -CONH-, T 9 However, substitution (C1-C 12 ) is alkyl, V 9 However, it is -CO-, T 10 However, it is AA, and V 10 However, it does not exist. T 11 However, it is PABC, and V 11 However, it does not exist. l is 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CO-, T 8 However, it is AA, and V 8 However, it is -NH-, T 9 However, (PEG) n V 9 However, it is -CO-, T 10 However, it is AA, and V 10 However, it does not exist. T 11 However, it is PABC, and V 11 However, it does not exist. l is 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CONH-, T 8 However, (PEG) n V 8 However, it is -CO-, T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PAP, and V 10 However, he is the COO, k and l are both 0.

[0026] In some embodiments, the compound is [ka] TIFF0007912544000035.tif157152 TIFF0007912544000036.tif164156 TIFF0007912544000037.tif216147 TIFF0007912544000038.tif165148 TIFF0007912544000039.tif172151 TIFF0007912544000040.tif148153TIFF0007912544000041.tif149153 TIFF0007912544000042.tif210149 TIFF0007912544000043.tif204147 TIFF0007912544000044.tif207149 TIFF0007912544000045.tif179150 TIFF0007912544000046.tif173151 TIFF0007912544000047.tif205150 Selected from TIFF0007912544000048.tif186148.

[0027] Aspects of this disclosure include a pharmaceutical composition comprising the conjugate provided for in this disclosure and a pharmaceutically acceptable excipient.

[0028] A part of this disclosure includes a method that involves administering an effective amount of the conjugate provided herein to a target.

[0029] Aspects of the present disclosure include a method for treating cancer in a subject, wherein the subject is administered a therapeutically effective amount of a pharmaceutical composition comprising the conjugate of the present disclosure, the administration being effective in treating cancer in the subject. [Brief explanation of the drawing]

[0030] [Figure 1] The chemical structures of the camptothecin family of topoisomerase I inhibitors are shown. (Figure 1, Panel A) Typical structure of camptothecin. (Figure 1, Panel B) Representative example of camptothecin used as a payload for antibody-drug conjugates (arrows indicate modification sites for linker conjugation). [Figure 2] A schematic diagram of HIPS ligation for ADC synthesis is shown. An antibody containing an aldehyde moiety is reacted with a Hydrazino-iso-Pictet-Spengler (HIPS) linker and payload to generate a site-specifically conjugated ADC with a stable azacarborin bond. [Figure 3] The polymer reversed-phase column (PLRP) trace of compound 12 conjugate 2941, which contains two tag sites and yielded a DAR of 2.75 and an HMW of 2.2%, is shown. [Figure 4] The analytical size exclusion chromatography (SEC) trace of compound 12 conjugate 2941, which contains two tag sites and yielded a DAR of 2.75 and a HMW of 2.2%, is shown. [Figure 5] The PLRP trace of compound 12 conjugate 2944, which includes two tag sites and yielded a DAR of 3.12 and a HMW of 4.5%, is shown. [Figure 6]The SEC trace of compound 12 conjugate 2944, which includes two tag sites and yielded a DAR of 3.12 and a HMW of 4.5%, is shown. [Figure 7] The PLRP trace of compound 12 conjugate 2746, which includes two tag sites and yielded a DAR of 2.78 and an HMW of 3.4%, is shown. [Figure 8] The hydrophobic interaction column (HIC) trace of compound 12 conjugate 2746, which contains two tag sites and yielded a DAR of 2.78 and a HMW of 3.4%, is shown. [Figure 9] The SEC trace of compound 12 conjugate 2746, which includes two tag sites and yielded a DAR of 2.78 and an HMW of 3.4%, is shown. [Figure 10] The PLRP trace of compound 12 conjugate 2749, which includes two tag sites and yielded a DAR of 3.04 and a HMW of 0.9%, is shown. [Figure 11] The SEC trace of compound 12 conjugate 2749, which includes two tag sites and yielded a DAR of 3.04 and an HMW of 0.9%, is shown. [Figure 12] The PLRP trace of compound 12 conjugate 2752, which includes two tag sites and yielded a DAR of 3.01 and an HMW of 4.3%, is shown. [Figure 13] The HIC trace of compound 12 conjugate 2752, which includes two tag sites and yielded a DAR of 3.01 and an HMW of 4.3%, is shown. [Figure 14] The SEC trace of compound 12 conjugate 2752, which includes two tag sites and yielded a DAR of 3.01 and an HMW of 4.3%, is shown. [Figure 15] The PLRP trace of compound 12 conjugate 2755, which includes two tag sites and yielded a DAR of 2.72 and an HMW of 3.2%, is shown. [Figure 16] The HIC trace of compound 12 conjugate 2755, which includes two tag sites and yielded a DAR of 2.72 and an HMW of 3.2%, is shown. [Figure 17]The SEC trace of compound 12 conjugate 2755, which includes two tag sites and yielded a DAR of 2.72 and an HMW of 3.2%, is shown. [Figure 18] The HIC trace of compound 12 conjugate 2758, which includes two tag sites and yielded a DAR of 1.54 and an HMW of 1.6%, is shown. [Figure 19] The SEC trace of compound 12 conjugate 2758, which contains one tag site and yielded a DAR of 1.54 and an HMW of 1.6%, is shown. [Figure 20] The PLRP trace of compound 12 conjugate 2762, which includes two tag sites and yielded a DAR of 2.95 and an HMW of 3.6%, is shown. [Figure 21] The SEC trace of compound 20 conjugate 2762, which contains two tag sites and yielded a DAR of 2.95 and an HMW of 3.6%, is shown. [Figure 22] The PLRP trace of compound 20 conjugate 2765, which includes two tag sites and yielded a DAR of 2.97 and an HMW of 1.2%, is shown. [Figure 23] The SEC trace of compound 20 conjugate 2765, which contains two tag sites and yielded a DAR of 2.97 and an HMW of 1.2%, is shown. [Figure 24] The PLRP trace of compound 20 conjugate 2768, which includes two tag sites and yielded a DAR of 2.92 and an HMW of 5.3%, is shown. [Figure 25] The SEC trace of compound 20 conjugate 2768, which contains two tag sites and yielded a DAR of 2.92 and an HMW of 5.3%, is shown. [Figure 26] The PLRP trace of compound 20 conjugate 2771, which includes two tag sites and yielded a DAR of 2.89 and an HMW of 4.3%, is shown. [Figure 27] The SEC trace of compound 20 conjugate 2771, which includes two tag sites and yielded a DAR of 2.89 and an HMW of 4.3%, is shown. [Figure 28]The HIC trace of compound 20 conjugate 2774, containing one tag site, yielded a DAR of 1.22 and an HMW of 1.8%. [Figure 29] The SEC trace of compound 20 conjugate 2774, containing one tag site, yielded a DAR of 1.22 and an HMW of 1.8%. [Figure 30] The PLRP trace of compound 2763, conjugate of compound 27, is shown, containing two tag sites and yielding a DAR of 2.43 and a HMW of 6.0%. [Figure 31] The SEC trace of compound 2763, conjugate of compound 27, is shown, containing two tag sites and yielding a DAR of 2.43 and a HMW of 6.0%. [Figure 32] The PLRP trace of compound 2766, conjugate of compound 27, is shown, containing two tag sites and yielding a DAR of 2.43 and a HMW of 2.2%. [Figure 33] The SEC trace of compound 2766, conjugate of compound 27, is shown, containing two tag sites and yielding a DAR of 2.43 and a HMW of 2.2%. [Figure 34] The PLRP trace of compound 2769, conjugate of compound 27, is shown, containing two tag sites and yielding a DAR of 2.42 and an HMW of 8.2%. [Figure 35] The SEC trace of compound 2769, conjugate of compound 27, is shown, containing two tag sites and yielding a DAR of 2.42 and an HMW of 8.2%. [Figure 36] The PLRP trace of compound 2772, conjugate of compound 27, is shown, containing two tag sites and yielding a DAR of 2.47 and a HMW of 6.0%. [Figure 37] The SEC trace of compound 2772, conjugate of compound 27, is shown, containing two tag sites and yielding a DAR of 2.47 and a HMW of 6.0%. [Figure 38] The HIC trace of compound 2775, conjugate of compound 27, is shown, containing one tag site and yielding a DAR of 0.45 and an HMW of 1.4%. [Figure 39]The SEC trace of compound 2775, conjugate of compound 27, is shown, containing one tag site and yielding a DAR of 0.45 and an HMW of 1.4%. [Figure 40] The PLRP trace of compound 34 conjugate 2942, which includes two tag sites and yielded a DAR of 2.78 and an HMW of 11.2%, is shown. [Figure 41] The SEC trace of compound 34 conjugate 2942, which contains two tag sites and yielded a DAR of 2.78 and an HMW of 11.2%, is shown. [Figure 42] The PLRP trace of compound 34 conjugate 2945, which includes two tag sites and yielded a DAR of 3.03 and an HMW of 5.2%, is shown. [Figure 43] The SEC trace of compound 34 conjugate 2945, which includes two tag sites and yielded a DAR of 3.03 and an HMW of 5.2%, is shown. [Figure 44] The PLRP trace of compound 42 conjugate 2943, which includes two tag sites and yielded a DAR of 5.44 and a HMW of 21.3%, is shown. [Figure 45] The SEC trace of compound 42 conjugate 2943, which contains two tag sites and yielded a DAR of 5.44 and an HMW of 21.3%, is shown. [Figure 46] The PLRP trace of compound 42 conjugate 2946, which includes two tag sites and yielded a DAR of 5.07 and a HMW of 15.3%, is shown. [Figure 47] The SEC trace of compound 42 conjugate 2946, which contains two tag sites and yielded a DAR of 5.07 and an HMW of 15.3%, is shown. [Figure 48] The PLRP trace of compound 45 conjugate 2748, which includes two tag sites and yielded a DAR of 3.51 and a HMW of 3.6%, is shown. [Figure 49] The HIC trace of compound 45 conjugate 2748, which includes two tag sites and yielded a DAR of 3.51 and an HMW of 3.6%, is shown. [Figure 50]The SEC trace of compound 45 conjugate 2748, which contains two tag sites and yielded a DAR of 3.51 and a HMW of 3.6%, is shown. [Figure 51] The PLRP trace of compound 45 conjugate 2751, which includes two tag sites and yielded a DAR of 2.98 and HMW of 2.1%, is shown. [Figure 52] The SEC trace of compound 45 conjugate 2751, which includes two tag sites and yielded a DAR of 2.98 and HMW of 2.1%, is shown. [Figure 53] The PLRP trace of compound 45 conjugate 2754, which contains two tag sites and yielded a DAR of 3.5 and an HMW of 2.3%, is shown. [Figure 54] The HIC trace of compound 45 conjugate 2754, which includes two tag sites and yielded a DAR of 3.5 and an HMW of 2.3%, is shown. [Figure 55] The SEC trace of compound 45 conjugate 2754, which contains two tag sites and yielded a DAR of 3.5 and an HMW of 2.3%, is shown. [Figure 56] The PLRP trace of compound 45 conjugate 2757, which includes two tag sites and yielded a DAR of 3.69 and a HMW of 2.0%, is shown. [Figure 57] The SEC trace of compound 45 conjugate 2757, which contains two tag sites and yielded a DAR of 3.69 and a HMW of 2.0%, is shown. [Figure 58] The HIC trace of compound 45 conjugate 2760, containing one tag site, yielded a DAR of 1.65 and an HMW of 0.8%. [Figure 59] The SEC trace of compound 45 conjugate 2760, containing one tag site, yielded a DAR of 1.65 and an HMW of 0.8%. [Figure 60] The PLRP trace of compound 47 conjugate 3065, which includes two tag sites and yielded a DAR of 6.82 and an HMW of 1.8%, is shown. [Figure 61]The SEC trace of compound 47 conjugate 3065, which includes two tag sites and yielded a DAR of 6.82 and an HMW of 1.8%, is shown. [Figure 62] The PLRP trace of compound 47 conjugate 3066, which includes two tag sites and yielded a DAR of 4.48, is shown. [Figure 63] The HIC trace of compound 47 conjugate 3067, which contains one tag site and yielded a DAR of 3.63 and an HMW of 4.4%, is shown. [Figure 64] The SEC trace of compound 47 conjugate 3067, containing one tag site, yielded a DAR of 3.63 and a HMW of 4.4%. [Figure 65] The HIC trace of compound 47 conjugate 3068, which contains one tag site and yielded a DAR of 3.52 and an HMW of 0.8%, is shown. [Figure 66] The SEC trace of compound 47 conjugate 3068, containing one tag site, yielded a DAR of 3.52 and an HMW of 0.8%. [Figure 67] The PLRP trace of compound 56 conjugate 3063, which includes two tag sites and yielded a DAR of 3.35 and an HMW of 3.3%, is shown. [Figure 68] The SEC trace of compound 56 conjugate 3063, which contains two tag sites and yielded a DAR of 3.35 and an HMW of 3.3%, is shown. [Figure 69] The PLRP trace of compound 56 conjugate 3064, which includes two tag sites and yielded a DAR of 2.8, is shown. [Figure 70] This graph shows the in vitro cytotoxic assay results of free topoisomerase inhibitors in NCI-N87 gastric cancer cells. [Figure 71] This graph shows the results of an in vitro cytotoxic assay of free topoisomerase inhibitors in Sk-Br-3 breast cancer cells. [Figure 72] This graph shows the results of an in vitro cytotoxic assay of free topoisomerase inhibitors in Granta NHL cells. [Figure 73]This graph shows the results of an in vitro cytotoxic assay of free topoisomerase inhibitors in MDA-MB-468 breast cancer cells. [Figure 74] This graph shows the results of an in vitro cytotoxic assay of a free topoisomerase inhibitor in MDA-PCa-2b prostate cancer cells. [Figure 75] The graph shows the results of an in vitro cytotoxicity assay of a TROP-2-targeting ADC prepared using compound 61 in MDA-MB-468 breast cancer cells, according to an embodiment of the present disclosure. [Figure 76] The graph shows the in vitro cytotoxicity assay of HER2-targeting ADCs prepared using compound 61 in NCI-N87 gastric cancer cells according to embodiments of this disclosure. [Figure 77] The graph shows the in vitro cytotoxicity assay of CD25-targeting ADCs prepared using compound 61 in SU-DHL-1 ALCL cells according to embodiments of this disclosure. [Figure 78] The graph shows the in vitro cytotoxicity assay of TROP-2-targeting ADCs prepared using compound 61 in BxPC-3 pancreatic cancer cells according to embodiments of this disclosure. [Figure 79] The graph shows the in vitro cytotoxicity assay of HER2-targeting ADCs prepared using compound 65 in NCI-N87 gastric cancer cells according to embodiments of this disclosure. [Figure 80] The graph shows the in vitro cytotoxicity assay of HER2-targeting ADCs prepared using compound 65 in Sk-Br-3 breast cancer cells according to embodiments of this disclosure. [Figure 81] A schematic diagram of the ELISA assay used to determine total antibody and ADC concentrations for pharmacokinetic (PK) sample analysis is shown. [Figure 82] This graph shows the concentration (μg / mL) of trastuzumab antibody as a percentage of the number of days after administration, following administration of 0.9 mg / kg of trastuzumab antibody. [Figure 83]This graph shows the concentration (μg / mL) as a percentage of days after administration of an ADC conjugated to a conventional HER2 topoisomerase inhibitor with a protease-cleaving linker, administered at a dose of 0.9 mg / kg. [Figure 84] The graph shows the concentration (μg / mL) as a percentage of post-administration days after administration of 0.9 mg / kg of CH1-3 / CT-tagged trastuzumab conjugated to construct 61 according to an embodiment of the present disclosure. [Figure 85] The graph shows the concentration (μg / mL) as a percentage of days after administration of CH1-3 / CT-tagged trastuzumab conjugated to construct 65 according to an embodiment of the present disclosure, at a dose of 0.9 mg / kg. [Figure 86] This graph shows the mean tumor volume (mm3) per day, demonstrating the in vivo efficacy of NCI-H292 xenografts of ADCs targeting TROP-2 with a topoisomerase inhibitor payload. n=8 mice / group. Drug administration is indicated by arrows. [Figure 87] This graph shows the mean tumor volume (mm3) per day, demonstrating the in vivo efficacy of NCI-H292 xenografts of ADCs targeting TROP-2 with a topoisomerase inhibitor payload. n=7 mice / group. A single intravenous administration was given on day 0. [Figure 88] This graph shows the mean tumor volume (mm3) per day, demonstrating the in vivo efficacy of NCI-H1781 xenografts of an ADC (artificial diuretic) targeting nectin-4 with a topoisomerase inhibitor payload. n=5 mice / group. A dose of 5 mg / kg was delivered intravenously on days 0 and 7. [Figure 89] The graphs show the in vitro efficacy of ADCs targeting TROP-2 having (165), (65), and (175), or isotype control ADCs, compared to (1) or (2) against MBA-MB-468 cells. [Figure 90] The graphs show the in vitro efficacy of TROP-2-targeting ADCs or isotype-controlled ADCs having (165), (65), or (175) compared to (1) or (2) against BxPC-3 cells. [Figure 91] The graphs show the in vitro efficacy of HER2-targeting ADCs or isotype-controlled ADCs having (65), (67), or (73) compared to (2) against SK-BR-3 cells. [Figure 92] The graphs show the in vitro efficacy of HER2-targeting ADCs or isotype-controlled ADCs having (65), (67), or (73) compared to (2) against NCI-N87 cells. [Figure 93] The graph shows the in vitro efficacy of ADCs targeting TROP-2 having (65) or (80), or isotype control ADCs, compared to (2) against MDA-MB-468 cells. [Figure 94] The graph shows the in vitro efficacy of ADCs targeting TROP-2 having (65) or (80), or isotype control ADCs, compared to (2) against BxPC-3 cells. [Figure 95] The graphs show the in vitro efficacy of HER2-targeting ADCs or isotype-controlled ADCs having (99), (103), or (110) compared to (2) against NCI-N87 cells. [Figure 96] The graphs show the in vitro efficacy of HER2-targeting ADCs or isotype-controlled ADCs having (65), (86), or (92) compared to (2) against SK-BR-3 cells. [Figure 97] The graphs show the in vitro efficacy of TROP-2-targeting ADCs having (65), or isotype-controlled ADCs, Trodelvy, or CL2A-SN38 isotype-controlled conjugates compared to (1) or (2) against SK-BR-3 cells. [Figure 98] The graph shows the in vitro efficacy of HER2-targeting ADCs, isotype-controlled ADCs, Enhertu, or MC-GGFG-Dxd isotype-controlled conjugates having (65) compared to (2) against NCI-N87 cells. [Figure 99]The graph shows the in vitro efficacy of ADCs targeting TROP-2 having (65) or (113), or isotype control ADCs, compared to (2) against MDA-MB-468 cells. [Figure 100] The graph shows the in vitro efficacy of HER2-targeting ADCs or isotype-controlled ADCs having (65), (136), or (142) compared to (2) against NCI-N87 cells. [Figure 101] The graphs show the in vitro efficacy of TROP-2-targeting ADCs or isotype-controlled ADCs having (65), (127), or (131) compared to (2) against MDA-MB-468 cells. [Figure 102] The graph shows the in vitro efficacy of HER2-targeting ADCs or isotype-controlled ADCs having (65), (127), or (131) compared to (2) against NCI-N87 cells. [Figure 103] The graphs show the in vitro efficacy of TROP-2-targeting ADCs or isotype-controlled ADCs having (151), (147), or (131) compared to (2), (148), or (144) against NCI-N87 cells. [Figure 104] The graphs show the in vitro efficacy of HER2-targeting ADCs having (151), (147), or (131) compared to (2), (148), or (144) against SK-BR-3 cells, or isotype-controlled ADCs. [Figure 105] The graph shows the in vitro efficacy of a TROP-2-targeting ADC having (155), or an isotype control ADC, or CL2A-SN38, compared to (1) against MDA-MB-468 cells. [Figure 106] The graph of compound 127 CH1-3 / CT-tagged trastuzumab conjugate is shown, and when determined by PLRP, a DAR of 7.15 is obtained. [Figure 107] The graph of compound 131 CH1-3 / CT-tagged trastuzumab conjugate is shown, and when determined by PLRP, it yields a DAR of 6.80. [Figure 108] The graph of compound 127 CH1-3 / CT-tagged trastuzumab conjugate shows that 94.4% is monomer, as determined by analysis SEC. [Figure 109] The graph of compound 131 CH1-3 / CT-tagged trastuzumab conjugate shows that 93.6% is monomer, as determined by analysis SEC. [Figure 110] The graph of compound 165 CH1-3 / CT-tagged sacituzumab conjugate is shown, and when determined by HIC, it yields a DAR of 3.41. [Figure 111] The graph of compound 165 CH1-3 / CT-tagged sacituzumab conjugate shows that, as determined by analysis SEC, 98.2% is monomer. [Figure 112] The graph of compound 165 CH1-3 / CT-tagged polatuzumab conjugate is shown, and when determined by HIC, it yields a DAR of 3.67. [Figure 113] The graph of compound 165 CH1-3 / CT-tagged polatuzumab conjugate shows that, as determined by analysis SEC, 97.4% is monomer. [Figure 114] The graph of compound 80 CH1-3 / CT-tagged trastuzumab conjugate is shown, and when determined by PLRP, a DAR of 5.86 is obtained. [Figure 115] The graph of compound 80 CH1-3 / CT-tagged trastuzumab conjugate shows that, as determined by analysis SEC, 97.4% is monomer. [Figure 116] The graph of compound 80 CH1-3 / CT-tagged sacituzumab conjugate is shown, and when determined by PLRP, a DAR of 6.19 is obtained. [Figure 117] The graph of compound 80 CH1-3 / CT-tagged sacituzumab conjugate shows that, as determined by analysis SEC, 97.1% is monomer. [Figure 118]The graph of compound 86 CH1-3 / CT-tagged anti-FITC conjugate is shown, and when determined by PLRP, a DAR of 5.46 is obtained. [Figure 119] The graph of compound 86 CH1-3 / CT-tagged anti-FITC conjugate shows that, as determined by analysis SEC, 98.0% is monomer. [Figure 120] The graph of compound 92 CH1-3 / CT-tagged anti-FITC conjugate is shown, and when determined by PLRP, a DAR of 1.58 is obtained. [Figure 121] The graph of compound 92 CH1-3 / CT-tagged anti-FITC conjugate shows that, as determined by analysis SEC, 96.1% is monomer. [Figure 122] The graph of compound 99 CH1-3 / CT-tagged anti-FITC conjugate is shown, and when determined by PLRP, a DAR of 3.07 is obtained. [Figure 123] The graph of compound 99 CH1-3 / CT-tagged anti-FITC conjugate shows that, as determined by analysis SEC, 97.9% is monomer. [Figure 124] The graph of compound 103 CH1-3 / CT-tagged trastuzumab conjugate is shown, and when determined by PLRP, it yields a DAR of 6.56. [Figure 125] The graph of compound 103 CH1-3 / CT-tagged trastuzumab conjugate shows that 97.3% is monomer, as determined by analysis SEC. [Figure 126] The graph of compound 110 CH1-3 / CT-tagged anti-FITC conjugate is shown, and when determined by PLRP, a DAR of 5.66 is obtained. [Figure 127] The graph of compound 110 CH1-3 / CT-tagged anti-FITC conjugate shows that 98.5% is monomer, as determined by analysis SEC. [Figure 128]The graph of compound 113 CH1-3 / CT-tagged sacituzumab conjugate is shown, and when determined by PLRP, a DAR of 6.41 is obtained. [Figure 129] The graph of compound 113 CH1-3 / CT-tagged sacituzumab conjugate shows that, as determined by analysis SEC, 97.4% is monomer. [Figure 130] The graph of compound 123 CH1-3 / CT-tagged anti-FITC conjugate is shown, and when determined by PLRP, a DAR of 5.56 is obtained. [Figure 131] The graph of compound 123 CH1-3 / CT-tagged anti-FITC conjugate shows that 95.5% is monomer, as determined by analysis SEC. [Figure 132] The graph of compound 151 CH1-3 / CT-tagged anti-FITC conjugate is shown, and when determined by PLRP, a DAR of 5.67 is obtained. [Figure 133] The graph of compound 151 CH1-3 / CT-tagged anti-FITC conjugate shows that, as determined by analysis SEC, 97.8% is monomer. [Figure 134] The graph of compound 147 CH1-3 / CT-tagged anti-FITC conjugate is shown, and when determined by PLRP, a DAR of 6.47 is obtained. [Figure 135] The graph of compound 147 CH1-3 / CT-tagged anti-FITC conjugate shows that, as determined by analysis SEC, 96.4% is monomer. [Figure 136] The graph of compound 73 CH1-3 / CT-tagged trastuzumab conjugate is shown, and when determined by PLRP, a DAR of 5.41 is obtained. [Figure 137] The graph of compound 67 CH1-3 / CT-tagged trastuzumab conjugate is shown, and when determined by PLRP, a DAR of 4.02 is obtained. [Figure 138]The graph of compound 136 CH1-3 / CT-tagged trastuzumab conjugate is shown, and when determined by PLRP, a DAR of 7.26 is obtained. [Figure 139] The graph of compound 136 CH1-3 / CT-tagged trastuzumab conjugate shows that, as determined by analysis SEC, 98.9% is monomer. [Figure 140] The graph of compound 142 CH1-3 / CT-tagged trastuzumab conjugate is shown, and when determined by PLRP, a DAR of 6.9 is obtained. [Figure 141] The graph of compound 175 CH1-3 / CT-tagged anti-FITC conjugate is shown, and when determined by PLRP, a DAR of 5.08 is obtained. [Figure 142] The graph of compound 175 CH1-3 / CT-tagged anti-FITC conjugate shows that 93.0% is monomer, as determined by analysis SEC. [Figure 143] The graph of compound 155 CH1-3 / CT-tagged trastuzumab conjugate is shown, and when determined by HIC, it yields a DAR of 2.82. [Figure 144] The graph of compound 155 CH1-3 / CT-tagged anti-FITC conjugate shows that, as determined by analysis SEC, 89.7% is monomer.

[0031] definition The following terms have the meanings set forth below unless otherwise indicated. Any undefined term has the meaning as recognized in the art.

[0032] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, for example, 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3 carbon atoms. This term includes, by example, linear and branched hydrocarbyl groups, such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).

[0033] The term "substituted alkyl" refers to a group in which one or more carbon atoms (excluding the C1 carbon atom) in the alkyl chain are optionally -O-, -N-, -S-, or -S(O). n -(wherein n is 0 to 2), -NR-(wherein R is hydrogen or alkyl), and are replaced by heteroatoms such as alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl, and -NR a R b Having 1 to 5 substituents selected from the group consisting of R ’ and R ”However, these may be the same or different and refer to alkyl groups as defined herein, selected from hydrogen, optionally substituted alkyls, cycloalkyls, alkenyls, cycloalkenyls, alkynyls, aryls, heteroaryls, and heterocycles.

[0034] "Alkylene" is a divalent aliphatic hydrocarbyl group, preferably having 1 to 6 carbon atoms in either a linear or branched chain, more preferably 1 to 3 carbon atoms, and optionally -O-, -NR 10 -, -NR 10 C(O)-, -C(O)NR 10 - This term refers to a group that is interrupted by one or more groups selected from the following. Examples of this term include methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), iso-propylene (-CH2CH(CH3)-), (-C(CH3)2CH2CH2-), (-C(CH3)2CH2C(O)-), (-C(CH3)2CH2C(O)NH-), (-CH(CH3)CH2-), etc.

[0035] "Substitutive alkylene" refers to an alkylene group having 1 to 3 hydrogen atoms replaced by substituents, as described in the definition of "substitution" below for carbon.

[0036] The term "alkane" refers to alkyl and alkylene groups as defined herein.

[0037] The terms "alkylaminoalkyl," "alkylaminoalkenyl," and "alkylaminoalkynyl" refer to an R'NHR"- group in which R' is an alkyl group as defined herein and R'' is an alkylene, alkenylene, or alkynylene group as defined herein.

[0038] The terms "alkaryl" or "aralkyl" refer to alkylene, substituted alkylene, and aryl, as defined herein, -alkylene-aryl and -substituted alkylene-aryl groups.

[0039] "Alkoxy" refers to an -O-alkyl group, where alkyl is as defined herein. Examples of alkoxys include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy. The term "alkoxy" also refers to alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O- groups, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are defined herein.

[0040] The term "substituted alkoxy" refers to the groups of substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O-, as defined herein.

[0041] The term "alkoxyamino" refers to an -NH-alkoxy group, where alkoxy is defined herein.

[0042] The term "haloalkoxy" refers to an alkyl-O- group in which one or more hydrogen atoms on the alkyl group are substituted with a halo group, and examples include groups such as trifluoromethoxy.

[0043] The term "haloalkyl" refers to the substituted alkyl group described above, in which one or more hydrogen atoms on the alkyl group are substituted with a halo group. Examples of such groups include, but are not limited to, fluoroalkyl groups, such as trifluoromethyl, difluoromethyl, and trifluoroethyl.

[0044] The term "alkylalkoxy" refers to alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl, where alkyl, substituted alkyl, alkyl, alkylene and substituted alkylene are as defined herein.

[0045] The term "alkylthioalkoxy" refers to alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl, and substituted alkylene-S-substituted alkyl, where alkyl, substituted alkyl, alkyl, alkylene and substituted alkylene are as defined herein.

[0046] "Alkenyl" refers to a linear or branched hydrocarbyl group having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and at least 1, preferably 1 to 2 double bond unsaturated sites. Examples of this term include be-vinyl, allyl, and buta-3-en-1-yl. This term includes cis and trans isomers, or mixtures thereof.

[0047] The term "substituted alkenyl" refers to an alkenyl group as defined herein, having 1 to 5 substituents selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl, or having 1 to 3 substituents.

[0048] "Alkynyl" refers to a monovalent hydrocarbyl group, either linear or branched, having 2 to 6 carbon atoms, preferably 2 to 3 carbon atoms, and at least 1, preferably 1 to 2 triple-bond unsaturated moieties. Examples of such alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CH2C≡CH).

[0049] The term "substituted alkynyl" refers to an alkynyl group as defined herein, having 1 to 5 substituents selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl, or having 1 to 3 substituents.

[0050] "Alkynyloxy" refers to an -O-alkynyl group, where alkynyl is defined herein. Examples of alkynyloxy include ethynyloxy and propynyloxy.

[0051] "Acyl" refers to the groups HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclyl-C(O)-, and substituted heterocyclyl-C(O)-, as defined herein. For example, acyls contain the "acetyl" group CH3C(O)-.

[0052] "Acylamino" is -NR 20 C(O)alkyl, -NR 20 C(O) substituted alkyl, NR 20 C(O) cycloalkyl, -NR 20 C(O) substituted cycloalkyl, -NR 20 C(O)cycloalkenyl, -NR 20 C(O)-substituted cycloalkenyl, -NR 20 C(O) alkenyl, -NR 20 C(O) substituted alkenyl, -NR 20 C(O)alkynyl, -NR 20 C(O) substituted alkynyl, -NR 20 C(O)aryl, -NR 20 C(O) substituted aryl, -NR 20 C(O) heteroaryl, -NR 20 C(O) substituted heteroaryl, -NR 20 C(O) heterocycle and -NR 20 It refers to the group of a C(O) substituted heterocycle, R 20The elements are hydrogen or alkyl, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0053] The terms "aminocarbonyl" or "aminoacyl" are defined as -C(O)NR 21 R 22 It refers to the base, R 21 and R 22 However, independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, R 21 and R 22 However, they are optionally linked with nitrogen atoms to form heterocycles or substituted heterocycle groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0054] "Aminocarbonylamino" is -NR 21 C(O)NR 22 R 23 It refers to the base, R 21 , R 22 , and R 23 However, independently, the R groups are selected from hydrogen, alkyl, aryl, or cycloalkyl, or two R groups are linked to form a heterocycline group.

[0055] The term "alkoxycarbonylamino" refers to the -NRC(O)OR group, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl, as defined herein.

[0056] The term "acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclyl-C(O)O-, where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0057] "Aminosulfonyl" is -SO2NR 21 R 22 It refers to the base, R 21 and R 22 However, independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, R 21 and R 22 However, they are optionally linked with nitrogen atoms to form heterocycles or substituted heterocycle groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0058] "Sulfonylamino" is -NR 21 SO2R 22 It refers to the base, R 21 and R 22However, independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, R 21 and R 22 However, they are linked with atoms that optionally bind to them, forming heterocycles or substituted heterocycle groups, such as alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle as defined herein.

[0059] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of 6 to 18 carbon atoms having a monocyclic ring (e.g., present in a phenyl group) or a ring system having multiple fused rings (examples of such aromatic ring systems include naphthyl, anthryl, and indanyl), where the fused rings may or may not be aromatic, provided that the connection points are through atoms of an aromatic ring. This term includes, by example, phenyl and naphthyl. Unless otherwise restricted by the definition of aryl substituents, such aryl groups may be optionally substituted with 1 to 5 substituents selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryloxy, azide, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and trihalomethyl, or 1 to 3 substituents.

[0060] "Aryloxy" refers to an -O-aryl group, where aryl is as defined herein, and includes, for example, phenoxy, naphthoxy, and optionally substituted aryl groups as defined herein.

[0061] "Amino" refers to the -NH2 group.

[0062] The term "substituted amino" refers to a -NRR group, where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclyl, provided that at least one R is not hydrogen.

[0063] The term "azide" refers to the -N3 group.

[0064] "Carboxyl," "carboxy," or "carboxylate" refers to -CO2H or its salts.

[0065] The terms "carboxyl ester" or "carboxyester," or "carboxyalkyl" or "carboxylalkyl" refer to -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-cycloalkenyl, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic groups, as defined herein, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.

[0066] "(carboxyl ester)oxy" or "carbonate" refers to -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-alkenyl, -OC(O)O-substituted alkenyl, -OC(O)O-alkynyl, -OC(O)O-substituted alkynyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O-cycloalkenyl, -OC(O)O-substituted cycloalkyl The terms refer to groups of kenyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocyclic, and -OC(O)O-substituted heterocyclic, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0067] "Cyano" or "nitrile" refers to the -CN group.

[0068] "Cycloalkyl" refers to a cyclic alkyl group of 3 to 10 hydrocarbon atoms having a monocyclic or polycyclic ring, including fused ring systems, crosslinked ring systems, and spiro-ring systems. Suitable examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. Such cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl, or polycyclic structures such as adamantanyl.

[0069] The term "substituted cycloalkyl" refers to a cycloalkyl group having 1 to 5 substituents selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl, or having 1 to 3 substituents.

[0070] "Cycloalkenyl" refers to a non-aromatic cyclic alkyl group having 3 to 10 carbon atoms, having a monocyclic or polycyclic structure and at least one double bond, preferably one to two double bonds.

[0071] The term "substituted cycloalkenyl" refers to a cycloalkenyl group having 1 to 5 substituents selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl, or having 1 to 3 substituents.

[0072] "Cycloalkynyl" refers to a non-aromatic cycloalkyl group consisting of 5 to 10 carbon atoms, having a monocyclic or polycyclic structure and at least one triple bond.

[0073] "Cycloalkoxy" refers to -O-cycloalkyl.

[0074] "Cycloalkenyloxy" refers to -O-cycloalkenyl.

[0075] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodine.

[0076] "Hydroxy" or "hydroxyl" refers to the -OH group.

[0077] A "heteroaryl" refers to an aromatic group consisting of 1 to 15 carbon atoms, for example, 1 to 10 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. Such a heteroaryl group may be monocyclic (e.g., pyridinyl, imidazolyl, or furyl) or may have multiple fused rings in its ring system (e.g., in groups such as indolidinyl, quinolinyl, benzofuran, benzimidazolyl, or benzothienyl), and at least one ring in the ring system is aromatic. To satisfy the valency requirements, any heteroatom in such a heteroaryl ring may or may not be bonded to H or a substituent, for example, an alkyl group or other substituent as described herein. In certain embodiments, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Examples of this term include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless otherwise restricted by the definition of heteroaryl substituents, such heteroaryl groups may be optionally substituted with 1 to 5 substituents, or 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azide, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl, as well as trihalomethyl.

[0078] The term "heteroaralkyl" refers to an alkylene-heteroaryl group, where alkylene and heteroaryl are as defined herein. Examples of this term include pyridylmethyl, pyridylethyl, and indolylmethyl.

[0079] "Heteroaryloxy" refers to -O-heteroaryl.

[0080] "Heterocycle," "heterocyclic," "heterocycloalkyl," and "heterocyclyl" refer to saturated or unsaturated groups having a monocyclic or multiple fused rings, including fused ring systems, bridging ring systems, and spiro-ring systems, and having 3 to 20 ring atoms containing 1 to 10 heteroatoms. These ring atoms are selected from nitrogen, sulfur, or oxygen, and in fused ring systems, one or more of the rings may be cycloalkyl, aryl, or heteroaryl, provided that the connection point is via a non-aromatic ring. In certain embodiments, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide an N-oxide, -S(O)-, or -SO2- moiety. To satisfy valency requirements, any heteroatom in such heterocyclic rings may or may not be bonded to one or more H atoms or one or more substituents, such as alkyl groups or other substituents described herein.

[0081] Examples of heterocyclic and heteroaryl compounds include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indidine, isoindole, indole, dihydroindole, indazole, purine, quinoridine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carborin, phenanthridine, acridine, phenanthroline, isothiazole, and phenazine. Examples include isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinil, thiomorpholinil (also called thiamorpholinil), 1,1-dioxothiomorpholinil, piperidinil, pyrrolidine, and tetrahydrofuranil.

[0082] Unless otherwise restricted by the definition of heterocyclic substituents, such heterocyclic groups may be optionally substituted with 1 to 5 or 1 to 3 substituents selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and condensed heterocyclic groups.

[0083] "Heterocyclyloxy" refers to the -O-heterocyclyl group.

[0084] The term "heterocyclilthio" refers to a heterocyclic -S-group.

[0085] The term "heterocyclene" refers to a diradical group formed from a heterocycle, as defined herein.

[0086] The term "hydroxyamino" refers to the -NHOH group.

[0087] "Nitro" refers to the -NO2 group.

[0088] "Oxo" refers to an atom (=O).

[0089] "Sulfonyl" refers to the groups of -SO2-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-cycloalkenyl, -SO2-substituted cycloalkenyl, -SO2-substituted aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, and -SO2-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Examples of sulfonyls include methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-.

[0090] "Sulfonyloxy" refers to the groups of -OSO2-alkyl, -OSO2-substituted alkyl, -OSO2-alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cycloalkyl, -OSO2-cycloalkenyl, -OSO2-substituted cycloalkenyl, -OSO2-aryl, -OSO2-substituted aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, and -OSO2-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0091] "Sulfate" or "sulfate ester" refers to -O-SO2-OH, -O-SO2-O-alkyl, -O-SO2-O-substituted alkyl, -O-SO2-O-alkenyl, -O-SO2-O-substituted alkenyl, -O-SO2-O-cycloalkyl, -O-SO2-O-substituted cycloalkyl, -O-SO2-O-cycloalkenyl, -O-SO2-O-substituted cycloalkenyl, -O-SO2-O-aryl, -O-SO2-O-substituted aryl, -O-SO2- The terms refer to the groups of O-heteroaryl, -O-SO2-O-substituted heteroaryl, -O-SO2-O-heterocyclic, and -O-SO2-O-substituted heterocyclic groups, while alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic groups are as defined herein.

[0092] The term "aminocarbonyloxy" refers to the -OC(O)NRR group, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocycle, and alkyl, substituted alkyl, aryl, heteroaryl, and heterocycle are as defined herein.

[0093] "Thiol" refers to the -SH group.

[0094] The terms "thioxo" or "thioketo" refer to an atom (=S).

[0095] The terms "alkylthio" or "thioalkoxy" refer to an -S-alkyl group, where alkyl is as defined herein. In certain embodiments, sulfur may be oxidized to -S(O)-. The sulfoxide may exist as one or more stereoisomers.

[0096] The term "substituted thioalkoxy" refers to an -S-substituted alkyl group.

[0097] The term "thioaryloxy" refers to an aryl-S- group, where the aryl group is as defined herein and also includes optionally substituted aryl groups as defined herein.

[0098] The term "thioheteroaryloxy" refers to a heteroaryl-S-group, where the heteroaryl group is as defined herein and includes optionally substituted aryl groups as defined herein.

[0099] The term "thioheterocyclooxy" refers to a heterocyclyl-S-group, where the heterocyclyl group is as defined herein and also includes any optionally substituted heterocyclyl groups as defined herein.

[0100] In addition to the disclosure herein, the term “substitution” may also mean, when used to modify a designated group or radical, that one or more hydrogen atoms of that designated group or radical are replaced, each independently of the others, by the same or different substituents as defined below.

[0101] In addition to the groups disclosed with respect to individual terms herein, substituents for substituting one or more hydrogens on a saturated carbon atom in a particular group or radical (any two hydrogens on a single carbon, =O, =NR) are also available.70 、=N-OR 70 (Can be replaced with =N2 or =S) Unless otherwise specified, -R 60 , halo, =O, -OR 70 , -SR 70 , -NR 80 R 80 , trihalomethyl, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -SO2R 70 , -SO2O - M + , -SO2OR 70 , -OSO2R 70 , -OSO2O - M + , -OSO2OR 70 ,-P(O)(O - )2(M + )2, -P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 ,-C(S)R 70 -C(NR 70 )R 70 ,-C(O)O - M + , -C(O)OR 70 , -C(S)OR 70 -C(O)NR 80 R 80 -C(NR 70 )NR 80 R 80 ,-OC(O)R 70 ,-OC(S)R 70 ,-OC(O)O - M + -OC(O)OR 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 , and -NR 70 C(NR 70 )NR 80 R 80 And R 60 However, each R is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, 70 However, independently, hydrogen or R 60 And each R 80 However, R is independent 70 Alternatively, two R 80’ However, together with the nitrogen atom to which they are bonded, they form 5-membered, 6-membered, or 7-membered heterocycloalkyl groups, which may optionally contain 1 to 4 additional heteroatoms, either the same or different, selected from the group consisting of O, N, and S, where N may have a -H or C1-C3 alkyl substitution, and each M + However, each M is a counterion with a single positive charge. + These are independent, for example, alkaline ions, for example, K + kaNa + Li + ; Ammonium ions, for example, + N(R 60 )4; or alkaline earth ions, for example, [Ca 2+ ] 0.5 [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5(The subscript 0.5 means that one of the counterions for such divalent alkaline earth ions may be the ionized form of the compound of the present invention, the other may be a typical counterion such as a chloride, or the two ionized compounds disclosed herein may function as counterions for such divalent alkaline earth ions, or the doubly ionized compound of the present invention may function as a counterion for such divalent alkaline earth ions.) For example, -NR 80 R 80 This means that it contains -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methylpiperazin-1-yl, and N-morpholinyl.

[0102] In addition to the disclosures herein, the substituents of hydrogen on unsaturated carbon atoms in "substituted" alkenes, alkynes, aryls, and heteroaryl groups are -R unless otherwise specified. 60 Hello, -O - M + , -OR 70 , -SR 70 , -S - M + , -NR 80 R 80 , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R 70 , -SO3 - M + , -SO3R 70 , -OSO2R 70 , -OSO3 - M + -OSO3R 70 , -PO3 -2 (M + )2, -P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 ,-C(S)R 70 -C(NR 70 )R 70 , -CO2 - M + , -CO2R 70, -C(S)OR 70 -C(O)NR 80 R 80 -C(NR 70 )NR 80 R 80 ,-OC(O)R 70 ,-OC(S)R 70 , -OCO2 - M + , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 , and -NR 70 C(NR 70 )NR 80 R 80 And R 60 , R 70 , R 80 , and M + This is as previously defined, except in the case of substituted alkenes or alkynes, the substituent is -O - M + , -OR 70 , -SR 70 , or -S - M + isn't it.

[0103] In addition to the groups disclosed with respect to the individual terms herein, substituents on the hydrogen atom of the nitrogen atom in "substituted" heteroalkyl and cycloheteralkyl groups are, unless otherwise specified, -R 60 , -O - M + , -OR 70 , -SR 70 , -S - M +, -NR 80 R 80 , trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R 70 , -S(O)2O - M + , -S(O)2OR 70 , -OS(O)2R 70 , -OS(O)2O - M + , -OS(O)2OR 70 , -P(O)(O - )2(M + )2, -P(O)(OR 70 )O - M + , -P(O)(OR 70 )(OR 70 ), -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -C(O)OR 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S)R 70 , -OC(O)OR 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 C(O)OR 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 , and -NR 70 C(NR 70 )NR 80 R 80 , wherein R 60 , R 70 , R 80 , and M+ This is as already defined.

[0104] In addition to the disclosures herein, in certain embodiments, the substituted group has one, two, three, or four substituents, one, two, or three substituents, one or two substituents, or one substituent.

[0105] It is understood that polymers obtained by defining substituents having further substituents on themselves (e.g., substituted aryls having substituted aryl groups as substituents, which themselves are substituted with substituted aryl groups and further substituted with substituted aryl groups) for all the substituted groups defined above are not intended to be included herein. In such cases, the maximum number of such substitutions is 3. For example, the sequential substitution of substituted aryl groups specifically intended herein is limited to substituted aryl-(substituted aryl)-substituted aryl.

[0106] Unless otherwise specified, the nomenclature of substituents not explicitly defined herein is achieved by naming the terminal portion of the functional group followed by adjacent functional groups toward the connection point. For example, the substituent "arylalkyloxycarbonyl" refers to the (aryl)-(alkyl)-OC(O)- group.

[0107] With respect to any of the groups disclosed herein that contain one or more substituents, it should be understood that such groups naturally do not contain any substitutions or substitution patterns that are sterically unfeasible and / or synthetically unfeasible. In addition, the compounds of this subject matter include all stereochemical isomers resulting from the substitutions of these compounds.

[0108] The term “pharmaceutically acceptable salt” means a salt that is acceptable for administration to a patient, e.g., a mammal (a salt having a counterion that has mammalian safety acceptable for a given drug regimen). Such salts may be derived from pharmaceutically acceptable inorganic or organic bases, and pharmaceutically acceptable inorganic or organic acids. “pharmaceutically acceptable salt” refers to a pharmaceutically acceptable salt of a compound, the salt being derived from a variety of organic and inorganic counterions well known in the art, including, but not limited to, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, if the molecule contains basic functionality, salts of organic or inorganic acids such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, etc.

[0109] The term "salt" refers to a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation. Where applicable, the salt is pharmaceutically acceptable, although this is not required for salts of intermediate compounds not intended for administration to patients. As an example, salts of the compounds of the present invention include those in which a conjugate base of an inorganic or organic acid is used as the anionic component of the salt, and the compound is protonated by the inorganic or organic acid to form a cation.

[0110] A "solvate" refers to a complex formed by a combination of solvent molecules and solute molecules or ions. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents, though not limited to them, include methanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. When the solvent is water, the solvate formed is a hydrate.

[0111] "Stereoisomers" refer to compounds that have the same atomic bonding but different atomic arrangements in space. Stereoiomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers.

[0112] "Tautomers" refer to alternative molecular forms that differ only in the electron bonding of atoms and / or the position of protons, such as enol-keto and imine-enamine tautomers, or tautomer forms of heteroaryl groups containing the -N=C(H)-NH-ring atomic configuration, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. Those skilled in the art will recognize that other tautomer ring atomic configurations are possible.

[0113] It should be understood that the term “or its salts, solvates, or stereoisomers” is intended to include all permutations of salts, solvates, and stereoisomers, such as solvates of pharmaceutically acceptable salts of stereoisomers of the compound in question.

[0114] "Pharmacologically effective dose" and "therapeutic dose" refer to the amount of a compound sufficient to treat one or more of a specific disorder or disease, or its symptoms, and / or to prevent the onset of that disease or disorder. With respect to tumorigenic proliferative disorders, the pharmaceutically effective dose or therapeutic dose includes, in particular, an amount sufficient to shrink the tumor or reduce the rate of tumor growth.

[0115] The term "patient" refers to both human and non-human subjects, particularly mammals.

[0116] As used herein, the terms “to treat” or “to treat” mean treating or treating a disease or medical condition in a patient, for example, a mammal (in particular human), and include (a) preventing the occurrence of a disease or medical condition, for example, prophylactic treatment of the subject; (b) mitigating a disease or medical condition, for example, eliminating or reversing the disease or medical condition in a patient; (c) suppressing a disease or medical condition, for example, by slowing or halting its progression in a patient; or (d) alleviating the symptoms of a disease or medical condition in a patient.

[0117] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to polymeric forms of amino acids of any length. Unless otherwise indicated, “polypeptide,” “peptide,” and “protein” may include genetically encoded and unencoded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having a modified peptide backbone. The term includes fusion proteins, which include, but are not limited to, fusion proteins having heterologous amino acid sequences, fusions having heterologous and homologous leader sequences, proteins containing at least one N-terminal methionine residue (e.g., for facilitating production in recombinant host cells), immunotagged proteins, and the like. In certain embodiments, the polypeptide is an antibody.

[0118] "Natural amino acid sequence" or "parent amino acid sequence" are used interchangeably herein and refer to the amino acid sequence of the unmodified polypeptide that contains at least one modified amino acid residue.

[0119] The terms "amino acid analog" and "non-natural amino acid" may be used interchangeably and include amino acid-like compounds that are structurally and / or in shape similar to one or more amino acids commonly found in naturally occurring proteins (e.g., Ala or A, Cys or C, Asp or D, Glu or E, Phe or F, Gly or G, His or H, Ile or I, Lys or K, Leu or L, Met or M, Asn or N, Pro or P, Gln or Q, Arg or R, Ser or S, Thr or T, Val or V, Trp or W, Tyr or Y). Amino acid analogs also include natural amino acids with modified side chains or backbone. Amino acid analogs also include amino acid analogs that have the same stereochemistry as the naturally occurring D form, as well as the L form of amino acid analogs. In some cases, amino acid analogs share the backbone structure and / or side chain structure of one or more natural amino acids, the difference being one or more modifying groups in the molecule. Such modifications may include, but are not limited to, substitution of an atom (e.g., N) with a related atom (e.g., S), addition of a group (e.g., methyl or hydroxyl) or an atom (e.g., Cl or Br), deletion of a group, substitution of a covalent bond (e.g., changing a single bond to a double bond), or combinations thereof. For example, amino acid analogs may include α-hydroxy acids and α-amino acids. Examples of amino acid analogs, but are not limited to, sulfoalanine.

[0120] Terms such as “amino acid side chain” or “side chain of amino acids” may be used to refer to substituents attached to the α-carbon of an amino acid residue, including natural amino acids, unnatural amino acids, and amino acid analogs. Amino acid side chains may also include amino acid side chains described herein in the context of modified amino acids and / or conjugates.

[0121] The term "carbohydrate" may be used to refer to monomeric units and / or polymers of monosaccharides, disaccharides, oligosaccharides, and polysaccharides. The term "sugar" may be used to refer to smaller carbohydrates such as monosaccharides and disaccharides. The term "carbohydrate derivative" includes compounds in which one or more functional groups of the carbohydrate of interest are substituted (replaced by any convenient substituent), modified (converted to another group using any convenient chemical), or absent (e.g., removed or replaced by H). A variety of carbohydrates and carbohydrate derivatives are available and may be suitable for use in the compounds and conjugates of this subject.

[0122] The terms “glycoside” or “glycosyl” refer to a sugar molecule or group linked to a part via a glycosidic bond. For example, the part to which a glycoside is linked may be a cleavable linker as described herein. Glycosidic bonds can link a glycoside to another part via various types of bonds, such as, but not limited to, O-glycosidic bonds (O-glycosides), N-glycosidic bonds (glycosylamines), S-glycosidic bonds (thioglycosides), or C-glycosidic bonds (C-glycosides or C-glycosyls). In some cases, glycosides may be cleaved from the part to which they are linked by, for example, chemically mediated hydrolysis or enzymatically mediated hydrolysis.

[0123] The term "antibody" is used in its broadest sense and includes monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and multispecific antibodies (e.g., bispecific antibodies), humanized antibodies, single-chain antibodies, chimeric antibodies, and antibody fragments (e.g., Fab fragments). Antibodies can bind to target antigens. (Janeway, C., Travers, P., Walport, M., Shlomchik (2001) Immuno Biology, 5th Ed., Garland Publishing, New York). Target antigens may have one or more binding sites, also called epitopes, that are recognized by complementarity-determining regions (CDRs) formed by one or more variable regions of the antibody.

[0124] The term "natural antibody" refers to an antibody in which the heavy and light chains have been produced and which is paired by the immune system of a multicellular organism. The spleen, lymph nodes, bone marrow, and serum are examples of tissues that produce natural antibodies. For example, antibodies produced by antibody-producing cells isolated from a first animal immunized with an antigen are natural antibodies.

[0125] The terms "humanized antibody" or "humanized immunoglobulin" refer to non-human (e.g., mouse or rabbit) antibodies that contain one or more amino acids (e.g., in the framework region, constant region, or CDR) that are substituted with correspondingly positioned amino acids from human antibodies. Generally, humanized antibodies produce a reduced immune response in the human host compared to the non-humanized version of the same antibody. Antibodies can be humanized using various techniques known in the art, including, for example, CDR grafting (EP239,400, PCT Publication No. WO91 / 09967, U.S. Patent Nos. 5,225,539, 5,530,101, and 5,585,089), veneering or resurfacing (EP592,106, EP519,596, Padlan, Molecular Immunology 28(4 / 5):489-498 (1991), Studnicka et al., Protein Engineering 7(6):805-814 (1994), Roguska et al., PNAS 91:969-973 (1994)), and chain shuffling (U.S. Patent No. 5,565,332). In certain embodiments, framework substitutions are identified by modeling the interaction between CDRs and framework residues to identify framework residues important for antigen binding and sequence comparison, and to identify abnormal framework residues at specific positions (see, for example, U.S. Patent No. 5,585,089, Riechmann et al., Nature 332:323 (1988)). Additional methods for humanizing antibodies intended for use in the present invention are described in U.S. Patents No. 5,750,078, No. 5,502,167, No. 5,705,154, No. 5,770,403, No. 5,698,417, No. 5,693,493, No. 5,558,864, No. 4,935,496, and No. 4,816,567, as well as PCT Publications WO98 / 45331 and WO98 / 45332. In certain embodiments, the rabbit antibody of the subject may be humanized according to the methods described in US2004 / 0086979 and US2005 / 0033031.Therefore, the antibodies described above can be humanized using methods well known in the art.

[0126] The term "chimeric antibody" refers to an antibody typically constructed through genetic engineering, in which the light and heavy chain genes are derived from the variable and constant regions of antibodies belonging to different species. For example, the variable segment of a gene from a mouse monoclonal antibody may bind to human constant segments such as gamma 1 and gamma 3. An example of a therapeutic chimeric antibody is a hybrid protein composed of a variable domain or antigen-binding domain derived from a mouse antibody and a constant domain or effector domain derived from a human antibody, although domains from other mammalian species may also be used.

[0127] The immunoglobulin light chain or heavy chain variable region of an immunoglobulin polypeptide consists of a framework region (FR) interrupted by three hypervariable regions, also called "complementarity-determining regions" or "CDRs." The extent of the framework region and CDRs is defined (see "Sequences of Proteins of Immunological Interest," E. Kabat et al., USD Department of Health and Human Services, 1991). The antibody framework region, which is the combined framework region of its constituent light and heavy chains, helps to locate and align the CDRs. The CDRs primarily contribute to the binding of the antigen to the epitope.

[0128] The "parent Ig polypeptide" is a polypeptide comprising an amino acid sequence lacking the aldehyde-tagged constant region described herein. The parent polypeptide may contain a natural sequence constant region, or it may contain a constant region having existing amino acid sequence modifications (such as additions, deletions, and / or substitutions).

[0129] As used herein, the term “isolated” means describing a compound of interest that is in an environment different from that in which it naturally occurs. “Isolated” means including a compound in a sample in which the compound of interest is substantially concentrated and / or partially or substantially purified.

[0130] As used herein, the term “substantially purified” means a compound that has been removed from its natural environment and contains at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or more than 98% of other components associated with its natural origin.

[0131] The term "physiological conditions" means those conditions that are compatible with living cells, such as temperature, pH, salinity, and other primarily aqueous conditions that are compatible with living cells.

[0132] A “reactive partner” means a molecule or molecular part that specifically reacts with another reactive partner to produce a reaction product. An exemplary reactive partner comprises cysteine ​​or serine of a sulfatase motif and formylglycine-producing enzyme (FGE), which react to form a reaction product of a converted aldehyde tag containing formylglycine (fGly) instead of cysteine ​​or serine in the motif. Another exemplary reactive partner comprises an “aldehyde-reactive reactive partner” comprising the aldehyde (e.g., a reactive aldehyde group) of the fGly residue of the converted aldehyde tag, as well as an aldehyde-reactive group and the moiety of interest, which react to form a reaction product of a modified aldehyde-tagged polypeptide having the moiety of interest conjugated to the modified polypeptide via the fGly residue.

[0133] The "N-terminus" refers to the terminal amino acid residue of a polypeptide that has a free amine group, and the amine group in the non-N-terminal amino acid residue usually forms part of the covalent backbone of the polypeptide.

[0134] The "C-terminus" refers to the terminal amino acid residue of a polypeptide that has a free carboxyl group, and the carboxyl groups in non-C-terminal amino acid residues usually form part of the covalent backbone of the polypeptide.

[0135] When used in reference to polypeptides or the amino acid sequences of polypeptides, the term "internal region" refers to the region of the polypeptide that is neither N-terminus nor C-terminus.

[0136] Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described and is therefore naturally subject to change. Furthermore, since the scope of the present invention is limited only by the appended claims, it should also be understood that the terms used herein are merely for describing specific embodiments and are not intended to limit them.

[0137] Where a range of values ​​is provided, unless the context explicitly indicates otherwise, each intervening value up to one-tenth of the lower limit between the upper and lower limits of that range, and any other stated or intervening values ​​within the stated range, are understood to be included within the present invention. The upper and lower limits of these smaller ranges may be independently included within the smaller ranges and, according to any specifically excluded boundaries within the stated range, are also included in this disclosure. Where a stated range includes one or both of the boundaries, ranges excluding either or both of the boundaries that they include are also included in the present invention.

[0138] For clarity, it is understood that certain features of the Invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the Disclosure described in the context of a single embodiment may also be provided separately or in any preferred subcombination. All combinations of embodiments relating to the Invention are specifically encompassed by the Disclosure and are disclosed herein as if every possible combination were individually and explicitly disclosed to the extent that such combinations encompass the subject matter of the Invention, which is, for example, a stable compound (i.e., a compound that can be prepared, isolated, characterized, and tested for biological activity). In addition, all subcombinations of various embodiments and their elements (e.g., elements of chemical groups enumerated in embodiments describing such variables) are also specifically encompassed by the Disclosure and are disclosed herein as if every possible such subcombination were individually and explicitly disclosed herein.

[0139] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs. Any methods and materials similar to or equivalent to those described herein may also be used in the implementation or testing of the present invention, but preferred methods and materials are described herein. All publications referenced herein are incorporated herein by reference to disclose and explain methods and / or materials relating to the cited publications.

[0140] It should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple subjects unless the context explicitly indicates otherwise. It should also be noted that claims may be written to exclude any optional elements. Therefore, this statement is intended to serve as an antecedent for the use of exclusive terms such as "simply" and "only," or for the use of "negative" limitations relating to the description of elements of the claims.

[0141] For clarity, it is understood that certain features of the present invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the present disclosure described in the context of a single embodiment may also be provided separately or in any preferred subcombination.

[0142] The publications discussed herein were made available solely for their disclosure prior to the filing date of this application. Nothing herein should be construed as acknowledging that the present invention does not have prior rights to such disclosure by prior art. Furthermore, the dates of the publications provided may differ from the actual publication dates which may need to be independently verified. [Modes for carrying out the invention]

[0143] This disclosure provides antibody-drug conjugate (ADC) structures comprising camptothecin or a camptothecin derivative linked to a polypeptide (e.g., an antibody) via a linker. This disclosure also includes compounds and methods for generating such conjugates, as well as methods for using the conjugates.

[0144] Antibody-drug conjugates This disclosure provides conjugates, such as antibody-drug conjugates (ADCs). “Conjugate” means a polypeptide (e.g., an antibody) covalently bound to one or more other parts (e.g., a drug or active agent). For example, an antibody-drug conjugate according to this disclosure comprises one or more drugs or active agents covalently bound to an antibody. In certain embodiments, the polypeptide (e.g., an antibody) and one or more drugs or active agents are linked to one or more functional groups and covalent bonds. For example, one or more functional groups and covalent bonds may include cleavable linkers as described herein.

[0145] In certain embodiments, the conjugate is a polypeptide conjugate comprising a polypeptide (e.g., an antibody) conjugated to one or more other parts. In certain embodiments, the one or more parts conjugated to the polypeptide may, independently and without limitation, be any of various parts for a variety of purposes, such as a drug, an active agent, a detectable label, a water-soluble polymer, or a part for immobilizing the polypeptide onto a membrane or surface. In certain embodiments, the conjugate is a drug conjugate, where the polypeptide is an antibody, and therefore provides an antibody-drug conjugate. For example, the conjugate may be a drug conjugate in which the polypeptide is conjugated to one or more drugs or active agents. In certain embodiments, the drug or active agent is camptothecin or a camptothecin derivative. Various types of camptothecin or camptothecin derivatives may be used in the conjugate, as described in more detail below.

[0146] One or more drugs or active agents can be conjugated to a polypeptide (e.g., an antibody) at any desired site of the polypeptide. Therefore, this disclosure provides polypeptides having a drug or active agent conjugated, for example, at or near the C-terminus of the polypeptide. Other examples include polypeptides having a drug or active agent conjugated at or near the N-terminus of the polypeptide. Examples also include polypeptides having a drug or active agent conjugated at a site between the C-terminus and N-terminus of the polypeptide (e.g., an internal site of the polypeptide). The above combinations are also possible when the polypeptide is conjugated with two or more drugs or active agents.

[0147] In certain embodiments, the conjugates of the Disclosure comprise one or more drugs or active agents conjugated to amino acid residues of a polypeptide at the α-carbon of an amino acid residue. In other words, the conjugate comprises a polypeptide in which the side chains of one or more amino acid residues in the polypeptide are modified and connected to one or more drugs or active agents (e.g., via a linker as described herein). For example, the conjugate comprises a polypeptide in which the α-carbon of one or more amino acid residues in the polypeptide is modified and connected to one or more drugs or active agents (e.g., via a linker as described herein).

[0148] Embodiments of the present disclosure include a conjugate in which a polypeptide is conjugated to one or more parts, for example, two, three, four, five, six, seven, eight, nine, or ten or more parts. A part can be conjugated to a polypeptide at one or more sites in the polypeptide. For example, one or more parts can be conjugated to a single amino acid residue of the polypeptide. In some cases, one part is conjugated to an amino acid residue of the polypeptide. In other embodiments, two parts can be conjugated to the same amino acid residue of the polypeptide. In other embodiments, a first part is conjugated to a first amino acid residue of the polypeptide, and a second part is conjugated to a second amino acid residue of the polypeptide. The above combinations are also possible, for example, the polypeptide is conjugated to a first amino acid residue by a first part and to a second amino acid residue by two other parts. Other combinations are also possible, for example, polypeptides in which the first and second portions are conjugated to a first amino acid residue, and the third and fourth portions are conjugated to a second amino acid residue. In some cases, two or more amino acid residues in the polypeptide are each conjugated to a pair of portions (i.e., two portions), and each pair of portions is conjugated to the polypeptide via a branched linker as described herein. In other cases, one amino acid residue in the polypeptide is conjugated to a pair of portions via a branched linker as described herein.

[0149] One or more amino acid residues of a polypeptide conjugated to one or more parts may be naturally occurring amino acids, unnatural amino acids, or a combination thereof. For example, the conjugate may comprise one or more drugs or active agents conjugated to naturally occurring amino acid residues of the polypeptide. In other cases, the conjugate may comprise one or more drugs or active agents conjugated to unnatural amino acid residues of the polypeptide. One or more drugs or active agents may be conjugated to the polypeptide with a single natural or unnatural amino acid residue, as described above. One or more natural or unnatural amino acid residues in the polypeptide may be conjugated to one or more parts as described herein. For example, two (or more) amino acid residues (e.g., natural or unnatural amino acid residues) in the polypeptide may each be conjugated to one or two parts, resulting in multiple sites in the polypeptide being conjugated to the desired parts.

[0150] In certain embodiments, a polypeptide (e.g., an antibody) and a moiety of interest (e.g., a drug or active agent) are conjugated via a conjugation moiety. For example, the polypeptide and the moiety of interest may each be bound (e.g., covalently) to the conjugation moiety, and thus indirectly linked together via the conjugation moiety. In some cases, the conjugation moiety includes a hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl compound, or a derivative of a hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl compound. For example, a general scheme for coupling a moiety of interest to a polypeptide via a hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugation moiety is shown in the general reaction scheme below. The hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugated moieties are also referred to herein as the hydrazino-iso-Pictet-Spengler (HIPS) conjugated moiety and the aza-hydrazino-iso-Pictet-Spengler (aza-HIPS) conjugated moiety, respectively. [ka]

[0151] In the above reaction scheme, R comprises a target portion (e.g., a drug or active agent) to be conjugated to the polypeptide (e.g., conjugated to the polypeptide via a cleavable linker as described herein). As shown in the above reaction scheme, a polypeptide comprising a 2-formylglycine residue (fGly) is reacted with a drug or active agent modified to include a conjugation moiety (e.g., a hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugation moiety) to produce a polypeptide conjugate ligated to the conjugation moiety, thereby ligating the drug or active agent to the polypeptide via the conjugation moiety.

[0152] As described herein, this part may be any of the following: a variety of parts, for example, a chemical entity, for example, a detectable label, or a drug or active agent. R' and R'' may each independently be any desired substituent, for example, but not limited to hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. Z is CR 21 , NR 22 It may be N, O, or S, in the formula, R 21 and R 22 Each of these substituents is independently selected from among the substituents described above for R' and R''.

[0153] Other hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl coupling moieties are also possible, as shown in the conjugates and compounds described herein. For example, hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl coupling moieties may be connected to a linker (e.g., covalently). Thus, embodiments of the present disclosure include hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugate moieties connected to a drug or active agent via a linker. Various embodiments of linkers capable of coupling hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugate moieties to a drug or active agent are described in detail herein. For example, in some cases, the linker is a cleavable linker, e.g., a cleavable linker as described herein.

[0154] In some cases, the hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugate moiety may be connected (e.g., covalently) to two or more linkers. Therefore, embodiments of the present disclosure include a hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugate moiety connected to two or more drugs or active agents via corresponding linkers. Thus, the conjugate of the present disclosure may include two or more linkers, each linker connecting the corresponding drug or active agent to the hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugate moiety. Therefore, the hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugate moiety and the two or more linkers can be considered as a “branched linker,” where the hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugate moiety is connected to two of many “branches,” each branch containing a linker connected to a drug or active agent.

[0155] In certain embodiments, the polypeptide may be conjugated to one or more moieties of interest, and one or more amino acid residues of the polypeptide are modified before conjugation to the moieties of interest. Modification of one or more amino acid residues of the polypeptide may produce a polypeptide containing one or more reactive groups suitable for conjugation to the moieties of interest. In some cases, the polypeptide may contain one or more modified amino acid residues and provide one or more reactive groups suitable for conjugation to the moieties of interest (e.g., one or more moieties containing a conjugation moiety such as the hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugated moieties described above). For example, the amino acids of the polypeptide may be modified to contain a reactive aldehyde group (e.g., a reactive aldehyde). Reactive aldehydes may be included in “aldehyde tags” or “ald-tags,” which, as used herein, refer to amino acid sequences derived from a sulfatase motif (e.g., L(C / S)TPSR) that have been converted by the action of formylglycinase (FGE) to contain a 2-formylglycine residue (referred to herein as “fGly”). The fGly residue produced by FGE may also be referred to as “formylglycine.” In other words, the term “aldehyde tag” is used herein to refer to an amino acid sequence containing a “converted” sulfatase motif (i.e., a sulfatase motif in which a cysteine ​​or serine residue has been converted to fGly by the action of FGE, e.g., L(fGly)TPSR). A converted sulfatase motif can be generated from an amino acid sequence containing an "unconverted" sulfatase motif (i.e., a sulfatase motif in which a cysteine ​​or serine residue has not been converted to FGly by FGE, but is capable of being converted, e.g., an unconverted sulfatase motif having the sequence L(C / S)TPSR). When used in the context of the action of formylglycine-producing enzymes (FGE) on a sulfatase motif, "conversion" refers to the biochemical modification of a cysteine ​​or serine residue to a formylglycine (fGly) residue (e.g., Cys to fGly, or Ser to fGly) in the sulfatase motif.Further embodiments of aldehyde tags in site-directed protein modification and their use are described in U.S. Patents No. 7,985,783 and No. 8,729,232, the respective disclosures of which are incorporated herein by reference.

[0156] In some cases, to generate a conjugate, a polypeptide containing an fGly residue may be conjugated to the desired moiety by a reaction between fGly and a compound (for example, a compound containing a hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugated moiety, as described above). For example, a fGly-containing polypeptide may be contacted with a drug containing a reactive partner under conditions suitable for providing drug conjugation to the polypeptide. In some cases, the drug containing the reactive partner may contain the hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugated moiety described above. For example, a drug or active agent may be modified to contain a hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugated moiety. In some cases, the drug or active agent is linked to hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl, covalently bound to hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl, for example, via a linker (e.g., a linker described in detail herein).

[0157] In certain embodiments, the conjugates of the present disclosure comprise a polypeptide (e.g., an antibody) having at least one amino acid residue conjugated to one or more moieties of interest (e.g., a drug or active agent). To construct a conjugate, the amino acid residues of the polypeptide may be modified and then coupled to one or more drugs or active agents conjugated to the hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugated moieties described above. In certain embodiments, the amino acid residues of the polypeptide (e.g., an antibody) are cysteine ​​or serine residues modified to fGly residues as described above. In certain embodiments, the modified amino acid residues (e.g., fGly residues) conjugate to the drugs or active agents containing the hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugated moieties described above, providing the conjugates of the present disclosure in which one or more drugs or active agents are conjugated to the polypeptide via the hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugated moieties. As used herein, the term 'fGly' refers to a modified amino acid residue of a polypeptide (e.g., an antibody) that is coupled to a moiety of interest (e.g., a drug or active agent).

[0158] In certain embodiments, the conjugate comprises a polypeptide (e.g., an antibody) having at least one amino acid residue that is conjugated to a linker described herein, which is then conjugated to one or more drugs or active agents. For example, the conjugate may comprise a polypeptide (e.g., an antibody) having at least one amino acid residue (fGly') that is conjugated to one or more portions of interest (e.g., one or more drugs or active agents) as described above.

[0159] A part of this disclosure is a conjugate of formula (I), [ka] During the ceremony, Z, CR 10 or N, R 7However, selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, R 8 and R 9 However, each is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or R 8 and R 9 However, they are optionally linked in a ring, forming a 5- or 6-membered heterocycline. Each R 10 However, independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, W is a polypeptide, L is R 1 , R 2 , R 3 , R 4 , R 5 or R 6 This is a linker connected to the compound of formula (II), [ka] R 1 and R 2However, each is independently selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or R 1 and R 2 However, they are optionally linked cyclically to form a 5 or 6-membered cycloalkyl or heterocyclyl ring, R 3 and R 4 However, each is independently selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or R 3 and R 4 However, they are optionally linked cyclically to form a 5 or 6-membered cycloalkyl or heterocyclyl ring, R 5 However, selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, R 6 However, OH and OC(O)R 11 Selected from, R 11 However, selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, at least one R 10 However, it includes a conjugate of formula (I) which is optionally linked to a second compound of formula (II).

[0160] The substituents associated with the conjugate of formula (I) are described in more detail below.

[0161] In certain embodiments, Z is CR 10 Or N. In certain embodiments, Z is CR 10 In certain embodiments, Z is N.

[0162] In a particular embodiment, R 7 R is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, R 7 is hydrogen. In a particular embodiment, R 7 is an alkyl or substituted alkyl, for example, C 1-6 Alkyl or C 1-6 Substituting alkyl, or C 1-4 Alkyl or C 1-4 Substituting alkyl, or C 1-3 Alkyl or C 1-3 It is a substituted alkyl. In certain embodiments, R 7 is methyl. In certain embodiments, R 7 This refers to an alkenyl or a substituted alkenyl, for example, C 2-6 Alkenil or C 2-6 Substituting alkenyl, or C 2-4 Alkenil or C 2-4 Substituting alkenyl, or C 2-3 Alkenil or C 2-3 It is a substituted alkenyl. In certain embodiments, R 7 This refers to alkynyl or substituted alkynyl, for example, C 2-6 Alkinyl or C 2-6 Substituting alkynyl, or C 2-4 Alkenil or C 2-4 Substituting alkenyl, or C 2-3 Alkenil or C 2-3It is a substituted alkenyl. In certain embodiments, R 7 is an aryl or substituted aryl, for example, C 5-8 Aryl or C 5-8 Substituting aryls, for example, C5 aryls or C5-substituted aryls, or C6 aryls or C6-substituted aryls. In certain embodiments, R 7 This refers to heteroaryl or substituted heteroaryl, for example, C 5-8 Heteroaryl or C 5-8 Substituting heteroaryls, for example, C5 heteroaryls or C5-substituted heteroaryls, or C6 heteroaryls or C6-substituted heteroaryls. In certain embodiments, R 7 This refers to cycloalkyl or substituted cycloalkyl, for example, C 3-8 Cycloalkyl or C 3-8 Substitutive cycloalkyls, for example, C 3-6 Cycloalkyl or C 3-6 Substituted cycloalkyl, or C 3-5 Cycloalkyl or C 3-5 It is a substituted cycloalkyl. In certain embodiments, R 7 This refers to heterocyclines or substituted heterocyclines, for example, C 3-8 Heterocycline or C 3-8 Substituting heterocyclyls, e.g., C 3-6 Heterocycline or C 3-6 Substituted heterocyclyl, or C 3-5 Heterocycline or C 3-5 It is a substituted heterocyclyl.

[0163] In a particular embodiment, R 8 and R 9Each is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or R 8 and R 9 However, they are optionally linked together in a ring, forming a 5- or 6-membered heterocycline.

[0164] In a specific method of operation, each R 8 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, R 8 is hydrogen. In a particular embodiment, R 8 is an alkyl or substituted alkyl, for example, C 1-6 Alkyl or C 1-6 Substituting alkyl, or C 1-4 Alkyl or C 1-4 Substituting alkyl, or C 1-3 Alkyl or C 1-3 It is a substituted alkyl. In certain embodiments, R 8 is methyl. In certain embodiments, R 8 This refers to an alkenyl or a substituted alkenyl, for example, C 2-6 Alkenil or C 2-6 Substituting alkenyl, or C 2-4 Alkenil or C 2-4 Substituting alkenyl, or C 2-3Alkenil or C 2-3 It is a substituted alkenyl. In certain embodiments, R 8 is an alkynyl or substituted alkynyl. In certain embodiments, R 8 is an alkoxy or substituted alkoxy. In certain embodiments, R 8 is an amino acid or a substituted amino acid. In certain embodiments, R 8 is a carboxyl or carboxyl ester. In certain embodiments, R 8 is an acyl or acyloxy. In certain embodiments, R 8 is acylamino or aminoacyl. In certain embodiments, R 8 is an alkylamide or a substituted alkylamide. In certain embodiments, R 8 is a sulfonyl. In certain embodiments, R 8 is a thioalkoxy or a substituted thioalkoxy. In certain embodiments, R 8 is an aryl or substituted aryl, for example, C 5-8 Aryl or C 5-8 Substituting aryls, for example, C5 aryls or C5-substituted aryls, or C6 aryls or C6-substituted aryls. In certain embodiments, R 8 This refers to heteroaryl or substituted heteroaryl, for example, C 5-8 Heteroaryl or C 5-8 Substituting heteroaryls, for example, C5 heteroaryls or C5-substituted heteroaryls, or C6 heteroaryls or C6-substituted heteroaryls. In certain embodiments, R 8 This refers to cycloalkyl or substituted cycloalkyl, for example, C 3-8 Cycloalkyl or C 3-8 Substitutive cycloalkyls, for example, C 3-6 Cycloalkyl or C 3-6 Substituted cycloalkyl, or C 3-5 Cycloalkyl or C 3-5 It is a substituted cycloalkyl. In certain embodiments, R 8 This refers to heterocyclines or substituted heterocyclines, for example, C 3-6Heterocycline or C 3-6 Substituted heterocyclyl, or C 3-5 Heterocycline or C 3-5 It is a substituted heterocyclyl.

[0165] In a specific method of operation, each R 9 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, R 9 is hydrogen. In a particular embodiment, R 9 is an alkyl or substituted alkyl, for example, C 1-6 Alkyl or C 1-6 Substituting alkyl, or C 1-4 Alkyl or C 1-4 Substituting alkyl, or C 1-3 Alkyl or C 1-3 It is a substituted alkyl. In certain embodiments, R 9 is methyl. In certain embodiments, R 9 This refers to an alkenyl or a substituted alkenyl, for example, C 2-6 Alkenil or C 2-6 Substituting alkenyl, or C 2-4 Alkenil or C 2-4 Substituting alkenyl, or C 2-3 Alkenil or C 2-3 It is a substituted alkenyl. In certain embodiments, R 9 is an alkynyl or substituted alkynyl. In certain embodiments, R 9 is an alkoxy or substituted alkoxy. In certain embodiments, R 9 is an amino acid or a substituted amino acid. In certain embodiments, R 9is a carboxyl or carboxyl ester. In certain embodiments, R 9 is an acyl or acyloxy. In certain embodiments, R 9 is acylamino or aminoacyl. In certain embodiments, R 9 is an alkylamide or a substituted alkylamide. In certain embodiments, R 9 is a sulfonyl. In certain embodiments, R 9 is a thioalkoxy or a substituted thioalkoxy. In certain embodiments, R 9 is an aryl or substituted aryl, for example, C 5-8 Aryl or C 5-8 Substituting aryls, for example, C5 aryls or C5-substituted aryls, or C6 aryls or C6-substituted aryls. In certain embodiments, R 9 This refers to heteroaryl or substituted heteroaryl, for example, C 5-8 Heteroaryl or C 5-8 Substituting heteroaryls, for example, C5 heteroaryls or C5-substituted heteroaryls, or C6 heteroaryls or C6-substituted heteroaryls. In certain embodiments, R 9 This refers to cycloalkyl or substituted cycloalkyl, for example, C 3-8 Cycloalkyl or C 3-8 Substitutive cycloalkyls, for example, C 3-6 Cycloalkyl or C 3-6 Substituted cycloalkyl, or C 3-5 Cycloalkyl or C 3-5 It is a substituted cycloalkyl. In certain embodiments, R 9 This refers to heterocyclines or substituted heterocyclines, for example, C 3-8 Heterocycline or C 3-8 Substituting heterocyclyls, e.g., C 3-6 Heterocycline or C 3-6 Substituted heterocyclyl, or C 3-5 Heterocycline or C 3-5 It is a substituted heterocyclyl.

[0166] In a particular embodiment, R8 and R 9 These are optionally linked in a ring to form a 5- or 6-membered heterocycline. In certain embodiments, R 8 and R 9 These are linked in a ring shape, forming a 5- or 6-membered heterocycline. In certain embodiments, R 8 and R 9 These are linked in a ring, forming a 5-membered heterocycline. In certain embodiments, R 8 and R 9 These are linked together in a ring, forming a six-membered heterocycline.

[0167] In a specific method of operation, each R 10 These are independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0168] Each R 10 Various possibilities regarding this are described in more detail below. In certain embodiments, R 10 is hydrogen. In a particular embodiment, each R 10 is hydrogen. In a particular embodiment, R 10 is a halogen such as F, Cl, Br, or I. In certain embodiments, R 10 is F. In a particular embodiment, R 10 is Cl. In certain embodiments, R 10 is Br. In certain embodiments, R 10 is I. In a particular embodiment, R 10 is an alkyl or substituted alkyl, for example, C 1-6 Alkyl or C 1-6 Substituting alkyl, or C 1-4Alkyl or C 1-4 Substituting alkyl, or C 1-3 Alkyl or C 1-3 It is a substituted alkyl. In certain embodiments, R 10 is methyl. In certain embodiments, R 10 This refers to an alkenyl or a substituted alkenyl, for example, C 2-6 Alkenil or C 2-6 Substituting alkenyl, or C 2-4 Alkenil or C 2-4 Substituting alkenyl, or C 2-3 Alkenil or C 2-3 It is a substituted alkenyl. In certain embodiments, R 10 is an alkynyl or substituted alkynyl. In certain embodiments, R 10 is an alkoxy or substituted alkoxy. In certain embodiments, R 10 is an amino acid or a substituted amino acid. In certain embodiments, R 10 is a carboxyl or carboxyl ester. In certain embodiments, R 10 is an acyl or acyloxy. In certain embodiments, R 10 is acylamino or aminoacyl. In certain embodiments, R 10 is an alkylamide or a substituted alkylamide. In certain embodiments, R 10 is a sulfonyl. In certain embodiments, R 10 is a thioalkoxy or a substituted thioalkoxy. In certain embodiments, R 10 is an aryl or substituted aryl, for example, C 5-8 Aryl or C 5-8 Substituting aryls, for example, C5 aryls or C5-substituted aryls, or C6 aryls or C6-substituted aryls (for example, phenyl or substituted phenyl). In certain embodiments, R 10 This refers to heteroaryl or substituted heteroaryl, for example, C 5-8 Heteroaryl or C 5-8Substituting heteroaryls, for example, C5 heteroaryls or C5-substituted heteroaryls, or C6 heteroaryls or C6-substituted heteroaryls. In certain embodiments, R 10 This refers to cycloalkyl or substituted cycloalkyl, for example, C 3-8 Cycloalkyl or C 3-8 Substitutive cycloalkyls, for example, C 3-6 Cycloalkyl or C 3-6 Substituted cycloalkyl, or C 3-5 Cycloalkyl or C 3-5 It is a substituted cycloalkyl. In certain embodiments, R 10 This refers to heterocyclines or substituted heterocyclines, for example, C 3-8 Heterocycline or C 3-8 Substituting heterocyclyls, e.g., C 3-6 Heterocycline or C 3-6 Substituted heterocyclyl, or C 3-5 Heterocycline or C 3-5 It is a substituted heterocyclyl.

[0169] In certain embodiments, W is a polypeptide. For example, W may be an antibody. In certain embodiments, W comprises one or more fGly' residues described herein. In certain embodiments, the polypeptide is connected to the rest of the conjugate via the fGly' residues described herein. Further descriptions of polypeptides and antibodies that find use in the conjugate of this subject can be found in the disclosure herein.

[0170] In certain embodiments, L is R 1 , R 2 , R 3 , R 4 , R 5 or R 6 This is a linker connected to the compound of formula (II). Suitable linkers for L are described in more detail below.

[0171] In certain embodiments, the conjugate of formula (I) comprises a linker L. The linker can be used to conjugate one or more moieties of interest (e.g., a drug or active agent) to one or more polypeptides via the conjugated moiety. The linker can be conjugated (e.g., covalently) to the conjugated moiety at any convenient position (e.g., as described herein). For example, the linker can be attached to a hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugated moiety to a drug (e.g., camptothecin or a camptothecin derivative). The linker (and therefore the drug) can be conjugated to a polypeptide, e.g., an antibody, using the hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugated moiety. For example, the linker (and therefore the drug) can be conjugated to a modified amino acid residue of a polypeptide, e.g., an fGly residue (reside) of an antibody, as described herein.

[0172] For example, as shown in formula (I) above, L is connected to W via a conjugated moiety, and therefore W indirectly binds to linker L via a conjugated moiety. As described above, W is a polypeptide (e.g., an antibody), and therefore L is connected to the polypeptide (e.g., an antibody) via a conjugated moiety, and for example, linker L indirectly binds to the polypeptide (e.g., an antibody) via a conjugated moiety (via the hydrazinyl-indol or hydrazinyl-pyrrolo-pyridinyl conjugated moiety as described herein).

[0173] Any suitable linker may be used for linker L in the conjugate and compound of this subject. In certain embodiments, linker L may include a group selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acylamino, alkylamide, substituted alkylamide, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, linker L may include alkyl or substituted alkyl groups. In certain embodiments, linker L may include alkenyl or substituted alkenyl groups. In certain embodiments, linker L may include alkynyl or substituted alkynyl groups. In certain embodiments, linker L may include alkoxy or substituted alkoxy groups. In certain embodiments, linker L may include amino or substituted amino groups. In certain embodiments, linker L may include carboxyl or carboxyl ester groups. In certain embodiments, linker L may contain an acylamino group. In certain embodiments, linker L may contain an alkylamide or substituted alkylamide group. In certain embodiments, linker L may contain an aryl or substituted aryl group. In certain embodiments, linker L may contain a heteroaryl or substituted heteroaryl group. In certain embodiments, linker L may contain a cycloalkyl or substituted cycloalkyl group. In certain embodiments, linker L may contain a heterocyclyl or substituted heterocyclyl group.

[0174] In certain embodiments, linker L may include a polymer. For example, the polymer may include polyalkylene glycols and their derivatives, including polyethylene glycol, methoxypolyethylene glycol, polyethylene glycol homopolymer, polypropylene glycol homopolymer, copolymer of ethylene glycol and propylene glycol (e.g., the homopolymer and copolymer are unsubstituted or substituted at one end with an alkyl group), polyvinyl alcohol, polyvinyl ethyl ether, polyvinylpyrrolidone, and combinations thereof. In certain embodiments, the polymer is polyalkylene glycol. In certain embodiments, the polymer is polyethylene glycol. Other linkers are also possible, as shown in the conjugates and compounds described in more detail below.

[0175] In some embodiments, L is expressed by the following formula -(L 1 ) a -(L 2 ) b -(L 3 ) c -(L 4 ) d -(L 5 ) e -(L 6 ) f - The linker described by (for example, the first linker), In the formula, L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 Each of them is an independent linker subunit, and a, b, c, d, e, and f are each independently 0 or 1, and the sum of a, b, c, d, e, and f is between 1 and 6.

[0176] In certain embodiments, the sum of a, b, c, d, e, and f is 1. In certain embodiments, the sum of a, b, c, d, e, and f is 2. In certain embodiments, the sum of a, b, c, d, e, and f is 3. In certain embodiments, the sum of a, b, c, d, e, and f is 4. In certain embodiments, the sum of a, b, c, d, e, and f is 5. In certain embodiments, the sum of a, b, c, d, e, and f is 6. In certain embodiments, a, b, c, d, e, and f are each 1. In certain embodiments, a, b, c, d, and e are each 1, and f is 0. In certain embodiments, a, b, c, and d are each 1, and e and f are each 0. In certain embodiments, a, b, and c are each 1, and d, e, and f are each 0. In certain embodiments, a and b are each 1, and c, d, e, and f are each 0.

[0177] In a particular embodiment, linker subunit L 1 This connects to a hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugate (for example, as shown in formula (I) above). In certain embodiments, linker subunit L 2 If present, it connects to camptothecin or a camptothecin derivative. In certain embodiments, linker subunit L 3 If present, it connects to camptothecin or a camptothecin derivative. In certain embodiments, linker subunit L 4 If present, it connects to camptothecin or a camptothecin derivative. In certain embodiments, linker subunit L 5 If present, it connects to camptothecin or a camptothecin derivative. In certain embodiments, linker subunit L 6 If present, it connects to camptothecin or a camptothecin derivative.

[0178] Any suitable linker subunit can be used for linker L. The linker subunit of interest may include, but are not limited to, polyethylene glycol, polyethylene and polyacrylates, amino acid residues, carbohydrate polymers or their carbohydrate residues and derivatives, polynucleotides, alkyl groups, aryl groups, heterocyclic groups, and other polymer units, combinations thereof, as well as substituted versions thereof. In some embodiments, L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 Each of (if present) comprises one or more groups independently selected from polyethylene glycol, modified polyethylene glycol, amino acid residues, alkyl groups, substituted alkyl groups, aryl groups, substituted aryl groups, and diamines (e.g., linking groups including alkylenediamines).

[0179] In some embodiments, L 1 (If present) includes polyethylene glycol, modified polyethylene glycol, amino acid residues, alkyl groups, substituted alkyl groups, aryl groups, substituted aryl groups, or diamines. In some embodiments, L 1 It contains polyethylene glycol. In some embodiments, L 1 It contains modified polyethylene glycol. In some embodiments, L 1 It contains an amino acid residue. In some embodiments, L 1 This includes an alkyl group or a substituted alkyl group. In some embodiments, L 1 This includes an aryl group or a substituted aryl group. In some embodiments, L 1 It contains a diamine (for example, a linking group including alkylenediamine).

[0180] In some embodiments, L 2 (If present) includes polyethylene glycol, modified polyethylene glycol, amino acid residues, alkyl groups, substituted alkyl groups, aryl groups, substituted aryl groups, or diamines. In some embodiments, L 2It contains polyethylene glycol. In some embodiments, L 2 It contains modified polyethylene glycol. In some embodiments, L 2 It contains an amino acid residue. In some embodiments, L 2 This includes an alkyl group or a substituted alkyl group. In some embodiments, L 2 This includes an aryl group or a substituted aryl group. In some embodiments, L 2 It contains a diamine (for example, a linking group including alkylenediamine).

[0181] In some embodiments, L 3 (If present) includes polyethylene glycol, modified polyethylene glycol, amino acid residues, alkyl groups, substituted alkyl groups, aryl groups, substituted aryl groups, or diamines. In some embodiments, L 3 It contains polyethylene glycol. In some embodiments, L 3 It contains modified polyethylene glycol. In some embodiments, L 3 It contains an amino acid residue. In some embodiments, L 3 This includes an alkyl group or a substituted alkyl group. In some embodiments, L 3 This includes an aryl group or a substituted aryl group. In some embodiments, L 3 It contains a diamine (for example, a linking group including alkylenediamine).

[0182] In some embodiments, L 4 (If present) includes polyethylene glycol, modified polyethylene glycol, amino acid residues, alkyl groups, substituted alkyl groups, aryl groups, substituted aryl groups, or diamines. In some embodiments, L 4 It contains polyethylene glycol. In some embodiments, L 4 It contains modified polyethylene glycol. In some embodiments, L 4 It contains an amino acid residue. In some embodiments, L 4 This includes an alkyl group or a substituted alkyl group. In some embodiments, L4 This includes an aryl group or a substituted aryl group. In some embodiments, L 4 It contains a diamine (for example, a linking group including alkylenediamine).

[0183] In some embodiments, L 5 (If present) includes polyethylene glycol, modified polyethylene glycol, amino acid residues, alkyl groups, substituted alkyl groups, aryl groups, substituted aryl groups, or diamines. In some embodiments, L 5 It contains polyethylene glycol. In some embodiments, L 5 It contains modified polyethylene glycol. In some embodiments, L 5 It contains an amino acid residue. In some embodiments, L 5 This includes an alkyl group or a substituted alkyl group. In some embodiments, L 5 This includes an aryl group or a substituted aryl group. In some embodiments, L 5 It contains a diamine (for example, a linking group including alkylenediamine).

[0184] In some embodiments, L 6 (If present) includes polyethylene glycol, modified polyethylene glycol, amino acid residues, alkyl groups, substituted alkyl groups, aryl groups, substituted aryl groups, or diamines. In some embodiments, L 6 It contains polyethylene glycol. In some embodiments, L 6 It contains modified polyethylene glycol. In some embodiments, L 6 It contains an amino acid residue. In some embodiments, L 6 This includes an alkyl group or a substituted alkyl group. In some embodiments, L 6 This includes an aryl group or a substituted aryl group. In some embodiments, L 6 It contains a diamine (for example, a linking group including alkylenediamine).

[0185] In some embodiments, L is -(L 1 )a -(L 2 ) b -(L 3 ) c -(L 4 ) d -(L 5 ) e -(L 6 ) f - is a linker that includes, in the formula, -(L 1 ) a -but,-(T 1 -V 1 ) a -and, -(L 2 ) b -but,-(T 2 -V 2 ) b -and, -(L 3 ) c -but,-(T 3 -V 3 ) c -and, -(L 4 ) d -but,-(T 4 -V 4 ) d -and, -(L 5 ) e -but,-(T 5 -V 5 ) e -and, -(L 6 ) f -but,-(T 6 -V 6 ) f -and, T 1 , T 2 , T 3 , T 4 , T 5 , and T 6 However, if present, it is a tether group, V 1 , V 2 , V 3 , V 4 , V 5 , and V 6 However, if present, it is a covalent bond or a linking functional group. a, b, c, d, e, and f are each independently either 0 or 1, and the sum of a, b, c, d, e, and f is between 1 and 6.

[0186] As described above, in a particular embodiment, L 1 This is connected to a hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugated moiety (for example, as shown in formula (I) above). Therefore, in certain embodiments, T 1 This is connected to a hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugated moiety (for example, as shown in formula (I) above). In certain embodiments, V 1 It is connected to camptothecin or a camptothecin derivative. In certain embodiments, L 2 If present, it is connected to camptothecin or a camptothecin derivative. Therefore, in certain embodiments, T 2 If present, it is either connected to camptothecin or a camptothecin derivative, or V 2 If present, it is connected to camptothecin or a camptothecin derivative. In certain embodiments, L 3 If present, it is connected to camptothecin or a camptothecin derivative. Therefore, in certain embodiments, T 3 If present, it is either connected to camptothecin or a camptothecin derivative, or V 3 If present, it is connected to camptothecin or a camptothecin derivative. In certain embodiments, L 4 If present, it is connected to camptothecin or a camptothecin derivative. Therefore, in certain embodiments, T 4 If present, it is either connected to camptothecin or a camptothecin derivative, or V 4 If present, it is connected to camptothecin or a camptothecin derivative. In certain embodiments, L 5 If present, it is connected to camptothecin or a camptothecin derivative. Therefore, in certain embodiments, T 5If present, it is either connected to camptothecin or a camptothecin derivative, or V 5 If present, it is connected to camptothecin or a camptothecin derivative. In certain embodiments, L 6 If present, it is connected to camptothecin or a camptothecin derivative. Therefore, in certain embodiments, T 6 If present, it is either connected to camptothecin or a camptothecin derivative, or V 6 If present, it is linked to camptothecin or a camptothecin derivative.

[0187] Tether group T 1 , T 2 , T 3 , T 4 , T 5 , and T 6 In relation to this, any convenient tether group can be used in the linker of this subject. In some embodiments, T 1 , T 2 , T 3 , T 4 , T 5 , and T 6 Each of them is a covalent bond, (C1-C 12 ) alkyl, substituted (C1-C 12 ) alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA) w (PEG) n , (AA) p ,-(CR 13 OH) m- comprises one or more groups independently selected from 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino-benzylamino (PABA), para-amino-phenyl (PAP), para-hydroxyphenyl (PHP), acetal groups, hydrazines, disulfides, and esters, where each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each m is an integer from 1 to 12.

[0188] In certain embodiments, a tether group (e.g., T 1 , T 2 , T 3 , T 4 , T 5 , and / or T 6 ) is (C1-C 12 ) alkyl or substituted (C1-C 12 ) Contains alkyl. In certain embodiments, (C1-C 12 Alkyl is a linear or branched alkyl group containing 1 to 12 carbon atoms, for example, 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms. In some cases, (C1-C 12 )Alkyl refers to alkyl or substituted alkyl, for example, (C1-C 12 ) alkyl, or (C1-C 10 It may be an alkyl, or (C1-C6) alkyl, or (C1-C3) alkyl. In some cases, (C1-C 12 )Alkyl is C2-alkyl. For example, (C1-C 12 )Alkyl refers to alkylene or substituted alkylene, for example, (C1-C 12 ) Alkylene, or (C1-C 10 ) may be alkylene, or (C1-C6)alkylene, or (C1-C3)alkylene. In some cases, (C1-C 12Alkyl is C2-alkylene (e.g., CH2CH2). In some cases, (C1-C 12 Alkyl is a C3-alkylene (e.g., CH2CH2CH2).

[0189] In certain embodiments, substitution (C1-C 12 Alkyl is a linear or branched substituted alkyl group containing 1 to 12 carbon atoms, for example, 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms. In some cases, substituted (C1-C 12 )alkyl refers to substituted alkyl, for example, substituted (C1-C 12 ) alkyl or substituted (C1-C 10 ) alkyl, or substituted (C1-C6) alkyl, or substituted (C1-C3) alkyl. In some cases, substituted (C1-C 12 )alkyl is a substituted C2-alkyl. For example, a substituted (C1-C 12 )Alkyl refers to substituted alkylenes, for example, substituted (C1-C 12 ) Alkylene, or substitution (C1-C 10 ) may be alkylene, or substituted (C1-C6) alkylene, or substituted (C1-C3) alkylene. In some cases, substituted (C1-C 12 )alkyl is a substituted C2 alkylene. In some cases, a substituted (C1-C 12 )alkyl is a substituted C3 alkylene. For example, a substituted (C1-C 12 ) Alkyl is (PEG) as described herein. n C1-C substituted with a group 12 It may contain alkylene (e.g., C3-alkylene or C5-alkylene) (e.g., -CONH(PEG)3 or -NHCO(PEG)7), or C1-C substituted with a -CONHCH2CH2SO3H group. 12 It may contain alkylene (e.g., C3-alkylene), or C1-C substituted with a -NHCOCH2SO3H group. 12 It may contain alkylenes (e.g., C5-alkylenes).

[0190] In certain embodiments, a tether group (e.g., T 1 , T 2 , T 3 , T 4 , T 5 , and / or T 6 ) includes aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl. In some cases, a tether group (e.g., T) may be included. 1 , T 2 , T 3 , T 4 , T 5 , and T 6 ) includes aryl or substituted aryl. For example, aryl can be phenyl. In some cases, substituted aryl is substituted phenyl. Substituted phenyl is (C1-C 12 ) alkyl, substituted (C1-C 12 The substituents may be substituted with one or more substituents selected from alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In some cases, the substituted aryl is a substituted phenyl, and the substituents include cleavable moieties as described herein (e.g., enzymatically cleavable moieties, e.g., glycosides or glycoside derivatives).

[0191] In some cases, a tether group (for example, T 1 , T 2 , T 3 , T 4 , T 5 , and / or T 6 ) includes heteroaryl or substituted heteroaryl groups. In some cases, a tether group (e.g., T) may be present. 1 , T 2 , T 3 , T 4 , T 5 , and T 6 ) includes cycloalkyl or substituted cycloalkyl groups. In some cases, a tether group (e.g., T) may be present. 1 , T 2 , T 3 , T 4, T 5 , and T 6 ) comprises a heterocyclyl or a substituted heterocyclyl. In some cases, a substituted heteroaryl, substituted cycloalkyl, or substituent on a substituted heterocyclyl comprises a cleavable moiety as described herein (e.g., an enzymatically cleavable moiety, e.g., a glycoside or glycoside derivative).

[0192] In certain embodiments, a tether group (e.g., T 1 , T 2 , T 3 , T 4 , T 5 , and / or T 6 ) includes an ethylenediamine (EDA) moiety, for example, an EDA-containing tether. In certain embodiments, (EDA) w The EDA moiety comprises one or more EDA moieties, for example, where w is an integer from 1 to 50, e.g., 1 to 40, 1 to 30, 1 to 20, 1 to 12, or 1 to 6, e.g., 1, 2, 3, 4, 5, or 6). The linked ethylenediamine (EDA) moieties may optionally be substituted at one or more favorable positions with any favorable substituent, e.g., alkyl, substituted alkyl, acyl, substituted acyl, aryl, or substituted aryl. In certain embodiments, the EDA moiety has the following structure [ka] Described by, In the formula, y is an integer from 1 to 6, or 0 or 1, and each R 12However, independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, y is 1, 2, 3, 4, 5, or 6. In certain embodiments, y is 1 and r is 0. In certain embodiments, y is 1 and r is 1. In certain embodiments, y is 2 and r is 0. In certain embodiments, y is 2 and r is 1. In certain embodiments, each R 12 These are independently selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl. In certain embodiments, any two adjacent R of EDA 12 The groups may be linked in a ring, for example, to form a piperazinyl ring. In certain embodiments, y is 1 and two adjacent R 12 The group is an alkyl group, linked cyclically to form a piperazinyl ring. In certain embodiments, y is 1, and adjacent R 12 The group is selected from hydrogen, alkyl (e.g., methyl), and substituted alkyl (e.g., lower alkyl-OH, e.g., ethyl-OH or propyl-OH).

[0193] In certain embodiments, a tether group (e.g., T 1 , T 2 , T 3 , T 4 , T 5 , and / or T 6) comprises a 4-amino-piperidine (4AP) moiety (also referred to herein as piperidine-4-amino, P4A). The 4AP moiety may optionally be substituted at one or more favorable positions with any favorable substituent, such as alkyl, substituted alkyl, polyethylene glycol moiety, acyl, substituted acyl, aryl, or substituted aryl. In certain embodiments, the 4AP moiety has the following structure [ka] Described by, in the formula, R 12 However, R is selected from hydrogen, alkyl, substituted alkyl, polyethylene glycol moiety (e.g., polyethylene glycol or modified polyethylene glycol), alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, R 12 This is the polyethylene glycol portion. In certain embodiments, R 12 This is carboxy-modified polyethylene glycol.

[0194] In a particular embodiment, R 12 This refers to the polyethylene glycol portion (PEG) described by the following formula. k It includes the following structure [ka] It may also be expressed by, In the formula, k is an integer between 1 and 20, for example, 1 to 18, or 1 to 16, or 1 to 14, or 1 to 12, or 1 to 10, or 1 to 8, or 1 to 6, or 1 to 4, or 1 or 2, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some cases, k is 2. In certain embodiments, R 17 R is selected from OH, OR, COOH, or COOR, and R is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, R 17 is COOH. In a particular embodiment, R 17 is OH. In a particular embodiment, R 17 This is an OR, for example, OCH3.

[0195] In certain embodiments, a tether group (e.g., T 1 , T 2 , T 3 , T 4 , T 5 , and / or T 6 ) is (PEG) n Includes, in the formula, (PEG) n However, it is a polyethylene glycol or modified polyethylene glycol linked unit. In a particular embodiment, (PEG) n The structure is as follows: [ka] Described by, In the formula, n is an integer between 1 and 50, for example, 1 to 40, 1 to 30, 1 to 20, 1 to 12, or 1 to 6, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some cases, n is 2. In some cases, n is 3. In some cases, n is 6. In some cases, n is 12.

[0196] In certain embodiments, a tether group (e.g., T 1 , T 2 , T 3 , T 4 , T 5 , and / or T 6 ) is (AA) p The formula includes, where AA is an amino acid residue. Any suitable amino acid may be used. The target amino acid may include, but is not limited to, L-amino acids and D-amino acids, naturally occurring amino acids, e.g., any of the 20 main alpha-amino acids and beta-alanine, or amino acids that do not exist naturally (e.g., amino acid analogs), e.g., alpha-amino acids or beta-amino acids that do not exist naturally. In certain embodiments, p is an integer from 1 to 50, e.g., 1 to 40, 1 to 30, 1 to 20, 1 to 12, or 1 to 6, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In certain embodiments, p is 1. In certain embodiments, p is 2.

[0197] In certain embodiments, a tether group (e.g., T 1 , T 2 , T 3 , T 4 , T 5 , and / or T 6) includes amino acid analogs. Amino acid analogs include amino acid-like compounds that are structurally and / or in shape similar to one or more amino acids commonly found in naturally occurring proteins (e.g., Ala or A, Cys or C, Asp or D, Glu or E, Phe or F, Gly or G, His or H, Ile or I, Lys or K, Leu or L, Met or M, Asn or N, Pro or P, Gln or Q, Arg or R, Ser or S, Thr or T, Val or V, Trp or W, Tyr or Y). Amino acid analogs also include natural amino acids that have modified side chains or backbone. Amino acid analogs also include amino acid analogs that have the same stereochemistry as the naturally occurring D form, as well as the L form of amino acid analogs. In some cases, amino acid analogs share the backbone structure and / or side chain structure of one or more natural amino acids, the difference being one or more modifying groups in the molecule. Such modifications may include, but are not limited to, substitution of an atom (e.g., N) with a related atom (e.g., S), addition of a group (e.g., methyl or hydroxyl) or an atom (e.g., Cl or Br), deletion of a group, substitution of a covalent bond (e.g., changing a single bond to a double bond), or combinations thereof. For example, amino acid analogs may include α-hydroxy acids and α-amino acids. Examples of amino acid analogs, but are not limited to, sulfoalanine.

[0198] In certain embodiments, a tether group (e.g., T 1 , T 2 , T 3 , T 4 , T 5 , and / or T 6 ) is formula - (CR 13 OH) m -Includes the portion described by, where m is 0 or n is an integer between 1 and 50, e.g., 1 to 40, 1 to 30, 1 to 20, 1 to 12, or 1 to 6, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, R 13is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, R 13 is hydrogen. In a particular embodiment, R 13 is an alkyl or substituted alkyl, for example, C 1-6 Alkyl or C 1-6 Substituting alkyl, or C 1-4 Alkyl or C 1-4 Substituting alkyl, or C 1-3 Alkyl or C 1-3 It is a substituted alkyl. In certain embodiments, R 13 This refers to an alkenyl or a substituted alkenyl, for example, C 2-6 Alkenil or C 2-6 Substituting alkenyl, or C 2-4 Alkenil or C 2-4 Substituting alkenyl, or C 2-3 Alkenil or C 2-3 It is a substituted alkenyl. In certain embodiments, R 13 is an alkynyl or substituted alkynyl. In certain embodiments, R 13 is an alkoxy or substituted alkoxy. In certain embodiments, R 13 is an amino acid or a substituted amino acid. In certain embodiments, R 13 is a carboxyl or carboxyl ester. In certain embodiments, R 13 is an acyl or acyloxy. In certain embodiments, R 13 is acylamino or aminoacyl. In certain embodiments, R 13 is an alkylamide or a substituted alkylamide. In certain embodiments, R 13 is a sulfonyl. In certain embodiments, R 13is a thioalkoxy or a substituted thioalkoxy. In certain embodiments, R 13 is an aryl or substituted aryl, for example, C 5-8 Aryl or C 5-8 Substituting aryls, for example, C5 aryls or C5-substituted aryls, or C6 aryls or C6-substituted aryls. In certain embodiments, R 13 This refers to heteroaryl or substituted heteroaryl, for example, C 5-8 Heteroaryl or C 5-8 Substituting heteroaryls, for example, C5 heteroaryls or C5-substituted heteroaryls, or C6 heteroaryls or C6-substituted heteroaryls. In certain embodiments, R 13 This refers to cycloalkyl or substituted cycloalkyl, for example, C 3-8 Cycloalkyl or C 3-8 Substitutive cycloalkyls, for example, C 3-6 Cycloalkyl or C 3-6 Substituted cycloalkyl, or C 3-5 Cycloalkyl or C 3-5 It is a substituted cycloalkyl. In certain embodiments, R 13 This refers to heterocyclines or substituted heterocyclines, for example, C 3-8 Heterocycline or C 3-8 Substituting heterocyclyls, e.g., C 3-6 Heterocycline or C 3-6 Substituted heterocyclyl, or C 3-5 Heterocycline or C 3-5 It is a substituted heterocyclyl.

[0199] In a particular embodiment, R 13 R is selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl. In these embodiments, alkyl, substituted alkyl, aryl, and substituted aryl are R 13 As stated above,

[0200] In certain embodiments, a tether group (e.g., T 1 , T 2 , T3 , T 4 , T 5 , and / or T 6 This includes meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino-benzylamino (PABA), para-amino-phenyl (PAP), or para-hydroxyphenyl (PHP).

[0201] In some embodiments, the tether has the following structure [ka] It contains the MABO group described by [the relevant authority].

[0202] In some embodiments, the tether has the following structure [ka] It contains the MABC group described by [the relevant authority].

[0203] In some embodiments, the tether has the following structure [ka] Contains the PABO group as described by [author's name].

[0204] In some embodiments, the tether has the following structure [ka] It contains the PABC group described by [the relevant authority].

[0205] In some embodiments, the tether has the following structure [ka] Contains the PAB group described by [the relevant authority].

[0206] In some embodiments, the tether has the following structure [ka] Contains PABA groups as described by [author's name].

[0207] In some embodiments, the tether has the following structure [ka] Contains the PAP group described by [translate].

[0208] In some embodiments, the tether has the following structure [ka] Includes the PHP base described by [the author / source].

[0209] In a specific method of operation, each R 14 These are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0210] In a particular embodiment, R 14 is hydrogen. In a particular embodiment, each R 14 is hydrogen. In a particular embodiment, R 14 is an alkyl or substituted alkyl, for example, C 1-6 Alkyl or C 1-6 Substituting alkyl, or C 1-4 Alkyl or C 1-4 Substituting alkyl, or C 1-3 Alkyl or C 1-3It is a substituted alkyl. In certain embodiments, R 14 This refers to an alkenyl or a substituted alkenyl, for example, C 2-6 Alkenil or C 2-6 Substituting alkenyl, or C 2-4 Alkenil or C 2-4 Substituting alkenyl, or C 2-3 Alkenil or C 2-3 It is a substituted alkenyl. In certain embodiments, R 14 is an alkynyl or substituted alkynyl. In certain embodiments, R 14 is an alkoxy or substituted alkoxy. In certain embodiments, R 14 is an amino acid or a substituted amino acid. In certain embodiments, R 14 is a carboxyl or carboxyl ester. In certain embodiments, R 14 is an acyl or acyloxy. In certain embodiments, R 14 is acylamino or aminoacyl. In certain embodiments, R 14 is an alkylamide or a substituted alkylamide. In certain embodiments, R 14 is a sulfonyl. In certain embodiments, R 14 is a thioalkoxy or a substituted thioalkoxy. In certain embodiments, R 14 is an aryl or substituted aryl, for example, C 5-8 Aryl or C 5-8 Substituting aryls, for example, C5 aryls or C5-substituted aryls, or C6 aryls or C6-substituted aryls. In certain embodiments, R 14 This refers to heteroaryl or substituted heteroaryl, for example, C 5-8 Heteroaryl or C 5-8 Substituting heteroaryls, for example, C5 heteroaryls or C5-substituted heteroaryls, or C6 heteroaryls or C6-substituted heteroaryls. In certain embodiments, R 14 This refers to cycloalkyl or substituted cycloalkyl, for example, C 3-8 Cycloalkyl or C 3-8 Substitutive cycloalkyls, for example, C 3-6Cycloalkyl or C 3-6 Substituted cycloalkyl, or C 3-5 Cycloalkyl or C 3-5 It is a substituted cycloalkyl. In certain embodiments, R 14 This refers to heterocyclines or substituted heterocyclines, for example, C 3-8 Heterocycline or C 3-8 Substituting heterocyclyls, e.g., C 3-6 Heterocycline or C 3-6 Substituted heterocyclyl, or C 3-5 Heterocycline or C 3-5 It is a substituted heterocyclyl.

[0211] In some embodiments of the MABO, MABC, PABO, PABC, PAB, PABA, PAP, and PHP tether structures shown above, the phenyl ring may be substituted with one or more additional groups selected from halogens, alkyls, substituted alkyls, alkenyls, substituted alkenyls, alkynyls, substituted alkynyls, alkoxys, substituted alkoxys, aminos, substituted aminos, carboxyls, carboxyl esters, acyls, acyloxys, acylaminos, aminoacyls, alkylamides, substituted alkylamides, sulfonyls, thioalkoxys, substituted thioalkoxys, aryls, substituted aryls, heteroaryls, substituted heteroaryls, cycloalkyls, substituted cycloalkyls, heterocyclyls, and substituted heterocyclyls.

[0212] In a particular embodiment of the linker L, the tether group T 1 , T 2 , T 3 , T 4 , T 5 , or T 6 One or more of these are optionally substituted with a glycoside or glycoside derivative. In certain embodiments, the glycoside or glycoside derivative is selected from glucuronide, galactoside, glucoside, mannoside, fucoside, O-GlcNAc, and O-GalNAc.

[0213] In certain embodiments, the MABO, MABC, PABO, PABC, PAB, PABA, PAP, and PHP tether structures shown above may be substituted with one or more additional groups selected from glycosides and glycoside derivatives. For example, in some embodiments of the MABO, MABC, PABO, PABC, PAB, PABA, PAP, and PHP tether structures shown above, the phenyl ring may be substituted with one or more additional groups selected from glycosides and glycoside derivatives. In certain embodiments, the glycoside or glycoside derivative may be selected from glucuronides, galactosides, glucosides, mannosides, fucosides, O-GlcNAc, and O-GalNAc.

[0214] For example, in some embodiments, the glycoside or glycoside derivative has the following structure [ka] It can be selected from the following.

[0215] Linking functional group V 1 , V 2 , V 3 , V 4 , V 5 , and V 6 Regarding this, any convenient linking functional group can be used in linker L. Examples of desired linking functional groups, but not limited to, include amino, carbonyl, amide, oxycarbonyl, carboxy, sulfonyl, sulfoxide, sulfonylamino, aminosulfonyl, thio, oxy, phospho, phosphoramidate, and thiophosphoride. In some embodiments, V 1 , V 2 , V 3 , V 4 , V 5 , and V 6 These are, independently, covalent, -CO-, and -NR bonds. 15 -, -NR 15 (CH2) q -, -NR 15 (C6H4)-, -CONR 15 -, -NR 15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR 15 -, -NR 15 Selected from SO2- and -P(O)OH-, q is an integer from 1 to 6. In certain embodiments, q is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6). In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 4. In certain embodiments, q is 5. In certain embodiments, q is 6.

[0216] Several embodiments, each R 15 These are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0217] In a particular embodiment, R 15 is hydrogen. In a particular embodiment, each R 15 is hydrogen. In a particular embodiment, R 15 is an alkyl or substituted alkyl, for example, C 1-6 Alkyl or C 1-6 Substituting alkyl, or C 1-4 Alkyl or C 1-4 Substituting alkyl, or C 1-3 Alkyl or C 1-3 It is a substituted alkyl. In certain embodiments, R 15 This refers to an alkenyl or a substituted alkenyl, for example, C 2-6 Alkenil or C 2-6 Substituting alkenyl, or C 2-4 Alkenil or C 2-4 Substituting alkenyl, or C 2-3Alkenil or C 2-3 It is a substituted alkenyl. In certain embodiments, R 15 is an alkynyl or substituted alkynyl. In certain embodiments, R 15 is an alkoxy or substituted alkoxy. In certain embodiments, R 15 is an amino acid or a substituted amino acid. In certain embodiments, R 15 is a carboxyl or carboxyl ester. In certain embodiments, R 15 is an acyl or acyloxy. In certain embodiments, R 15 is acylamino or aminoacyl. In certain embodiments, R 15 is an alkylamide or a substituted alkylamide. In certain embodiments, R 15 is a sulfonyl. In certain embodiments, R 15 is a thioalkoxy or a substituted thioalkoxy. In certain embodiments, R 15 is an aryl or substituted aryl, for example, C 5-8 Aryl or C 5-8 Substituting aryls, for example, C5 aryls or C5-substituted aryls, or C6 aryls or C6-substituted aryls. In certain embodiments, R 15 This refers to heteroaryl or substituted heteroaryl, for example, C 5-8 Heteroaryl or C 5-8 Substituting heteroaryls, for example, C5 heteroaryls or C5-substituted heteroaryls, or C6 heteroaryls or C6-substituted heteroaryls. In certain embodiments, R 15 This refers to cycloalkyl or substituted cycloalkyl, for example, C 3-8 Cycloalkyl or C 3-8 Substitutive cycloalkyls, for example, C 3-6 Cycloalkyl or C 3-6 Substituted cycloalkyl, or C 3-5 Cycloalkyl or C 3-5 It is a substituted cycloalkyl. In certain embodiments, R 15 This refers to heterocyclines or substituted heterocyclines, for example, C 3-8Heterocycline or C 3-8 Substituting heterocyclyls, e.g., C 3-6 Heterocycline or C 3-6 Substituted heterocyclyl, or C 3-5 Heterocycline or C 3-5 It is a substituted heterocyclyl.

[0218] In a specific method of operation, each R 15 The substituents are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In these embodiments, the substituents are R 15 As stated above,

[0219] In certain embodiments, the tether group includes an acetal group, a disulfide, a hydrazine, or an ester. In some embodiments, the tether group includes an acetal group. In some embodiments, the tether group includes a hydrazine. In some embodiments, the tether group includes a disulfide. In some embodiments, the tether group includes an ester.

[0220] As described above, in some embodiments, L is -(T 1 -V 1 ) a -(T 2 -V 2 ) b -(T 3 -V 3 ) c -(T 4 -V 4 ) d -(T 5 -V 5 )e -(T 6 -V 6 ) f - is a linker containing a, b, c, d, e, and f, where a, b, c, d, e, and f are each independently 0 or 1, and the sum of a, b, c, d, e, and f is between 1 and 6.

[0221] In some embodiments, in the linker L, T 1 However, (C1-C 12 )alkyl and substituted (C1-C 12 ) Selected from alkyl groups, T 2 , T 3 , T 4 , T 5 , and T 6 However, each operates independently, (C1-C 12 ) alkyl, substituted (C1-C 12 ) alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA) w (PEG) n , (AA) p ,-(CR 13 OH) m - Selected from 4-amino-piperidine (4AP), MABO, MABC, PABO, PABC, PAB, PABA, PAP, PHP, acetal group, disulfide, hydrazine, and ester, V 1 , V 2 , V 3 , V 4 , V 5 , and V 6 However, each operates independently as a covalent bond, -CO-, -NR. 15 -, -NR 15 (CH2) q -, -NR 15 (C6H4)-, -CONR 15 -, -NR 15 CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR 15 -, -NR 15Selected from SO2- and -P(O)OH-, where q is an integer from 1 to 6. (PEG) n but, [ka] In the formula, n is an integer between 1 and 30. EDA has the following structure [ka] The ethylenediamine moiety has the following characteristics, where y is an integer from 1 to 6, and r is 0 or 1. 4-amino-piperidine (4AP) [ka] And, AA represents an amino acid residue, and in the formula, p is an integer from 1 to 20. Each R 12 However, independently selected from hydrogen, alkyl, substituted alkyl, polyethylene glycol moiety, aryl, and substituted aryl, any two adjacent R 12 The groups may be linked in a ring to form a piperazinyl ring. Each R 13 However, they are independently selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl. Each R 15 However, these are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0222] In a particular embodiment, T 1 , T 2 , T 3 , T 4 , T 5 , and T 6 , and V 1 , V 2 , V3 , V 4 , V 5 , and V 6 The following can be selected: T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. T 6 However, it is EDA, V 6 However, it is either -CO- or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it does not exist, V 5 However, -NR 15 It is (C6H4)-, T 6 However, it does not exist, V 6 However, it is either -CO- or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, -NR 15 -and, T 6 However, (C1-C 12 ) is alkyl, V 6 However, it is either -CO- or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is AA, and V 2 However, it does not exist. T 3 However, it is PABC, and V 3 However, it does not exist. T 4 However, it is EDA, V 4 However, it is -CO-, e and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12) is alkyl, V 1 However, it is -CO-, T 2 However, it is AA, and V 2 However, it does not exist. T 3 However, it is PABC, and V 3 However, it does not exist. d, e, and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABA, and V 5 However, it is -CO-, T 6 However, (C1-C 12 ) is alkyl, V 6 However, it is either -SO2- or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T 2 However, (PEG) n V 2 However, it is -CO-, T 3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PABC, and V 4 However, it does not exist. e and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T2 However, substitution (C1-C 12 ) is alkyl, V 2 However, it is -CO-, T 3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PABC, and V 4 However, it does not exist. e and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T 2 However, (PEG) n V 2 However, it is -CO-, T 3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PABC, and V 4 However, it does not exist. T 5 However, (C1-C 12 ) is alkyl, V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is 4AP, V 2 However, it is -CO-, T 3 However, (C1-C 12 ) is alkyl, V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V1 However, it is -CO-, T 2 However, it is 4AP, V 2 However, it is -CO-, T 3 However, (C1-C 12 ) is alkyl, V 3 However, it is -O-, T 4 However, (C1-C 12 ) is alkyl, V 4 However, it is -CO-, T 5 However, it is AA, and V 5 However, it does not exist. T 6 However, it is PABC, and V 6 However, it does not exist, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it does not exist. T 3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PABC, and V 4 However, it does not exist. e and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T 2 However, (PEG) n V 2 However, it is -CONH-, T 3 However, substitution (C1-C 12 ) is alkyl, V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is AA, and V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABO, V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4However, it does not exist. T 5 However, it is PAP, and V 5 However, he is the COO, f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T 2 However, (PEG) n V 2 However, it is -CO-, T 3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PAP, and V 4 However, he is the COO, e and f are both 0.

[0223] In certain embodiments, the left side of the linker structure is connected to a hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugated moiety, while the right side of the linker structure is connected to camptothecin or a camptothecin derivative.

[0224] In certain embodiments of the conjugate of formula (I), the linker L is connected to camptothecin or a camptothecin derivative. In some cases, the linker L is R 1 , R 2 , R 3 , R 4 , R 5 or R 6 It is connected to the compound of formula (II), [ka] During the ceremony, R 1 and R 2However, each is independently selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or R 1 and R 2 However, they are optionally linked cyclically to form a 5 or 6-membered cycloalkyl or heterocyclyl ring, R 3 and R 4 However, each is independently selected from hydrogen, halo, hydroxy, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or R 3 and R 4 However, they are optionally linked cyclically to form a 5 or 6-membered cycloalkyl or heterocyclyl ring, R 5 However, selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, R 6 However, OH and OC(O)R 11 Selected from, R 11 However, selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, at least one R 10 However, it is optionally linked to the second compound of formula (II).

[0225] In a particular embodiment, R 1 and R 2 Each is independently selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or R 1 and R 2 However, they are optionally linked cyclically to form a 5- or 6-membered cycloalkyl or heterocyclyl ring.

[0226] In a particular embodiment, R 1 R is selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, R 1 is hydrogen. In a particular embodiment, R 1 is a halogen (e.g., F, Cl, Br, I). In certain embodiments, R 1 is hydroxyl. In certain embodiments, R 1 is an amino acid or a substituted amino acid. In certain embodiments, R 1 is an alkyl or substituted alkyl, for example, C 1-6 Alkyl or C 1-6 Substituting alkyl, or C 1-4 Alkyl or C 1-4 Substituting alkyl, or C 1-3 Alkyl or C 1-3 It is a substituted alkyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 This refers to an alkenyl or a substituted alkenyl, for example, C 2-6 Alkenil or C 2-6 Substituting alkenyl, or C 2-4Alkenil or C 2-4 Substituting alkenyl, or C 2-3 Alkenil or C 2-3 It is a substituted alkenyl. In certain embodiments, R 1 is an alkynyl or substituted alkynyl. In certain embodiments, R 1 is an alkoxy or substituted alkoxy. In certain embodiments, R 1 is an aryl or substituted aryl, for example, C 5-8 Aryl or C 5-8 Substituting aryls, for example, C5 aryls or C5-substituted aryls, or C6 aryls or C6-substituted aryls. In certain embodiments, R 1 This refers to heteroaryl or substituted heteroaryl, for example, C 5-8 Heteroaryl or C 5-8 Substituting heteroaryls, for example, C5 heteroaryls or C5-substituted heteroaryls, or C6 heteroaryls or C6-substituted heteroaryls. In certain embodiments, R 1 This refers to cycloalkyl or substituted cycloalkyl, for example, C 3-8 Cycloalkyl or C 3-8 Substitutive cycloalkyls, for example, C 3-6 Cycloalkyl or C 3-6 Substituted cycloalkyl, or C 3-5 Cycloalkyl or C 3-5 It is a substituted cycloalkyl. In certain embodiments, R 1 This refers to heterocyclines or substituted heterocyclines, for example, C 3-6 Heterocycline or C 3-6 Substituted heterocyclyl, or C 3-5 Heterocycline or C 3-5 It is a substituted heterocyclyl.

[0227] In a particular embodiment, R 2R is selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, R 2 is hydrogen. In a particular embodiment, R 2 is a halogen (e.g., F, Cl, Br, I). In certain embodiments, R 2 is hydroxyl. In certain embodiments, R 2 is an amino acid or a substituted amino acid. In certain embodiments, R 2 is an alkyl or substituted alkyl, for example, C 1-6 Alkyl or C 1-6 Substituting alkyl, or C 1-4 Alkyl or C 1-4 Substituting alkyl, or C 1-3 Alkyl or C 1-3 It is a substituted alkyl. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 This refers to an alkenyl or a substituted alkenyl, for example, C 2-6 Alkenil or C 2-6 Substituting alkenyl, or C 2-4 Alkenil or C 2-4 Substituting alkenyl, or C 2-3 Alkenil or C 2-3 It is a substituted alkenyl. In certain embodiments, R 2 is an alkynyl or substituted alkynyl. In certain embodiments, R 2 is an alkoxy or substituted alkoxy. In certain embodiments, R 2 is an aryl or substituted aryl, for example, C 5-8 Aryl or C 5-8 Substituting aryls, for example, C5 aryl or C5-substituted aryl, or C6 aryl or C6-substituted aryl. In certain embodiments, R 2 This refers to heteroaryl or substituted heteroaryl, for example, C 5-8Heteroaryl or C 5-8 Substituting heteroaryls, for example, C5 heteroaryls or C5-substituted heteroaryls, or C6 heteroaryls or C6-substituted heteroaryls. In certain embodiments, R 2 This refers to cycloalkyl or substituted cycloalkyl, for example, C 3-8 Cycloalkyl or C 3-8 Substitutive cycloalkyls, for example, C 3-6 Cycloalkyl or C 3-6 Substituted cycloalkyl, or C 3-5 Cycloalkyl or C 3-5 It is a substituted cycloalkyl. In certain embodiments, R 2 This refers to heterocyclines or substituted heterocyclines, for example, C 3-6 Heterocycline or C 3-6 Substituted heterocyclyl, or C 3-5 Heterocycline or C 3-5 It is a substituted heterocyclyl.

[0228] In a particular embodiment, R 1 and R 2 These are optionally linked cyclically to form a 5 or 6-membered cycloalkyl or heterocyclyl ring. In certain embodiments, R 1 and R 2 These are linked in a ring, forming a 5 or 6-membered cycloalkyl group. In certain embodiments, R 1 and R 2 These are linked in a ring shape to form a 5 or 6-membered heterocycline. In certain embodiments, R 1 and R 2 These are linked in a ring, forming a 5-membered cycloalkyl group. In certain embodiments, R 1 and R 2 These are linked in a ring, forming a 6-membered cycloalkyl group. In certain embodiments, R 1 and R 2 These are linked in a ring, forming a 5-membered heterocycline. In certain embodiments, R 1 and R 2 These are linked together in a ring, forming a six-membered heterocycline.

[0229] In a particular embodiment, R 3 and R 4 Each is independently selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or R 3 and R 4 However, they are optionally linked cyclically to form a 5- or 6-membered cycloalkyl or heterocyclyl ring.

[0230] In a particular embodiment, R 3 R is selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, R 3 is hydrogen. In a particular embodiment, R 3 is a halogen (e.g., F, Cl, Br, I). In certain embodiments, R 3 is hydroxyl. In certain embodiments, R 3 is an amino acid or a substituted amino acid. In certain embodiments, R 3 is an alkyl or substituted alkyl, for example, C 1-6 Alkyl or C 1-6 Substituting alkyl, or C 1-4 Alkyl or C 1-4 Substituting alkyl, or C 1-3 Alkyl or C 1-3 It is a substituted alkyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 This refers to an alkenyl or a substituted alkenyl, for example, C 2-6 Alkenil or C 2-6 Substituting alkenyl, or C2-4 Alkenil or C 2-4 Substituting alkenyl, or C 2-3 Alkenil or C 2-3 It is a substituted alkenyl. In certain embodiments, R 3 is an alkynyl or substituted alkynyl. In certain embodiments, R 3 is an alkoxy or substituted alkoxy. In certain embodiments, R 3 is an aryl or substituted aryl, for example, C 5-8 Aryl or C 5-8 Substituting aryls, for example, C5 aryl or C5-substituted aryl, or C6 aryl or C6-substituted aryl. In certain embodiments, R 3 This refers to heteroaryl or substituted heteroaryl, for example, C 5-8 Heteroaryl or C 5-8 Substituting heteroaryls, for example, C5 heteroaryls or C5-substituted heteroaryls, or C6 heteroaryls or C6-substituted heteroaryls. In certain embodiments, R 3 This refers to cycloalkyl or substituted cycloalkyl, for example, C 3-8 Cycloalkyl or C 3-8 Substitutive cycloalkyls, for example, C 3-6 Cycloalkyl or C 3-6 Substituted cycloalkyl, or C 3-5 Cycloalkyl or C 3-5 It is a substituted cycloalkyl. In certain embodiments, R 3 This refers to heterocyclines or substituted heterocyclines, for example, C 3-6 Heterocycline or C 3-6 Substituted heterocyclyl, or C 3-5 Heterocycline or C 3-5 It is a substituted heterocyclyl.

[0231] In a particular embodiment, R 4R is selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, R 4 is hydrogen. In a particular embodiment, R 4 is a halogen (e.g., F, Cl, Br, I). In certain embodiments, R 4 is hydroxyl. In certain embodiments, R 4 is an amino acid or a substituted amino acid. In certain embodiments, R 4 is an alkyl or substituted alkyl, for example, C 1-6 Alkyl or C 1-6 Substituting alkyl, or C 1-4 Alkyl or C 1-4 Substituting alkyl, or C 1-3 Alkyl or C 1-3 It is a substituted alkyl. In certain embodiments, R 4 is methyl. In certain embodiments, R 4 This refers to an alkenyl or a substituted alkenyl, for example, C 2-6 Alkenil or C 2-6 Substituting alkenyl, or C 2-4 Alkenil or C 2-4 Substituting alkenyl, or C 2-3 Alkenil or C 2-3 It is a substituted alkenyl. In certain embodiments, R 4 is an alkynyl or substituted alkynyl. In certain embodiments, R 4 is an alkoxy or substituted alkoxy. In certain embodiments, R 4 is an aryl or substituted aryl, for example, C 5-8 Aryl or C 5-8 Substituting aryls, for example, C5 aryls or C5-substituted aryls, or C6 aryls or C6-substituted aryls. In certain embodiments, R 4 This refers to heteroaryl or substituted heteroaryl, for example, C 5-8Heteroaryl or C 5-8 Substituting heteroaryls, for example, C5 heteroaryls or C5-substituted heteroaryls, or C6 heteroaryls or C6-substituted heteroaryls. In certain embodiments, R 4 This refers to cycloalkyl or substituted cycloalkyl, for example, C 3-8 Cycloalkyl or C 3-8 Substitutive cycloalkyls, for example, C 3-6 Cycloalkyl or C 3-6 Substituted cycloalkyl, or C 3-5 Cycloalkyl or C 3-5 It is a substituted cycloalkyl. In certain embodiments, R 4 This refers to heterocyclines or substituted heterocyclines, for example, C 3-6 Heterocycline or C 3-6 Substituted heterocyclyl, or C 3-5 Heterocycline or C 3-5 It is a substituted heterocyclyl.

[0232] In a particular embodiment, R 3 and R 4 These are optionally linked cyclically to form a 5 or 6-membered cycloalkyl or heterocyclyl ring. In certain embodiments, R 3 and R 4 These are linked in a ring, forming a 5 or 6-membered cycloalkyl group. In certain embodiments, R 3 and R 4 These are linked in a ring shape to form a 5 or 6-membered heterocycline. In certain embodiments, R 3 and R 4 These are linked in a ring, forming a 5-membered cycloalkyl group. In certain embodiments, R 3 and R 4 These are linked in a ring, forming a 6-membered cycloalkyl group. In certain embodiments, R 3 and R 4 These are linked in a ring, forming a 5-membered heterocycline. In certain embodiments, R 3 and R 4 These are linked together in a ring, forming a six-membered heterocycline.

[0233] In a particular embodiment, R 5 R is selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, R 5 is hydrogen. In a particular embodiment, R 5 is a halogen (e.g., F, Cl, Br, I). In certain embodiments, R 5 is hydroxyl. In certain embodiments, R 5 is an amino acid or a substituted amino acid. In certain embodiments, R 5 is an alkyl or substituted alkyl, for example, C 1-6 Alkyl or C 1-6 Substituting alkyl, or C 1-4 Alkyl or C 1-4 Substituting alkyl, or C 1-3 Alkyl or C 1-3 It is a substituted alkyl. In certain embodiments, R 5 is methyl. In certain embodiments, R 5 This refers to an alkenyl or a substituted alkenyl, for example, C 2-6 Alkenil or C 2-6 Substituting alkenyl, or C 2-4 Alkenil or C 2-4 Substituting alkenyl, or C 2-3 Alkenil or C 2-3 It is a substituted alkenyl. In certain embodiments, R 5 is an alkynyl or substituted alkynyl. In certain embodiments, R 5 is an alkoxy or substituted alkoxy. In certain embodiments, R 5 is an aryl or substituted aryl, for example, C 5-8 Aryl or C 5-8 Substituting aryls, for example, C5 aryls or C5-substituted aryls, or C6 aryls or C6-substituted aryls. In certain embodiments, R5 This refers to heteroaryl or substituted heteroaryl, for example, C 5-8 Heteroaryl or C 5-8 Substituting heteroaryls, for example, C5 heteroaryls or C5-substituted heteroaryls, or C6 heteroaryls or C6-substituted heteroaryls. In certain embodiments, R 5 This refers to cycloalkyl or substituted cycloalkyl, for example, C 3-8 Cycloalkyl or C 3-8 Substitutive cycloalkyls, for example, C 3-6 Cycloalkyl or C 3-6 Substituted cycloalkyl, or C 3-5 Cycloalkyl or C 3-5 It is a substituted cycloalkyl. In certain embodiments, R 5 This refers to heterocyclines or substituted heterocyclines, for example, C 3-6 Heterocycline or C 3-6 Substituted heterocyclyl, or C 3-5 Heterocycline or C 3-5 It is a substituted heterocyclyl.

[0234] In a particular embodiment, R 6 OH and OC(O)R 11 Selected from. In a particular embodiment, R 6 is OH. In a particular embodiment, R 6 O(O)R 11 That is the case.

[0235] In a particular embodiment, R 11 R is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, R 11 is hydrogen. In a particular embodiment, R 11 is an alkyl or substituted alkyl, for example, C 1-6 Alkyl or C 1-6 Substituting alkyl, or C 1-4Alkyl or C 1-4 Substituting alkyl, or C 1-3 Alkyl or C 1-3 It is a substituted alkyl. In certain embodiments, R 11 This refers to an alkenyl or a substituted alkenyl, for example, C 2-6 Alkenil or C 2-6 Substituting alkenyl, or C 2-4 Alkenil or C 2-4 Substituting alkenyl, or C 2-3 Alkenil or C 2-3 It is a substituted alkenyl. In certain embodiments, R 11 is an alkynyl or substituted alkynyl. In certain embodiments, R 11 is an aryl or substituted aryl, for example, C 5-8 Aryl or C 5-8 Substituting aryls, for example, C5 aryls or C5-substituted aryls, or C6 aryls or C6-substituted aryls. In certain embodiments, R 11 This refers to heteroaryl or substituted heteroaryl, for example, C 5-8 Heteroaryl or C 5-8 Substituting heteroaryls, for example, C5 heteroaryls or C5-substituted heteroaryls, or C6 heteroaryls or C6-substituted heteroaryls. In certain embodiments, R 11 This refers to cycloalkyl or substituted cycloalkyl, for example, C 3-8 Cycloalkyl or C 3-8 Substitutive cycloalkyls, for example, C 3-6 Cycloalkyl or C 3-6 Substituted cycloalkyl, or C 3-5 Cycloalkyl or C 3-5 It is a substituted cycloalkyl. In certain embodiments, R 11 This refers to heterocyclines or substituted heterocyclines, for example, C 3-6 Heterocycline or C 3-6 Substituted heterocyclyl, or C 3-5 Heterocycline or C 3-5 It is a substituted heterocyclyl.

[0236] In certain embodiments, the compound of formula (II) has the structure of formula (IIa). [ka]

[0237] In certain embodiments of the compound of formula (IIa), R 3 This is as described above.

[0238] In certain embodiments of the compound of formula (IIa), R 6 This is as described above.

[0239] In certain embodiments of the compound of formula (IIa), R 3 is OH, and L is R 6 It is connected to. In certain embodiments of the compound of formula (IIa), L is R 3 It is connected to R 6 It is OH.

[0240] In certain embodiments, the compound of formula (II) has the structure of formula (IIb). [ka]

[0241] In certain embodiments of the compound of formula (IIb), R 1a R is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl. In certain embodiments, R 1a is hydrogen. In a particular embodiment, R 1a is an alkyl or substituted alkyl, for example, C 1-6 Alkyl or C 1-6 Substituting alkyl, or C 1-4 Alkyl or C 1-4 Substituting alkyl, or C 1-3 Alkyl or C 1-3It is a substituted alkyl. In certain embodiments, R 1a is an aryl or substituted aryl, for example, C 5-8 Aryl or C 5-8 Substituting aryls, for example, C5 aryls or C5-substituted aryls, or C6 aryls or C6-substituted aryls. In certain embodiments, R 1a This refers to heteroaryl or substituted heteroaryl, for example, C 5-8 Heteroaryl or C 5-8 Substituting heteroaryls, for example, C5 heteroaryls or C5-substituted heteroaryls, or C6 heteroaryls or C6-substituted heteroaryls. In certain embodiments, R 1a This refers to cycloalkyl or substituted cycloalkyl, for example, C 3-8 Cycloalkyl or C 3-8 Substitutive cycloalkyls, for example, C 3-6 Cycloalkyl or C 3-6 Substituted cycloalkyl, or C 3-5 Cycloalkyl or C 3-5 It is a substituted cycloalkyl. In certain embodiments, R 1a This refers to heterocyclines or substituted heterocyclines, for example, C 3-6 Heterocycline or C 3-6 Substituted heterocyclyl, or C 3-5 Heterocycline or C 3-5 It is a substituted heterocyclyl. In certain embodiments, R 1a is a carboxyl. In certain embodiments, R 1a R is a carboxyl ester. In certain embodiments, R 1a is an acyl. In certain embodiments, R 1a It is a sulfonyl compound.

[0242] In certain embodiments of the compound of formula (IIb), R 6 This is as described above.

[0243] In certain embodiments of the compound of formula (IIb), R 1aL is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and L is R 6 It is connected to. In certain embodiments of the compound of formula (IIb), L is R 1a It is connected to R 6 It is OH.

[0244] In certain embodiments, the compound of formula (II) has the structure of formula (IIc). [ka]

[0245] In certain embodiments of the compound of formula (IIc), R 1b R is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl. In certain embodiments, R 1b is hydrogen. In a particular embodiment, R 1b is an alkyl or substituted alkyl, for example, C 1-6 Alkyl or C 1-6 Substituting alkyl, or C 1-4 Alkyl or C 1-4 Substituting alkyl, or C 1-3 Alkyl or C 1-3 It is a substituted alkyl. In certain embodiments, R 1b is an aryl or substituted aryl, for example, C 5-8 Aryl or C 5-8 Substituting aryls, for example, C5 aryls or C5-substituted aryls, or C6 aryls or C6-substituted aryls. In certain embodiments, R 1b This refers to heteroaryl or substituted heteroaryl, for example, C 5-8 Heteroaryl or C 5-8Substituting heteroaryls, for example, C5 heteroaryls or C5-substituted heteroaryls, or C6 heteroaryls or C6-substituted heteroaryls. In certain embodiments, R 1b This refers to cycloalkyl or substituted cycloalkyl, for example, C 3-8 Cycloalkyl or C 3-8 Substitutive cycloalkyls, for example, C 3-6 Cycloalkyl or C 3-6 Substituted cycloalkyl, or C 3-5 Cycloalkyl or C 3-5 It is a substituted cycloalkyl. In certain embodiments, R 1b This refers to heterocyclines or substituted heterocyclines, for example, C 3-6 Heterocycline or C 3-6 Substituted heterocyclyl, or C 3-5 Heterocycline or C 3-5 It is a substituted heterocyclyl. In certain embodiments, R 1b is a carboxyl. In certain embodiments, R 1b R is a carboxyl ester. In certain embodiments, R 1b is an acyl. In certain embodiments, R 1b It is a sulfonyl compound.

[0246] In certain embodiments of the compound of formula (IIc), R 6 This is as described above.

[0247] In certain embodiments of the compound of formula (IIc), R 1b L is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and L is R 6 It is connected to. In certain embodiments of the compound of formula (IIc), L is R 1b It is connected to R 6 It is OH.

[0248] In certain embodiments, the compound of formula (II) has the structure of formula (IId). [ka]

[0249] In certain embodiments of the compound of formula (IId), R 2a and R 2b Each of these is independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl.

[0250] In certain embodiments of the compound of formula (IId), R 2a R is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl. In certain embodiments, R 2a is hydrogen. In a particular embodiment, R 2a is an alkyl or substituted alkyl, for example, C 1-6 Alkyl or C 1-6 Substituting alkyl, or C 1-4 Alkyl or C 1-4 Substituting alkyl, or C 1-3 Alkyl or C 1-3 It is a substituted alkyl. In certain embodiments, R 2a is an aryl or substituted aryl, for example, C 5-8 Aryl or C 5-8 Substituting aryls, for example, C5 aryls or C5-substituted aryls, or C6 aryls or C6-substituted aryls. In certain embodiments, R 2a This refers to heteroaryl or substituted heteroaryl, for example, C 5-8 Heteroaryl or C 5-8Substituting heteroaryls, for example, C5 heteroaryls or C5-substituted heteroaryls, or C6 heteroaryls or C6-substituted heteroaryls. In certain embodiments, R 2a This refers to cycloalkyl or substituted cycloalkyl, for example, C 3-8 Cycloalkyl or C 3-8 Substitutive cycloalkyls, for example, C 3-6 Cycloalkyl or C 3-6 Substituted cycloalkyl, or C 3-5 Cycloalkyl or C 3-5 It is a substituted cycloalkyl. In certain embodiments, R 2a This refers to heterocyclines or substituted heterocyclines, for example, C 3-6 Heterocycline or C 3-6 Substituted heterocyclyl, or C 3-5 Heterocycline or C 3-5 It is a substituted heterocyclyl. In certain embodiments, R 2a is a carboxyl. In certain embodiments, R 2a R is a carboxyl ester. In certain embodiments, R 2a is an acyl. In certain embodiments, R 2a It is a sulfonyl compound.

[0251] In certain embodiments of the compound of formula (IId), R 2b R is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl. In certain embodiments, R 2b is hydrogen. In a particular embodiment, R 2b is an alkyl or substituted alkyl, for example, C 1-6 Alkyl or C 1-6 Substituting alkyl, or C 1-4 Alkyl or C 1-4 Substituting alkyl, or C 1-3 Alkyl or C 1-3 It is a substituted alkyl. In certain embodiments, R2b is an aryl or substituted aryl, for example, C 5-8 Aryl or C 5-8 Substituting aryls, for example, C5 aryls or C5-substituted aryls, or C6 aryls or C6-substituted aryls. In certain embodiments, R 2b This refers to heteroaryl or substituted heteroaryl, for example, C 5-8 Heteroaryl or C 5-8 Substituting heteroaryls, for example, C5 heteroaryls or C5-substituted heteroaryls, or C6 heteroaryls or C6-substituted heteroaryls. In certain embodiments, R 2b This refers to cycloalkyl or substituted cycloalkyl, for example, C 3-8 Cycloalkyl or C 3-8 Substitutive cycloalkyls, for example, C 3-6 Cycloalkyl or C 3-6 Substituted cycloalkyl, or C 3-5 Cycloalkyl or C 3-5 It is a substituted cycloalkyl. In certain embodiments, R 2b This refers to heterocyclines or substituted heterocyclines, for example, C 3-6 Heterocycline or C 3-6 Substituted heterocyclyl, or C 3-5 Heterocycline or C 3-5 It is a substituted heterocyclyl. In certain embodiments, R 2b is a carboxyl. In certain embodiments, R 2b R is a carboxyl ester. In certain embodiments, R 2b is an acyl. In certain embodiments, R 2b It is a sulfonyl compound.

[0252] In certain embodiments of the compound of formula (IId), R 6 This is as described above.

[0253] In certain embodiments of the compound of formula (IId), R 2a and R 2bEach is independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and L is R 6 It is connected to. In certain embodiments of the compound of formula (IId), L is R 2a or R 2b It is connected to R 6 is OH. In certain embodiments of the compound of formula (IId), L is R 2a It is connected to R 6 is OH. In certain embodiments of the compound of formula (IId), L is R 2b It is connected to R 6 It is OH.

[0254] In certain embodiments, the compound of formula (II) has the structure of formula (IIe). [ka]

[0255] In certain embodiments of the compound of formula (IIe), R 2c The elements are selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and the connection to L is indicated by a wavy line.

[0256] In a particular embodiment, R 2c is an alkyl or substituted alkyl, for example, C 1-6 Alkyl or C 1-6 Substituting alkyl, or C 1-4 Alkyl or C 1-4 Substituting alkyl, or C 1-3 Alkyl or C 1-3 It is a substituted alkyl. In certain embodiments, R 2cThis refers to an alkenyl or a substituted alkenyl, for example, C 2-6 Alkenil or C 2-6 Substituting alkenyl, or C 2-4 Alkenil or C 2-4 Substituting alkenyl, or C 2-3 Alkenil or C 2-3 It is a substituted alkenyl. In certain embodiments, R 2c This refers to alkynyl or substituted alkynyl, for example, C 2-6 Alkinyl or C 2-6 Substituting alkynyl, or C 2-4 Alkinyl or C 2-4 Substituting alkynyl, or C 2-3 Alkinyl or C 2-3 It is a substituted alkynyl. In certain embodiments, R 2c is an aryl or substituted aryl, for example, C 5-8 Aryl or C 5-8 Substituting aryls, for example, C5 aryls or C5-substituted aryls, or C6 aryls or C6-substituted aryls. In certain embodiments, R 2c This refers to heteroaryl or substituted heteroaryl, for example, C 5-8 Heteroaryl or C 5-8 Substituting heteroaryls, for example, C5 heteroaryls or C5-substituted heteroaryls, or C6 heteroaryls or C6-substituted heteroaryls. In certain embodiments, R 2c This refers to cycloalkyl or substituted cycloalkyl, for example, C 3-8 Cycloalkyl or C 3-8 Substitutive cycloalkyls, for example, C 3-6 Cycloalkyl or C 3-6 Substituted cycloalkyl, or C 3-5 Cycloalkyl or C 3-5 It is a substituted cycloalkyl. In certain embodiments, R 2c This refers to heterocyclines or substituted heterocyclines, for example, C 3-6 Heterocycline or C 3-6 Substituted heterocyclyl, or C 3-5 Heterocycline or C 3-5It is a substituted heterocyclyl. In certain embodiments, R 2c is a carboxyl. In certain embodiments, R 2c R is a carboxyl ester. In certain embodiments, R 2c is an acyl. In certain embodiments, R 2c It is a sulfonyl compound.

[0257] In certain embodiments of the compound of formula (IIe), the connection to L is indicated by a wavy line. In other words, the connection with the wavy line indicates a connection that links the compound of formula (IIe) to the linker.

[0258] In certain embodiments of the conjugate of formula (I), a polypeptide (e.g., an antibody) may be linked to one drug or active agent via the conjugated moiety. In some cases, a polypeptide (e.g., an antibody) may be linked to more than one drug or active agent via the conjugated moiety. For example, the conjugated moiety may be linked to two or more drugs or active agents. Each drug or active agent may be linked to the same conjugated moiety via a corresponding linker, which can then be linked to a polypeptide (e.g., an antibody) as described herein, thus linking the polypeptide (e.g., an antibody) to two or more drugs or active agents.

[0259] For example, in a particular embodiment of the conjugate of formula (I), one or more R 10 It is optionally linked to the second compound of formula (II). In some cases, one or more R 10 It is linked to the second compound of formula (II). In other cases, R 10 is not linked to the second compound of formula (II). For example, at least one R 10 It is optionally linked to the second compound of formula (II). In some cases, one R 10 This is linked to the second compound of formula (II).

[0260] In a particular embodiment, one R 10 This is the second linker L2 It is linked to the second compound of formula (II) via . In certain embodiments, the second linker L 2 The following formula -(L 7 ) g -(L 8 ) h -(L 9 ) i -(L 10 ) j -(L 11 ) k -(L 12 ) l - The linker described by (for example, the second linker), In the formula, L 7 , L 8 , L 9 , L 10 , L 11 , and L 12 Each of these is an independent linker subunit, and g, h, i, j, k, and l are each independently 0 or 1, and the sum of g, h, i, j, k, and l is between 1 and 6.

[0261] In certain embodiments, the sum of g, h, i, j, k, and l is 1. In certain embodiments, the sum of g, h, i, j, k, and l is 2. In certain embodiments, the sum of g, h, i, j, k, and l is 3. In certain embodiments, the sum of g, h, i, j, k, and l is 4. In certain embodiments, the sum of g, h, i, j, k, and l is 5. In certain embodiments, the sum of g, h, i, j, k, and l is 6. In certain embodiments, g, h, i, j, k, and l are each 1. In certain embodiments, g, h, i, j, and k are each 1, and l is 0. In certain embodiments, g, h, i, and j are each 1, and k and l are each 0. In certain embodiments, g, h, and i are each 1, and j, k, and l are each 0. In certain embodiments, g and h are each 1, and i, j, k, and l are each 0.

[0262] In a particular embodiment, linker subunit L 7 This connects to a hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugate (for example, as shown in formula (I) above). In certain embodiments, linker subunit L 8 If present, it connects to camptothecin or a camptothecin derivative. In certain embodiments, linker subunit L 9 If present, it connects to camptothecin or a camptothecin derivative. In certain embodiments, linker subunit L 10 If present, it connects to camptothecin or a camptothecin derivative. In certain embodiments, linker subunit L 11 If present, it connects to camptothecin or a camptothecin derivative. In certain embodiments, linker subunit L 12 If present, it connects to camptothecin or a camptothecin derivative.

[0263] Any convenient linker subunit, second linker L B It can be used for this purpose. For example, L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 In relation to this, one of the linker subunits listed above, linker subunit L 7 , L 8 , L 9 , L 10 , L 11 , and L 12 It may be used for this purpose.

[0264] In certain embodiments, a second linker L B teeth, -(L 7 ) g -(L 8 ) h -(L 9 ) i -(L 10 ) j -(L 11 )k -(L 12 ) l - is a linker that includes, in the formula, -(L 7 ) g -but,-(T 7 -V 7 ) g -and, -(L 8 ) h -but,-(T 8 -V 8 ) h -and, -(L 9 ) i -but,-(T 9 -V 9 ) i -and, -(L 10 ) j -but,-(T 10 -V 10 ) j -and, -(L 11 ) k -but,-(T 11 -V 11 ) k -and, -(L 12 ) l -but,-(T 12 -V 12 ) l -and, T 7 , T 8 , T 9 , T 10 , T 11 , and T 12 However, if present, it is a tether group, V 7 , V 8 , V 9 , V 10 , V 11 , and V 12 However, if present, it is a covalent bond or a linking functional group. g, h, i, j, k, and l are each independently either 0 or 1, and the sum of g, h, i, j, k, and l is between 1 and 6.

[0265] Therefore, in certain embodiments, the second linker L B teeth, -(T 7 -V 7 ) g -(T 8 -V 8 ) h -(T 9 -V 9 ) i -(T 10 -V 10 ) j -(T 11 -V 11 ) k -(T 12 -V 12 ) l - Includes, During the ceremony, g, h, i, j, k, and l are each independently either 0 or 1. T 7 , T 8 , T 9 , T 10 , T 11 , and T 12 However, each is independent, and a covalent bond is formed, (C1-C 12 ) alkyl, substituted (C1-C 12 ) alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA) w (PEG) n , (AA) p ,-(CR 13 OH) m-, selected from 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino-benzylamino (PABA), para-amino-phenyl (PAP), para-hydroxyphenyl (PHP), acetal group, hydrazine, disulfide, and ester, where EDA is the ethylenediamine moiety, PEG is polyethylene glycol, AA is an amino acid residue or amino acid analog, each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each m is an integer from 1 to 12. V 7 , V 8 , V 9 , V 10 , V 11 , and V 12 However, each operates independently as a covalent bond, -CO-, -NR. 15 -, -NR 15 (CH2) q -, -NR 15 (C6H4)-, -CONR 15 -, -NR 15 CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR 15 -, -NR 15 Selected from the group consisting of SO2- and -P(O)OH-, where each q is an integer from 1 to 6. Each R 13 However, they are independently selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl. Each R 15 However, these are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0266] Any convenient tether group, T7 , T 8 , T 9 , T 10 , T 11 , and T 12 It can be used for the following purposes. For example, T 1 , T 2 , T 3 , T 4 , T 5 , and T 6 In relation to this, any of the tether groups listed above, tether group T 7 , T 8 , T 9 , T 10 , T 11 , and T 12 It may be used for this purpose.

[0267] Any convenient linking functional group, V 7 , V 8 , V 9 , V 10 , V 11 , and V 12 It can be used for V. 1 , V 2 , V 3 , V 4 , V 5 , and V 6 In relation to the above, any of the linked functional groups, linked functional group V 7 , V 8 , V 9 , V 10 , V 11 , and V 12 It may be used for this purpose.

[0268] In a specific method of operation, each R 13 R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl. In these embodiments, alkyl, substituted alkyl, aryl, and substituted aryl are R 13 As stated above,

[0269] In a specific method of operation, each R 15The substituents are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In these embodiments, the substituents are R 15 As described above, in these embodiments, various possible substituents are R 15 As stated above,

[0270] Second Linker L B In a particular embodiment, the tether group T 7 , T 8 , T 9 , T 10 , T 11 , and T 12 One or more of these are optionally substituted with a glycoside or glycoside derivative. In certain embodiments, the glycoside or glycoside derivative is selected from glucuronide, galactoside, glucoside, mannoside, fucoside, O-GlcNAc, and O-GalNAc.

[0271] Second Linker L BIn certain embodiments, the MABO, MABC, PABO, PABC, PAB, PABA, PAP, and PHP tether structures shown above may be substituted with one or more additional groups selected from glycosides and glycoside derivatives. For example, in some embodiments of the MABO, MABC, PABO, PABC, PAB, PABA, PAP, and PHP tether structures shown above, the phenyl ring may be substituted with one or more additional groups selected from glycosides and glycoside derivatives. In certain embodiments, the glycoside or glycoside derivative may be selected from glucuronides, galactosides, glucosides, mannosides, fucosides, O-GlcNAc, and O-GalNAc.

[0272] In a particular embodiment, T 7 , T 8 , T 9 , T 10 , T 11 , and T 12 , and V 7 , V 8 , V 9 , V 10 , V 11 , and V 12 The following can be selected: T 7 However, it does not exist, V 7 However, -NR 15 CO-, T 8 However, (C1-C 12 ) is alkyl, V 8 However, it is -CO-, T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PABC, and V 10 However, it does not exist. T 11 However, it is EDA, V 11 However, it is -CO-, l is 0, or T 7 However, it does not exist, V 7 However, -NR 15 CO-, T 8 However, (C1-C12 ) is alkyl, V 8 However, it is -CO-, T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PABC, and V 10 However, it does not exist. k and l are each 0, or T 7 However, it does not exist, V 7 However, it is -NHCO-, T 8 However, (C1-C 12 ) is alkyl, V 8 However, it is -CO-, T 9 However, it is an amino acid analog, V 9 However, it is -NH-, T 10 However, (PEG) n V 10 However, it is -CO-, T 11 However, it is AA, and V 11 However, it does not exist. T 12 However, it is PABC, and V 12 However, it does not exist, or T 7 However, it does not exist, V 7 However, it is -NHCO-, T 8 However, (C1-C 12 ) is alkyl, V 8 However, it is -CONH-, T 9 However, (PEG) n V 9 However, it is -CO-, T 10 However, it is AA, and V 10 However, it does not exist. T 11 However, it is PABC, and V 11 However, it does not exist. l is 0, or T 7 However, (C1-C 12 ) is alkyl, V7 However, it is -CONH-, T 8 However, substitution (C1-C 12 ) is alkyl, V 8 However, it is -CO-, T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PABC, and V 10 However, it does not exist. k and l are each 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CONH-, T 8 However, (PEG) n V 8 However, it is -CO-, T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PABC, and V 10 However, it does not exist. T 11 However, (C1-C 12 ) is alkyl, V 11 However, it does not exist. l is 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CO-, T 8 However, it is 4AP, V 8 However, it is -CO-, T 9 However, (C1-C 12 ) is alkyl, V 9 However, it is -CO-, T 10 However, it is AA, and V 10 However, it does not exist. T 11 However, it is PABC, and V 11 However, it does not exist. l is 0, or T 7However, (C1-C 12 ) is alkyl, V 7 However, it is -CO-, T 8 However, it is 4AP, V 8 However, it is -CO-, T 9 However, (C1-C 12 ) is alkyl, V 9 However, it is -O-, T 10 However, (C1-C 12 ) is alkyl, V 10 However, it is -CO-, T 11 However, it is AA, and V 11 However, it does not exist. T 12 However, it is PABC, and V 12 However, it does not exist, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CO-, T 8 However, it is an amino acid analog, V 8 However, it does not exist. T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PABC, and V 10 However, it does not exist. k and l are each 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CONH-, T 8 However, (PEG) n V 8 However, it is -CONH-, T 9 However, substitution (C1-C 12 ) is alkyl, V 9 However, it is -CO-, T 10 However, it is AA, and V 10 However, it does not exist. T 11However, it is PABC, and V 11 However, it does not exist. l is 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CO-, T 8 However, it is AA, and V 8 However, it is -NH-, T 9 However, (PEG) n V 9 However, it is -CO-, T 10 However, it is AA, and V 10 However, it does not exist. T 11 However, it is PABC, and V 11 However, it does not exist. l is 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CONH-, T 8 However, (PEG) n V 8 However, it is -CO-, T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PAP, and V 10 However, he is the COO, k and l are both 0.

[0273] Second Linker L B In certain embodiments, the left side of the linker structure is connected to a hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugated moiety, and the right side of the linker structure is connected to camptothecin or a camptothecin derivative. Second linker L B In certain embodiments, the left side of the linker structure is connected to a hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugated moiety via a linking functional group such as -NHCO-.

[0274] In certain embodiments, the conjugate is such that the antibody and drug are linked to a linker (e.g., L or L) as described above. B An antibody-drug conjugate is linked together by a linker. In some cases, the linker is a cleavable linker. A cleavable linker is a linker containing one or more cleavable moieties, each containing one or more bonds that can dissociate under certain conditions, and thus separate the cleavable linker into two or more separable parts. For example, each cleavable moiety may contain one or more covalent bonds, each containing one or more covalent bonds that can dissociate or separate under certain conditions to separate the cleavable linker into two or more parts. Such a cleavable linker may be contained in an antibody-drug conjugate, and as a result, under appropriate conditions, the cleavable linker is cleaved, separating or releasing the drug from the antibody at a desired target site of action for that drug.

[0275] In some cases, a cleavable linker includes two cleavable portions, for example, a first cleavable portion and a second cleavable portion. The cleavable portions may be configured such that cleavage of both cleavable portions is required to separate or release the drug from the antibody at a desired target site of action for the drug. For example, cleavage of a cleavable linker can be achieved by first cleaving one of the two cleavable portions and then cleaving the other of the two cleavable portions. In certain embodiments, a cleavable linker includes a first cleavable portion and a second cleavable portion that interferes with the cleavage of the first cleavable portion. "Interfering with cleavage" means that the presence of the uncleaved second cleavable portion reduces the possibility of cleavage of the first cleavable portion or substantially inhibits cleavage, and therefore substantially reduces or prevents cleavage of the cleavable linker. For example, the presence of an uncleaved second cleavable portion can interfere with the cleavage of the first cleavable portion. The presence of a second cleavable portion interferes with the cleavage of the first cleavable portion, thereby substantially reducing or preventing the release of the drug from the antibody. For example, premature release of the drug from the antibody can be substantially reduced or prevented until the antibody-drug conjugate is at or near the desired target site of action for the drug.

[0276] In some cases, the second cleavable portion interferes with the cleavage of the first cleavable portion, so cleavage of the cleavable linker can be achieved by first cleaving the second cleavable portion and then the first cleavable portion. Cleavage of the second cleavable portion can reduce or eliminate the interference with cleavage of the first cleavable portion, and thus enable cleavage of the first cleavable portion. Cleavage of the first cleavable portion allows the cleavable linker to dissociate or separate into two or more portions as described above, thereby releasing the drug from the antibody-drug conjugate. In some cases, cleavage of the first cleavable portion does not substantially occur in the presence of the uncleaved second cleavable portion. "Substantially" means that, in the presence of a second, uncuttable portion, the cutting of the first cleavable portion is less than approximately 10%; for example, in the presence of a second, uncuttable portion, the cutting of the first cleavable portion is less than approximately 9%, or less than approximately 8%, or less than approximately 7%, or less than approximately 6%, or less than approximately 5%, or less than approximately 4%, or less than approximately 3%, or less than approximately 2%, or less than approximately 1%, or less than approximately 0.5%, or less than approximately 0.1%.

[0277] In other words, the second cleavable portion can protect the first cleavable portion from being cleaved. For example, the presence of an uncleaved second cleavable portion can protect the first cleavable portion from being cleaved, and thus substantially reduce or prevent premature release of the drug from the antibody until the antibody-drug conjugate is at or near the desired target site of action for the drug. Thus, cleavage of the second cleavable portion exposes the first cleavable portion (e.g., deprotects the first cleavable portion), and thus enables cleavage of the first cleavable portion, resulting in cleavage of the cleavable linker, and then separation or release of the drug from the antibody at the desired target site of action for the drug. In certain cases, cleavage of the second cleavable portion exposes the first cleavable portion to subsequent cleavage, but the second cleavable portion is not in the cleavable linker and does not cause cleavage of the cleavable linker itself (i.e., cleavage of the first cleavable portion is still required to cleave the cleavable linker).

[0278] Each cleavable portion within a cleavable linker may be an enzymatically cleavable portion. For example, the first cleavable portion may be the first enzymatically cleavable portion, and the second cleavable portion may be the second enzymatically cleavable portion. An enzymatically cleavable portion is a cleavable portion that can be separated into two or more parts as described above by the enzymatic action of an enzyme. An enzymatically cleavable portion may be any cleavable portion that can be cleaved by the enzymatic action of an enzyme, such as, but not limited to, peptides, glycosides, etc. In some cases, the enzyme that cleaves the enzymatically cleavable portion is present at the desired target site of action, such as the desired target site of action of the drug released from the antibody-drug conjugate. In other cases, the enzyme that cleaves the enzymatically cleavable portion is not present in significant amounts in other regions such as whole blood, plasma, or serum. Therefore, cleavage of the enzymatically cleavable portion can be controlled so that substantial cleavage occurs at the desired site of action, while significant cleavage does not occur in other regions or before the antibody-drug conjugate reaches the desired site of action.

[0279] For example, as described herein, the antibody-drug conjugates of this disclosure can be used for the treatment of cancer, for example, for the delivery of cancer-therapeutic drugs to a desired site of action where cancer cells are present. In some cases, an enzyme, for example, the protease enzyme cathepsin B, may be a biomarker for cancer that is overexpressed in cancer cells. The overexpression, and therefore localization, of a specific enzyme in cancer can be used in the context of an enzymatically cleavable moiety contained in the cleavable linker of the antibody-drug conjugate of this disclosure to specifically release a drug at a desired site of action (i.e., the site of cancer (and the overexpressed enzyme)). Thus, in some embodiments, the enzymatically cleavable moiety is a cleavable moiety (e.g., a peptide) that can be cleaved by an enzyme overexpressed in cancer cells. For example, the enzyme may be the protease enzyme cathepsin B. Thus, in some cases, the enzymatically cleavable moiety is a cleavable moiety (e.g., a peptide) that can be cleaved by a protease enzyme (e.g., cathepsin B).

[0280] In certain embodiments, the enzymatically cleavable portion is a peptide. The peptide can be any peptide that is suitable for use in a cleavable linker and can be cleaved by the enzymatic action of an enzyme. Non-limiting examples of peptides that can be used as an enzymatically cleavable portion include, for example, Val-Ala and Phe-Lys. For example, the first cleavable portion described above (i.e., the cleavage portion protected from premature cleavage by the second cleavable portion) may include a peptide. The presence of an uncleaved second cleavable portion can protect the first cleavable portion (peptide) from cleavage by a protease enzyme (e.g., cathepsin B), and thus substantially reduce or prevent premature release of the drug from the antibody until the antibody-drug conjugate is at or near the desired target site of action for the drug. In some cases, one of the amino acid residues of the peptide containing the first cleavable portion is linked to or contains a substituent, the substituent contains the second cleavable portion. In some cases, the second cleavable portion contains a glycoside.

[0281] In some embodiments, the enzymatically cleavable portion is a sugar moiety, such as a glycoside (or glycosyl). In some cases, the glycoside can promote increased hydrophilicity of the cleavable linker compared to a cleavable linker that does not contain a glycoside. The glycoside can be any glycoside or glycoside derivative that is suitable for use in a cleavable linker and can be cleaved by the enzymatic action of an enzyme. For example, the second cleavable portion (i.e., a cleavable portion that protects the first cleavable portion from premature cleavage) can be a glycoside. For example, in some embodiments, the first cleavable portion includes a peptide, and the second cleavable portion includes a glycoside. In certain embodiments, the second cleavable portion is a glycoside or glycoside derivative selected from glucuronides, galactosides, glucosides, mannosides, fucosides, O-GlcNAc, and O-GalNAc. In some cases, the second cleavable portion is a glucuronide. In some cases, the second cleavable portion is a galactoside. In some cases, the second cleavable portion is a glucoside. In some cases, the second cleavable portion is a mannoside. In some cases, the second cleavable portion is a fucoside. In some cases, the second cleavable portion is O-GlcNAc. In some cases, the second cleavable portion is O-GalNAc.

[0282] Glycosides can be linked (covalently) to cleavable linkers via glycosidic bonds. Glycosidic bonds can link glycosides to cleavable linkers via various types of bonds, including, but are not limited to, O-glycosidic bonds (O-glycosid), N-glycosidic bonds (glycosylamine), S-glycosidic bonds (thioglycoside), or C-glycosidic bonds (C-glycosid or C-glycosyl). In some cases, the glycosidic bond is an O-glycosidic bond (O-glycosid). In other cases, glycosides can be cleaved from cleavable linkers by enzymes (e.g., via enzyme-mediated hydrolysis of the glycosidic bond). Glycosides can be removed or cleaved from cleavable linkers by any convenient enzyme capable of performing the cleavage (hydrolysis) of the glycosidic bond linking the glycoside to the cleavable linker. Examples of enzymes that can be used to mediate the cleavage (hydrolysis) of glycosidic bonds connecting glycosides to cleavable linkers include glucuronidases, glycosidases, e.g., galactosidases, glucosidases, mannosidases, and fucosidases. Other suitable enzymes can also be used to mediate the cleavage (hydrolysis) of glycosidic bonds connecting glycosides to cleavable linkers. In some cases, the enzyme used to mediate the cleavage (hydrolysis) of glycosidic bonds connecting glycosides to cleavable linkers is found at or near the desired site of action for the drug in the antibody-drug conjugate. For example, the enzyme may be a lysosomal enzyme, e.g., a lysosomal glycosidase, found in cells at or near the desired site of action for the drug in the antibody-drug conjugate. In some cases, the enzyme is found at or near the target site where the enzyme mediating the cleavage of the first cleavable portion is found.

[0283] In a particular embodiment, the conjugate of formula (I) is as follows: [ka] TIFF0007912544000075.tif162152 TIFF0007912544000076.tif218148 TIFF0007912544000077.tif166149 TIFF0007912544000078.tif152152 TIFF0007912544000079.tif229149TIFF0007912544000080.tif208149 TIFF0007912544000081.tif206148TIFF0007912544000082.tif202150 TIFF0007912544000083.tif175149TIFF0007912544000084.tif173148TIFF0007912544000085.tif199149 It has a structure selected from TIFF0007912544000086.tif184150.

[0284] Any of the chemical entities, linkers, and coupling components shown in the above structure may be adapted for use in the compounds and conjugates of this subject.

[0285] Additional disclosures relating to hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl compounds and methods for producing conjugates are found in U.S. Patents 9,310,374 and 9,493,413, the respective disclosures of which are incorporated herein by reference. Additional disclosures relating to cleavable linkers are found in U.S. Provisional Patent Application No. 63 / 116,632, filed November 20, 2020, the respective disclosures of which are incorporated herein by reference.

[0286] Compounds useful for generating conjugates This disclosure provides hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl compounds useful for generating the conjugates described herein. In certain embodiments, the hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl compounds may be conjugate moieties useful for conjugating polypeptides (e.g., antibodies) with drugs or active agents (e.g., camptothecin or camptothecin derivatives). For example, the hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl compounds may bind to polypeptides (antibodies) and also to drugs or active agents, and thus indirectly conjugate both polypeptides (antibodies) and drugs.

[0287] In certain embodiments, the compound is a compound of formula (III), [ka] During the ceremony, Z, CR 4 or N, R 8 and R 9However, each is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or R 8 and R 9 However, they are optionally linked in a ring, forming a 5- or 6-membered heterocycline. Each R 10 However, independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, L is R 1 , R 2 , R 3 , R 4 , R 5 or R 6 This is a linker connected to the compound of formula (II), [ka] R 1 and R 2 However, each is independently selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or R 1 and R 2However, they are optionally linked cyclically to form a 5 or 6-membered cycloalkyl or heterocyclyl ring, R 3 and R 4 However, each is independently selected from hydrogen, halo, hydroxy, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or R 3 and R 4 However, they are optionally linked cyclically to form a 5 or 6-membered cycloalkyl or heterocyclyl ring, R 5 However, selected from hydrogen, halo, hydroxy, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, R 6 However, OH and OC(O)R 11 Selected from, R 11 However, selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, at least one R 10 However, it is optionally linked to the second compound of formula (II).

[0288] In some cases, the compound of formula (II) has the structure of formula (IIa). [ka] It has, in the formula, R 3 OH is, L is R 6 Connected to, or L is R 3 It is connected to R6 That is OH.

[0289] In some cases, the compound of formula (II) has the structure of formula (IIb). [ka] It has, in the formula, R 1a The is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and L is R 6 Connected to, or L is R 1a It is connected to R 6 That is OH.

[0290] In some cases, the compound of formula (II) has the structure of formula (IIc). [ka] It has, in the formula, R 1b The is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and L is R 6 Connected to, or L is R 1b It is connected to R 6 That is OH.

[0291] In some cases, the compound of formula (II) has the structure of formula (IId). [ka] It has, in the formula, R 2a and R 2bHowever, each is independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and L is R 6 Connected to, or L is R 2a Or R 2b It is connected to R 6 That is OH.

[0292] In some cases, the compound of formula (II) has the structure of formula (IIe). [ka] It has, in the formula, R 2c The following are selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and the connection to L is indicated by a wavy line.

[0293] Substitutions associated with the compounds of formulas (II), (IIa), (IIb), (IIc), (IId), and (IIe) are listed above. References to formula (II) are intended to also encompass formulas (IIa), (IIb), (IIc), (IId), and (IIe).

[0294] Regarding the compound of formula (III), substituents Z and R 8 , R 9 , R 10 L, L B , and W are as described above with respect to the conjugate of equation (I). Similarly, the first linker L and the second linker L of equation (III) B Regarding T 1 , T 2 , T 3 , T 4 , T 5 , T 6 , V 1 , V2 , V 3 , V 4 , V 5 , and V 6 , and T 7 , T 8 , T 9 , T 10 , T 11 , T 12 , V 7 , V 8 , V 9 , V 10 , V 11 , and V 12 The substituents are as described above with respect to the conjugate of formula (I).

[0295] For example, in some cases, T 1 , T 2 , T 3 , T 4 , T 5 , and T 6 , and V 1 , V 2 , V 3 , V 4 , V 5 , and V 6 The following can be selected: T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. T 6 However, it is EDA, V 6 However, it is either -CO- or T 1 However, (C1-C 12 ) is alkyl, V1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it does not exist, V 5 However, -NR 15 It is (C6H4)-, T 6 However, it does not exist, V 6 However, it is either -CO- or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, -NR 15 -and, T 6 However, (C1-C 12 ) is alkyl, V 6 However, it is either -CO- or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is AA, and V 2 However, it does not exist. T 3 However, it is PABC, and V 3 However, it does not exist. T4 However, it is EDA, V 4 However, it is -CO-, e and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is AA, and V 2 However, it does not exist. T 3 However, it is PABC, and V 3 However, it does not exist. d, e, and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABA, and V 5 However, it is -CO-, T 6 However, (C1-C 12 ) is alkyl, V 6 However, it is either -SO2- or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T 2 However, (PEG) n V 2 However, it is -CO-, T 3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PABC, and V 4 However, it does not exist. e and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T 2 However, substitution (C1-C 12 ) is alkyl, V 2 However, it is -CO-, T 3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PABC, and V 4 However, it does not exist. e and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T 2 However, (PEG) n V 2 However, it is -CO-, T 3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PABC, and V 4 However, it does not exist. T 5 However, (C1-C12 ) is alkyl, V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is 4AP, V 2 However, it is -CO-, T 3 However, (C1-C 12 ) is alkyl, V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is 4AP, V 2 However, it is -CO-, T 3 However, (C1-C 12 ) is alkyl, V 3 However, it is -O-, T 4 However, (C1-C 12 ) is alkyl, V 4 However, it is -CO-, T 5 However, it is AA, and V 5 However, it does not exist. T 6 However, it is PABC, and V 6 However, it does not exist, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it does not exist. T3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PABC, and V 4 However, it does not exist. e and f are each 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T 2 However, (PEG) n V 2 However, it is -CONH-, T 3 However, substitution (C1-C 12 ) is alkyl, V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is AA, and V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABC, and V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PABO, V 5 However, it does not exist. f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CO-, T 2 However, it is an amino acid analog, V 2 However, it is -NH-, T 3 However, (PEG) n V 3 However, it is -CO-, T 4 However, it is AA, and V 4 However, it does not exist. T 5 However, it is PAP, and V 5 However, he is the COO, f is 0, or T 1 However, (C1-C 12 ) is alkyl, V 1 However, it is -CONH-, T 2 However, (PEG) n V 2 However, it is -CO-, T 3 However, it is AA, and V 3 However, it does not exist. T 4 However, it is PAP, and V 4 However, he is the COO, e and f are both 0.

[0296] For example, in some cases, T 7 , T 8 , T 9 , T 10 , T 11 , and T12 , and V 7 , V 8 , V 9 , V 10 , V 11 , and V 12 The following can be selected: T 7 However, it does not exist, V 7 However, it is -NHCO-, T 8 However, (C1-C 12 ) is alkyl, V 8 However, it is -CO-, T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PABC, and V 10 However, it does not exist. T 11 However, it is EDA, V 11 However, it is -CO-, l is 0, or T 7 However, it does not exist, V 7 However, it is -NHCO-, T 8 However, (C1-C 12 ) is alkyl, V 8 However, it is -CO-, T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PABC, and V 10 However, it does not exist. k and l are each 0, or T 7 However, it does not exist, V 7 However, it is -NHCO-, T 8 However, (C1-C 12 ) is alkyl, V 8 However, it is -CO-, T 9 However, it is an amino acid analog, V 9 However, it is -NH-, T 10 However, (PEG) n V10 However, it is -CO-, T 11 However, it is AA, and V 11 However, it does not exist. T 12 However, it is PABC, and V 12 However, it does not exist, or T 7 However, it does not exist, V 7 However, it is -NHCO-, T 8 However, (C1-C 12 ) is alkyl, V 8 However, it is -CONH-, T 9 However, (PEG) n V 9 However, it is -CO-, T 10 However, it is AA, and V 10 However, it does not exist. T 11 However, it is PABC, and V 11 However, it does not exist. l is 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CONH-, T 8 However, substitution (C1-C 12 ) is alkyl, V 8 However, it is -CO-, T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PABC, and V 10 However, it does not exist. k and l are each 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CONH-, T 8 However, (PEG) n V 8 However, it is -CO-, T 9 However, it is AA, and V9 However, it does not exist. T 10 However, it is PABC, and V 10 However, it does not exist. T 11 However, (C1-C 12 ) is alkyl, V 11 However, it does not exist. l is 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CO-, T 8 However, it is 4AP, V 8 However, it is -CO-, T 9 However, (C1-C 12 ) is alkyl, V 9 However, it is -CO-, T 10 However, it is AA, and V 10 However, it does not exist. T 11 However, it is PABC, and V 11 However, it does not exist. l is 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CO-, T 8 However, it is 4AP, V 8 However, it is -CO-, T 9 However, (C1-C 12 ) is alkyl, V 9 However, it is -O-, T 10 However, (C1-C 12 ) is alkyl, V 10 However, it is -CO-, T 11 However, it is AA, and V 11 However, it does not exist. T 12 However, it is PABC, and V 12 However, it does not exist, or T 7 However, (C1-C 12) is alkyl, V 7 However, it is -CO-, T 8 However, it is an amino acid analog, V 8 However, it does not exist. T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PABC, and V 10 However, it does not exist. k and l are each 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CONH-, T 8 However, (PEG) n V 8 However, it is -CONH-, T 9 However, substitution (C1-C 12 ) is alkyl, V 9 However, it is -CO-, T 10 However, it is AA, and V 10 However, it does not exist. T 11 However, it is PABC, and V 11 However, it does not exist. l is 0, or T 7 However, (C1-C 12 ) is alkyl, V 7 However, it is -CO-, T 8 However, it is AA, and V 8 However, it is -NH-, T 9 However, (PEG) n V 9 However, it is -CO-, T 10 However, it is AA, and V 10 However, it does not exist. T 11 However, it is PABC, and V 11 However, it does not exist. l is 0, or T 7 However, (C1-C12 ) is alkyl, V 7 However, it is -CONH-, T 8 However, (PEG) n V 8 However, it is -CO-, T 9 However, it is AA, and V 9 However, it does not exist. T 10 However, it is PAP, and V 10 However, he is the COO, k and l are both 0.

[0297] The compound of formula (III) can be used in the conjugation reactions described herein, and the drug or active agent connected to the hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugate moiety is conjugated to a polypeptide (e.g., an antibody) to form an antibody-drug conjugate.

[0298] In a particular embodiment, the compound of formula (III) is as follows: [ka] TIFF0007912544000095.tif211150 TIFF0007912544000096.tif225152TIFF0007912544000097.tif162148 TIFF0007912544000098.tif152148 TIFF0007912544000099.tif230150TIFF0007912544000100.tif215149 TIFF0007912544000101.tif205149 TIFF0007912544000102.tif212149 TIFF0007912544000103.tif180150 TIFF0007912544000104.tif171148 It has the structure TIFF0007912544000105.tif202149TIFF0007912544000106.tif189153.

[0299] Any of the chemical entities, linkers, and conjugated portions shown in the above structure may be adapted for use in the compounds and conjugates of this subject.

[0300] Polypeptides and antibodies As shown above, the subject conjugate may include a polypeptide (e.g., an antibody) as substituent W. The amino acid sequence of the polypeptide (antibody) is modified to include a 2-formylglycine (fGly) residue. As used herein, amino acids may be referred to by their standard names, their standard three-letter abbreviations, and / or their standard one-letter abbreviations, for example, alanine or Ala or A, cysteine ​​or Cys or C, aspartic acid or Asp or D, glutamic acid or Glu or E, phenylalanine or Phe or F, glycine or Gly or G, histidine or His or H, isoleucine or Ile or I, lysine or Lys or K, leucine or Leu or L, methionine or Met or M, asparagine or Asn or N, proline or Pro or P, glutamine or Gln or Q, arginine or Arg or R, serine or Ser or S, threonine or Thr or T, valine or Val or V, tryptophan or Trp or W, and tyrosine or Tyr or Y.

[0301] In certain embodiments, the amino acid sequence of a polypeptide (antibody) is modified to include a sulfatase motif containing a serine or cysteine ​​residue that can be converted (oxidized) to a 2-formylglycine (fGly) residue by the action of formylglycine-producing enzyme (FGE) either in vivo (e.g., during translation of an aldehyde tag-containing protein in cells) or in vitro (e.g., by contacting an aldehyde tag-containing protein with FGE in a cell-free system). Such a sulfatase motif may also be referred to herein as an FGE modification site.

[0302] Sulfatase motif The minimum sulfatase motif of an aldehyde tag is typically 5 or 6 amino acid residues long, and usually 6 or fewer amino acid residues long. The sulfatase motif provided in an Ig polypeptide is at least 5 or 6 amino acid residues, and can be 5-16, 6-16, 5-15, 6-15, 5-14, 6-14, 5-13, 6-13, 5-12, 6-12, 5-11, 6-11, 5-10, 6-10, 5-9, 6-9, 5-8, or 6-8 amino acid residues long, for example, to define a sulfatase motif with an amino acid residue length of 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, or less than 6 amino acid residues.

[0303] In certain embodiments, the polypeptide of interest includes one or more amino acid residues, for example, two or more, or three or more, or four or more, or five or more, or six or more, or seven or more, or eight or more, or nine or more, or ten or more, or eleven or eleven or twelve or thirteen or thirteen or fourteen or fifteen or fifteen or sixteen or seven or seventeen or seven or eight or nine or twenty or more amino acid residues, compared to the native amino acid sequence for providing a sequence of sulfatase motifs in the polypeptide. In certain embodiments, the polypeptide includes modifications (insertions, additions, deletions, and / or substitutions) of 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or fewer than two amino acid residues in the amino acid sequence compared to the native amino acid sequence of the polypeptide. If the native amino acid sequence of a polypeptide (e.g., an antibody) contains one or more residues of a desired sulfatase motif, the total number of residue modifications can be reduced, for example, by site-specific modifications (insertion, addition, deletion, substitution / replacement) of amino acid residues adjacent to native amino acid residues that provide the sequence of the desired sulfatase motif. In certain embodiments, the degree of modification of the native amino acid sequence of the target antibody is minimized so as to minimize the number of amino acid residues inserted, deleted, substituted (replaced), and / or added (e.g., relative to the N-terminus or C-terminus). By minimizing the degree of modification of the amino acid sequence of the target antibody, the potential impact of such modifications on the antibody's function and / or structure can be minimized.

[0304] While aldehyde tags for specific purposes include at least one minimal sulfatase motif (also referred to as the “consensus sulfatase motif”), it should be noted that longer aldehyde tags are intended and included in this disclosure and may find applications in the compositions and methods of this disclosure. Accordingly, aldehyde tags may include a minimal sulfatase motif of five or six residues, or may be longer, and may include a minimal sulfatase motif that can be flanked at the N-terminal and / or C-terminal side of the motif by additional amino acid residues. For example, aldehyde tags of five or six amino acid residues, as well as longer amino acid sequences of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acid residues, are intended.

[0305] The aldehyde tag may be located at or near the C-terminus of the Ig heavy chain. For example, the aldehyde tag may be located within the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, or 10th amino acids at the C-terminus of the natural wild-type Ig heavy chain. The aldehyde tag may be located within the CH1 domain of the Ig heavy chain. The aldehyde tag may be located within the CH2 domain of the Ig heavy chain. The aldehyde tag may be located within the CH3 domain of the Ig heavy chain. The aldehyde tag may be located within the constant region of the Ig light chain, for example, within the kappa light chain constant region or the lambda light chain constant region.

[0306] In certain embodiments, the sulfatase motif used may be described by the following formula: X 1 Z 10 X 2 Z 20 X 3 Z 30 (I') During the ceremony, Z 10 However, it is cysteine ​​or serine (which can also be represented by (C / S)), Z 20 However, it is either a proline or alanine residue (which can also be represented by (P / A)), Z 30However, basic amino acids (for example, arginine (R), lysine (K) or histidine (H), for example, lysine), or aliphatic amino acids (alanine (A), glycine (G), leucine (L), valine (V), isoleucine (I), or proline (P), for example, A, G, L, V, or I, X 1 However, whether present or absent, if present, any amino acid, e.g., aliphatic amino acid, sulfur-containing amino acid, or polar uncharged amino acid (i.e., other than aromatic amino acids or charged amino acids), e.g., L, M, V, S, or T, e.g., L, M, S, or V, provided that the sulfatase motif is at the N-terminus of the target polypeptide, X 1 There exists, X 2 and X 3 However, independently, any amino acid may be used, but usually it may be an aliphatic amino acid, a polar uncharged amino acid, or a sulfur-containing amino acid (i.e., an amino acid other than an aromatic amino acid or a charged amino acid), such as S, T, A, V, G, or C, for example, S, T, A, V, or G.

[0307] The amino acid sequence of the antibody heavy chain and / or light chain is given by formula X 1 Z 10 X 2 Z 20 X 3 Z 30 It may be modified to provide a sequence of at least 5 amino acids, in the formula, Z 10 However, it is cysteine ​​or serine, Z 20 However, it is a proline or alanine residue, Z 30 However, they are aliphatic amino acids or basic amino acids. X 1 However, it may or may not exist, and if it exists, it is any amino acid, provided that a heterologous sulfatase motif is at the N-terminus of the polypeptide, X 1 There exists, X 2 and X 3 However, each of them is an arbitrary amino acid, independently of the others.

[0308] The sulfatase motif is generally selected so as to be convertible by a selected FGE, for example, an FGE present in a host cell expressing an aldehyde-tagged polypeptide, or an FGE that is contacted with the aldehyde-tagged polypeptide in a cell-free in vitro method.

[0309] For example, if FGE is a eukaryotic FGE (e.g., mammalian FGE, including human FGE), the sulfatase motif is given by the following formula. X 1 CX 2 PX 3 Z 30 (I'') It could also be a sulfatase motif. During the ceremony, X 1 However, it may or may not be present, and if present, it may be any amino acid, for example, an aliphatic amino acid, a sulfur-containing amino acid, or a polar uncharged amino acid (i.e., other than an aromatic amino acid or a charged amino acid), for example, L, M, S, or V, provided that the sulfatase motif is at the N-terminus of the target polypeptide, X 1 There exists, X 2 and X 3 However, independently, any amino acid, for example, an aliphatic amino acid, a sulfur-containing amino acid, or a polar uncharged amino acid (i.e., something other than an aromatic amino acid or a charged amino acid), for example, S, T, A, V, G, or C, for example, S, T, A, V, or G. Z 30 However, it may be a basic amino acid (for example, arginine (R), lysine (K) or histidine (H), for example, lysine), or an aliphatic amino acid (alanine (A), glycine (G), leucine (L), valine (V), isoleucine (I), or proline (P), for example, A, G, L, V, or I).

[0310] Specific examples of sulfatase motifs include LCTPSR(sequence code: / / ), MCTPSR(sequence code: / / ), VCTPSR(sequence code: / / ), LCSPSR(sequence code: / / ), LCAPSR(sequence code: / / ), LCVPSR(sequence code: / / ), LCGPSR(sequence code: / / ), ICTPAR(sequence code: / / ), LCTPSK(sequence code: / / ), MCTPSK(sequence code: / / ), VCTPSK(sequence code: / / ), LCSPSK(sequence code: / / ), LCAPSK(sequence code: / / ), LCVPSK(sequence code: / / ), LCGPSK(sequence code: / / ), LCTPSA(sequence code: / / ), ICTPAA(sequence code: / / ), MCTPSA(sequence code: / / ), VCTPSA(sequence code: / / ), LCSPSA(sequence code: / / ), LCAPSA(sequence code: / / ), LCVPSA(sequence code: / / ), and LCGPSA(sequence code: / / ).

[0311] fGly-containing sequences When FGE acts on the heavy and / or light chains of an antibody, serine or cysteine ​​in the sulfatase motif is modified to fGly. Therefore, the fGly-containing sulfatase motif is given by the following formula: X 1 (fGly)X 2 Z 20 X 3 Z 30 (I''') It could also be a sulfatase motif. During the ceremony, fGly is a formylglycine residue, Z 20 However, it is either a proline or alanine residue (which can also be represented by (P / A)), Z 30 However, basic amino acids (for example, arginine (R), lysine (K), or histidine (H), usually lysine is also acceptable), or aliphatic amino acids (alanine (A), glycine (G), leucine (L), valine (V), isoleucine (I), or proline (P), for example, A, G, L, V, or I, X 1However, it may or may not be present, and if present, any amino acid, for example, an aliphatic amino acid, a sulfur-containing amino acid, or a polar uncharged amino acid (i.e., other than an aromatic amino acid or a charged amino acid), for example, L, M, V, S, or T, for example, L, M, or V, provided that the sulfatase motif is at the N-terminus of the target polypeptide, X 1 There exists, X 2 and X 3 However, independently, any amino acid may be used, for example, an aliphatic amino acid, a sulfur-containing amino acid, or a polar uncharged amino acid (i.e., an amino acid other than an aromatic amino acid or a charged amino acid), for example, S, T, A, V, G, or C, for example, S, T, A, V, or G.

[0312] As described above, in order to generate a conjugate, a polypeptide containing fGly residues can be conjugated to a drug or active agent by a reaction between fGly and the reactive portion of a linker linked to the drug or active agent (for example, a hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugated portion, as described above), thereby generating an fGly'-containing sulfatase motif. As used herein, the term fGly' refers to the amino acid residue of the sulfatase motif coupled to the drug or active agent via a linker, as described herein. Thus, the fGly'-containing sulfatase motif is given by the following formula X 1 (fGly')X 2 Z 20 X 3 Z 30 (II) It could also be a sulfatase motif. During the ceremony, fGly' is an amino acid residue that is coupled to a drug or active agent via the linker described herein. Z 20 However, it is either a proline or alanine residue (which can also be represented by (P / A)), Z 30However, basic amino acids (for example, arginine (R), lysine (K), or histidine (H), usually lysine is also acceptable), or aliphatic amino acids (alanine (A), glycine (G), leucine (L), valine (V), isoleucine (I), or proline (P), for example, A, G, L, V, or I, X 1 However, it may or may not be present, and if present, any amino acid, for example, an aliphatic amino acid, a sulfur-containing amino acid, or a polar uncharged amino acid (i.e., other than an aromatic amino acid or a charged amino acid), for example, L, M, V, S, or T, for example, L, M, or V, provided that the sulfatase motif is at the N-terminus of the target polypeptide, X 1 There exists, X 2 and X 3 However, independently, any amino acid may be used, for example, an aliphatic amino acid, a sulfur-containing amino acid, or a polar uncharged amino acid (i.e., an amino acid other than an aromatic amino acid or a charged amino acid), for example, S, T, A, V, G, or C, for example, S, T, A, V, or G.

[0313] Modification site As shown above, the amino acid sequence of the polypeptide (antibody) is modified to include a sulfatase motif containing a serine or cysteine ​​residue that can be converted (oxidized) to an fGly residue by the action of FGE, either in vivo (e.g., during translation of an aldehyde tag-containing protein in cells) or in vitro (e.g., by contacting an aldehyde tag-containing protein with FGE in a cell-free system). The antibody used to generate the conjugate of this disclosure includes at least an Ig constant region, e.g., an Ig heavy chain constant region (e.g., at least a CH1 domain; at least CH1 and CH2 domains; CH1, CH2, and CH3 domains; or CH1, CH2, CH3, and CH4 domains), or an Ig light chain constant region. Such an Ig polypeptide is referred to herein as a “targeted Ig polypeptide” or “targeted antibody”.

[0314] The site in the antibody to which the sulfatase motif is introduced can be any convenient site. As shown above, in some cases the degree of modification of the native amino acid sequence of the target polypeptide is kept to a minimum so as to minimize the number of amino acid residues inserted, deleted, substituted, and / or added (e.g., to the N-terminus or C-terminus). By minimizing the degree of modification of the amino acid sequence of the target antibody, the potential impact of such modifications on the antibody's function and / or structure can be minimized.

[0315] The antibody heavy chain constant region may include the Ig constant region of any heavy chain isotype, or an Ig heavy chain constant region that does not exist naturally (including the consensus Ig heavy chain constant region). The Ig constant region amino acid sequence may be modified to include an aldehyde tag, which is located within or adjacent to the solvent-accessible loop region of the Ig constant region. The Ig constant region amino acid sequence may be modified by insertions and / or substitutions of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 amino acids, or more than 16 amino acids, to provide the amino acid sequence of the sulfatase motif as described above.

[0316] In some cases, the aldehyde-tagged antibody comprises an aldehyde-tagged Ig heavy chain constant region (e.g., at least a CH1 domain; at least CH1 and CH2 domains; CH1, CH2, and CH3 domains; or CH1, CH2, CH3, and CH4 domains). The aldehyde-tagged Ig heavy chain constant region may comprise an IgA, IgM, IgD, IgE, IgG1, IgG2, IgG3, or IgG4 isotype heavy chain, or any allotype variant thereof, such as a human heavy chain constant region sequence or a mouse heavy chain constant region sequence, a hybrid heavy chain constant region, a synthetic heavy chain constant region, or a consensus heavy chain constant region sequence modified by FGE to include at least one sulfatase motif capable of producing an fGly-modified Ig polypeptide. Allotype variants of Ig heavy chains are known in the art. See, for example, Jefferis and Lefranc (2009) MAbs 1:4.

[0317] In some cases, an aldehyde-tagged antibody includes an aldehyde-tagged Ig light chain constant region. The aldehyde-tagged Ig light chain constant region may include a kappa light chain, a lambda light chain, for example, a human kappa or lambda light chain constant region, a hybrid light chain constant region, a synthetic light chain constant region, or a consensus light chain constant region sequence modified by FGE and containing at least one sulfatase motif capable of producing an fGly-modified antibody. An exemplary constant region includes the human gamma 1 and gamma 3 regions. Except for the sulfatase motif, the modified constant region may have a wild-type amino acid sequence, or an amino acid sequence that is at least 70% identical (e.g., at least 80%, at least 90%, or at least 95% identical) to the wild-type amino acid sequence.

[0318] In some embodiments, the sulfatase motif is located at a position other than the C-terminus of the Ig polypeptide heavy chain, or at a position added to the C-terminus of the Ig polypeptide heavy chain. As shown above, the isolated aldehyde-tagged antibody may contain a heavy chain constant region amino acid sequence modified to include the sulfatase motif described above, where the sulfatase motif is located within or adjacent to a surface-accessible loop region of the antibody heavy chain constant region.

[0319] The sulfatase motif may be provided within or adjacent to one or more of these amino acid sequences of the modified site of the Ig heavy chain. For example, if the Ig heavy chain polypeptide amino acid sequence is modified by one or more of these amino acid sequences (e.g., the modification involves the insertion, deletion, and / or substitution of one or more amino acid residues), a sulfatase motif can be provided adjacent to these modified sites at the N-terminus and / or adjacent to the C-terminus. Alternatively, or in addition to the above, if the Ig heavy chain polypeptide amino acid sequence is modified by one or more of these amino acid sequences (e.g., the modification involves the insertion, deletion, and / or substitution of one or more amino acid residues), a sulfatase motif can be provided between any two residues of the Ig heavy chain modified site. In some embodiments, the Ig heavy chain polypeptide amino acid sequence may be modified to include two motifs, which may be adjacent to each other, or separated by one, two, three, four or more amino acids (e.g., about 1 to about 25, about 25 to about 50, or about 50 to about 100 or more amino acids). Alternatively, or in addition thereto, if the native amino acid sequence provides one or more amino acid residues of a sulfatase motif sequence, selected amino acid residues of the modification site of the Ig heavy chain polypeptide amino acid sequence may be modified to provide a sulfatase motif at the modification site (e.g., if the modification involves the insertion, deletion, and / or substitution of one or more amino acid residues).

[0320] The antibodies used in the antibody-drug conjugates of this disclosure are, but are not limited to, antigens present on cancer cells, antigens present on autoimmune cells, antigens present on pathogenic microorganisms, antigens present on virus-infected cells (e.g., human immunodeficiency virus-infected cells), and antigens present on disease cells, and may have any of the following antigen-binding specificities. For example, the antibody conjugate may bind to an antigen, and the antigen may be present on the surface of a cell. The antibody conjugates of this disclosure have a suitable binding affinity, for example, 5 × 10⁻⁶ -6 M~10 -7 M, 10 -7 M~5×10 -7 M, 5×10 -7 M~10 -8 M, 10 -8 M~5×10 -8 M, 5×10 -8 M~10 -9 M, or 10 -9 It can bind to antigens with a binding affinity greater than M.

[0321] As a non-limiting example, the antibody conjugate of the subject may bind to an antigen present on cancer cells (e.g., tumor-specific antigen, antigen overexpressed on cancer cells, etc.), and the conjugated portion may be a drug, such as a cytotoxic compound (e.g., a cytotoxic small molecule, a cytotoxic synthetic peptide, etc.). For example, the antibody conjugate of the subject may be specific to an antigen on cancer cells, and the conjugated portion may be a drug, such as a cytotoxic compound (e.g., a cytotoxic small molecule, a cytotoxic synthetic peptide, etc.).

[0322] As a further non-limiting example, the antibody conjugate of the subject may bind to an antigen present on a virus-infected cell (for example, if the antigen is encoded by a virus, or if the antigen is expressed on a cell type that is infected by the virus), and the conjugated portion may be a drug, such as a viral fusion inhibitor.

[0323] Drugs for conjugation into polypeptides This disclosure provides drug-polypeptide conjugates (e.g., antibody-drug conjugates). Suitable drugs for use, or drugs that can be modified to be suitable for use, as reactive partners for conjugating with polypeptides (e.g., antibodies) described herein include camptothecin or camptothecin derivatives. For example, suitable camptothecin and camptothecin derivatives for use in the conjugates and compounds described herein are not limited to the compounds of formulas (II), (IIa), (IIb), (IIc), and (IId), as described above.

[0324] Embodiments of the present disclosure include a conjugate in which a polypeptide (e.g., an antibody) is conjugated to one or more drug moieties, for example, two, three, four, five, six, seven, eight, nine, or ten drug moieties. The drug moieties can be conjugated to the antibody at one or more sites in the peptide (antibody) as described herein. In certain embodiments, the conjugate has an average drug-to-antibody ratio (DAR) (molar ratio) in the range of 0.1 to 10, or 0.5 to 10, or 1 to 10, for example, 1 to 9, or 1 to 8, or 1 to 7, or 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 to 2. In certain embodiments, the conjugate has an average DAR of 1 to 3, for example, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3. In certain embodiments, the conjugate has an average DAR of 1 to 2. In certain embodiments, the conjugate has an average DAR of 2 to 3. Average means arithmetic mean.

[0325] formulation The conjugates of this disclosure may be formulated in a variety of different ways. Generally, if the conjugate is a gradient-drug conjugate, the conjugate is formulated in a manner that is appropriate to the drug, antibody, the condition being treated, and the route of administration used.

[0326] In some embodiments, a pharmaceutical composition is provided comprising one of the conjugates of the present disclosure and a pharmaceutically acceptable excipient.

[0327] The conjugate (e.g., antibody-drug conjugate) may be provided in any preferred form, for example, in the form of a pharmaceutically acceptable salt, and may be formulated for any preferred route of administration, e.g., oral, topical, or parenteral administration. Where the conjugate is provided as an injectable liquid (such as in those embodiments where they are administered intravenously or directly to tissue), the conjugate may be provided as a ready-to-use dosage form, or as a reconstituted, storage-stable powder or liquid composed of a pharmaceutically acceptable carrier and excipients.

[0328] Methods for formulating the conjugate can be adapted from those readily available. For example, the conjugate may be provided as a pharmaceutical composition comprising a therapeutically effective amount of the conjugate and a pharmaceutically acceptable carrier (e.g., physiological saline). The pharmaceutical composition may optionally contain other additives (e.g., buffers, stabilizers, preservatives, etc.). In some embodiments, the formulation is suitable for administration to mammals, for example, to humans.

[0329] Treatment method The antibody-drug conjugates of this disclosure find applications in the treatment of conditions or diseases in subjects suitable for treatment by administration of the parent drug (i.e., camptothecin or a camptothecin derivative before conjugation to an antibody).

[0330] In some embodiments, methods are provided that include administering an effective amount (e.g., a therapeutically effective amount) of any of the conjugates of this disclosure to a target.

[0331] In certain embodiments, a method is provided for delivering a drug to a target site in a subject, the method comprising administering a pharmaceutical composition comprising one of the conjugates of the Disclosure to the subject, wherein the administration is effective in releasing a therapeutically effective amount of the drug (e.g., camptothecin or a camptothecin derivative) from the conjugate to a target site in the subject. For example, as described herein, the antibody-drug conjugate of the Disclosure may comprise a cleavable linker, for example, an enzymatically cleavable linker comprising a first enzymatically cleavable portion and a second enzymatically cleavable portion. In some cases, the cleavable linker may be cleaved under appropriate conditions to separate or release the drug from the antibody at a desired target site of action for the drug. For example, a second cleavable portion protecting the first ...

Claims

1. The conjugate of equation (I), 【Chemistry 1】 During the ceremony, Z is CR １０ or N, R ７ However, it is selected from hydrogen, alkyl, and substituted alkyl, R ８ and R ９ However, each is independently selected from hydrogen, alkyl, and substituted alkyl. Each R １０ However, they are independently selected from hydrogen, alkyl, and substituted alkyl, W is a polypeptide, L is R １ , R ２ , R ３ , R ４ , R ５ or R ６ a linker connected to the compound of formula (II), 【Chemistry 2】 R １ and R ２ However, each is independently selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, and substituted alkyl, or R １ and R ２ However, they are optionally linked in a cyclic manner to form a 5 or 6-membered cycloalkyl or heterocyclyl ring. R ３ and R ４ However, each is independently selected from hydrogen, halo, hydroxyl, amino, substituted amino, alkyl, and substituted alkyl. R ５ However, it is selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, and substituted alkyl. R ６ However, OH and OC(O)R １１ Selected from, R １１ However, it is selected from hydrogen, alkyl, and substituted alkyl, at least one R １０ However, a conjugate of formula (I) is optionally linked to a second compound of formula (II).

2. The compound of formula (II) has the structure of formula (IIa). 【Transformation 3】 It has, in the formula, R ３ OH is, L is R ６ Connected to, or L is R ３ It is connected to R ６ Either is an OH group, or the compound of formula (II) has the structure of formula (IIb). 【Chemistry 4】 It has, in the formula, R １ａ However, L is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and L is R ６ Connected to, or L is R １ａ It is connected to R ６ Either is OH, or the compound of formula (II) has the structure of formula (IIc). 【Transformation 5】 It has, in the formula, R １ｂ However, L is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and L is R ６ Connected to, or L is R １ｂ It is connected to R ６ Either is OH, or the compound of formula (II) has the structure of formula (IId). 【Transformation 6】 It has, in the formula, R ２ａ and R ２ｂ However, each is independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and L is R ６ Connected to, or L is R ２ａ Or R ２ｂ It is connected to R ６ Either is OH, or the compound of formula (II) has the structure of formula (IIe). 【Transformation 7】 It has, in the formula, R ２ｃ The conjugate according to claim 1, wherein the conjugate is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and the connection to L is indicated by a wavy line.

3. L is - (T １ -V １ ) ａ - (T ２ -V ２ ) ｂ - (T ３ -V ３ ) ｃ - (T ４ -V ４ ) ｄ - (T ５ -V ５ ) ｅ - (T ６ -V ６ ) ｆ - including, During the ceremony, a, b, c, d, e, and f are each independently 0 or 1. T １ , T ２ , T ３ , T ４ , T ５ , and T ６ However, each is independent, and covalently bonded, (C １ -C １２ ) alkyl, substituted (C １ -C １２ ) alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA) ｗ (PEG) ｎ (AA) ｐ ,-(CR １３ OH) ｍ -, 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino-benzylamino (PABA), para-amino-phenyl (PAP), para-hydroxyphenyl (PHP), acetal group, hydrazine, disulfide, and ester are selected, EDA is the ethylenediamine moiety, PEG is polyethylene glycol, AA is an amino acid residue or amino acid analog, each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each m is an integer from 1 to 12. V １ , V ２ , V ３ , V ４ , V ５ and V ６ are each independently selected from the group consisting of a covalent bond, -CO-, -NR １５ -, -NR １５ (CH ２ ) ｑ -, -NR １５ (C ６ H ４ )-, -CONR １５ -, -NR １５ CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO ２ -, -SO ２ NR １５ -, -NR １５ SO ２ -, and -P(O)OH-, and each q is an integer from 1 to 6, Each R １３ However, they are independently selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl. Each R １５ The conjugate according to claim 1 or 2, wherein the element is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

4. T １ is (C １ -C １２ )alkyl and substituted (C １ -C １２ )alkyl, T ２ , T ３ , T ４ , T ５ , and T ６ However, each is independent, and covalently bonded, (C １ -C １２ ) alkyl, substituted (C １ -C １２ ) alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA) ｗ (PEG) ｎ (AA) ｐ ,-(CR １３ OH) ｍ - Selected from 4-amino-piperidine (4AP), MABO, MABC, PABO, PABC, PAB, PABA, PAP, PHP, acetal group, hydrazine, and ester, V １ , V ２ , V ３ , V ４ , V ５ , and V ６ However, each is independent of the covalent bond, -CO-, -NR １５ -, -NR １５ (CH ２ ) ｑ -, -NR １５ (C ６ H ４ )-,-CONR １５ -, -NR １５ CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO ２ -, -SO ２ NR １５ -, -NR １５ SO ２ Selected from the group consisting of - and -P(O)OH-, (PEG) ｎ but, 【Transformation 8】 In the formula, n is an integer between 1 and 30. EDA has the following structure 【Chemistry 9】 The ethylenediamine moiety has the following characteristics, where y is an integer from 1 to 6, and r is 0 or 1. 4-amino-piperidine (4AP) 【Chemistry 10】 And, Each R １２ However, independently selected from hydrogen, alkyl, substituted alkyl, polyethylene glycol moiety, aryl, and substituted aryl, any two adjacent R １２ The conjugate according to claim 3, wherein the groups may be linked in a ring to form a piperazinyl ring.

5. T １ , T ２ , T ３ , T ４ , T ５ , and T ６ The conjugate according to claim 3 or 4, wherein each of the molecules is optionally substituted with a glycoside.

6. The conjugate according to claim 3 or 4, wherein MABO, MABC, PABO, PABC, PAB, PABA, PAP, and PHP are each optionally substituted with a glycoside.

7. The conjugate according to claim 5 or 6, wherein the glycoside is selected from glucuronide, galactoside, glucoside, mannoside, fucoside, O-GlcNAc, and O-GalNAc.

8. T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, it is an amino acid analog, V ２ However, it is -NH-, T ３ However, (PEG) ｎ V ３ However, it is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it is PABC, and V ５ However, it does not exist. T ６ However, it is EDA, V ６ However, it is either -CO- or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, it is an amino acid analog, V ２ However, it is -NH-, T ３ However, (PEG) ｎ V ３ However, it is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it does not exist, V ５ However, -NR １５ (C ６ H ４ ) - and T ６ However, it does not exist, V ６ However, it is either -CO- or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, it is an amino acid analog, V ２ However, it is -NH-, T ３ However, (PEG) ｎ V ３ However, it is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it is PABC, and V ５ However, -NR １５ - and T ６ However, (C １ -C １２ ) is alkyl, V ６ However, it is either -CO- or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, AA and V ２ However, it does not exist. T ３ However, it is PABC, and V ３ However, it does not exist. T ４ However, it is EDA, V ４ However, it is -CO-, e and f are both 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, it is an amino acid analog, V ２ However, it is -NH-, T ３ However, (PEG) ｎ V ３ However, it is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it is PABC, and V ５ However, it does not exist. f is 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, AA and V ２ However, it does not exist. T ３ However, it is PABC, and V ３ However, it does not exist. d, e, and f are each 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, it is an amino acid analog, V ２ However, it is -NH-, T ３ However, (PEG) ｎ V ３ However, it is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it is PABA, V ５ However, it is -CO-, T ６ However, (C １ -C １２ ) is alkyl, V ６ However, -SO ２ - or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CONH-, T ２ However, (PEG) ｎ V ２ However, it is -CO-, T ３ However, AA and V ３ However, it does not exist. T ４ However, it is PABC, and V ４ However, it does not exist. e and f are both 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CONH-, T ２ However, substitution (C １ -C １２ ) is alkyl, V ２ However, it is -CO-, T ３ However, AA and V ３ However, it does not exist. T ４ However, it is PABC, and V ４ However, it does not exist. e and f are both 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CONH-, T ２ However, (PEG) ｎ V ２ However, it is -CO-, T ３ However, AA and V ３ However, it does not exist. T ４ However, it is PABC, and V ４ However, it does not exist. T ５ However, (C １ -C １２ ) is alkyl, V ５ However, it does not exist. f is 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, it is 4AP, V ２ However, it is -CO-, T ３ However, (C １ -C １２ ) is alkyl, V ３ However, it is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it is PABC, and V ５ However, it does not exist. f is 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, it is 4AP, V ２ However, it is -CO-, T ３ However, (C １ -C １２ ) is alkyl, V ３ However, it is -O-, T ４ However, (C １ -C １２ ) is alkyl, V ４ However, it is -CO-, T ５ However, AA and V ５ However, it does not exist. T ６ However, it is PABC, and V ６ However, it does not exist, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, it is an amino acid analog, V ２ However, it does not exist. T ３ However, AA and V ３ However, it does not exist. T ４ However, it is PABC, and V ４ However, it does not exist. e and f are both 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CONH-, T ２ However, (PEG) ｎ V ２ However, it is -CONH-, T ３ However, substitution (C １ -C １２ ) is alkyl, V ３ However, it is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it is PABC, and V ５ However, it does not exist. f is 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, AA and V ２ However, it is -NH-, T ３ However, (PEG) ｎ V ３ However, it is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it is PABC, and V ５ However, it does not exist. f is 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, it is an amino acid analog, V ２ However, it is -NH-, T ３ However, (PEG) ｎ V ３ However, it is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it is PABO, V ５ However, it does not exist. f is 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, it is an amino acid analog, V ２ However, it is -NH-, T ３ However, (PEG) ｎ V ３ However, it is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it is PAP, V ５ However, he is the COO, f is 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CONH-, T ２ However, (PEG) ｎ V ２ However, it is -CO-, T ３ However, AA and V ３ However, it does not exist. T ４ However, it is PAP, V ４ However, he is the COO, The conjugate according to any one of claims 3 to 7, wherein e and f are each 0.

9. One R １０ However, the second linker L Ｂ The conjugate according to any one of claims 1 to 8, which is linked to the second compound of formula (II) via a .

10. L Ｂ But, - (T ７ -V ７ ) ｇ - (T ８ -V ８ ) ｈ - (T ９ -V ９ ) ｉ - (T １０ -V １０ ) ｊ - (T １１ -V １１ ) ｋ - (T １２ -V １２ ) ｌ - including, During the ceremony, g, h, i, j, k, and l are each independently 0 or 1. T ７ , T ８ , T ９ , T １０ , T １１ , and T １２ However, each is independent, and covalently bonded, (C １ -C １２ ) alkyl, substituted (C １ -C １２ ) alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA) ｗ (PEG) ｎ (AA) ｐ ,-(CR １３ OH) ｍ -, 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino-benzylamino (PABA), para-amino-phenyl (PAP), para-hydroxyphenyl (PHP), acetal group, hydrazine, disulfide, and ester are selected, EDA is the ethylenediamine moiety, PEG is polyethylene glycol, AA is an amino acid residue or amino acid analog, each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each m is an integer from 1 to 12. V ７ , V ８ , V ９ , V １０ , V １１ , and V １２ However, each is independent of the covalent bond, -CO-, -NR １５ -, -NR １５ (CH ２ ) ｑ -, -NR １５ (C ６ H ４ )-,-CONR １５ -, -NR １５ CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO ２ -, -SO ２ NR １５ -, -NR １５ SO ２ Selected from the group consisting of - and -P(O)OH-, where each q is an integer from 1 to 6, Each R １３ However, they are independently selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl. Each R １５ The conjugate according to claim 9, wherein the elements are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

11. T ７ , T ８ , T ９ , T １０ , T １１ , and T １２ The conjugate according to claim 10, wherein each of the molecules is optionally substituted with a glycoside.

12. The conjugate according to claim 10, wherein MABO, MABC, PABO, PABC, PAB, PABA, PAP, and PHP are each optionally substituted with a glycoside.

13. The conjugate according to claim 11 or 12, wherein the glycoside is selected from glucuronide, galactoside, glucoside, mannoside, fucoside, O-GlcNAc, and O-GalNAc.

14. T ７ However, it does not exist, V ７ However, it is NHKCO, T ８ However, (C １ -C １２ ) is alkyl, V ８ However, it is -CO-, T ９ However, AA and V ９ However, it does not exist. T １０ However, it is PABC, and V １０ However, it does not exist. T １１ However, it is EDA, V １１ However, it is -CO-, l is 0, or T ７ However, it does not exist, V ７ However, it is NHKCO, T ８ However, (C １ -C １２ ) is alkyl, V ８ However, it is -CO-, T ９ However, AA and V ９ However, it does not exist. T １０ However, it is PABC, and V １０ However, it does not exist. k and l are each 0, or T ７ However, it does not exist, V ７ However, it is NHKCO, T ８ However, (C １ -C １２ ) is alkyl, V ８ However, it is -CO-, T ９ However, it is an amino acid analog, V ９ However, it is -NH-, T １０ However, (PEG) ｎ V １０ However, it is -CO-, T １１ However, AA and V １１ However, it does not exist. T １２ However, it is PABC, and V １２ However, it does not exist, or T ７ However, it does not exist, V ７ However, it is NHKCO, T ８ However, (C １ -C １２ ) is alkyl, V ８ However, it is -CONH-, T ９ However, (PEG) ｎ V ９ However, it is -CO-, T １０ However, AA and V １０ However, it does not exist. T １１ However, it is PABC, and V １１ However, it does not exist. l is 0, or T ７ However, (C １ -C １２ ) is alkyl, V ７ However, it is -CONH-, T ８ However, substitution (C １ -C １２ ) is alkyl, V ８ However, it is -CO-, T ９ However, AA and V ９ However, it does not exist. T １０ However, it is PABC, and V １０ However, it does not exist. k and l are each 0, or T ７ However, (C １ -C １２ ) is alkyl, V ７ However, it is -CONH-, T ８ However, (PEG) ｎ V ８ However, it is -CO-, T ９ However, AA and V ９ However, it does not exist. T １０ However, it is PABC, and V １０ However, it does not exist. T １１ However, (C １ -C １２ ) is alkyl, V １１ However, it does not exist. l is 0, or T ７ However, (C １ -C １２ ) is alkyl, V ７ However, it is -CO-, T ８ However, it is 4AP, V ８ However, it is -CO-, T ９ However, (C １ -C １２ ) is alkyl, V ９ However, it is -CO-, T １０ However, AA and V １０ However, it does not exist. T １１ However, it is PABC, and V １１ However, it does not exist. l is 0, or T ７ However, (C １ -C １２ ) is alkyl, V ７ However, it is -CO-, T ８ However, it is 4AP, V ８ However, it is -CO-, T ９ However, (C １ -C １２ ) is alkyl, V ９ However, it is -O-, T １０ However, (C １ -C １２ ) is alkyl, V １０ However, it is -CO-, T １１ However, AA and V １１ However, it does not exist. T １２ However, it is PABC, and V １２ However, it does not exist, or T ７ However, (C １ -C １２ ) is alkyl, V ７ However, it is -CO-, T ８ However, it is an amino acid analog, V ８ However, it does not exist. T ９ However, AA and V ９ However, it does not exist. T １０ However, it is PABC, and V １０ However, it does not exist. k and l are each 0, or T ７ However, (C １ -C １２ ) is alkyl, V ７ However, it is -CONH-, T ８ However, (PEG) ｎ V ８ However, it is -CONH-, T ９ However, substitution (C １ -C １２ ) is alkyl, V ９ However, it is -CO-, T １０ However, AA and V １０ However, it does not exist. T １１ However, it is PABC, and V １１ However, it does not exist. l is 0, or T ７ However, (C １ -C １２ ) is alkyl, V ７ However, it is -CO-, T ８ However, AA and V ８ However, it is -NH-, T ９ However, (PEG) ｎ V ９ However, it is -CO-, T １０ However, AA and V １０ However, it does not exist. T １１ However, it is PABC, and V １１ However, it does not exist. l is 0, or T ７ However, (C １ -C １２ ) is alkyl, V ７ However, it is -CONH-, T ８ However, (PEG) ｎ V ８ However, it is -CO-, T ９ However, AA and V ９ However, it does not exist. T １０ However, it is PAP, V １０ However, he is the COO, The conjugate according to any one of claims 10 to 13, wherein k and l are each 0.

15. The aforementioned conjugate, 【Chemistry 11】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 A conjugate according to any one of claims 1 to 14, selected from the above.

16. A compound of formula (III), 【Chemistry 12】 During the ceremony, Z is CR １０ or N, R ８ and R ９ However, each is independently selected from hydrogen, alkyl, and substituted alkyl. Each R １０ However, they are independently selected from hydrogen, alkyl, and substituted alkyl. L is R １ , R ２ , R ３ , R ４ , R ５ or R ６ This is a linker connected to the compound of formula (II), 【Chemistry 13】 R １ and R ２ However, each is independently selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, and substituted alkyl, or R １ and R ２ However, they are optionally linked in a cyclic manner to form a 5 or 6-membered cycloalkyl or heterocyclyl ring. R ３ and R ４ However, each is independently selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, and substituted alkyl. R ５ However, it is selected from hydrogen, halogen, hydroxyl, amino, substituted amino, alkyl, and substituted alkyl. R ６ However, OH and OC(O)R １１ Selected from, R １１ However, it is selected from hydrogen, alkyl, and substituted alkyl, at least one R １０ However, a compound of formula (III) is optionally linked to a second compound of formula (II).

17. The compound of formula (II) has the structure of formula (IIa). 【Chemistry 14】 It has, in the formula, R ３ OH is, L is R ６ Connected to, or L is R ３ It is connected to R ６ Either is an OH group, or the compound of formula (II) has the structure of formula (IIb). 【Chemistry 15】 It has, in the formula, R １ａ However, L is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and L is R ６ Connected to, or L is R １ａ It is connected to R ６ Either is OH, or the compound of formula (II) has the structure of formula (IIc). 【Chemistry 16】 It has, in the formula, R １ｂ However, L is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and L is R ６ Connected to, or L is R １ｂ It is connected to R ６ Either is OH, or the compound of formula (II) has the structure of formula (IId). 【Chemistry 17】 It has, in the formula, R ２ａ and R ２ｂ However, each is independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and L is R ６ Connected to, or L is R ２ａ Or R ２ｂ It is connected to R ６ Either is OH, or the compound of formula (II) has the structure of formula (IIe). [Chemistry 18] It has, in the formula, R ２ｃ The compound according to claim 16, wherein the connection to L is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, acyl, and sulfonyl, and the connection to L is indicated by a wavy line.

18. L is - (T １ -V １ ) ａ - (T ２ -V ２ ) ｂ - (T ３ -V ３ ) ｃ - (T ４ -V ４ ) ｄ - (T ５ -V ５ ) ｅ - (T ６ -V ６ ) ｆ - including, During the ceremony, a, b, c, d, e, and f are each independently 0 or 1. T １ , T ２ , T ３ , T ４ , T ５ , and T ６ However, each is independent, and covalently bonded, (C １ -C １２ ) alkyl, substituted (C １ -C １２ ) alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA) ｗ (PEG) ｎ (AA) ｐ ,-(CR １３ OH) ｍ -, 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino-benzylamino (PABA), para-amino-phenyl (PAP), para-hydroxyphenyl (PHP), acetal group, hydrazine, disulfide, and ester are selected, EDA is the ethylenediamine moiety, PEG is polyethylene glycol, AA is an amino acid residue or amino acid analog, each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each m is an integer from 1 to 12. V １ , V ２ , V ３ , V ４ , V ５ , and V ６ However, each is independent of the covalent bond, -CO-, -NR １５ -, -NR １５ (CH ２ ) ｑ -, -NR １５ (C ６ H ４ )-,-CONR １５ -, -NR １５ CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO ２ -, -SO ２ NR １５ -, -NR １５ SO ２ Selected from the group consisting of - and -P(O)OH-, where each q is an integer from 1 to 6, Each R １３ However, they are independently selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl. Each R １５ The compound according to claim 16 or 17, which is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

19. T １ However, (C １ -C １２ ) alkyl and substituted (C １ -C １２ ) Selected from alkyl groups, T ２ , T ３ , T ４ , T ５ , and T ６ However, each is independent, and covalently bonded, (C １ -C １２ ) alkyl, substituted (C １ -C １２ ) alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA) ｗ (PEG) ｎ (AA) ｐ ,-(CR １３ OH) ｍ - Selected from 4-amino-piperidine (4AP), MABO, MABC, PABO, PABC, PAB, PABA, PAP, PHP, acetal group, hydrazine, and ester, V １ , V ２ , V ３ , V ４ , V ５ , and V ６ However, each is independent of the covalent bond, -CO-, -NR １５ -, -NR １５ (CH ２ ) ｑ -, -NR １５ (C ６ H ４ )-,-CONR １５ -, -NR １５ CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO ２ -, -SO ２ NR １５ -, -NR １５ SO ２ Selected from the group consisting of - and -P(O)OH-, (PEG) ｎ but, 【Chemistry 19】 In the formula, n is an integer between 1 and 30. EDA has the following structure 【Chemistry 20】 The ethylenediamine moiety has the following characteristics, where y is an integer from 1 to 6, and r is 0 or 1. 4-amino-piperidine (4AP) 【Chemistry 21】 And, Each R １２ However, independently selected from hydrogen, alkyl, substituted alkyl, polyethylene glycol moiety, aryl, and substituted aryl, any two adjacent R １２ The compound according to claim 18, wherein the groups may be linked in a cyclic manner to form a piperazinyl ring.

20. T １ , T ２ , T ３ , T ４ , T ５ , and T ６ The compound according to claim 18 or 19, wherein each of the compounds is optionally substituted with a glycoside.

21. The compound according to claim 18 or 19, wherein MABO, MAC, PABO, PABC, PAB, PABA, PAP, and PHP are each optionally substituted with a glycoside.

22. The compound according to claim 20 or 21, wherein the glycoside is selected from glucuronide, galactoside, glucoside, mannoside, fucoside, O-GlcNAc, and O-GalNAc.

23. T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, it is an amino acid analog, V ２ However, it is -NH-, T ３ However, (PEG) ｎ V ３ However, it is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it is PABC, and V ５ However, it does not exist. T ６ However, it is EDA, V ６ However, it is either -CO- or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, it is an amino acid analog, V ２ However, it is -NH-, T ３ However, (PEG) ｎ V ３ However, it is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it does not exist, V ５ However, -NR １５ (C ６ H ４ ) - and T ６ However, it does not exist, V ６ However, it is either -CO- or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, it is an amino acid analog, V ２ However, it is -NH-, T ３ However, (PEG) ｎ V ３ However, it is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it is PABC, and V ５ However, -NR １５ - and T ６ However, (C １ -C １２ ) is alkyl, V ６ However, it is either -CO- or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, AA and V ２ However, it does not exist. T ３ However, it is PABC, and V ３ However, it does not exist. T ４ However, it is EDA, V ４ However, it is -CO-, e and f are both 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, it is an amino acid analog, V ２ However, it is -NH-, T ３ However, (PEG) ｎ V ３ However, it is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it is PABC, and V ５ However, it does not exist. f is 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, AA and V ２ However, it does not exist. T ３ However, it is PABC, and V ３ However, it does not exist. d, e, and f are each 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, it is an amino acid analog, V ２ However, it is -NH-, T ３ However, (PEG) ｎ V ３ However, it is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it is PABA, V ５ However, it is -CO-, T ６ However, (C １ -C １２ ) is alkyl, V ６ However, -SO ２ - or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CONH-, T ２ However, (PEG) ｎ V ２ However, it is -CO-, T ３ However, AA and V ３ However, it does not exist. T ４ However, it is PABC, and V ４ However, it does not exist. e and f are both 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CONH-, T ２ However, substitution (C １ -C １２ ) is alkyl, V ２ However, it is -CO-, T ３ However, AA and V ３ However, it does not exist. T ４ However, it is PABC, and V ４ However, it does not exist. e and f are both 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CONH-, T ２ However, (PEG) ｎ V ２ However, it is -CO-, T ３ However, AA and V ３ However, it does not exist. T ４ However, it is PABC, and V ４ However, it does not exist. T ５ However, (C １ -C １２ ) is alkyl, V ５ However, it does not exist. f is 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, it is 4AP, V ２ However, it is -CO-, T ３ is (C １ -C １２ ) alkyl, and V ３ is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it is PABC, and V ５ However, it does not exist. f is 0, or T １ is (C １ -C １２ ) alkyl, and V １ is -CO-, T ２ However, it is 4AP, V ２ However, it is -CO-, T ３ However, (C １ -C １２ ) is alkyl, V ３ However, it is -O-, T ４ However, (C １ -C １２ ) is alkyl, V ４ However, it is -CO-, T ５ However, AA and V ５ However, it does not exist. T ６ However, it is PABC, and V ６ However, it does not exist, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, it is an amino acid analog, V ２ However, it does not exist. T ３ However, AA and V ３ However, it does not exist. T ４ However, it is PABC, and V ４ However, it does not exist. e and f are both 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CONH-, T ２ However, (PEG) ｎ V ２ However, it is -CONH-, T ３ However, substitution (C １ -C １２ ) is alkyl, V ３ However, it is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it is PABC, and V ５ However, it does not exist. f is 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, AA and V ２ However, it is -NH-, T ３ However, (PEG) ｎ V ３ However, it is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it is PABC, and V ５ However, it does not exist. f is 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, it is an amino acid analog, V ２ However, it is -NH-, T ３ is (PEG) ｎ , and V ３ is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it is PABO, V ５ However, it does not exist. f is 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CO-, T ２ However, it is an amino acid analog, V ２ However, it is -NH-, T ３ However, (PEG) ｎ V ３ However, it is -CO-, T ４ However, AA and V ４ However, it does not exist. T ５ However, it is PAP, V ５ However, he is the COO, f is 0, or T １ However, (C １ -C １２ ) is alkyl, V １ However, it is -CONH-, T ２ However, (PEG) ｎ V ２ However, it is -CO-, T ３ However, AA and V ３ However, it does not exist. T ４ However, it is PAP, V ４ However, he is the COO, The compound according to any one of claims 18 to 22, wherein e and f are each 0.

24. One R １０ However, the second linker L Ｂ The compound according to any one of claims 16 to 23, which is linked to the second compound of formula (II) via a certain linkage.

25. L Ｂ but, -(T ７ -V ７ ) ｇ -(T ８ -V ８ ) ｈ -(T ９ -V ９ ) ｉ -(T １０ -V １０ ) ｊ -(T １１ -V １１ ) ｋ -(T １２ -V １２ ) ｌ , which comprises During the ceremony, g, h, i, j, k, and l are each independently 0 or 1. T ７ , T ８ , T ９ , T １０ , T １１ , and T １２ However, each is independent, and covalently bonded, (C １ -C １２ ) alkyl, substituted (C １ -C １２ ) alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA) ｗ (PEG) ｎ (AA) ｐ ,-(CR １３ OH) ｍ -, 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino-benzylamino (PABA), para-amino-phenyl (PAP), para-hydroxyphenyl (PHP), acetal group, hydrazine, disulfide, and ester are selected, EDA is the ethylenediamine moiety, PEG is polyethylene glycol, AA is an amino acid residue or amino acid analog, each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each m is an integer from 1 to 12. V ７ , V ８ , V ９ , V １０ , V １１ , and V １２ However, each is independent of the covalent bond, -CO-, -NR １５ -, -NR １５ (CH ２ ) ｑ -, -NR １５ (C ６ H ４ )-,-CONR １５ -, -NR １５ CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO ２ -, -SO ２ NR １５ -, -NR １５ SO ２ Selected from the group consisting of - and -P(O)OH-, where each q is an integer from 1 to 6, Each R １３ However, they are independently selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl. Each R １５ The compound according to claim 24, wherein the compound is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

26. T ７ , T ８ , T ９ , T １０ , T １１ , and T １２ The compound according to claim 25, wherein each of the compounds is optionally substituted with a glycoside.

27. The compound according to claim 25, wherein MABO, MAC, PABO, PABC, PAB, PABA, PAP, and PHP are each optionally substituted with a glycoside.

28. The compound according to claim 26 or 27, wherein the glycoside is selected from glucuronide, galactoside, glucoside, mannoside, fucoside, O-GlcNAc, and O-GalNAc.

29. T ７ However, it does not exist, V ７ However, it is NHKCO, T ８ However, (C １ -C １２ ) is alkyl, V ８ However, it is -CO-, T ９ However, AA and V ９ However, it does not exist. T １０ However, it is PABC, and V １０ However, it does not exist. T １１ However, it is EDA, V １１ However, it is -CO-, l is 0, or T ７ However, it does not exist, V ７ However, it is NHKCO, T ８ However, (C １ -C １２ ) is alkyl, V ８ However, it is -CO-, T ９ However, AA and V ９ However, it does not exist. T １０ However, it is PABC, and V １０ However, it does not exist. k and l are each 0, or T ７ However, it does not exist, V ７ However, it is NHKCO, T ８ However, (C １ -C １２ ) is alkyl, V ８ However, it is -CO-, T ９ However, it is an amino acid analog, V ９ However, it is -NH-, T １０ However, (PEG) ｎ V １０ However, it is -CO-, T １１ However, AA and V １１ However, it does not exist. T １２ However, it is PABC, and V １２ However, it does not exist, or T ７ However, it does not exist, V ７ However, it is NHKCO, T ８ However, (C １ -C １２ ) is alkyl, V ８ However, it is -CONH-, T ９ However, (PEG) ｎ V ９ However, it is -CO-, T １０ However, AA and V １０ However, it does not exist. T １１ However, it is PABC, and V １１ However, it does not exist. l is 0, or T ７ However, (C １ -C １２ ) is alkyl, V ７ However, it is -CONH-, T ８ However, substitution (C １ -C １２ ) is alkyl, V ８ However, it is -CO-, T ９ However, AA and V ９ However, it does not exist. T １０ However, it is PABC, and V １０ However, it does not exist. k and l are each 0, or T ７ However, (C １ -C １２ ) is alkyl, V ７ However, it is -CONH-, T ８ However, (PEG) ｎ V ８ However, it is -CO-, T ９ However, AA and V ９ However, it does not exist. T １０ However, it is PABC, and V １０ However, it does not exist. T １１ However, (C １ -C １２ ) is alkyl, V １１ However, it does not exist. l is 0, or T ７ However, (C １ -C １２ ) is alkyl, V ７ However, it is -CO-, T ８ However, it is 4AP, V ８ However, it is -CO-, T ９ However, (C １ -C １２ ) is alkyl, V ９ However, it is -CO-, T １０ However, AA and V １０ However, it does not exist. T １１ However, it is PABC, and V １１ However, it does not exist. l is 0, or T ７ However, (C １ -C １２ ) is alkyl, V ７ However, it is -CO-, T ８ However, it is 4AP, V ８ However, it is -CO-, T ９ However, (C １ -C １２ ) is alkyl, V ９ However, it is -O-, T １０ However, (C １ -C １２ ) is alkyl, V １０ However, it is -CO-, T １１ However, AA and V １１ However, it does not exist. T １２ However, it is PABC, and V １２ However, it does not exist, or T ７ However, (C １ -C １２ ) is alkyl, V ７ However, it is -CO-, T ８ However, it is an amino acid analog, V ８ However, it does not exist. T ９ However, AA and V ９ However, it does not exist. T １０ However, it is PABC, and V １０ However, it does not exist. k and l are each 0, or T ７ However, (C １ -C １２ ) is alkyl, V ７ However, it is -CONH-, T ８ However, (PEG) ｎ V ８ However, it is -CONH-, T ９ However, substitution (C １ -C １２ ) is alkyl, V ９ However, it is -CO-, T １０ However, AA and V １０ However, it does not exist. T １１ However, it is PABC, and V １１ However, it does not exist. l is 0, or T ７ However, (C １ -C １２ ) is alkyl, V ７ However, it is -CO-, T ８ However, AA and V ８ However, it is -NH-, T ９ However, (PEG) ｎ V ９ However, it is -CO-, T １０ However, AA and V １０ However, it does not exist. T １１ However, it is PABC, and V １１ However, it does not exist. l is 0, or T ７ However, (C １ -C １２ ) is alkyl, V ７ However, it is -CONH-, T ８ However, (PEG) ｎ V ８ However, it is -CO-, T ９ However, AA and V ９ However, it does not exist. T １０ However, it is PAP, V １０ However, he is the COO, The compound according to any one of claims 25 to 28, wherein k and l are each 0.

30. The aforementioned compound, 【Chemistry 22】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 A compound according to any one of claims 16 to 29, selected from the above.

31. A pharmaceutical composition, A conjugate according to any one of claims 1 to 15, A pharmaceutical composition comprising a pharmaceutically acceptable excipient.

32. A pharmaceutical composition comprising an effective amount of the conjugate described in any one of claims 1 to 15.

33. A pharmaceutical composition for treating cancer in a subject, wherein the pharmaceutical composition is A pharmaceutical composition comprising a therapeutically effective amount of the conjugate described in any one of claims 1 to 15.

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