Tubricin and protein-tubricin conjugate

Abstract

Provided herein are compounds, compositions, and methods for the treatment of cancer-related diseases and disorders, including tubulysin and its protein (eg, antibody) drug conjugates.

Description

[Technical Field]

[0001] (cross reference) This application claims the interests of U.S. Provisional Patent Application No. 63 / 043,771, filed on 24 June 2020, which is hereby incorporated in its entirety by reference.

[0002] (Field) Provided herein are novel tubulsin and its protein conjugate, as well as methods for treating various diseases, disorders, and conditions, comprising administering the tubulsin and its protein conjugate. [Background technology]

[0003] (background) Antibody-drug conjugates (ADCs) are increasingly being used in cancer treatment regimens, but novel or treatment-induced resistance mechanisms can impair clinical benefits. Two resistance mechanisms that occur under continuous in vitro ADC exposure are the upregulation of transporters that confer multidrug resistance (MDR) and the loss of homologous antigen expression. Novel technologies to circumvent these resistance mechanisms will help extend the usefulness of next-generation ADCs.

[0004] Tubricins, first isolated from myxobacteria cultures, are a group of extremely potent tubulin polymerization inhibitors that rapidly disrupt the cytoskeleton of dividing cells and induce apoptosis. Tubricins are composed of N-methyl-D-pipecolic acid (Mep), L-isoleucine (Ile), and tubuvaline (Tuv), which contain rare N,O-acetals and secondary alcohols or acetoxy groups. Tubricins A, B, C, G, and I contain the C-terminal tubutyrosine (Tut)γ-amino acid, while Tubricins D, E, F, and H instead have tubuphenylalanine (Tup) in that position (Angew. Chem. Int. Ed. Engl. 43, 4888-4892).

[0005] Tubricin emerged as a promising anti-cancer lead compound due to its potent activity in drug-resistant cells based on a validated mechanism of action. Its mean cell proliferation inhibitory activity, including activity against multidrug-resistant carcinomas, is 10 to over 1000 times higher than that of well-known epothilon, vinblastine, and taxol (Biochem. J. 2006, 396, 235-242; Nat. Prod. Rep. 2015, 32, 654-662). Tubricin exhibits extremely potent antiproliferative activity against cancer cells, including multidrug-resistant KB-V1 cervical cancer cells (Angew. Chem. Int. Ed. 2004, 43, 4888-4892; and Biochemical Journal 2006, 396, 235-242). [Overview of the Initiative]

[0006] (overview) Provided herein are, for example, compounds useful in anti-cancer and anti-angiogenic therapies.

[0007] In one embodiment, the formula provided is: [ka] A compound having or a pharmaceutically acceptable salt thereof. (In the formula, BA is a binder; L is a linker covalently bonded to BA and T; T is [ka] And here, R 1 is a bond, hydrogen, C1-C 10 Alkyl, first N-terminal amino acid residue, first amino acid residue, -C1-C 10 Alkyl-NR 3a R 3b , or -C1-C 10 It is alkyl-OH; R 3 is hydroxyl, -O-, -O-C1-C5 alkyl, -OC(O)C1-C5 alkyl, -OC(O)N(H)C1-C 10 alkyl, -OC(O)N(H)C1-C 10 alkyl-NR 3a R 3b , -NHC(O)C1-C5 alkyl, or -OC(O)N(H)(CH2CH2O) n C1-C 10 alkyl-NR 3a R 3b , and wherein R 3a and R 3b are in each occurrence independently a bond, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted; R 4 and R 5 are in each occurrence independently hydrogen or C1-C5 alkyl; R 6 is -OH, -O-, -NHNH2, -NHNH-, -NHSO2(CH2) a1 -aryl-(CH2) a2 NR 6a R 6b , and wherein aryl is substituted or unsubstituted; and R 6a and R 6b are in each occurrence independently a bond, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted; R 7 is in each occurrence independently hydrogen, -OH, -O-, halogen, or -NR 7a R 7b , and wherein R 7a and R 7bIn each case, independently, are a bond, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, acyl, -C(O)CH2OH, -C(O)CH2O-, first N-terminal amino acid residue, first amino acid residue, first N-terminal peptide residue, first peptide residue, -CH2CH2NH2, and -CH2CH2NH-; where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted; R 8 In each case, independently, hydrogen, -NHR 9 , or halogen, Here, R 9 is hydrogen, -C1-C5 alkyl, or -C(O)C1-C5 alkyl; and m is either 1 or 2; R 10 If present, it is a -C1-C5 alkyl group; Q is -CH2- or -O-, where R 2 These are alkyl, alkylene, alkynyl, alkynylene, positional isomer triazole, and positional isomer triazolylene; Here, the positional isomer triazole or positional isomer triazolylene is either unsubstituted or substituted with alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or acyl; n is an integer between 1 and 10; r is an integer between 1 and 6; a, a1, and a2 are independently 0 or 1; and k is an integer between 1 and 30; T is not one of the compounds IVa, IVa′, IVb, IVc, IVd, IVe, IVf, IVg, IVh, IVj, IVk, IVl, IVm, IVn, IVo, IVp, IVq, IVr, IVs, IVt, IVu, IVvA, IVvB, IVw, IVx, IVy, Va, Va′, Vb, Vc, Vd, Ve, Vf, Vg, Vh, Vi, Vj, Vk, VIa, IVb, VIc, VId, VIe, VIf, VIg, VIh, Vl, VIi, VII, VIII, IX, X, D-5a, and D-5c, or any pharmaceutically acceptable salts thereof, covalently bonded to L.

[0008] In one embodiment, the provided material is a compound having the structure of formula I or a pharmaceutically acceptable salt thereof: [ka] (In the formula, R 1 is hydrogen, C1-C 10 Alkyl, first N-terminal amino acid residue, -C1-C 10 Alkyl-NR 3a R 3b , or -C1-C 10 It is alkyl-OH; R 3 These are hydroxyl, -O-C1-C5 alkyl, -OC(O)C1-C5 alkyl, -OC(O)N(H)C1-C 10 Alkyl, -OC(O)N(H)C1-C 10 Alkyl-NR 3a R 3b -NHC(O)C1-C5 alkyl, or -OC(O)N(H)(CH2CH2O) n C1-C 10 Alkyl-NR 3a R 3b And, Here, R 3a and R 3b In each case, independently, are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl; where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted; R 4 and R 5 In each case, is independently hydrogen or a C1-C5 alkyl group; R 6 -OH, -NHNH2, -NHSO2(CH2) a1 -Aryl-(CH2) a2 NR 6a R 6b And, Here, aryl is either substituted or not substituted; and R 6a and R 6b In each case, independently, are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl; where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted; R 7 In each case, independently, hydrogen, -OH, halogen, or -NR 7a R 7b And, Here, R 7a and R 7b In each case, independently, are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, acyl, -C(O)CH2OH, the first N-terminal amino acid residue, the first N-terminal peptide residue, and -CH2CH2NH2; where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted; R 8 In each case, independently, hydrogen, -NHR 9 , or halogen, Here, R 9 is hydrogen, -C1-C5 alkyl, or -C(O)C1-C5 alkyl; and m is either 1 or 2; R 10 If present, it is a -C1-C5 alkyl group; Q is -CH2- or -O-, where R 2 It is an alkyl, alkynyl, or positional isomer triazole; Here, the triazole of the positional isomer is either unsubstituted or substituted with alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl; n is an integer between 1 and 10; r is an integer between 1 and 6; a, a1, and a2 are independently 0 or 1; and T is the compound IVa, IVa′, IVb, IVc, IVd, IVe, IVf, IVg, IVh, IVj, IVk, IVl, IVm, IVn, IVo, IVp, IVq, IVr, IVs, IVt, IVu, IVvA, IVvB, IVw, IVx, IVy, Va, Va′, Vb , Vc, Vd, Ve, Vf, Vg, Vh, Vi, Vj, Vk, VIa, IVb, VIc, VId, VIe, VIf, VIg, VIh, Vl, VIi, VII, VIII, IX, 14 (Not desacetoxytublicin H)

[0009] In another embodiment, a method is provided for treating a tumor that expresses an antigen selected from the group consisting of PRLR and STEAP2.

[0010] Another embodiment provided is: formula: [ka] (In the formula, L is a linker covalently bonded to T; T is [ka] And here, R 1 is a bond, hydrogen, C1-C 10 Alkyl, first N-terminal amino acid residue, first amino acid residue, -C1-C 10 Alkyl-NR 3a R 3b , or -C1-C 10is alkyl-OH; R 3 is hydroxyl, -O-, -O-C1-C5 alkyl, -OC(O)C1-C5 alkyl, -OC(O)N(H)C1-C 10 alkyl, -OC(O)N(H)C1-C 10 alkyl-NR 3a R 3b , -NHC(O)C1-C5 alkyl, or -OC(O)N(H)(CH2CH2O) n C1-C 10 alkyl-NR 3a R 3b wherein here, R 3a and R 3b are in each case independently a bond, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted; R 4 and R 5 are in each case independently hydrogen or C1-C5 alkyl; R 6 is -OH, -O-, -NHNH2, -NHNH-, -NHSO2(CH2) a1 -aryl-(CH2) a2 NR 6a R 6b wherein herein, aryl is substituted or unsubstituted; and R 6a and R 6b are in each case independently a bond, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted; R 7 is in each case independently hydrogen, -OH, -O-, halogen, or -NR 7a R 7b wherein here, R 7a and R 7bIn each case, independently, are a bond, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, acyl, -C(O)CH2OH, -C(O)CH2O-, first N-terminal amino acid residue, first amino acid residue, first N-terminal peptide residue, first peptide residue, -CH2CH2NH2, and -CH2CH2NH-; where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted; R 8 In each case, independently, hydrogen, -NHR 9 , or halogen, Here, R 9 is hydrogen, -C1-C5 alkyl, or -C(O)C1-C5 alkyl; and m is either 1 or 2; R 10 If present, it is a -C1-C5 alkyl group; Q is -CH2- or -O-, where R 2 These are alkyl, alkylene, alkynyl, alkynylene, positional isomer triazole, and positional isomer triazolylene; Here, the positional isomer triazole or positional isomer triazolylene is either unsubstituted or substituted with alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or acyl; n is an integer between 1 and 10; r is an integer between 1 and 6; a, a1, and a2 are independently either 0 or 1. A linker-payload having or a pharmaceutically acceptable salt thereof; The linker-payload is the linker-payload or a pharmaceutically acceptable salt thereof, but is not LP1-IVa, LP2-Va, LP3-IVd, LP4-Ve, LP5-IVd, LP6-Vb, LP7-IVd, LP9-IVvB, LP10-VIh, LP11-IVvB, LP12-VIi, LP13-Ve, LP14-Ve, LP15-VIh, LP16-Ve, LP17-Ve, LP18-Ve, LP19-Ve, LP20-Ve, LP21-Ve, LP22-Ve, LP23-Vb, LP24-Vb, LP25-Ve, and LP26-Ve or a pharmaceutically acceptable salt thereof.

[0011] In another embodiment, the antibody-drug conjugate described herein comprises an antibody or an antigen-binding fragment thereof, wherein the antibody or the antigen-binding fragment is conjugated to a compound described herein.

[0012] In another embodiment, methods for preparing the compounds, linker-payloads, or antibody-drug conjugates and compositions described herein are described herein. [Brief explanation of the drawing]

[0013] (Brief explanation of the drawing) [Figure 1] Figure 1 shows the synthetic chemical schemes of tubulyisin payloads and tubulyisin linker payloads that can be conjugated to or are conjugated to antibodies or their antigen-binding fragments. [Figure 2] Figure 2 shows the synthetic chemical schemes of tubulinin payloads and tubulinin linker-payloads that can be conjugated to or are conjugated to antibodies or their antigen-binding fragments. [Figure 3] Figure 3 shows the synthetic chemical schemes of tubulinin payloads and tubulinin linker-payloads that can be conjugated to or are conjugated to antibodies or their antigen-binding fragments. [Figure 4] Figure 4 shows the synthetic chemical schemes of tubulinin payloads and tubulinin linker-payloads that can be conjugated to or are conjugated to antibodies or their antigen-binding fragments. [Figure 5] Figure 5 shows the synthetic chemical schemes of tubulinin payloads and tubulinin linker-payloads that can be conjugated to or are conjugated to antibodies or their antigen-binding fragments. [Figure 6] Figure 6 shows the synthetic chemical schemes of tubulinin payloads and tubulinin linker-payloads that can be conjugated to or are conjugated to antibodies or their antigen-binding fragments. [Figure 7] Figure 7 shows the synthetic chemical schemes of tubulinin payloads and tubulinin linker-payloads that can be conjugated to or are conjugated to antibodies or their antigen-binding fragments. [Figure 8] Figure 8 shows the synthetic chemical schemes of tubulinin payloads and tubulinin linker-payloads that can be conjugated to or are conjugated to antibodies or their antigen-binding fragments. [Figure 9] Figure 9 shows the synthetic chemical schemes of tubulinin payloads and tubulinin linker-payloads that can be conjugated to or are conjugated to antibodies or their antigen-binding fragments. [Figure 10] Figure 10 shows the synthetic chemical schemes of tubulinin payloads and tubulinin linker-payloads that can be conjugated to or are conjugated to antibodies or their antigen-binding fragments. [Figure 11] Figure 11 shows the synthetic chemical schemes of tubulinin payloads and tubulinin linker-payloads that can be conjugated to or are conjugated to antibodies or their antigen-binding fragments. [Figure 12]Figures 12A and 12B show the synthetic chemical schemes of the tubulinin payload and tubulinin linker-payload, respectively, which can be conjugated to or are conjugated to an antibody or its antigen-binding fragment. [Figure 13] Figures 13A and 13B show the synthetic chemical schemes of the tubulinin payload and tubulinin linker-payload, respectively, which can be conjugated to or are conjugated to an antibody or its antigen-binding fragment. [Figure 14] Figure 14 shows the synthetic chemical schemes of tubulinin payloads and tubulinin linker-payloads that can be conjugated to or are conjugated to antibodies or their antigen-binding fragments. [Figure 15] Figures 15A, 15B, and 15C show the synthetic chemical schemes of tubulinin payloads and tubulinin linker-payloads that can be conjugated to or are conjugated to antibodies or their antigen-binding fragments, respectively. [Figure 16] Figure 16 shows the synthetic chemical schemes of tubulinin payloads and tubulinin linker-payloads that can be conjugated to or are conjugated to antibodies or their antigen-binding fragments. [Modes for carrying out the invention]

[0014] (Description of exemplary embodiments) Provided herein are compounds, compositions, and methods useful for treating, for example, cancer.

[0015] (definition) When referring to the compounds provided herein, the following terms have the meanings set forth below unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art. If there are multiple definitions for a term provided herein, these definitions shall prevail unless otherwise stated.

[0016] As used herein, “alkyl” refers to a monovalent saturated hydrocarbon radical moiety. The alkyl may be optionally substituted and may be linear, branched, or cyclic, i.e., cycloalkyl. The alkyl may be a radical having 1 to 20 carbon atoms, i.e., C 1-20 Alkyl; a radical having 1 to 12 carbon atoms, i.e., C 1-12 Alkyl; a radical having 1 to 10 carbon atoms, i.e., C 1-10 Alkyl; a radical having 1 to 8 carbon atoms, i.e., C 1-8 Alkyl; a radical having 5 to 10 carbon atoms, i.e., C 5-10 Alkyl; a radical having 1 to 5 carbon atoms, i.e., C 1-5 Alkyl; a radical having 1 to 6 carbon atoms, i.e., C 1-6 Alkyl; and radicals having 1 to 3 carbon atoms, i.e., C 1-3 Examples of alkyl groups include, but are not limited to, alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, i-butyl, pentyl groups, hexyl groups, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of pentyl groups include, but are not limited to, n-pentyl and i-pentyl. Examples of hexyl groups include, but are not limited to, n-hexyl.

[0017] As used herein, “alkylene” refers to a divalent alkyl group. Unless otherwise specified, alkylenes contain, but are not limited to, 1 to 20 carbon atoms. The alkylene group is optionally substituted, as is described herein for alkyls. In some embodiments, the alkylene is unsubstituted.

[0018] The notation of an amino acid or amino acid residue without specifying its stereochemistry is intended to include the L-type amino acid, the D-type amino acid, or a racemic mixture thereof.

[0019] As used herein, “haloalkyl” refers to an alkyl group as defined above, wherein the alkyl group comprises at least one substituent selected from halogens, such as fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Examples of haloalkyl groups include, but are not limited to, -CF3, -CH2CF3, -CCl2F, and -CCl3.

[0020] As used herein, “alkenyl” refers to a monovalent hydrocarbon radical moiety containing at least two carbon atoms and one or more non-aromatic carbon-carbon double bonds. Alkenyls are optionally substituted and can be linear, branched, or cyclic. Alkenyls are radicals having 2 to 20 carbon atoms, i.e., C 2-20 Alkenyl; a radical having 2 to 12 carbon atoms, i.e., C 2-12 Alkenyl; a radical having 2 to 8 carbon atoms, i.e., C 2-8 Alkenyl; a radical having 2 to 6 carbon atoms, i.e., C 2-6 Alkenyls; and radicals having 2 to 4 carbon atoms, i.e., C 2-4 Examples of alkenyl moieties include, but are not limited to, vinyl, propenyl, butenyl, and cyclohexenyl.

[0021] As used herein, “alkynyl” refers to a monovalent hydrocarbon radical moiety containing at least two carbon atoms and one or more carbon-carbon triple bonds. Alkynnyls are optionally substituted and can be linear, branched, or cyclic. Alkynnyls are radicals having 2 to 20 carbon atoms, i.e., C 2-20 Alkynyl; a radical having 2 to 12 carbon atoms, i.e., C 2-12 Alkynyl; a radical having 2 to 8 carbon atoms, i.e., C 2-8 Alkynyl; a radical having 2 to 6 carbon atoms, i.e., C 2-6Alkynnyl; and radicals having 2 to 4 carbon atoms, i.e., C 2-4 Examples of alkynyl moieties include, but are not limited to, ethynyl, propynyl, and butynyl.

[0022] As used herein, “alkoxy” refers to a monovalent saturated hydrocarbon radical moiety, where the hydrocarbon contains a single bond to an oxygen atom, and the radical is located on the oxygen atom, for example, CH3CH2-O· in the case of ethoxy. The alkoxy substituent is bonded to the compound it substitutes via this oxygen atom of the alkoxy substituent. The alkoxy is optionally substituted and can be linear, branched, or cyclic, i.e., cycloalkoxy. As alkoxy, it can have 1 to 20 carbon atoms, i.e., C 1-20 Alkoxy; having 1 to 12 carbon atoms, i.e., C 1-12 Alkoxy; having 1 to 8 carbon atoms, i.e., C 1-8 Alkoxy; having 1 to 6 carbon atoms, i.e., C 1-6 Alkoxy; and those having 1 to 3 carbon atoms, i.e., C 1-3 Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, i-butoxy, pentoxy moieties, hexoxy moieties, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[0023] As used herein, “haloalkoxy” means an alkoxy as defined above, wherein the alkoxy comprises at least one substituent selected from halogens, e.g., F, Cl, Br, or I.

[0024] As used herein, "aryl" refers to a monovalent site, which is a radical of an aromatic compound whose ring atoms are carbon atoms. The aryl is optionally substituted and can be monocyclic or polycyclic, for example, bicyclic or tricyclic. An example of an aryl site is one having 6 to 20 ring carbon atoms, i.e., C 6-20 Aryl; having 6 to 15 ring carbon atoms, i.e., C 6-15 Aryls, and those having 6 to 10 ring carbon atoms, i.e., C 6-10 Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, fluorenyl, azlenyl, anthryl, phenanthryl, and pyrenyl.

[0025] As used herein, “arylalkyl” refers to a monovalent radical of an alkyl compound, where the alkyl compound is substituted with an aromatic substituent, i.e., the aromatic compound contains a single bond to the alkyl group, and the radical is located on the alkyl group. The arylalkyl group is bonded to the exemplified chemical structure via the alkyl group. The arylalkyl group is structured, for example, [ka] (wherein B is an aromatic moiety, e.g., aryl or phenyl) can be represented by the following: The arylalkyl is optionally substituted, i.e., the aryl group and / or alkyl group can be substituted as disclosed herein. Examples of arylalkyls include, but are not limited to, benzyl.

[0026] As used herein, “alkylaryl” refers to a monovalent radical of an aryl compound, where the aryl compound is substituted with an alkyl substituent, i.e., the aryl compound contains a single bond to an alkyl group, and the radical is located on the aryl group. The alkylaryl group is bonded to the exemplified chemical structure via the aryl group. The alkylaryl is structured, for example, [ka] It can be represented by (wherein B is an aromatic moiety, e.g., phenyl). The alkylaryl is optionally substituted, i.e., the aryl group and / or alkyl group may be substituted as disclosed herein. Examples of alkylaryls include, but are not limited to, toluyl.

[0027] As used herein, "aryloxy" refers to a monovalent site that is a radical of an aromatic compound in which the ring atom is a carbon atom and the ring is substituted with an oxygen radical; that is, the aromatic compound contains a single bond to the oxygen atom and the radical is located on the oxygen atom, for example, in the case of phenoxy, [ka] The aryloxy substituent is bonded to the compound it substitutes for via this oxygen atom. The aryloxy is optionally substituted. The aryloxy is a radical having 6 to 20 ring carbon atoms, i.e., C 6-20 Aryloxy; having 6 to 15 ring carbon atoms, i.e., C 6-15 Aryloxy, and those having 6 to 10 ring carbon atoms, i.e., C 6-10 Examples of aryloxy groups include, but are not limited to, aryloxy groups. Examples of aryloxy groups include, but are not limited to, phenoxy, naphthoxy, and anthroxy.

[0028] As used herein, "arylene" refers to the divalent site of an aromatic compound in which the ring atoms consist solely of carbon atoms. Arylenes are optionally substituted and can be monocyclic or polycyclic, for example, bicyclic or tricyclic. Examples of arylene sites include those having 6 to 20 ring carbon atoms, i.e., C 6-20 Arylene; having 6 to 15 ring carbon atoms, i.e., C 6-15 Arylenes, and those having 6 to 10 ring carbon atoms, i.e., C 6-10Arrines are one example, but are not limited to them.

[0029] As used herein, “heteroalkyl” refers to an alkyl group in which one or more carbon atoms are substituted by a heteroatom. As used herein, “heteroalkenyl” refers to an alkenyl group in which one or more carbon atoms are substituted by a heteroatom. As used herein, “heteroalkynyl” refers to an alkynyl group in which one or more carbon atoms are substituted by a heteroatom. Preferred heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur atoms. Heteroalkyl groups, heteroalkenyl groups, and heteroalkynyl groups are optionally substituted. Examples of heteroalkyl groups include, but are not limited to, aminoalkyl groups, sulfonylalkyl groups, and sulfinylalkyl groups. Examples of heteroalkyl groups also include, but are not limited to, methylamino groups, methylsulfonyl groups, and methylsulfinyl groups.

[0030] As used herein, “heteroaryl” refers to a monovalent site in an aromatic compound where the ring atoms are radicals containing a carbon atom and at least one oxygen, sulfur, nitrogen, or phosphorus atom. Examples of heteroaryl sites include, but are not limited to, those having 5 to 20 ring atoms; 5 to 15 ring atoms; and 5 to 10 ring atoms. Heteroaryls are optionally substituted.

[0031] As used herein, "heteroarylene" refers to a divalent heteroaryl compound in which one or more ring atoms of an aromatic ring are substituted with oxygen, sulfur, nitrogen, or phosphorus atoms. Heteroarylenes are optionally substituted.

[0032] As used herein, “heterocycloalkyl” refers to a cycloalkyl group in which one or more carbon atoms are substituted by heteroatoms. Preferred heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur atoms. Heterocycloalkyl groups are optionally substituted. Examples of heterocycloalkyl moieties include, but are not limited to, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, dioxolanyl, dithiolanyl, oxanyl, or thianyl.

[0033] As used herein, “Lewis acid” refers to a molecule or ion that accepts a lone pair of electrons. Lewis acids used in the methods described herein are non-protons. Examples of Lewis acids include, but are not limited to, nonmetallic acids, metallic acids, hard Lewis acids, and soft Lewis acids. Examples of Lewis acids include, but are not limited to, those of aluminum, boron, iron, tin, titanium, magnesium, copper, antimony, phosphorus, silver, ytterbium, scandium, nickel, and zinc. Examples of Lewis acids include AlBr3, AlCl3, BCl3, boron trichloride methyl sulfide, BF3, boron trifluoride methyl etherate, boron trifluoride methyl sulfide, boron trifluoride tetrahydrofuran, dicyclohexylboron trifluoromethanesulfonate, iron(III) bromide, iron(III) chloride, tin(IV) chloride, titanium(IV) chloride, titanium(IV) isopropoxide, Cu(OTf)2, CuCl2, CuBr2, zinc chloride, alkylaluminum halides (R n AlX 3-n Examples include, but are not limited to, Zn(OTf)2, ZnCl2, Yb(OTf)3, Sc(OTf)3, MgBr2, NiCl2, Sn(OTf)2, Ni(OTf)2, and Mg(OTf)2 (wherein R is hydrocarbyl).

[0034] As used herein, "N-containing heterocycloalkyl" refers to a cycloalkyl group in which one or more carbon atoms are substituted by heteroatoms, and at least one of the substituted heteroatoms is a nitrogen atom. Suitable heteroatoms other than nitrogen include, but are not limited to, oxygen and sulfur atoms. N-containing heterocycloalkyl groups are optionally substituted. Examples of N-containing heterocycloalkyl moieties include, but are not limited to, morpholinyl, piperidinyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, or thiazolidinyl.

[0035] As used herein, the term "optionally substituted," used to describe a radical site, for example, an optionally substituted alkyl, means that such a site is optionally bonded to one or more substituents. Examples of such substituents include halo, cyano, nitro, amino, hydroxyl, optionally substituted haloalkyl, aminoalkyl, hydroxyalkyl, azide, epoxy, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, [ka] (In the formula, R A , R B , and R C Each instance is independently either a hydrogen atom, an alkyl, an alkenyl, an alkynyl, an aryl, an alkylaryl, an arylalkyl, a heteroalkyl, a heteroaryl, or a heterocycloalkyl, or R A and R BExamples include, but are not limited to, groups that, together with the atoms to which they are bonded, form a saturated or unsaturated carbon ring, where the ring is optionally substituted, and one or more ring atoms are optionally substituted with heteroatoms. In some embodiments, if the radical moiety is optionally substituted with an optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted saturated or unsaturated carbon ring, the substituents on the optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted saturated or unsaturated carbon ring are not substituted with substituents that are further optionally substituted with further substituents if they are substituted. In some embodiments, if the groups described herein are optionally substituted, the substituents bonded to the group are unsubstituted unless otherwise specified.

[0036] As used herein, “binding agent” means any molecule that can bind with specificity to a given binding partner, for example, an antigen, such as a protein, antibody, or a fragment thereof.

[0037] As used herein, “linker” refers to a divalent, trivalent, or polyvalent site that can covalently link the binder to one or more compounds described herein, e.g., payload compounds, reinforcing agents, and / or prodrug payload compounds (e.g., via a reactive group at one end; and, in some embodiments, via an amino acid and / or spacer at another end). As used herein, “payload” refers to tubulisin or a tubulisin derivative. As used herein, “prodrug payload compound” or “prodrug” refers to a payload terminated with one or more amino acid residues, or another chemical residue as described elsewhere herein. Thus, in some embodiments, the linker can ultimately be cleaved to release a payload compound in the form of a tubulisin derivative. In other embodiments, the linker can ultimately be cleaved to release a prodrug payload compound in the form of a tubulisin derivative having one or more terminal amino acid residues. Such prodrug payload compounds may be further processed by accepted biological processes (e.g., amide bond hydrolysis) that ultimately result in payload compounds in the form of tubulisin payload compounds that do not have terminal amino acid residues.

[0038] As used herein, “amide synthesis conditions” refer to reaction conditions suitable for achieving amide formation by, for example, the reaction of a carboxylic acid, an activated carboxylic acid, or an acyl halide with an amine. In some examples, amide synthesis conditions refer to reaction conditions suitable for achieving the formation of an amide bond between a carboxylic acid and an amine. In some of these examples, the carboxylic acid is first converted to an activated carboxylic acid, and then the activated carboxylic acid reacts with the amine to form an amide. Suitable conditions for achieving amide formation include, but are not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), and (7-azabenzotriazole-1-yloxy)tripyrrolidinophosphonium hexa Fluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium Examples of reagents used to achieve the reaction between carboxylic acids and amines include, but are not limited to, 3-oxide hexafluorophosphate (HATU), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDC), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), and carbonyldiimidazole (CDI). In some examples, the carboxylic acid is first converted to an activated carboxylic acid ester, and then the activated carboxylic acid ester is treated with an amine to form an amide bond.In one embodiment, a carboxylic acid is treated with a reagent. The reagent deprotonates the carboxylic acid and then activates it by causing a nucleophilic attack by the deprotonated carboxylic acid on the protonated reagent, resulting in the formation of a product complex with the deprotonated carboxylic acid. Subsequently, the activated carboxylic acid ester of a particular carboxylic acid is more susceptible to nucleophilic attack by the amine than before the carboxylic acid was activated. As a result, amide bond formation occurs. Therefore, the carboxylic acid is described as activated. Exemplary reagents include DCC and DIC.

[0039] As used herein, “positional isomer (singular),” “positional isomers (plural),” or “mixture of positional isomers” refers to the products of 1,3-cyclization or strain-enhanced alkyne-azide cyclization (SPAAC)—also known as click reactions—derived from a suitable azide (e.g., -N3, or PEG-N3 derivatized antibody) treated with a suitable alkyne. In some embodiments, for example, positional isomers and mixtures of positional isomers are characterized by the click reaction products shown below. [ka] In one embodiment, two or more suitable azides and two or more suitable alkynes can be utilized in an intermediate synthesis scheme to the product, in which each azide-alkyne pair can participate in one or more independent click reactions to produce a mixture of click reaction products of positional isomers. For example, those skilled in the art will recognize that in the intermediate synthesis to the product, a first suitable azide may independently react with a first suitable alkyne, and a second suitable azide may independently react with a second suitable alkyne, resulting in the formation of four possible click reaction positional isomers, or a mixture of the four possible click reaction positional isomers.

[0040] As used herein, the term “residue” refers to a chemical site in a compound that remains after a chemical reaction. For example, the terms “amino acid residue,” “N-alkyl amino acid residue,” or “N-terminal amino acid residue” refer to the product of an amide coupling or peptide coupling reaction with an amino acid, an N-alkyl amino acid, or a suitable coupling partner of an N-terminal amino acid; where, after the amide or peptide coupling of the amino acid or N-alkyl amino acid, for example, a water molecule is expelled, resulting in a product in which the amino acid residue, N-alkyl amino acid residue, or N-terminal amino acid residue is incorporated. The term “amino acid” refers to natural and synthetic α, β, γ, or δ amino acids, including, but not limited to, amino acids found in proteins, namely glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, and histidine. In some embodiments, the amino acid is in the L-stereoconfiguration. Alternatively, the amino acids may be derivatives of alanyl, valinel, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, arginine, histidinyl, β-alanyl, β-valinel, β-leucinyl, β-isoleucinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-arginine, or β-histidinyl. The term "amino acid derivative" refers to a group that can be derived from natural or non-natural amino acids, as described and illustrated herein. Amino acid derivatives are obvious to those skilled in the art and include, but are not limited to, esters of natural and non-natural amino acids, amino alcohols, amino aldehydes, amino lactones, and N-methyl derivatives.In one embodiment, the amino acid residue is... [ka] That is (In the formula, S c is a side chain or bond of a natural or unnatural amino acid (e.g., hydrogen in the case of glycine; -CH2OH in the case of serine; -CH2SH in the case of cysteine; -CH2CH2CH2CH2NH2 in the case of lysine; -CH2CH2COOH in the case of glutamic acid; -CH2CH2C(O)NH2 in the case of glutamine; or -CH2C6H5OH in the case of tyrosine; etc.); and [ka] (This refers to binding to another chemical entity, such as another amino acid residue or an N-alkyl amino acid residue, which results in a peptide or peptide residue, but is not limited to these.) In one embodiment, S c The element is selected from the group consisting of hydrogen, alkyl, heteroalkyl, arylalkyl, and heteroarylalkyl.

[0041] As used herein, “therapeutic dose” means an amount (e.g., of a compound) that is sufficient to provide a therapeutic benefit to a patient in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with said disease or disorder.

[0042] As used herein, “structural isomer” refers to a compound having the same molecular formula but different chemical structures due to the arrangement of its atoms. Exemplary structural isomers include n-propyl and isopropyl; n-butyl, sec-butyl, and tert-butyl; and n-pentyl, isopentyl, and neopentyl.

[0043] Specific groups, sites, substituents, and atoms are depicted using wavy lines that intersect with the bonds (one or more), indicating the atoms to which the group, site, substituent, or atom is bonded. For example: [ka] The phenyl group substituted with a propyl group, as depicted, has the following structure: [ka] Where used herein, diagrams showing substituents bonded to a cyclic group (e.g., aromatic, heteroaromatic, fused ring, and saturated or unsaturated cycloalkyl or heterocycloalkyl) via bonds between ring atoms mean, unless otherwise specified, that the cyclic group may be substituted with the substituent at any ring position on any ring within the cyclic group or on any ring within the fused ring group, according to the art described herein or known in the art to which this disclosure relates. For example, the following groups [ka] (In the formula, the subscript q is an integer between 0 and 4, and the substituent R 1 The position of the substituent R is generally described as being at any vertex of the bond line structure, i.e., not directly bonded to a specific ring carbon atom. 1 Examples of non-restrictive groups that are bonded to specific ring carbon atoms include the following: [ka] .

[0044] Where used herein, the phrase "reactive linker" or the abbreviation "RL" means, for example, [ka] (In the formula, RG is a reactive group and SP is a spacer group.) This refers to a monovalent group comprising a reactive group ("RG") and a spacer group ("SP") as illustrated. The reactive linkers described herein may comprise two or more reactive groups and two or more spacer groups. The spacer group is any bivalent site that crosslinks the reactive group to another group, such as a payload or prodrug payload. The reactive linker (RL), together with the payload or prodrug payload to which it is bound, provides an intermediate ("linker-payload" or LP; or linker-prodrug payload) that is useful as a synthetic precursor for the preparation of antibody conjugates described herein. The reactive linker comprises a reactive group that is a functional group or functional site capable of reacting with another group, such as an antibody or its antigen-binding fragment, a modified antibody or its antigen-binding fragment, a transglutaminase-modified antibody or its antigen-binding fragment, or a reactive moiety of a reinforcing group. The site resulting from the reaction between an antibody or its antigen-binding fragment, a modified antibody or its antigen-binding fragment, or a transglutaminase-modified antibody or its antigen-binding fragment and a reactive group, together with the linking group, comprises the “binding linker” ("BL") portion of the conjugate described herein. In some embodiments, the “reactive group” is a functional group or functional site that reacts with a cysteine ​​or lysine residue of the antibody or its antigen-binding fragment (e.g., maleimide or N-hydroxysuccinimide (NHS) ester). In some embodiments, the “reactive group” is a functional group or functional site that can undergo a click chemistry reaction (see, for example, click chemistry, Huisgen's Proc. Chem. Soc. 1961, Wang et al.'s J. Am. Chem. Soc. 2003, and Agard et al.'s J. Am. Chem. Soc. 2004). In some embodiments of the click chemistry reaction, the reactive group is an alkyne that can undergo a 1,3-cycloaddition reaction with an azide.Suitable reactive groups include, but are not limited to, strained alkynes, such as those suitable for strain-enhanced alkyne-azide cycloaddition (SPAAC), cycloalkynes, such as cyclooctyne, benzannulated alkynes, and alkynes that can undergo 1,3-cycloaddition reactions with alkynes in the absence of a copper catalyst. Suitable alkynes include dibenzoazacyclooctyne or... [ka] Dibenzocyclooctin or [ka] Biaryl azacyclooctinone or [ka] Difluorinated cyclooctin or [ka] Substituted alkynes, e.g., fluorinated alkynes, aza-cycloalkynes, bicycle[6.1.0]nonyne or [ka] (BCNs (wherein R is alkyl, alkoxy, or acyl) and their derivatives are also examples, but are not limited to these. Particularly useful alkynes include: [ka] Examples include linker-payloads or linker-prodrug payloads containing such reactive groups are useful for conjugating antibodies functionalized with azide groups. As used herein, “transglutaminase-modified antibody or its antigen-binding fragment” means an antibody or its antigen-binding fragment having one or more glutamine (Gln or Q) residues that can react with a compound having a primary or secondary amino functional group in the presence of the enzyme transglutaminase. Such a transglutaminase-modified antibody or its antigen-binding fragment includes an antibody or its antigen-binding fragment functionalized with an azide-polyethylene glycol group by transglutaminase-mediated coupling of a primary amine having an azide-polyethylene glycol moiety with the antibody or its antigen-binding fragment. In some embodiments, such a transglutaminase-modified antibody or its antigen-binding fragment is induced by treating an antibody or its antigen-binding fragment having at least one glutamine residue, e.g., heavy chain Gln295, with a compound having an amino group and an azide group in the presence of the enzyme transglutaminase, as further described elsewhere herein.

[0045] In some examples, the reactive group is an alkyne, for example, [ka] And this is azed by click chemistry, for example, [ka] It reacts with click chemistry products, for example, [ka] It can form a reactive group. In some examples, the reactive group reacts with an azide on a modified antibody or its antigen-binding fragment. In some examples, the reactive group is an alkyne, for example, [ka] And this is azed by click chemistry, for example, [ka] It reacts with click chemistry products, for example, [ka] It is possible to form an alkyne. In some examples, the reactive group is an alkyne, for example, [ka] And this is azed by click chemistry, for example, [ka] It reacts with click chemistry products, for example, [ka] It can form a functional group, for example, [ka] This reacts with cysteine ​​residues on the antibody or its antigen-binding fragment, forming a carbon-sulfur bond thereto, for example, [ka] (In the formula, Ab represents an antibody or its antigen-binding fragment, and S represents a sulfur (S) atom on a cysteine ​​residue through which a functional group is bound to Ab.) It forms a functional group, for example, [ka] This reacts with a lysine residue on the antibody or its antigen-binding fragment, forming an amide bond thereto, for example, [ka] (In the formula, Ab represents an antibody or its antigen-binding fragment, and -NH- represents an -NH- atom on a lysine side-chain residue through which a functional group is bound to Ab.) It forms.

[0046] As used herein, the phrase “biodegradable site” refers to a site that degrades in vivo to become a non-toxic, biocompatible component that can be removed from the body by normal biological processes. In some embodiments, the biodegradable site is substantially or completely degraded in vivo within about 90 days or less, about 60 days or less, or about 30 days or less, where the degree of degradation is based on a percentage mass loss of the biodegradable site, and complete degradation corresponds to a 100% mass loss. Examples of biodegradable sites include, but are not limited to, aliphatic polyesters such as poly(ε-caprolactone) (PCL), poly(3-hydroxybutyrate) (PHB), poly(glycolic acid) (PGA), poly(lactic acid) (PLA), and copolymers thereof with glycolic acid (i.e., poly(D,L-lactide-coglycolide) (PLGA) (References: Vert M, Schwach G, Engel R and Coudane J, (1998) J Control Release 53(1-3):85-92; Jain RA, (2000) Biomaterials 21(23):2475-2490; Uhrich KE, Cannizzaro SM, Langer RS ​​and Shakesheff KM, (1999) Chemical Reviews 99(11):3181-3198; and Park TG, (1995) Biomaterials 16(15):1123–1130 (Each of these references is incorporated herein by reference in its entirety).

[0047] As used herein, the phrase “binding linker” or “BL” refers to any divalent, trivalent, or polyvalent group or site that links, connects, or binds a binding agent (e.g., an antibody or its antigen-binding fragment) to a payload compound (e.g., tubulisin) as described herein and optionally one or more side-chain compounds. Generally, a binding linker suitable for an antibody conjugate as described herein is stable enough to take advantage of the cyclic half-life of the antibody conjugate and, at the same time, can release its payload after antigen-mediated internalization of the conjugate. The linker may be cleavable or incleavable. A cleavable linker is one that is cleaved by intracellular metabolism after internalization, such as hydrolysis, reduction, or enzymatic cleavage. An incleavable linker is one that releases the attached payload by lysosomal degradation of the antibody after internalization. Suitable linkers include, but are not limited to, acid-unstable linkers, hydrolyzable linkers, enzymatically cleavable linkers, reduction-unstable linkers, self-destructive linkers, and incleavable linkers. Suitable linkers also include, but are not limited to, peptides, glucuronides, succinimide-thioethers, polyethylene glycol (PEG) units, hydrazones, mar-caproyl units, dipeptide units, valine-citrulline units, and para-aminobenzyloxycarbonyl (PABC), para-aminobenzyl (PAB) units or those containing these. In some embodiments, the binder linker (BL) includes a site formed by the reaction of the reactive group (RG) of the reactive linker (RL) with a binder, such as an antibody, a modified antibody, or the reactive portion of its antigen-binding fragment.

[0048] In some cases, BL is located in the following areas: [ka] (In the formula, [ka] This includes binding to a binder. In some examples, BL is located at the following sites: [ka] (In the formula, [ka] This includes binding to a binder. In some examples, BL is located at the following sites: [ka] (In the formula, [ka] This includes binding to a binder. In some examples, BL is located at the following sites: [ka] (In the formula, [ka] This includes the binding of an antibody or its antigen-binding fragment to cysteine. In some examples, BL is the following site: [ka] (In the formula, [ka] This includes the binding of an antibody or its antigen-binding fragment to lysine.

[0049] When applied to polypeptides, the phrase “substantial similarity” or “substantially identical” means two peptide sequences that share at least 95% sequence identity, or at least 98% or 99% sequence identity, when optimally aligned using default gap weights, for example, by the program GAP or BESTFIT. Sequence similarity may also be determined using the BLAST algorithm, as described in Altschul et al., J. Mol. Biol. 215: 403-10 (using the published default settings) or available at blast.ncbi.nlm.nih.gov / Blast.cgi. In some embodiments, the non-identical residue positions differ by the amount of conserved amino acid substitutions. A “conservative amino acid substitution” is when an amino acid residue is replaced by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). Generally, conservative amino acid substitutions do not substantially alter the functional properties of the protein. If two or more amino acid sequences differ from each other by a conservative substitution, the degree of percent sequence identity or similarity may be adjusted upward to compensate for the conservative nature of the substitution. Methods for making this adjustment are well known to those skilled in the art. See, for example, Pearson's work, (1994) Methods Mol. Biol. 24: 307-331. Examples of amino acid groups having side chains with similar chemical properties include: (1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; (2) aliphatic-hydroxyl side chains: serine and threonine; (3) amide side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartic acid and glutamic acid; and (7) sulfur-containing side chains: cysteine ​​and methionine. Particularly useful conserved amino acid substituents are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic acid-aspartic acid, and asparagine-glutamine.Alternatively, a conservative substitution is any change that has a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al.'s literature, (1992) Science 256: 1443-1445. A "moderately conservative" substitution is any change that has a non-negative value in the PAM250 log-likelihood matrix.

[0050] As used herein, “enantiomer excess (ee)” refers to a dimensionless molar ratio describing the purity of, for example, a chiral substance having a single chiral center. For example, an enantiomer excess of zero would indicate a racemic compound (e.g., a 50:50 mixture of enantiomers, or one enantiomer not in excess of the other). As a further example, an enantiomer excess of 99 would indicate a nearly sterically pure enantiomer compound (i.e., one enantiomer in great excess of the other). The enantiomeric excess in percentage %ee = ([(R)-compound] - [(S)-compound]) / ([(R)-compound] + [(S)-compound]) × 100 (where (R)-compound > (S)-compound); or %ee = ([(S)-compound] - [(R)-compound]) / ([(S)-compound] + [(R)-compound]) × 100 (where (S)-compound > (R)-compound). Furthermore, as used herein, “diastereomer excess (de)” means a dimensionless molar ratio that describes the purity of a chiral substance having two or more chiral centers. For example, a diastereomer excess of zero would indicate an equimolar mixture of diastereoisomers. As a further example, a diastereomer excess of 99 would indicate a nearly sterically pure diastereomer compound (i.e., one diastereomer is in large excess relative to the other). The diastereomer excess can be calculated in a manner similar to that of ee. As will be recognized by those skilled in the art, de is usually reported as percent de (%de). %de can be calculated in a manner similar to that of %ee.

[0051] In one embodiment, certain compounds or payloads listed in Table P below are excluded from the subject matter described herein.

[0052] In one embodiment, the compounds provided herein include any or all of the compounds IVa, IVa′, IVb, IVc, IVd, IVe, IVf, IVg, IVh, IVj, IVk, IVl, IVm, IVn, IVo, IVp, IVq, IVr, IVs, IVt, IVu, IVvA, IVvB, IVw, IVx, IVy, Va, Va′, Vb, Vc, Vd, Ve, Vf, Vg, Vh, Vi, Vj, Vk, VIa, IVb, VIc, VId, VIe, VIf, VIg, VIh, Vl, VIi, VII, VIII, IX, X, D-5a, and D-5c of Table P. In one embodiment, the compounds provided herein do not include any or all of the compounds IVa, IVa′, IVb, IVc, IVd, IVe, IVf, IVg, IVh, IVj, IVk, IVl, IVm, IVn, IVo, IVp, IVq, IVr, IVs, IVt, IVu, IVvA, IVvB, IVw, IVx, IVy, Va, Va′, Vb, Vc, Vd, Ve, Vf, Vg, Vh, Vi, Vj, Vk, VIa, IVb, VIc, VId, VIe, VIf, VIg, VIh, Vl, VIi, VII, VIII, IX, X, D-5a, and D-5c of Table P. For example, in one embodiment, the compounds provided herein include any or all residues of compounds IVa, IVa′, IVb, IVc, IVd, IVe, IVf, IVg, IVh, IVj, IVk, IVl, IVm, IVn, IVo, IVp, IVq, IVr, IVs, IVt, IVu, IVvA, IVvB, IVw, IVx, IVy, Va, Va′, Vb, Vc, Vd, Ve, Vf, Vg, Vh, Vi, Vj, Vk, VIa, IVb, VIc, VId, VIe, VIf, VIg, VIh, Vl, VIi, VII, VIII, IX, X, D-5a, and D-5c, linked to a linker and / or binder as described herein.In one embodiment, the compounds provided herein do not contain any or all residues of compounds IVa, IVa′, IVb, IVc, IVd, IVe, IVf, IVg, IVh, IVj, IVk, IVl, IVm, IVn, IVo, IVp, IVq, IVr, IVs, IVt, IVu, IVvA, IVvB, IVw, IVx, IVy, Va, Va′, Vb, Vc, Vd, Ve, Vf, Vg, Vh, Vi, Vj, Vk, VIa, IVb, VIc, VId, VIe, VIf, VIg, VIh, Vl, VIi, VII, VIII, IX, X, D-5a, and D-5c linked to the linker and / or binder described herein. (Table P) [Table 1] TIFF0007912488000048.tif214170TIFF0007912488000049.tif209170TIFF0007912488000050.t if222170TIFF0007912488000051.tif206170TIFF0007912488000052.tif211170TIFF00079124880 00053.tif218170TIFF0007912488000054.tif233170TIFF0007912488000055.tif199170TIFF000 7912488000056.tif232170TIFF0007912488000057.tif207170TIFF0007912488000058.tif173170

[0053] In one embodiment, some of the compounds or linker payloads listed in Table P1 below are excluded from the subject matter described herein.

[0054] In one embodiment, the compounds provided herein include any or all of the compounds LP1-IVa, LP2-Va, LP3-IVd, LP4-Ve, LP5-IVd, LP6-Vb, LP7-IVd, LP9-IVvB, LP10-VIh, LP11-IVvB, LP12-VIi, LP13-Ve, LP14-Ve, LP15-VIh, LP16-Ve, LP17-Ve, LP18-Ve, LP19-Ve, LP20-Ve, LP21-Ve, LP22-Ve, LP23-Vb, LP24-Vb, LP25-Ve, and LP26-Ve of Table P1. In one embodiment, the compounds provided herein do not include any or all of the compounds LP1-IVa, LP2-Va, LP3-IVd, LP4-Ve, LP5-IVd, LP6-Vb, LP7-IVd, LP9-IVvB, LP10-VIh, LP11-IVvB, LP12-VIi, LP13-Ve, LP14-Ve, LP15-VIh, LP16-Ve, LP17-Ve, LP18-Ve, LP19-Ve, LP20-Ve, LP21-Ve, LP22-Ve, LP23-Vb, LP24-Vb, LP25-Ve, and LP26-Ve of Table P1. For example, in one embodiment, the compounds provided herein include any or all residues of the compounds LP1-IVa, LP2-Va, LP3-IVd, LP4-Ve, LP5-IVd, LP6-Vb, LP7-IVd, LP9-IVvB, LP10-VIh, LP11-IVvB, LP12-VIi, LP13-Ve, LP14-Ve, LP15-VIh, LP16-Ve, LP17-Ve, LP18-Ve, LP19-Ve, LP20-Ve, LP21-Ve, LP22-Ve, LP23-Vb, LP24-Vb, LP25-Ve, and LP26-Ve, linked to a binder described herein.In one embodiment, the compounds provided herein do not contain any or all residues of compounds LP1-IVa, LP2-Va, LP3-IVd, LP4-Ve, LP5-IVd, LP6-Vb, LP7-IVd, LP9-IVvB, LP10-VIh, LP11-IVvB, LP12-VIi, LP13-Ve, LP14-Ve, LP15-VIh, LP16-Ve, LP17-Ve, LP18-Ve, LP19-Ve, LP20-Ve, LP21-Ve, LP22-Ve, LP23-Vb, LP24-Vb, LP25-Ve, and LP26-Ve linked to the binder described herein. (Table P1) [Table 2] TIFF0007912488000060.tif241170TIFF0007912488000061.tif242170TIFF0007912488000062.t if242170TIFF0007912488000063.tif242170TIFF0007912488000064.tif241170TIFF00079124880 00065.tif227170TIFF0007912488000066.tif228170TIFF0007912488000067.tif228170TIFF000 7912488000068.tif227170TIFF0007912488000069.tif228170TIFF0007912488000070.tif226170

[0055] (Compound, payload, or prodrug payload) Provided herein are compounds, bioactive compounds, or payloads. While not bound by any particular theory of action, compounds include tubulicin and its derivatives, such as their prodrugs. The terms or phrases “compound,” “bioactive compound,” “prodrug,” “prodrug payload,” and “payload” are used interchangeably throughout this disclosure.

[0056] In one embodiment, the physiologically active compound (D*) or its residues include, for example, amino, hydroxyl, carboxylic acid, and / or amide functionalities (e.g., D*-NH2 or D*-NH-R; D*-OH or D*-OR; D*-COOH or D*-C(O)OR; and / or D*-CONH2, D*-CONH-R, or D*-NHC(O)-R). In one embodiment of this specification, as an example and for convenience, heterocyclic nitrogen, R 2 , R 3 , R 6 , and / or R 7 As will be recognized by those skilled in the art, R represents the amino, hydroxyl, carboxylic acid, and amide functional groups in the physiologically active compounds described herein. In other words, those skilled in the art will recognize heterocyclic nitrogen, R 2 , R 3 , R 6 , and / or R 7However, it will be recognized that these may be part of the physiologically active compounds described herein (e.g., D*) and may also be used as functional groups for conjugation. In one embodiment, the hydroxyl functionality is a primary hydroxyl moiety (e.g., D*-CH2OH or D*-CH2O-R; or D*-C(O)CH2OH or D*-C(O)CH2O-R). In another embodiment, the hydroxyl functionality is a secondary hydroxyl moiety (e.g., D*-CH(OH)R or D*-CH(OR)R; or D*-C(O)CH(R)(OH) or D*-C(O)CH(R)(OR)). In another embodiment, the hydroxyl function is a tertiary hydroxyl moiety (e.g., D*-C(R1)(R2)(OH) or D*-C(R1)(R2)(OR); or D*-C(O)C(R1)(R2)(OH) or D*-C(O)C(R1)(R2)(OR)). In one embodiment, the physiologically active compound (D*) or its residues include amino function (e.g., D*-NR2 or D*-N(R)-R). In one embodiment, the amino function is a primary amino moiety (e.g., D*-CH2NR2 or D*-CH2N(R)-R; or D*-C(O)CH2NR2 or D*-C(O)CH2N(R)-R). In another embodiment, the amino-functionality is a secondary amino moiety (e.g., D*-CH(NR2)R or D*-CH(NR-R)R; or D*-C(O)CH(R)(NR2) or D*-C(O)CH(R)(NR-R)). In another embodiment, the amino-functionality is a tertiary amino moiety (e.g., D*-C(R1)(R2)(NR2) or D*-C(R1)(R2)(N(R)-R); or D*-C(O)C(R1)(R2)(NR2) or D*-C(O)C(R1)(R2)(N(R)-R)). In another embodiment, the amino-functionality is quaternary, as would be recognized by those skilled in the art. In another embodiment, D* containing the amino-functionality is an arylamine (e.g., D*-Ar-NR2, D*-Ar-N(R)-R). Those skilled in the art will recognize that each functional group in the preceding text can be part of a physiologically active compound D*, and at the same time, can be shown in the formula for clarity, convenience, and / or emphasis.In another embodiment, D* containing hydroxyl functionality is an arylhydroxyl or phenolic hydroxyl (e.g., D*-Ar-OH, D*-Ar-OR). In another embodiment, D* containing amide functionality is a tubulisin prodrug residue resulting from the reaction of a tubulisin compound or derivative, such as R as described herein. 7 The amino acid compounds are also described herein. For example, in one embodiment, D*-NHC(O)C(S c )(H)NH2 represents a tubulicin prodrug having an N-terminal amino acid residue, where S c represents the amino acid side chain. As a further example, in one embodiment, D*-NH[C(O)C(S c )(H)NH] aa C(O)C(S c )(H)NH2 represents a tubulicin prodrug having an N-terminal peptide residue, where S c ∫ represents the amino acid side chain, and aa is an integer from 1 to 100. In one embodiment, aa is 1. In one embodiment, aa is 2. In one embodiment, aa is 3. In one embodiment, aa is 4. In one embodiment, aa is 5. As used herein, “amino acid side chain” means an additional chemical site on the same carbon as the carbon having the primary or secondary amine and carboxylic acid of the amino acid. As will be recognized by those skilled in the art, there are 21 “standard” amino acids. Exemplary “standard” amino acids include, but are not limited to, alanine, serine, proline, arginine, and aspartic acid. Other amino acids include cysteine, selenocysteine, and glycine (for example, here the additional chemical site on the same carbon as the carbon having the primary amine and carboxylic acid of glycine is hydrogen). Examples of amino acid side chains include, but are not limited to, methyl (i.e., alanine), sec-butyl (i.e., isoleucine), iso-butyl (i.e., leucine), -CH2CH2SCH3 (i.e., methionine), -CH2Ph ​​(i.e., phenylalanine), [ka] (That is, tryptophan), [ka] (i.e., tyrosine), iso-propyl (i.e., valine), hydroxymethyl (i.e., serine), -CH(OH)CH3 (i.e., threonine), -CH2C(O)NH2 (i.e., asparagine), -CH2CH2C(O)NH2 (i.e., glutamine), -CH2SH (i.e., cysteine), -CH2SeH (i.e., selenocysteine), -CH2NH2 (i.e., glycine), propylene or -CH2CH2CH2- (i.e., proline), -CH2CH2CH2NHC(=NH)NH2 (i.e., arginine), [ka] Examples include histidine (i.e., -CH2CH2CH2CH2NH2), lysine (i.e., -CH2COOH), and glutamic acid (i.e., -CH2CH2COOH).

[0057] In one embodiment, for example, a physiologically active compound (D*) is R 7 The compound containing amide functionality (D*-NHC(O)-R) is a prodrug compound of formula Ia: [ka] In one embodiment, prodrug formula Iaa: [ka] This can be linked to a linker or binder, as described elsewhere in this specification, where, [ka] This indicates bonding to the linker and / or binder, as described elsewhere in this specification.

[0058] In one embodiment, the compound can be delivered to cells as part of a conjugate. In one embodiment, the compound can exert any activity of tubulinin or a tubulinin derivative in or within a target, such as a target cell. A particular compound may have one or more additional activities. In one embodiment, the compound can modulate the activity of folate receptors, somatostatin receptors, and / or bombesin receptors.

[0059] (Compound, payload, or prodrug payload-Q is carbon) In one embodiment, the compound described herein has the structure of formula I, where r is 4.

[0060] In one embodiment of the above formula I, a useful R 3 The groups include hydroxyl, -O-C1-C5 alkyl, -OC(O)C1-C5 alkyl, and -OC(O)N(H)C1-C 10 Alkyl, -OC(O)N(H)C1-C 10 Alkyl-NR 3a R 3b -NHC(O)C1-C5 alkyl, or -OC(O)N(H)(CH2CH2O) n C1-C 10 Alkyl-NR 3a R 3b These are listed, and here, R 3a and R 3b In each case, independently, are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted. In one embodiment, R 3 is hydroxyl. In one embodiment, R 3 is an -O-C1-C5 alkyl group. In one embodiment, R 3 is -OMe. In one embodiment, R 3 is -OEt. In one embodiment, R 3is -O-propyl, and its structural isomers, and its structural isomers. In one embodiment, R 3 R is -O-butyl and its structural isomers. In one embodiment, R 3 R is -O-pentyl and its structural isomers. In one embodiment, R 3 is a -OC(O)C1-C5 alkyl group. In one embodiment, R 3 is -OC(O)Me. In one embodiment, R 3 is -OC(O)Et. In one embodiment, R 3 R is -OC(O)-propyl and its structural isomers. In one embodiment, R 3 is -OC(O)-butyl and its structural isomers. In one embodiment, R 3 is -OC(O)-pentyl and its structural isomers. In one embodiment, R 3 is -OC(O)N(H)C1-C 10 It is alkyl. In one embodiment, R 3 is -OC(O)N(H)Me. In one embodiment, R 3 is -OC(O)N(H)Et. In one embodiment, R 3 R is -OC(O)N(H)-propyl and its structural isomers. In one embodiment, R 3 These are -OC(O)N(H)-butyl and its structural isomers. In one embodiment, R 3 is -OC(O)N(H)-pentyl and its structural isomers. In one embodiment, R 3 is -OC(O)N(H)-hexyl and its structural isomers. In one embodiment, R 3 is -OC(O)N(H)-heptyl and its structural isomers. In one embodiment, R 3 This is -OC(O)N(H)-octyl and its structural isomers. In one embodiment, R 3 This is -OC(O)N(H)-nonyl and its structural isomers. In one embodiment, R 3 is -OC(O)N(H)-decyl and its structural isomers. In one embodiment, R3 is -OC(O)N(H)C1-C 10 Alkyl-NR 3a R 3b In one embodiment, R 3 is -OC(O)N(H)CH2NR 3a R 3b In one embodiment, R 3 is -OC(O)N(H)CH2CH2NR 3a R 3b In one embodiment, R 3 is -OC(O)N(H)CH2CH2CH2NR 3a R 3b In one embodiment, R 3 is -OC(O)N(H)CH2CH2CH2CH2NR 3a R 3b In one embodiment, R 3 is -OC(O)N(H)CH2CH2CH2CH2CH2NR 3a R 3b In one embodiment, R 3 is -OC(O)N(H)CH2CH2CH2CH2CH2CH2NR 3a R 3b In one embodiment, R 3 is -OC(O)N(H)CH2CH2CH2CH2CH2CH2CH2NR 3a R 3b In one embodiment, R 3 is -OC(O)N(H)CH2CH2CH2CH2CH2CH2CH2CH2NR 3a R 3b In one embodiment, R 3 is -OC(O)N(H)CH2CH2CH2CH2CH2CH2CH2CH2CH2NR 3a R 3b In one embodiment, R 3 is -OC(O)N(H)CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2NR 3a R 3b In any of the 11 preceding embodiments, R 3a and R 3bis hydrogen. In one embodiment, R 3 is a -NHC(O)C1-C5 alkyl group. In one embodiment, R 3 is -NHC(O)Me. In one embodiment, R 3 is -NHC(O)Et. In one embodiment, R 3 R is -NHC(O)-propyl and its structural isomers. In one embodiment, R 3 R is -NHC(O)-butyl and its structural isomers. In one embodiment, R 3 is -NHC(O)-pentyl and its structural isomers. In one embodiment, R 3 is -OC(O)N(H)(CH2CH2O) n C1-C 10 Alkyl-NR 3a R 3b (wherein the formula, n is an integer from 1 to 10). In one embodiment, R 3 is -OC(O)N(H)(CH2CH2O) n CH2NR 3a R 3b (wherein the formula, n is an integer from 1 to 10). In one embodiment, R 3 is -OC(O)N(H)(CH2CH2O) n CH2 CH2NR 3a R 3b (wherein the formula, n is an integer from 1 to 10). In one embodiment, R 3 is -OC(O)N(H)(CH2CH2O) n CH2 CH2NR 3a R 3b (wherein n is 3) In one embodiment, R 3 is -OC(O)N(H)(CH2CH2O) n CH2CH2CH2NR 3a R 3b (wherein the formula, n is an integer from 1 to 10). In one embodiment, R 3 is -OC(O)N(H)(CH2CH2O) n CH2CH2CH2CH2NR 3a R 3b(wherein the formula, n is an integer from 1 to 10). In one embodiment, R 3 is -OC(O)N(H)(CH2CH2O) n CH2CH2CH2CH2CH2NR 3a R 3b (wherein the formula, n is an integer from 1 to 10). In one embodiment, R 3 is -OC(O)N(H)(CH2CH2O) n CH2CH2CH2CH2CH2CH2NR 3a R 3b (wherein the formula, n is an integer from 1 to 10). In one embodiment, R 3 is -OC(O)N(H)(CH2CH2O) n CH2CH2CH2CH2CH2CH2CH2NR 3a R 3b (wherein the formula, n is an integer from 1 to 10). In one embodiment, R 3 is -OC(O)N(H)(CH2CH2O) n CH2CH2CH2CH2CH2CH2CH2CH2NR 3a R 3b (wherein the formula, n is an integer from 1 to 10). In one embodiment, R 3 is -OC(O)N(H)(CH2CH2O) n CH2CH2CH2CH2CH2CH2CH2CH2CH2NR 3a R 3b (wherein the formula, n is an integer from 1 to 10). In one embodiment, R 3 is -OC(O)N(H)(CH2CH2O) n CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2NR 3a R 3b (wherein n is an integer between 1 and 10) In any of the preceding 12 embodiments, R 3a and R 3b It is hydrogen.

[0061] In one embodiment of the above formula I, a useful R 7 The possible bases are, independently, hydrogen, -OH, fluoro, chloro, bromo, iodine, and -NR. 7a R7b Examples include: One embodiment, R 7 is hydrogen. In one embodiment, R 7 is -OH. In one embodiment, R 7 In another embodiment, R 7 In another embodiment, R 7 This is bromo. In another embodiment, R 7 is iodine. In one embodiment, R 7 -NR 7a R 7b In one embodiment, R 7a and R 7b is hydrogen. In one embodiment, R 7a is hydrogen, and R 7b is -C(O)CH2OH. In one embodiment, R 7a is hydrogen, and R 7b R is the first N-terminal amino acid residue. 7b This distinguishes the amino acid residue from a second amino acid residue in the linker, as described elsewhere in this specification. In one embodiment, R 7a is hydrogen, and R 7b R is the first N-terminal peptide residue. 7b This distinguishes the peptide residue from a second peptide residue in the linker, as described elsewhere in this specification. In one embodiment, R 7a is hydrogen, and R 7b It is -CH2CH2NH2.

[0062] In one embodiment of the above formula I, a useful R 8 As a base, independently, hydrogen, -NHR 9 Examples include halogens. In one embodiment, R 8 is hydrogen. In one embodiment, R 8 -NHR 9 And here, R 9 is hydrogen. In one embodiment, R 8In another embodiment, R 8 In another embodiment, R 8 This is bromo. In another embodiment, R 8 m is iodine. In one embodiment, m is 1. In another embodiment, m is 2.

[0063] In one embodiment, the following are described herein: a compound having the structure of formula I, or a pharmaceutically acceptable salt or prodrug thereof: [ka] (In the formula, Q is -CH2- and R 1 C1-C 10 Alkyl; R 2 is alkyl; R 4 and R 5 It is a C1-C5 alkyl group; R 6 is -OH; R 10 (is not present; r is 4; and a is 1). In formula I, in one embodiment, useful R 1 Examples of groups include methyl and ethyl. In one embodiment, a useful R 1 Examples of the groups include propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and their structural isomers. In one embodiment, R 1 is methyl. In one embodiment, R 1 is ethyl. In one embodiment, R 1 R is propyl and its structural isomers. In one embodiment, R 1 is butyl and its structural isomers. In one embodiment, R 1 These are pentyl and its structural isomers. In one embodiment, R 1 is hexyl and its structural isomers. In one embodiment, R 1 These are heptyl and its structural isomers. In one embodiment, R 1 octyl and its structural isomers. In one embodiment, R 1These are nonyl and its structural isomers. In one embodiment, R 1 These are decyl and its structural isomers. In formula I, in one embodiment described above, useful R 2 Examples of groups include n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. In one embodiment, R 2 is n-pentyl or its structural isomer. In another embodiment, R 2 is n-hexyl or a structural isomer thereof. In another embodiment, R 2 is n-heptyl or its structural isomer. In another embodiment, R 2 is n-octyl or its structural isomer. In another embodiment, R 2 is n-nonyl or its structural isomer. In another embodiment, R 2 is n-decyl or its structural isomer. In one embodiment, QR 2 is n-hexyl. In formula I, in one embodiment, useful R 3 The basis is as described above. In one embodiment of the above formula I, a useful R 4 Examples of groups include methyl, ethyl, propyl, butyl, and pentyl. In one embodiment, R 4 is methyl. In another embodiment, R 4 is ethyl. In another embodiment, R 4 R is propyl and its structural isomers. In another embodiment, R 4 is butyl and its structural isomers. In another embodiment, R 4 These are pentyl and its structural isomers. In one embodiment of the above formula I, useful R 5 Examples of groups include methyl, ethyl, propyl, butyl, and pentyl. In one embodiment, R 5 is methyl. In another embodiment, R 5 is ethyl. In another embodiment, R 5 R is propyl and its structural isomers. In another embodiment, R 5is butyl and its structural isomers. In another embodiment, R 5 R is pentyl and its structural isomers. In one embodiment of the above formula I, R 4 and R 5 Independent combinations of are assumed herein. For example, in one embodiment, R 4 and R 5 is methyl. In one embodiment, R 4 and R 5 is ethyl. In one embodiment, R 4 and R 5 These are independently propyl and structural isomers. In one embodiment, R 4 and R 5 These are independently butyl and structural isomers. In one embodiment, R 4 and R 5 These are independently pentyl and structural isomers. In one embodiment, R 4 is ethyl, and R 5 is methyl. In one embodiment, R 4 is ethyl, and R 5 R is independently propyl and its structural isomers. In one embodiment, R 4 R is independently propyl and its structural isomers; and R 5 These are independently butyl and its structural isomers. In one embodiment, R 4 These are independently butyl and its structural isomers; and R 5 These are independently pentyl and its structural isomers.

[0064] In one embodiment, the following is described herein: a compound having the structure of formula II, or a pharmaceutically acceptable salt or prodrug thereof: [ka] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8, and m are as described above in relation to formula I. In one embodiment, R 3 is hydroxyl, -OEt, -OC(O)N(H)CH2CH2NH2, -NHC(O)Me, or -OC(O)N(H)CH2CH2OCH2CH2OCH2CH2OCH2CH2NH2. In one embodiment, R 3 is hydroxyl. In one embodiment, R 3 is -OEt. In one embodiment, R 3 This is -OC(O)N(H)CH2CH2NH2. In one embodiment, R 3 is -NHC(O)Me. In one embodiment, R 3 This is -OC(O)N(H)CH2CH2OCH2CH2OCH2CH2OCH2CH2NH2.

[0065] In one embodiment, provided herein is [ka] A compound according to formula II selected from the group consisting of TIFF0007912488000080.tif127170, or a pharmaceutically acceptable salt thereof.

[0066] In one embodiment, the following is described herein: a compound having the structure of formula I, or a pharmaceutically acceptable salt or prodrug thereof: [ka] (In the formula, Q is -CH2- and R 1 is hydrogen or C1-C 10 Alkyl; R 2 is alkyl; R 4 and R 5 However, it is a C1-C5 alkyl group; R 6 (where r is -OH; where r is 3 or 4; and a is 1). In one embodiment of formula I, R 1 is hydrogen. In formula I, in one embodiment, useful R 1Examples of groups include methyl and ethyl. In one embodiment, a useful R 1 Examples of the groups include propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and their structural isomers. In one embodiment, R 1 is methyl. In one embodiment, R 1 is ethyl. In one embodiment, R 1 R is propyl and its structural isomers. In one embodiment, R 1 is butyl and its structural isomers. In one embodiment, R 1 These are pentyl and its structural isomers. In one embodiment, R 1 is hexyl and its structural isomers. In one embodiment, R 1 These are heptyl and its structural isomers. In one embodiment, R 1 octyl and its structural isomers. In one embodiment, R 1 These are nonyl and its structural isomers. In one embodiment, R 1 These are decyl and its structural isomers. In formula I, in one embodiment described above, useful R 2 Examples of groups include n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. In one embodiment, R 2 is n-pentyl or its structural isomer. In another embodiment, R 2 is n-hexyl or a structural isomer thereof. In another embodiment, R 2 is n-heptyl or its structural isomer. In another embodiment, R 2 is n-octyl or its structural isomer. In another embodiment, R 2 is n-nonyl or its structural isomer. In another embodiment, R 2 is n-decyl or its structural isomer. In one embodiment, QR 2 is n-hexyl. In formula I, in one embodiment, useful R 3 The basis is as described above. In one embodiment of the above formula I, a useful R 4Examples of groups include methyl, ethyl, propyl, butyl, and pentyl. In one embodiment, R 4 is methyl. In another embodiment, R 4 is ethyl. In another embodiment, R 4 R is propyl and its structural isomers. In another embodiment, R 4 is butyl and its structural isomers. In another embodiment, R 4 These are pentyl and its structural isomers. In one embodiment of the above formula I, useful R 5 Examples of groups include methyl, ethyl, propyl, butyl, and pentyl. In one embodiment, R 5 is methyl. In another embodiment, R 5 is ethyl. In another embodiment, R 5 R is propyl and its structural isomers. In another embodiment, R 5 is butyl and its structural isomers. In another embodiment, R 5 R is pentyl and its structural isomers. In one embodiment of the above formula I, R 4 and R 5 Independent combinations of are assumed herein. For example, in one embodiment, R 4 and R 5 is methyl. In one embodiment, R 4 and R 5 is ethyl. In one embodiment, R 4 and R 5 These are independently propyl and structural isomers. In one embodiment, R 4 and R 5 These are independently butyl and structural isomers. In one embodiment, R 4 and R 5 These are independently pentyl and structural isomers. In one embodiment, R 4 is ethyl, and R 5 is methyl. In one embodiment, R 4 is ethyl, and R 5 R is independently propyl and its structural isomers. In one embodiment, R 4R is independently propyl and its structural isomers; and R 5 These are independently butyl and its structural isomers. In one embodiment, R 4 These are independently butyl and its structural isomers; and R 5 These are independently pentyl and its structural isomers. In formula I, in one embodiment, useful R 7 and R 8 The basis is as described above. In one embodiment of formula I, R 10 is a C1-C5 alkyl group. In one embodiment, a useful R 10 Examples of the groups include propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and their structural isomers. In one embodiment, R 10 is methyl. In one embodiment, R 10 is ethyl. In one embodiment, R 10 R is propyl and its structural isomers. In one embodiment, R 10 is butyl and its structural isomers. In one embodiment, R 10 These are pentyl and its structural isomers. In one embodiment, R 10 is hexyl and its structural isomers. In one embodiment, R 10 These are heptyl and its structural isomers. In one embodiment, R 10 octyl and its structural isomers. In one embodiment, R 10 These are nonyl and its structural isomers. In one embodiment, R 10 is decyl and its structural isomers. In one embodiment, r is 3. In another embodiment, r is 4.

[0067] In one embodiment, the following is described herein: a compound having the structure of formula III, or a pharmaceutically acceptable salt or prodrug thereof: [ka] In one embodiment, R 1 , R 2 , R3 , R 4 , R 5 , R 7 , R 8 , R 10 , and m are as described above in relation to formula I. In one embodiment, R 1 is hydrogen or methyl; and R 10 is methyl. In one embodiment, R 1 is hydrogen; and R 10 is methyl. In one embodiment, R 1 is methyl; and R 10 It is methyl.

[0068] In one embodiment, provided herein is [ka] A compound according to formula III selected from the group consisting of TIFF0007912488000084.tif211170 and TIFF0007912488000085.tif88170, or a pharmaceutically acceptable salt thereof.

[0069] In one embodiment, the following is described herein: a compound having the structure of formula I, or a pharmaceutically acceptable salt or prodrug thereof: [ka] (In the formula, Q is -CH2- and R 1 is hydrogen or C1-C 10 Alkyl; R 2 is alkyl; R 4 and R 5 It is a C1-C5 alkyl group; R 6 is -OH; R 10 (is not present; r is 4; and a is 1). In formula I, in one embodiment, R 1 is hydrogen. In formula I, in one embodiment, useful R 1 Examples of groups include methyl and ethyl. In one embodiment, a useful R1 Examples of the groups include propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and their structural isomers. In one embodiment, R 1 is methyl. In one embodiment, R 1 is ethyl. In one embodiment, R 1 R is propyl and its structural isomers. In one embodiment, R 1 is butyl and its structural isomers. In one embodiment, R 1 These are pentyl and its structural isomers. In one embodiment, R 1 is hexyl and its structural isomers. In one embodiment, R 1 These are heptyl and its structural isomers. In one embodiment, R 1 octyl and its structural isomers. In one embodiment, R 1 These are nonyl and its structural isomers. In one embodiment, R 1 These are decyl and its structural isomers. In formula I, in one embodiment described above, useful R 2 Examples of groups include n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. In one embodiment, R 2 is n-pentyl or its structural isomer. In another embodiment, R 2 is n-hexyl or a structural isomer thereof. In another embodiment, R 2 is n-heptyl or its structural isomer. In another embodiment, R 2 is n-octyl or its structural isomer. In another embodiment, R 2 is n-nonyl or its structural isomer. In another embodiment, R 2 is n-decyl or its structural isomer. In one embodiment, QR 2 is n-hexyl. In formula I, in one embodiment, useful R 3 The basis is as described above. In one embodiment of the above formula I, a useful R 4Examples of groups include methyl, ethyl, propyl, butyl, and pentyl. In one embodiment, R 4 is methyl. In another embodiment, R 4 is ethyl. In another embodiment, R 4 R is propyl and its structural isomers. In another embodiment, R 4 is butyl and its structural isomers. In another embodiment, R 4 These are pentyl and its structural isomers. In one embodiment of the above formula I, useful R 5 Examples of groups include methyl, ethyl, propyl, butyl, and pentyl. In one embodiment, R 5 is methyl. In another embodiment, R 5 is ethyl. In another embodiment, R 5 R is propyl and its structural isomers. In another embodiment, R 5 is butyl and its structural isomers. In another embodiment, R 5 R is pentyl and its structural isomers. In one embodiment of the above formula I, R 4 and R 5 Independent combinations of are assumed herein. For example, in one embodiment, R 4 and R 5 is methyl. In one embodiment, R 4 and R 5 is ethyl. In one embodiment, R 4 and R 5 These are independently propyl and structural isomers. In one embodiment, R 4 and R 5 These are independently butyl and structural isomers. In one embodiment, R 4 and R 5 These are independently pentyl and structural isomers. In one embodiment, R 4 is ethyl, and R 5 is methyl. In one embodiment, R 4 is ethyl, and R 5 R is independently propyl and its structural isomers. In one embodiment, R 4R is independently propyl and its structural isomers; and R 5 These are independently butyl and its structural isomers. In one embodiment, R 4 These are independently butyl and its structural isomers; and R 5 These are independently pentyl and its structural isomers. In formula I, in one embodiment, useful R 7 and R 8 The basis is as described above.

[0070] In one embodiment, the following is described herein: a compound having the structure of formula II, or a pharmaceutically acceptable salt or prodrug thereof: [ka] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and m are as described above in relation to formula I. In one embodiment, R 7 is hydrogen, -N(H)C(O)CH2NH2, -N(H)C(O)CH2OH, or -N(H)CH2CH2NH2; and R 8 is hydrogen or fluorocarbon. In one embodiment, R 7 is -N(H)C(O)CH2NH2; and R 8 is fluoro. In one embodiment, R 7 is -N(H)C(O)CH2NH2; and R 8 is hydrogen. In one embodiment, R 7 is -N(H)C(O)CH2OH; and R 8 is hydrogen. In one embodiment, R 7 is -N(H)CH2CH2NH2; and R 8 It is hydrogen.

[0071] In one embodiment, provided herein is [ka] A compound according to formula II, selected from the group consisting of TIFF0007912488000089.tif220170 and TIFF0007912488000090.tif76170, and a pharmaceutically acceptable salt thereof.

[0072] (Compound, payload, or prodrug payload-Q is oxygen) In one embodiment, the following are described herein: a compound having the structure of formula I, or a pharmaceutically acceptable salt or prodrug thereof: [ka] (In the formula, Q is -O- and R 1 is hydrogen or C1-C 10 Alkyl; R 2 is alkyl or alkynyl; R 3 R is a hydroxyl or -OC(O)C1-C5 alkyl group; 4 and R 5 It is a C1-C5 alkyl group; R 6 is -OH; R 10 (where present, is a C1-C5 alkyl group; r is 3 or 4; and a is 1). In one embodiment of formula I, R 1 is hydrogen. In formula I, in one embodiment, useful R 1 Examples of groups include methyl and ethyl. In one embodiment, a useful R 1 Examples of the groups include propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and their structural isomers. In one embodiment, R 1 is methyl. In one embodiment, R 1 is ethyl. In one embodiment, R 1 R is propyl and its structural isomers. In one embodiment, R 1 is butyl and its structural isomers. In one embodiment, R 1 These are pentyl and its structural isomers. In one embodiment, R1 is hexyl and its structural isomers. In one embodiment, R 1 These are heptyl and its structural isomers. In one embodiment, R 1 octyl and its structural isomers. In one embodiment, R 1 These are nonyl and its structural isomers. In one embodiment, R 1 These are decyl and its structural isomers. In formula I, in one embodiment described above, useful R 2 Examples of groups include n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. In one embodiment, R 2 is n-pentyl or its structural isomer. In another embodiment, R 2 is n-hexyl or a structural isomer thereof. In another embodiment, R 2 is n-heptyl or its structural isomer. In another embodiment, R 2 is n-octyl or its structural isomer. In another embodiment, R 2 is n-nonyl or its structural isomer. In another embodiment, R 2 is n-decyl or its structural isomer. In one embodiment of formula I, R 2 is -CH2CCH. In one embodiment of formula I, R 2 is -CH2CH2CCH. In one embodiment of formula I, R 2 is -CH2CH2CH2CCH. In one embodiment of formula I, R 2 is -CH2CH2CH2CH2CCH. In one embodiment of formula I, R 2 is -CH2CH2CH2CH2CH2CCH. In one embodiment of formula I, R 2 is -CH2CH2CH2CH2CH2CH2CCH. In one embodiment of equation I, R 2 is -CH2CH2CH2CH2CH2CH2CH2CCH. In one embodiment of equation I, R 2 is -CH2CH2CH2CH2CH2CH2CH2CH2CCH. In one embodiment of equation I, R 2This is -CH2CH2CH2CH2CH2CH2CH2CH2CH2CCH. In one embodiment of equation I, R 2 is -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CCH. One embodiment of equation I, R 3 is hydroxyl. In one embodiment of the above formula I, useful R 3 Examples of groups include -C(O)Me, -C(O)Et, -C(O)propyl, -C(O)butyl, and -C(O)pentyl. In one embodiment, R 3 In another embodiment, R 3 is -C(O)Et. In another embodiment, R 3 R is -C(O)propyl and its structural isomers. In another embodiment, R 3 is -C(O)butyl and its structural isomers. In another embodiment, R 3 is -C(O)pentyl and its structural isomers. In one embodiment of the above formula I, useful R 4 Examples of groups include methyl, ethyl, propyl, butyl, and pentyl. In one embodiment, R 4 is methyl. In another embodiment, R 4 is ethyl. In another embodiment, R 4 R is propyl and its structural isomers. In another embodiment, R 4 is butyl and its structural isomers. In another embodiment, R 4 These are pentyl and its structural isomers. In one embodiment of the above formula I, useful R 5 Examples of groups include methyl, ethyl, propyl, butyl, and pentyl. In one embodiment, R 5 is methyl. In another embodiment, R 5 is ethyl. In another embodiment, R 5 R is propyl and its structural isomers. In another embodiment, R 5 is butyl and its structural isomers. In another embodiment, R 5R is pentyl and its structural isomers. In one embodiment of the above formula I, R 4 and R 5 Independent combinations of are assumed herein. For example, in one embodiment, R 4 and R 5 is methyl. In one embodiment, R 4 and R 5 is ethyl. In one embodiment, R 4 and R 5 These are independently propyl and structural isomers. In one embodiment, R 4 and R 5 These are independently butyl and structural isomers. In one embodiment, R 4 and R 5 These are independently pentyl and structural isomers. In one embodiment, R 4 is ethyl, and R 5 is methyl. In one embodiment, R 4 is ethyl, and R 5 R is independently propyl and its structural isomers. In one embodiment, R 4 R is independently propyl and its structural isomers; and R 5 These are independently butyl and its structural isomers. In one embodiment, R 4 These are independently butyl and its structural isomers; and R 5 These are independently pentyl and its structural isomers. In formula I, in one embodiment, useful R 7 and R 8 The basis is as described above. In one embodiment of formula I, R 10 It does not exist. In one embodiment of formula I, R 10 is a C1-C5 alkyl group. In one embodiment, a useful R 10 Examples of the groups include propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and their structural isomers. In one embodiment, R 10 is methyl. In one embodiment, R 10 is ethyl. In one embodiment, R 10R is propyl and its structural isomers. In one embodiment, R 10 is butyl and its structural isomers. In one embodiment, R 10 These are pentyl and its structural isomers. In one embodiment, R 10 is hexyl and its structural isomers. In one embodiment, R 10 These are heptyl and its structural isomers. In one embodiment, R 10 octyl and its structural isomers. In one embodiment, R 10 These are nonyl and its structural isomers. In one embodiment, R 10 is decyl and its structural isomers. In one embodiment, r is 3. In another embodiment, r is 4.

[0073] In one embodiment, the following is described herein: a compound having the structure of formula IV, or a pharmaceutically acceptable salt or prodrug thereof: [ka] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 10 , and m are as described above in relation to formula I. In one embodiment, R 7 is hydrogen or -NH2; and R 8 is hydrogen or fluorocarbon. In one embodiment, R 7 is -NH2; and R 8 is hydrogen. In one embodiment, R 7 is -NH2; and R 8 It is fluoro.

[0074] In one embodiment, provided herein, the following is provided: [ka] A compound according to formula IV selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

[0075] In one embodiment, the following is described herein: a compound having the structure of formula I, or a pharmaceutically acceptable salt or prodrug thereof: [ka] (In the formula, Q is -O- and R 1 C1-C 10 Alkyl; R 2 is alkinyl; R 3 It is a -OC(O)C1-C5 alkyl; R 4 and R 5 It is a C1-C5 alkyl group; R 6 is -OH; R 10 (is not present; r is 4; and a is 1). In formula I, in one embodiment, useful R 1 Examples of groups include methyl and ethyl. In one embodiment, a useful R 1 Examples of the groups include propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and their structural isomers. In one embodiment, R 1 is methyl. In one embodiment, R 1 is ethyl. In one embodiment, R 1 R is propyl and its structural isomers. In one embodiment, R 1 is butyl and its structural isomers. In one embodiment, R 1 These are pentyl and its structural isomers. In one embodiment, R 1 is hexyl and its structural isomers. In one embodiment, R 1 These are heptyl and its structural isomers. In one embodiment, R 1 octyl and its structural isomers. In one embodiment, R 1 These are nonyl and its structural isomers. In one embodiment, R 1 is decyl and its structural isomers. In one embodiment of formula I, R2 is -CH2CCH. In one embodiment of formula I, R 2 is -CH2CH2CCH. In one embodiment of formula I, R 2 is -CH2CH2CH2CCH. In one embodiment of formula I, R 2 is -CH2CH2CH2CH2CCH. In one embodiment of formula I, R 2 is -CH2CH2CH2CH2CH2CCH. In one embodiment of formula I, R 2 is -CH2CH2CH2CH2CH2CH2CCH. In one embodiment of equation I, R 2 is -CH2CH2CH2CH2CH2CH2CH2CCH. In one embodiment of equation I, R 2 is -CH2CH2CH2CH2CH2CH2CH2CH2CCH. In one embodiment of equation I, R 2 This is -CH2CH2CH2CH2CH2CH2CH2CH2CH2CCH. In one embodiment of equation I, R 2 is -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CCH. One embodiment of equation I, R 3 is hydroxyl. In one embodiment of the above formula I, useful R 3 Examples of groups include -C(O)Me, -C(O)Et, -C(O)propyl, -C(O)butyl, and -C(O)pentyl. In one embodiment, R 3 In another embodiment, R 3 is -C(O)Et. In another embodiment, R 3 R is -C(O)propyl and its structural isomers. In another embodiment, R 3 is -C(O)butyl and its structural isomers. In another embodiment, R 3 is -C(O)pentyl and its structural isomers. In one embodiment of the above formula I, useful R 4 Examples of groups include methyl, ethyl, propyl, butyl, and pentyl. In one embodiment, R 4 is methyl. In another embodiment, R 4is ethyl. In another embodiment, R 4 R is propyl and its structural isomers. In another embodiment, R 4 is butyl and its structural isomers. In another embodiment, R 4 These are pentyl and its structural isomers. In one embodiment of the above formula I, useful R 5 Examples of groups include methyl, ethyl, propyl, butyl, and pentyl. In one embodiment, R 5 is methyl. In another embodiment, R 5 is ethyl. In another embodiment, R 5 R is propyl and its structural isomers. In another embodiment, R 5 is butyl and its structural isomers. In another embodiment, R 5 R is pentyl and its structural isomers. In one embodiment of the above formula I, R 4 and R 5 Independent combinations of are assumed herein. For example, in one embodiment, R 4 and R 5 is methyl. In one embodiment, R 4 and R 5 is ethyl. In one embodiment, R 4 and R 5 These are independently propyl and structural isomers. In one embodiment, R 4 and R 5 These are independently butyl and structural isomers. In one embodiment, R 4 and R 5 These are independently pentyl and structural isomers. In one embodiment, R 4 is ethyl, and R 5 is methyl. In one embodiment, R 4 is ethyl, and R 5 R is independently propyl and its structural isomers. In one embodiment, R 4 R is independently propyl and its structural isomers; and R 5 These are independently butyl and its structural isomers. In one embodiment, R 4These are independently butyl and its structural isomers; and R 5 These are independently pentyl and its structural isomers. In formula I, in one embodiment, useful R 7 and R 8 The basis is as described above.

[0076] In one embodiment, the following is described herein: a compound having the structure of formula V, or a pharmaceutically acceptable salt or prodrug thereof: [ka] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and m are as described above in relation to formula I. In one embodiment, R 7 is hydrogen or -N(H)C(O)CH2OH, -N(H)C(O)CH2NHC(O)CH2NH2, or [ka] And R 8 is hydrogen. In one embodiment, R 7 is -N(H)C(O)CH2OH; and R 8 is hydrogen. In one embodiment, R 7 is -N(H)C(O)CH2NHC(O)CH2NH2; and R 8 is hydrogen. In one embodiment, R 7 teeth, [ka] And R 8 It is hydrogen.

[0077] In one embodiment, provided herein is [ka] A compound according to formula V selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

[0078] (Compound, payload, or prodrug payload-Q is carbon or oxygen) In one embodiment, the following is described herein: a compound having the structure of formula I, or a pharmaceutically acceptable salt or prodrug thereof: [ka] (wherein Q is -CH2- or -O-; R 1 C1-C 10 Alkyl; R 2 is alkyl or alkynyl; R 3 ;R 4 and R 5 It is a C1-C5 alkyl group; R 6 is -NHSO2(CH2) a1 -Aryl-(CH2) a2 NR 6a R 6b And; R 10 (is not present; r is 4; and a, a1, and a2 are independently 0 or 1). In one embodiment of formula I, Q is -CH2-. In one embodiment of formula I, Q is -O-. In one embodiment of formula I, useful R 1 Examples of groups include methyl and ethyl. In one embodiment, a useful R 1 Examples of the groups include propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and their structural isomers. In one embodiment, R 1 is methyl. In one embodiment, R 1 is ethyl. In one embodiment, R 1 R is propyl and its structural isomers. In one embodiment, R 1 is butyl and its structural isomers. In one embodiment, R 1 These are pentyl and its structural isomers. In one embodiment, R 1is hexyl and its structural isomers. In one embodiment, R 1 These are heptyl and its structural isomers. In one embodiment, R 1 octyl and its structural isomers. In one embodiment, R 1 These are nonyl and its structural isomers. In one embodiment, R 1 These are decyl and its structural isomers. In formula I, in one embodiment described above, useful R 2 Examples of groups include n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. In one embodiment, R 2 is n-pentyl or its structural isomer. In another embodiment, R 2 is n-hexyl or a structural isomer thereof. In another embodiment, R 2 is n-heptyl or its structural isomer. In another embodiment, R 2 is n-octyl or its structural isomer. In another embodiment, R 2 is n-nonyl or its structural isomer. In another embodiment, R 2 is n-decyl or its structural isomer. In one embodiment of formula I, R 2 is -CH2CCH. In one embodiment of formula I, R 2 is -CH2CH2CCH. In one embodiment of formula I, R 2 is -CH2CH2CH2CCH. In one embodiment of formula I, R 2 is -CH2CH2CH2CH2CCH. In one embodiment of formula I, R 2 is -CH2CH2CH2CH2CH2CCH. In one embodiment of formula I, R 2 is -CH2CH2CH2CH2CH2CH2CCH. In one embodiment of equation I, R 2 is -CH2CH2CH2CH2CH2CH2CH2CCH. In one embodiment of equation I, R 2 is -CH2CH2CH2CH2CH2CH2CH2CH2CCH. In one embodiment of equation I, R 2This is -CH2CH2CH2CH2CH2CH2CH2CH2CH2CCH. In one embodiment of equation I, R 2 is -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CCH. In equation I, at certain interfaces, useful R 3 The basis is as described above. In one embodiment of the above formula I, a useful R 4 Examples of groups include methyl, ethyl, propyl, butyl, and pentyl. In one embodiment, R 4 is methyl. In another embodiment, R 4 is ethyl. In another embodiment, R 4 R is propyl and its structural isomers. In another embodiment, R 4 is butyl and its structural isomers. In another embodiment, R 4 These are pentyl and its structural isomers. In one embodiment of the above formula I, useful R 5 Examples of groups include methyl, ethyl, propyl, butyl, and pentyl. In one embodiment, R 5 is methyl. In another embodiment, R 5 is ethyl. In another embodiment, R 5 R is propyl and its structural isomers. In another embodiment, R 5 is butyl and its structural isomers. In another embodiment, R 5 R is pentyl and its structural isomers. In one embodiment of the above formula I, R 4 and R 5 Independent combinations of are assumed herein. For example, in one embodiment, R 4 and R 5 is methyl. In one embodiment, R 4 and R 5 is ethyl. In one embodiment, R 4 and R 5 These are independently propyl and structural isomers. In one embodiment, R 4 and R 5 These are independently butyl and structural isomers. In one embodiment, R 4 and R5 These are independently pentyl and structural isomers. In one embodiment, R 4 is ethyl, and R 5 is methyl. In one embodiment, R 4 is ethyl, and R 5 R is independently propyl and its structural isomers. In one embodiment, R 4 R is independently propyl and its structural isomers; and R 5 These are independently butyl and its structural isomers. In one embodiment, R 4 These are independently butyl and its structural isomers; and R 5 These are independently pentyl and its structural isomers. In formula I, in one embodiment, useful R 6a and R 6b The base is hydrogen. In formula I, in one embodiment, a is zero. In formula I, in one embodiment, a is 1. In formula I, in one embodiment, a1 is zero and a2 is 1. In formula I, in one embodiment, a1 is zero and a2 is zero. In formula I, in one embodiment, a1 is 1 and a2 is zero. In formula I, in one embodiment, a is zero, a1 is zero and a2 is 1. In formula I, in one embodiment, a is zero, a1 is zero and a2 is zero. In formula I, in one embodiment, a is zero, a1 is 1 and a2 is zero. In formula I, in one embodiment, a is 1, a1 is zero and a2 is 1. In Equation I, in one embodiment, a is 1, a1 is 0, and a2 is 0.

[0079] In one embodiment, the following is described herein: a compound having the structure of formula VI, or a pharmaceutically acceptable salt or prodrug thereof: [ka] In one example, Q, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 This is as described above in relation to formula I. In one embodiment, R 6 teeth, [ka] In one embodiment, R 6 teeth, [ka] In one embodiment, R 6 teeth, [ka] In one embodiment, R 6 teeth, [ka] In one embodiment, a is zero; and R 6 teeth, [ka] In one embodiment, a is zero; and R 6 teeth, [ka] In one embodiment, a is zero; and R 6 teeth, [ka] In one embodiment, a is zero; and R 6 teeth, [ka] In one embodiment, a is 1 and R 6 teeth, [ka] In one embodiment, a is 1 and R 6 teeth, [ka] In one embodiment, a is 1 and R 6 teeth, [ka] In one embodiment, a is 1 and R 6 teeth, [ka] That is the case.

[0080] In one embodiment, provided herein, the following is provided: [ka] A compound according to formula VI, or a pharmaceutically acceptable salt thereof, selected from the group consisting of TIFF0007912488000114.tif208170 and TIFF0007912488000115.tif45170.

[0081] (Binder) Suitable binders for any of the conjugates provided in this disclosure include, but are not limited to, antibodies, lymphokines (e.g., IL-2 or IL-3), hormones (e.g., insulin and glucocorticoids), growth factors (e.g., EGF, transferrin, and type III fibronectin), viral receptors, interleukins, or any other cell-binding or peptide-binding molecules or substances. Other suitable binders include, but are not limited to, ankyrin repeat proteins and interferons.

[0082] In some embodiments, the binder is an antibody or an antigen-binding fragment thereof. The antibody may be in any form known to those skilled in the art. As used herein, the term “antibody” means any antigen-binding molecule or molecular complex comprising at least one complementarity-determining region (CDR) that specifically binds to or interacts with a particular antigen. The term “antibody” includes an immunoglobulin molecule comprising four polypeptide chains, two heavy (H) chains and two light (L) chains, linked together by disulfide bonds, and its polymer (e.g., IgM). Each heavy chain comprises a heavy chain variable region (HCVR or V) as used herein. H It includes the heavy chain constant region (abbreviated as C). The heavy chain constant region consists of three domains, C H 1. C H 2, and C H Includes 3. Each light chain has a light chain variable region (LCVR or V in this specification). L It includes a light chain steady region (abbreviated as C). The light chain steady region consists of one domain (C L Includes 1). V H and V L The region can be further divided into hypervariable regions called complementary determination regions (CDRs), which are scattered with more highly conserved regions called framework regions (FRs). H and V LIt consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In the various embodiments disclosed herein, the FRs of the antibody (or its antigen-binding moiety) suitable for the compound herein may be identical to the human germline sequence or may be naturally or artificially modified. The amino acid consensus sequence can be defined based on comparative analysis of two or more CDRs. As used in this specification, the term “antibody” also includes the antigen-binding fragment of a complete antibody molecule. As used herein, terms such as “antigen-binding moiety” and “antigen-binding fragment” of an antibody include any naturally occurring, enzymatically obtained, synthetic, or genetically modified polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be obtained from a complete antibody molecule using any suitable standard technique, e.g., proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding the antibody variable domain and optionally a constant domain. Such DNA is publicly known and / or readily available, for example, from commercial sources, DNA libraries (including phage-antibody libraries), or can be synthesized. DNA can be sequenced and manipulated by chemical or molecular biological techniques to, for example, position one or more variable and / or constant domains in a preferred configuration, or to introduce codons, generate cysteine ​​residues, modify, add, or delete amino acids. Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv(scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable region of an antibody (e.g., isolated CDRs such as the CDR3 peptide), or restrictive FR3-CDR3-FR4 peptides.Other modified molecules, such as domain-specific antibodies, single-domain antibodies, domain-deletion antibodies, chimeric antibodies, CDR-implanted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunotherapy drugs (SMIPs), and shark variable IgNAR domains, are also included in the expression “antigen-binding fragment” as used herein. Antigen-binding fragments of antibodies typically include at least one variable domain. The variable domain may be of any size or amino acid composition and typically includes at least one CDR adjacent to or in-framed with one or more framework sequences. V. H Domain is V L In the antigen-binding fragment associated with the domain, V H Domain and V L The domains may be in any preferred arrangement relative to each other. For example, the variable region is a dimer, and V H -V H , V H -V L , or V L -V L It may contain a dimer. Alternatively, the antigen-binding fragment of the antibody may contain a monomer V H or V L The antibody may contain domains. In one embodiment, the antigen-binding fragment of the antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting and exemplary configurations of variable and constant domains that may be found in the antigen-binding fragment of the antibody of this disclosure include: (i)V H -C H 1;(ii)V H -C H 2; (iii)V H -C H 3;(iv)V H -C H 1-C H 2;(v)V H -C H 1-C H 2-C H 3;(vi)V H -C H 2-C H 3;(vii)VH -C L ;(viii)V L -C H 1;(ix)V L -C H 2;(x)V L -C H 3;(xi)V L -C H 1-C H 2;(xii)V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv)V L -C LExamples include: In any configuration of variable domains and constant domains, including any of the exemplary configurations described above, the variable domains and constant domains may be directly linked to each other or linked by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids that create a flexible or semi-flexible linkage between adjacent variable domains and / or constant domains in a single polypeptide molecule. As with a complete antibody molecule, the antigen-binding fragment may be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody typically comprises at least two different variable domains, each of which can specifically bind to a different antigen or to a different epitope on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, can be adapted for use with the antibody antigen-binding fragments of this disclosure using routine techniques available in the art. In some embodiments described herein, the antibody described herein is a human antibody. As used herein, the term “human antibody” is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies of this disclosure may, for example, contain amino acid residues in the CDR, particularly in CDR3, that are not encoded by the human germline immunoglobulin sequence (e.g., mutations introduced by random or site-directed mutagenesis in vitro, or by somatic mutation in vivo). However, as used herein, the term “human antibody” is not intended to include antibodies in which a CDR sequence derived from the germline of another mammalian species, such as mouse, has been transplanted into a human framework sequence. The term “human antibody” does not include naturally occurring molecules that normally exist in naturally occurring unmodified organisms without modification or human intervention / manipulation. In some embodiments, the antibodies disclosed herein may be recombinant human antibodies.As used herein, the term “recombinant human antibody” is intended to include all human antibodies prepared, expressed, produced, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (as further described below), antibodies isolated from a recombinant combinatorial human antibody library (as further described below), antibodies isolated from an animal transgenic for the human immunoglobulin gene (e.g., mouse) (see, for example, Taylor et al., (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, produced, or isolated by any other means involving splicing the human immunoglobulin gene sequence to another DNA sequence. Such recombinant human antibodies have variable and constant regions derived from the human germline immunoglobulin sequence. However, in some embodiments, such recombinant human antibodies undergo in vitro mutagenesis (or, if using an animal transgenic for the human Ig sequence, in vivo somatic mutagenesis), and therefore the V of the recombinant antibody. H and V L The amino acid sequence of the region is human germline V H and V LThese are sequences derived from and related to the sequence, but which may not be naturally present in the human antibody germline repertoire in vivo. Human antibodies can exist in two forms associated with hinge heterogeneity. In one form, the immunoglobulin molecule contains a stable 4-chain construct of approximately 150–160 kDa, where the dimers are linked by interchain heavy-chain disulfide bonds. In the second form, the dimers are not linked by interchain disulfide bonds, and a molecule of approximately 75–80 kDa is formed, consisting of a light chain and a heavy chain (half the antibody) linked by covalent bonds. These forms are extremely difficult to separate, even after affinity purification. The frequency of occurrence of the second form in various intact IgG isotypes is not limited but is due to structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second morph to the level normally observed using the human IgG1 hinge (Angal et al., (1993) Molecular Immunology 30:105). This disclosure relates to the hinge region, C H 2 regions, or C HThe three regions include, for example, antibodies having one or more mutations that are suitable for manufacture and can improve the yield of the desired antibody form. The antibodies described herein may be isolated antibodies. As used herein, “isolated antibody” means an antibody that has been identified and isolated and / or recovered from at least one component of its natural environment. For example, an antibody isolated or extracted from at least one component of an organism, or from a tissue or cell in which the antibody is naturally present or naturally produced, is an “isolated antibody” for the purposes of this disclosure. Isolated antibodies also include antibodies in situ within recombinant cells. Isolated antibodies are antibodies that have undergone at least one purification or isolation step. According to one embodiment, isolated antibodies may be substantially free of other cellular material and / or chemicals. The antibodies used herein may include one or more amino acid substitutions, insertions, and / or deletions in the framework of heavy and light chain variable domains and / or CDR regions compared to the corresponding germline sequence from which the antibody is derived. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein with germline sequences available, for example, from public antibody sequence databases. This disclosure includes antibodies and antigen-binding fragments derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids in one or more frameworks and / or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody is derived, or to the corresponding residue(s) of another human germline sequence, or to a conserved amino acid substitution of the corresponding germline residue(s) (such sequence changes are collectively referred to herein as “germline mutations”). Those skilled in the art can readily generate a number of antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof, starting from the heavy and light chain variable region sequences disclosed herein. In one embodiment, V H and / or V LAll framework and / or CDR residues within the domain are mutated to revert to residues found in the original germline sequence from which the antibody originated. In another embodiment, only specific residues are mutated, for example, the first eight amino acids of FR1 or the last eight amino acids of FR4. Only mutant residues found in amino acids, or only mutant residues found in CDR1, CDR2, or CDR3, are mutated to return to the original germline sequence. In another embodiment, one or more of the framework and / or CDR residues are mutated to corresponding residues in a different germline sequence (i.e., a germline sequence different from the germline sequence from which the antibody originally originated). Furthermore, the antibodies of this disclosure may contain any combination of two or more germline mutations within the framework and / or CDR region, for example, in which specific individual residues are mutated to corresponding residues in a specific germline sequence, while other specific residues different from the original germline sequence are maintained or mutated to corresponding residues in a different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be easily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced antagonistic or operative biocompatibility (if applicable), or reduced immunogenicity. Antibodies and antigen-binding fragments obtained by this general method are included within the scope of this disclosure. Furthermore, antibodies useful for the compounds herein include those comprising any variant of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein, having one or more conservative substitutions. The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule, known as a paratope. A single antigen may have two or more epitopes. Therefore, different antibodies may bind to different parts of an antigen and have different biological effects. Epitopes can be either conformal or linear. Conformal epitopes arise from spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear epitopes arise from adjacent amino acid residues in a polypeptide chain. In some circumstances, epitopes may include saccharide, phosphoryl, or sulfonyl group sites on an antigen.

[0083] In some embodiments, the antibody includes a light chain. In some embodiments, the light chain is a kappa light chain. In some embodiments, the light chain is a lambda light chain. In some embodiments, the antibody includes a heavy chain. In some embodiments, the heavy chain is IgA. In some embodiments, the heavy chain is IgD. In some embodiments, the heavy chain is IgE. In some embodiments, the heavy chain is IgG. In some embodiments, the heavy chain is IgM. In some embodiments, the heavy chain is IgG1. In some embodiments, the heavy chain is IgG2. In some embodiments, the heavy chain is IgG3. In some embodiments, the heavy chain is IgG4. In some embodiments, the heavy chain is IgA1. In some embodiments, the heavy chain is IgA2.

[0084] In some embodiments, the antibody is an antibody fragment. In some embodiments, the antibody fragment is an Fv fragment. In some embodiments, the antibody fragment is a Fab fragment. In some embodiments, the antibody fragment is an F(ab′)2 fragment. In some embodiments, the antibody fragment is a Fab′ fragment. In some embodiments, the antibody fragment is an scFv(sFv) fragment. In some embodiments, the antibody fragment is an scFv-Fc fragment.

[0085] In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a polyclonal antibody. In some embodiments, the antibody is a bispecific antibody comprising a first antigen-binding domain (also referred to herein as "D1") and a second antigen-binding domain (also referred to herein as "D2").

[0086] As used herein, the term "antigen-binding domain" means any peptide, polypeptide, nucleic acid molecule, scaffold molecule, peptide display molecule, or polypeptide-containing construct that can specifically bind to a particular antigen of interest (e.g., PRLR or STEAP2). As used herein, the term "specifically binds" means that the antigen-binding domain has a dissociation constant (K) of 1 μM or less. D This means that it forms a complex with a specific antigen characterized by ) and does not bind to other unrelated antigens under normal test conditions. An "unrelated antigen" is a protein, peptide, or polypeptide in which the amino acid identity of each other is less than 95%.

[0087] Exemplary categories of antigen-binding domains that can be used in the context of this disclosure include antibodies that specifically interact with a particular antigen (e.g., a peptide body), antigen-binding portions of antibodies, peptides, receptor molecules that specifically interact with a particular antigen, proteins containing ligand-binding portions of receptors that specifically bind to a particular antigen, antigen-binding scaffolds (e.g., DARPins, HEAT repeat proteins, ARM repeat proteins, tetratricopeptide repeat sequence proteins, and other scaffolds based on naturally occurring repeat proteins [see, for example, Boersma and Pluckthun, 2011, Curr. Opin. Biotechnol. 22:849-857 and the literature cited therein]), and aptamers or portions thereof.

[0088] Methods for determining whether two molecules bind specifically to each other are well known in the art, and include, for example, equilibrium dialysis and surface plasmon resonance. For example, the antigen-binding domain used in the context of this disclosure binds to a specific antigen (e.g., a target molecule [T] or an internally distributed effector protein [E]) or a portion thereof, as measured by a surface plasmon resonance assay, at concentrations of less than approximately 1 μM, less than approximately 500 nM, less than approximately 250 nM, less than approximately 125 nM, less than approximately 60 nM, less than approximately 30 nM, less than approximately 10 nM, less than approximately 5 nM, less than approximately 2 nM, less than approximately 1 nM, and less than approximately 500 pM. K levels less than approximately 400 pM, less than approximately 300 pM, less than approximately 200 pM, less than approximately 100 pM, less than approximately 90 pM, less than approximately 80 pM, less than approximately 70 pM, less than approximately 60 pM, less than approximately 50 pM, less than approximately 40 pM, less than approximately 30 pM, less than approximately 20 pM, less than approximately 10 pM, less than approximately 5 pM, less than approximately 4 pM, less than approximately 2 pM, less than approximately 1 pM, less than approximately 0.5 pM, less than approximately 0.2 pM, less than approximately 0.1 pM, or less than approximately 0.05 pM. D It contains polypeptides that bind together.

[0089] In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody.

[0090] In some embodiments, the antibody is an anti-PSMA, anti-PRLR, anti-MUC16, anti-HER2, anti-EGFRvIII, anti-MET, or anti-STEAP2 antibody. In some embodiments, the antibody or antigen-binding fragment is anti-PSMA. In some embodiments, the antibody or antigen-binding fragment is anti-MUC16. In some embodiments, the antibody or antigen-binding fragment is anti-HER2. In some embodiments, the antibody or antigen-binding fragment is anti-EGFRvIII. In some embodiments, the antibody or antigen-binding fragment is anti-MET. In some embodiments, the antibody or antigen-binding fragment is anti-PRLR or anti-STEAP2. In some embodiments, the antibody is an anti-PRLR or anti-HER2 antibody. In some embodiments, the antibody or its antigen-binding fragment is anti-STEAP2. In some embodiments, the antibody or its antigen-binding fragment is anti-PRLR.

[0091] Antibodies may have binding specificity to any antigen considered suitable by those skilled in the art. In some embodiments, the antigen is a transmembrane molecule (e.g., a receptor). In one embodiment, the antigen is expressed on a tumor. In some embodiments, the binder interacts with or binds to a tumor antigen, which includes an antigen specific to a type of tumor or antigen that is common, overexpressed, or modified on a particular type of tumor. In one embodiment, the antigen is expressed on a solid tumor. Exemplary antigens include lipoproteins; alpha-1 antitrypsin; cytotoxic T-lymphocyte association antigens (CTLAs) such as CTLA-4; vascular endothelial growth factor (VEGF); hormone or growth factor receptors; proteins A or D; fibroblast growth factor receptor 2 (FGFR2), EpCAM, GD3, FLT3, PSMA, PSCA, MUC1, MUC16, STEAP, STEAP2, CEA, TENB2, EphA receptor, EphB receptor, folate receptor, FOLRI, mesothelin, cripto, alphavbeta6, integrins, VEGF, VEGFR, EGFR, transferrin receptor, IRTA1, IRTA2, IRTA3, IRTA4, IRTA5; CD2, CD3, CD4, CD5, CD6, CD8, CD11, CD14, CD19, C CD proteins such as D20, CD21, CD22, CD25, CD26, CD28, CD30, CD33, CD36, CD37, CD38, CD40, CD44, CD52, CD55, CD56, CD59, CD70, CD79, CD80, CD81, CD103, CD105, CD134, CD137, CD138, CD152, or antibodies that bind to one or more tumor-associated antigens or cell surface receptors disclosed in U.S. Public Notice No. 2008 / 0171040 or U.S. Public Notice No. 2008 / 0305044, each incorporated in whole by reference; erythropoietin; bone-inducible factors; immunotoxins; bone morphogenetic proteins (BMPs); T cell receptors; surface membrane proteins; integrins such as CD11a, CD11b, CD11c, CD18, ICAM, VLA-4, and VCAM;AFP, ALK, B7H4, BAGE protein, β-catenin, brc-abl, BRCA1, BORIS, CA9 (carbonic anhydrase IX), caspase-8, CD20, CD40, CD123, CDK4, CEA, CLEC12A, c-kit, cMET, CTLA4, cyclin-B1, CYP1B1, EGFR, EGFRvIII, endoglin, Epcam, EphA2, ErbB2 / Her2, ErbB3 / Her3, ErbB4 / Her4, ETV6-AML, Fra-1, FOLR1, GAGE ​​protein, GD2, GD3, GloboH, Glypican-3, GM3, gp100, Her2, HLA / B-raf, HLA / EBNA1, HLA / k-ras, HLA / MAGE-A3, hTERT, IGF1R, LGR5, LMP2, MAGE protein, MART-1, Mesothelin, ML-I AP, Muc1, Muc16, CA-125, MUM1, NA17, NGEP, NY-BR1, NY-BR62, NY-BR85, NY-ESO1, OX40, p15, p53, PAP, PAX3, PA X5, PCTA-1, PDGFR-α, PDGFR-β, PDGF-A, PDGF-B, PDGF-C, PDGF-D, PLAC1, PRLR, PRAME, PSCA, PSGR, PSMA(FOLH1 ), tumor-associated antigens such as RAGE protein, Ras, RGS5, Rho, SART-1, SART-3, Steap-1, Steap-2, STn, Survivin, TAG-72, TGF-β, TMPRSS2, Tn, TNFRSF17, TRP-1, TRP-2, tyrosinase, and uroplakin-3, as well as fragments of any of the polypeptides listed above; cell surface expression antigens; MUC16; c-MET;Examples of membrane proteins include, but are not limited to, class A scavenger receptors, including scavenger receptor A (SR-A), as well as B7 family-related members, including V-set and Ig domain-containing 4 (VSIG4), colony-stimulating factor 1 receptor (CSF1R), asialoglycoprotein receptor (ASGPR), and amyloid-beta precursor-like protein 2 (APLP-2). In some embodiments, the antigen is PRLR or HER2. In some embodiments, the antigen is STEAP2. In some embodiments, the antigen is human STEAP2. In some examples, the MAGE protein is selected from MAGE-1, -2, -3, -4, -6, and -12. In some examples, the GAGE ​​protein is selected from GAGE-1 and GAGE-2.

[0092] Examples of exemplary antigens include, but are not limited to, BCMA, SLAMF7, GPNMB, and UPK3A. Examples of exemplary antigens also include, but are not limited to, MUC16, STEAP2, and HER2.

[0093] In some embodiments, the antigen includes MUC16. In some embodiments, the antigen includes STEAP2. In some embodiments, the antigen includes PSMA. In some embodiments, the antigen includes HER2. In some embodiments, the antigen is prolactin receptor (PRLR) or prostate-specific membrane antigen (PSMA). In some embodiments, the antigen is MUC16. In some embodiments, the antigen includes PSMA. In some embodiments, the antigen is HER2. In some embodiments, the antigen is STEAP2.

[0094] In one embodiment, the antibody contains a glutamine residue at one or more heavy chain positions numbered 295 in the EU numbering system. In this disclosure, this position is referred to as glutamine 295, Gln295, or Q295. Those skilled in the art will recognize that this is a conserved glutamine residue in the wild-type sequences of many antibodies. In another useful embodiment, the antibody can be manipulated to contain a glutamine residue. In one embodiment, the antibody contains one or more N297Q mutations. Techniques for modifying the antibody sequence to contain a glutamine residue are within the realm of the art (see, for example, Ausubel et al., Current Protoc. Mol. Biol.).

[0095] In some embodiments, the linker-payload or the antibody conjugated to the payload, or the antigen-binding fragment thereof, can be an antibody that targets STEAP2. Suitable anti-STEAP2 antibodies or antigen-binding fragments thereof include, for example, those of International Publication No. WO2018 / 058001A1 (including those containing the amino acid sequence disclosed in Table 1 on page 75). In some embodiments, the anti-STEAP2 antibody is H1H7814N of WO2018 / 058001A1 (including the CDR of H1M7814N of the same publication). In some embodiments, the anti-STEAP2 antibody includes a heavy chain complementarity-determining region (HCDR)-1 containing SEQ ID NO: 2; HCDR2 containing SEQ ID NO: 3; HCDR3 containing SEQ ID NO: 4; a light chain complementarity-determining region (LCDR)-1 containing SEQ ID NO: 6; LCDR2 containing SEQ ID NO: 7; and LCDR3 containing SEQ ID NO: 8. In some embodiments, the anti-STEAP2 antibody comprises a heavy chain variable region (HCVR) containing SEQ ID NO: 1 and a light chain variable region (LCVR) containing SEQ ID NO: 5. In any of the embodiments described above, the anti-STEAP2 antibody can be prepared by site-directed mutagenesis, in which a glutamine residue is inserted into a site that does not result in invalidation of antibody function or binding. For example, in any of the embodiments described above, the anti-STEAP2 antibody may contain the Asn297Gln(N297Q) mutation. Furthermore, such an antibody having the N297Q mutation may contain in its variable region one or more additional native glutamine residues that may be available to transglutaminase and can therefore be conjugated into the payload or linker-payload (Table A). In one embodiment, the antibody or its antigen-binding fragment comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID NO: 1; and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) within the light chain variable region (LCVR) amino acid sequence of SEQ ID NO: 5. In another embodiment, the antibody or its antigen-binding fragment comprises the HCVR amino acid sequence of SEQ ID NO: 1; and the LCVR amino acid sequence of SEQ ID NO: 5.International Publication No. WO2018 / 058001A1 is thus incorporated in its entirety by reference herein.

[0096] In some embodiments, the linker-payload or the antibody conjugated to the payload, or the antigen-binding fragment thereof, can be an antibody that targets the human prolactin receptor (PRLR). Suitable anti-PRLR antibodies or antigen-binding fragments include, for example, those of International Publication No. WO2015 / 026907A1 (including those containing the amino acid sequence disclosed in Table 1 on page 36 of the same publication). In some embodiments, the anti-PRLR antibody is H1H6958N2 of WO2015 / 026907A1 (including the CDR of H2M6958N2 of the same publication). In some embodiments, the anti-PRLR antibody includes heavy chain complementarity-determining region (HCDR)-1 containing SEQ ID NO: 10; HCDR2 containing SEQ ID NO: 11; HCDR3 containing SEQ ID NO: 12; light chain complementarity-determining region (LCDR)-1 containing SEQ ID NO: 14; LCDR2 containing SEQ ID NO: 15; and LCDR3 containing SEQ ID NO: 16. In some embodiments, the anti-PRLR antibody comprises a heavy chain variable region (HCVR) containing SEQ ID NO: 9 and a light chain variable region (LCVR) containing SEQ ID NO: 13. In any of the embodiments described above, the anti-PRLR antibody can be prepared by site-directed mutagenesis, in which a glutamine residue is inserted at a position that does not result in invalidation of antibody function or binding. For example, in any of the embodiments described above, the anti-PRLR antibody may contain the Asn297Gln(N297Q) mutation. Such an antibody having the N297Q mutation may also contain one or more additional native glutamine residues in its variable region that may be available to transglutaminase and therefore can be conjugated into the payload or linker-payload (Table A). In one embodiment, the antibody or its antigen-binding fragment comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID NO: 9; and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) within the light chain variable region (LCVR) amino acid sequence of SEQ ID NO: 13. In another embodiment, the antibody or its antigen-binding fragment comprises the HCVR amino acid sequence of SEQ ID NO: 9; and the LCVR amino acid sequence of SEQ ID NO: 13.International Publication No. WO2015 / 026907A1 is thus incorporated in its entirety by reference herein. (Table A. Sequences of exemplary antibodies H1H7814N (anti-STEAP2) and H1H6958N2 (anti-PRLR)) [Table 3]

[0097] This disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to STEAP2, comprising an HCVR containing an amino acid sequence selected from any of the HCVR amino acid sequences listed in Table A, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0098] Furthermore, the present disclosure also provides an antibody or antigen-binding fragment thereof that specifically binds to STEAP2, comprising an LCVR containing an amino acid sequence selected from any of the LCVR amino acid sequences listed in Table A, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0099] The Disclosure also provides antibodies or antigen-binding fragments thereof that specifically bind to STEAP2, comprising HCVR and LCVR amino acid sequence pairs (HCVR / LCVR) which include one of the HCVR amino acid sequences listed in Table A in conjunction with any of the LCVR amino acid sequences listed in Table A. According to one embodiment, the Disclosure provides an antibody or antigen-binding fragment thereof comprising an HCVR / LCVR amino acid sequence pair contained in one of the exemplary anti-STEAP2 antibodies listed in Table A. In one embodiment, the HCVR / LCVR amino acid sequence pair is selected from the group consisting of :250 / 258; described in International Publication No. WO2018 / 058001A1, the entire contents of which are incorporated herein by reference.

[0100] Furthermore, the disclosure also provides an antibody or antigen-binding fragment thereof that specifically binds to STEAP2 and contains an HCDR1 amino acid sequence selected from any of the heavy chain CDR1 (HCDR1) amino acid sequences listed in Table A, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

[0101] Furthermore, the disclosure also provides an antibody or antigen-binding fragment thereof that specifically binds to STEAP2, comprising an HCDR2 containing an amino acid sequence selected from any of the heavy chain CDR2 (HCDR2) amino acid sequences listed in Table A, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

[0102] Furthermore, the disclosure also provides an antibody or antigen-binding fragment thereof that specifically binds to STEAP2 and contains an HCDR3 containing an amino acid sequence selected from any of the heavy chain CDR3 (HCDR3) amino acid sequences listed in Table A, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

[0103] Furthermore, the disclosure also provides an antibody or antigen-binding fragment thereof that specifically binds to STEAP2 and includes an LCDR1 containing an amino acid sequence selected from any of the light chain CDR1 (LCDR1) amino acid sequences listed in Table A, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

[0104] Furthermore, the disclosure also provides an antibody or antigen-binding fragment thereof that specifically binds to STEAP2, comprising an LCDR2 containing an amino acid sequence selected from any of the light chain CDR2 (LCDR2) amino acid sequences listed in Table A, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

[0105] Furthermore, the disclosure also provides an antibody or antigen-binding fragment thereof that specifically binds to STEAP2 and contains an LCDR3 containing an amino acid sequence selected from any of the light chain CDR3 (LCDR3) amino acid sequences listed in Table A, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

[0106] The Disclosure also provides an antibody or antigen-binding fragment thereof that specifically binds to STEAP2, comprising an HCDR3 and LCDR3 amino acid sequence pair (HCDR3 / LCDR3) containing one of the HCDR3 amino acid sequences listed in Table A in conjunction with any of the LCDR3 amino acid sequences listed in Table A. According to one embodiment, the Disclosure provides an antibody or antigen-binding fragment thereof that contains an HCDR3 / LCDR3 amino acid sequence pair contained in one of the exemplary anti-STEAP2 antibodies listed in Table A. In one embodiment, the HCDR3 / LCDR3 amino acid sequence pair is selected from the group consisting of:256 / 254; described in International Publication No. WO2018 / 058001A1, the entire contents of which are incorporated herein by reference.

[0107] The Disclosure also provides antibodies or antigen-binding fragments thereof that specifically bind to STEAP2, comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within any of the exemplary anti-STEAP2 antibodies listed in Table A. In one embodiment, the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequence set is selected from the group consisting of:252-254-256-260-262-264; described in full in International Publication No. WO2018 / 058001A1, the full contents of which are incorporated herein by reference.

[0108] In a relevant embodiment, the present disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to STEAP2, comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within an HCVR / LCVR amino acid sequence pair as defined by any of the exemplary anti-STEAP2 antibodies listed in Table A. For example, the present disclosure includes an antibody or antigen-binding fragment thereof that specifically binds to STEAP2, comprising the set of HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequences contained within an HCVR / LCVR amino acid sequence pair selected from the group consisting of:250 / 258; described in International Publication No. WO2018 / 058001A1, the entirety of which is incorporated herein by reference. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify the specific CDRs within the HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify CDR boundaries include, for example, the definitions of Kabat, Chothia, and AbM. Generally, Kabat's definition is based on sequence variability, Chothia's definition is based on the location of structural loop regions, and AbM's definition is a compromise between Kabat's and Chothia's approaches. See, for example, Kabat's literature, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); and Martin et al., Proc. Natl. Acad. Sci. USA 86:9268-9272 (1989). Public databases are also available for identifying CDR sequences within antibodies.

[0109] This disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to PRLR, comprising an HCVR containing an amino acid sequence selected from any of the HCVR amino acid sequences listed in Table A, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0110] Furthermore, the present disclosure also provides an antibody or antigen-binding fragment thereof that specifically binds to PRLR, comprising an LCVR containing an amino acid sequence selected from any of the LCVR amino acid sequences listed in Table A, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0111] The Disclosure also provides antibodies or antigen-binding fragments thereof that specifically bind to PRLR, comprising HCVR and LCVR amino acid sequence pairs (HCVR / LCVR) which include one of the HCVR amino acid sequences listed in Table A in conjunction with any of the LCVR amino acid sequences listed in Table A. According to one embodiment, the Disclosure provides an antibody or antigen-binding fragment thereof that includes an HCVR / LCVR amino acid sequence pair contained in one of the exemplary anti-PRLR antibodies listed in Table A. In one embodiment, the HCVR / LCVR amino acid sequence pair is selected from the group consisting of: 18 / 26; 66 / 74; 274 / 282; 290 / 298; and 370 / 378; whose entire contents are described in International Publication No. WO2015 / 026907A1, which is incorporated herein by reference.

[0112] Furthermore, the present disclosure also provides an antibody or antigen-binding fragment thereof that specifically binds to PRLR, comprising a heavy chain CDR1 (HCDR1) containing an amino acid sequence selected from any of the HCDR1 amino acid sequences listed in Table A, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

[0113] Furthermore, the disclosure also provides antibodies or antigen-binding fragments thereof that specifically bind to PRLR, comprising a heavy chain CDR2 (HCDR2) containing an amino acid sequence selected from any of the HCDR2 amino acid sequences listed in Table A, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

[0114] Furthermore, the disclosure also provides antibodies or antigen-binding fragments thereof that specifically bind to PRLR, comprising a heavy chain CDR3 (HCDR3) containing an amino acid sequence selected from any of the HCDR3 amino acid sequences listed in Table A, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

[0115] Furthermore, the disclosure also provides an antibody or antigen-binding fragment thereof that specifically binds to PRLR, comprising a light chain CDR1 (LCDR1) containing an amino acid sequence selected from any of the LCDR1 amino acid sequences listed in Table A, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

[0116] Furthermore, the present disclosure also provides an antibody or antigen-binding fragment thereof that specifically binds to PRLR, comprising a light chain CDR2 (LCDR2) containing an amino acid sequence selected from any of the LCDR2 amino acid sequences listed in Table A, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

[0117] Furthermore, the disclosure also provides antibodies or antigen-binding fragments thereof that specifically bind to PRLR, comprising a light chain CDR3 (LCDR3) containing an amino acid sequence selected from any of the LCDR3 amino acid sequences listed in Table A, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

[0118] The Disclosure also provides antibodies or antigen-binding fragments thereof that specifically bind to PRLR, comprising an HCDR3 and LCDR3 amino acid sequence pair (HCDR3 / LCDR3) containing one of the HCDR3 amino acid sequences listed in Table A in conjunction with any of the LCDR3 amino acid sequences listed in Table A. According to one embodiment, the Disclosure provides an antibody or antigen-binding fragment thereof containing an HCDR3 / LCDR3 amino acid sequence pair contained in one of the exemplary anti-PRLR antibodies listed in Table A. In one embodiment, the HCDR3 / LCDR3 amino acid sequence pair is selected from the group consisting of: 24 / 32; 72 / 80; 280 / 288; 296 / 304; and 376 / 384; as described in International Publication No. WO2015 / 026907A1, which is incorporated herein by reference.

[0119] The disclosure also provides antibodies or antigen-binding fragments thereof that specifically bind to PRLR, comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within any of the exemplary anti-PRLR antibodies listed in Table A. In one embodiment, the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequence set is selected from the group consisting of: 20-22-24-28-30-32;68-70-72-76-78-80;276-278-280-284-286-288;292-294-296-300-302-304; and 372-374-376-380-382-384; as described in its entirety in International Publication No. WO2015 / 026907A1, which is incorporated herein by reference.

[0120] In a relevant embodiment, the present disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to PRLR, comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within an HCVR / LCVR amino acid sequence pair as defined by any of the exemplary anti-PRLR antibodies listed in Table A. For example, the present disclosure comprises an antibody or antigen-binding fragment thereof that specifically binds to PRLR, comprising the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequence set contained within an HCVR / LCVR amino acid sequence pair selected from the group consisting of: 18 / 26; 66 / 74; 274 / 282; 290 / 298; and 370 / 378; as described in International Publication No. WO2015 / 026907A1, which is incorporated herein by reference. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within specific HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventional methods that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. Generally, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. For example, see Kabat's literature, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); and Martin et al., Proc. Natl. Acad. Sci. USA 86:9268-9272 (1989). Public databases are also available for identifying CDR sequences within antibodies.

[0121] A binder linker can be attached to a binder, such as an antibody or antigen-binding molecule, by attachment of specific amino acids within the antibody or antigen-binding molecule. Exemplary amino acid attachments that can be used in connection with this embodiment of the present disclosure include, for example, lysine (e.g., US5,208,020; US2010 / 0129314; Holander et al., Bioconjugate Chem., 2008). See 19:358-361;WO2005 / 089808;US5,714,586;US2013 / 0101546; and US2012 / 0585592), cysteine ​​(see, e.g., US2007 / 0258987;WO2013 / 055993;WO2013 / 055990;WO2013 / 053873;WO2013 / 053872;WO2011 / 130598;US2013 / 0101546; and US7,750,116), selenocysteine ​​(see, e.g., WO2008 / 122039; and the literature of Hofer et al., Proc. Natl. Acad. Sci., USA, 2008, Examples include 105:12451-12456), formylglycine (see, for example, Carrico et al., Nat. Chem. Biol., 2007, 3:321-322; Agarwal et al., Proc. Natl. Acad. Sci., USA, 2013, 110:46-51; and Rabuka et al., Nat. Protocols, 2012, 10:1052-1067), unnatural amino acids (see, for example, WO2013 / 068874 and WO2012 / 166559), and acidic amino acids (see, for example, WO2012 / 05982). Linkers can also be conjugated to antigen-binding proteins via attachment to carbohydrates (see, for example, US2008 / 0305497, WO2014 / 065661, and Ryan et al., Food & Agriculture Immunol., 2001, 13:127-130).

[0122] In some examples, the binder is an antibody or antigen-binding molecule, and the antibody is bound to the linker via a lysine residue. In some embodiments, the antibody or antigen-binding molecule is bound to the linker via a cysteine ​​residue.

[0123] Furthermore, the linker can be conjugated to one or more glutamine residues via transglutaminase-based chemoenzymatic conjugation (see, e.g., Dennler et al., Bioconjugate Chem. 2014, 25, 569-578). For example, one or more glutamine residues of an antibody can be coupled to a primary amine compound in the presence of transglutaminase. The primary amine compound may include, for example, a payload or linker-payload that directly provides a transglutaminase-modified antibody-drug conjugate via transglutaminase-mediated coupling. The primary amine compound may also include linkers and spacers functionalized with reactive groups that can later be reacted with further compounds toward the synthesis of an antibody-drug conjugate (e.g., in one embodiment, a transglutaminase-modified antibody-drug conjugate). Antibodies containing glutamine residues can be isolated from natural sources or modified to contain one or more glutamine residues. Techniques for artificially producing glutamine residues (glutaminyl-modified antibodies or antigen-binding molecules) in antibody polypeptide chains are within the scope of the art. In one embodiment, the antibody is aglycosylated.

[0124] In one embodiment, the antibody, glutaminyl-modified antibody, or transglutaminase-modified antibody, or their antigen-binding fragment, contains at least one glutamine residue in at least one polypeptide chain sequence. In another embodiment, the antibody, glutaminyl-modified antibody, or transglutaminase-modified antibody, or their antigen-binding fragment, contains two heavy-chain polypeptides, each having one Gln295 or Q295 residue. In a further embodiment, the antibody, glutaminyl-modified antibody, or transglutaminase-modified antibody, or their antigen-binding fragment, contains one or more glutamine residues at a site other than heavy-chain 295. The antibodies of this section having the N297Q mutation(s) described herein are included herein.

[0125] (Primary amine compounds) In one embodiment, a primary amine compound useful for transglutaminase-mediated coupling of an antibody (or antigen-binding compound) containing one or more glutamines (i.e., resulting in a transglutaminase-modified antibody or its antigen-binding fragment) can be any primary amine compound that is considered useful by those skilled in the art. Typically, the primary amine compound has the formula H2N-R, where R can be any group compatible with the antibody and reaction conditions. In one embodiment, R is an alkyl, substituted alkyl, heteroalkyl, or substituted heteroalkyl.

[0126] In some embodiments, the primary amine compound comprises a reactive group or a protected reactive group. Useful reactive groups include azides, alkynes, cycloalkynes, thiols, alcohols, ketones, aldehydes, carboxylic acids, esters, amides, hydrazides, anilines, and amines. In some embodiments, the reactive group is selected from the group consisting of azides, alkynes, sulfhydryls, cycloalkynes, aldehydes, and carboxyls.

[0127] In one embodiment, the primary amine compound is of the formula H2N-LL-X, where LL is a divalent spacer and X is a reactive group or a protected reactive group. In a particular embodiment, LL is a divalent polyethylene glycol (PEG) group. In one embodiment, X is selected from the group consisting of -SH, -N3, alkynes, aldehydes, and tetrazoles. In a particular embodiment, X is -N3.

[0128] In one embodiment, the primary amine compound is represented by one of the following formulas: H2N-(CH2) n -X; H2N-(CH2CH2O) n -(CH2) p -X; H2N-(CH2) n -N(H)C(O)-(CH2) m -X; H2N-(CH2CH2O) n -N(H)C(O)-(CH2CH2O) m -(CH2) p -X; H2N-(CH2) n -C(O)N(H)-(CH2) m -X; H2N-(CH2CH2O) n -C(O)N(H)-(CH2CH2O) m -(CH2) p -X; H2N-(CH2) n -N(H)C(O)-(CH2CH2O) m -(CH2) p -X; H2N-(CH2CH2O) n -N(H)C(O)-(CH2) m -X; H2N-(CH2) n -C(O)N(H)-(CH2CH2O) m -(CH2) p -X; and H2N-(CH2CH2O) n -C(O)N(H)-(CH2) m -X; (In the formula, n is an integer selected from 1 to 12; m is an integer selected from 0 to 12; p is an integer selected from 0 to 2; and X is -SH, -N3, -C≡CH, -C(O)H, tetrazole, and [ka] (Selected from the group consisting of any of the following).

[0129] In the above, the alkyl or alkylene (i.e., -CH2-) group is, for example, C 1-8 It can be optionally substituted with alkyl, methylformyl, or -SO3H. In one embodiment, the alkyl group is not substituted.

[0130] In one embodiment, the primary amine compound is: [ka] It is selected from the group consisting of the following.

[0131] In certain embodiments, the primary amine compound is [ka] That is the case. Exemplary conditions for the above reaction are provided in the examples described below.

[0132] (Linker) In one embodiment, the linker L portion of the conjugate described herein is a site that covalently links the binder to the payload compound described herein, for example, a divalent site. In another example, linker L is a trivalent or polyvalent site that covalently links the binder to the payload compound described herein. Suitable linkers can be found, for example, in Antibody-Drug Conjugates and Immunotoxins; edited by Phillips, GL; Springer Verlag: New York, 2013; Antibody-Drug Conjugates; edited by Ducry, L.; Humana Press, 2013; Antibody-Drug Conjugates; edited by Wang, J., Shen, W.-C., and Zaro, JL; Springer International Publishing, 2015, the contents of which are fully incorporated herein by reference. In one embodiment, the linker L portion of the linker-payload or linker-prodrug payload described herein is a site covalently linked to the payload or prodrug payload compound described herein, and a binder can be covalently linked to the payload or prodrug payload compound described herein in a divalent manner. In another example, the linker L portion of the linker-payload described herein is a site covalently linked to the payload or prodrug payload compound described herein, and as a trivalent or polyvalent site, a binder can be covalently linked to the payload or prodrug payload compound described herein. The payload or prodrug payload compound includes the compounds of formulas I, Ia, Iaa, II, III, IV, V, and VI, and the residues after binding to or incorporation with linker L constitute the linker-payload or linker-prodrug payload.The linker-payload can be further conjugated to a binder, such as an antibody or its antigen-binding fragment, to form an antibody-drug conjugate. Those skilled in the art will recognize that certain functional groups of the payload site are convenient for linking to a linker and / or binder. For example, in one embodiment, there is no linker, and the payload or prodrug payload is directly conjugated to the binder. In one embodiment, the payload or prodrug payload comprises a binder containing terminal alkynes and azides, where each alkyne and azide participates in positional isomer click chemistry to directly conjugate the payload or prodrug payload residue to the binder residue. In another embodiment, the payload or prodrug payload comprises a binder containing carboxylic acids and lysines, where each carboxylic acid and lysine participates in amide bond formation to directly conjugate the payload or prodrug payload residue to the binder residue. The payload functional groups further include amines (e.g., formulas C, D, E, LPc, LPd, and LPe), quaternary ammonium ions (e.g., formulas A and LPa), hydroxyls (e.g., formulas C, D, E, LPc, LPd, and LPe), phosphates, carboxylic acids (e.g., in ester form when linked to L, as in the cases of formulas B, D, LPb, and LPd), hydrazides (e.g., formulas B and LPb), amides (e.g., aniline of formulas C and LPc, or derived from amines of formulas D, E, LPd, and LPe), and sugars.

[0133] In some embodiments, the linker is stable under physiological conditions. In some embodiments, the linker is cleavable and can release at least the payload portion, for example, in the presence of an enzyme or within a specific pH range or value. In some embodiments, the linker includes sites that are enzymatically cleavable. Exemplary enzymatically cleavable sites include, but are not limited to, peptide bonds (i.e., distinct from prodrug payloads having peptide bonds, as described elsewhere herein), ester links, hydrazones, β-glucuronide links, and disulfide links. In some embodiments, the linker includes a linker that is cathepsin-cleavable. In some embodiments, the linker includes a linker that is β-glucuronidase (GUSB)-cleavable (see, for example, Creative Biolabs, creative-biolabs.com / adc / beta-glucuronide-linker.htm, or GUSB linker in ACS Med. Chem. Lett. 2010, 1: 277-280).

[0134] In some embodiments, the linker includes an inseparable portion. In some embodiments, the inseparable linker is [ka] or derived from such residues. In some embodiments, the non-cleavable linker-payload residue is [ka] or a positional isomer thereof. In some embodiments, the inseparable linker is [ka] or derived from such residues. In some embodiments, the non-cleavable linker-payload residue is [ka] or a positional isomer thereof. In one embodiment, the linker is maleimidocyclohexanecarboxylate or 4-(N-maleimidomethyl)cyclohexanecarboxylic acid (MCC). In this structure, [ka] This indicates binding to the binder. In this structure, in some examples, [ka] This indicates, for example, a click chemistry residue resulting from the reaction of a binder having azide or alkyne functionality with a linker-payload having complementary alkyne or azide functionality. In this structure, in another example, [ka] This represents, for example, a divalent sulfide resulting from a Michael addition reaction with one or more linkers or linker-payloads having maleimide functionality of one or more binder cysteine. In this structure, in another example, [ka] This represents an amide bond resulting from the reaction of one or more binders, lysine, with one or more linkers or linker-payloads having activated or deactivated carboxyl functionality, as would be recognized by those skilled in the art. In one embodiment, [ka] This refers to an amide bond resulting from the reaction of, for example, one or more binders (lysine) with one or more linkers or linker-payloads having activated carboxyl functionality, as would be recognized by those skilled in the art.

[0135] In some embodiments, preferred linkers include, but are not limited to, a single binder, such as one chemically bound to two cysteine ​​residues of the antibody. Such linkers can mimic the disulfide bonds of the antibody that are disrupted as a result of the conjugation process.

[0136] In some embodiments, the linker comprises one or more amino acids (i.e., distinct from a prodrug payload comprising peptide bonds derived from distinguishable amino acids, as described elsewhere herein). Preferred amino acids include natural, unnatural, standard, non-standard, protein-constitutive, non-protein-constitutive, and L- or D-α-amino acids. In some embodiments, the linker comprises alanine, valine, glycine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, their derivatives, or combinations thereof (e.g., dipeptides, tripeptides, oligopeptides, polypeptides, etc.). In some embodiments, one or more side chains of amino acids are linked to the side-chain groups described below. In some embodiments, the linker is a peptide containing or derived from the amino acids valine and citrulline (e.g., divalent -Val-Cit- or divalent -VCit-). In some embodiments, the linker is a peptide containing or derived from the amino acids alanine and alanine, or divalent -AA-. In some embodiments, the linker is a peptide containing or derived from the amino acids glutamic acid and alanine or -EA-. In some embodiments, the linker is a peptide containing or derived from the amino acids glutamic acid and glycine, or -EG-. In some embodiments, the linker is a peptide containing or derived from the amino acids glycine and glycine, or -GG-. In some embodiments, the linker is a peptide containing or derived from the amino acids glutamine, valine, and citrulline, or -QV-Cit- or -QVCit-. In some embodiments, the linker is a peptide containing or derived from the amino acids glutamic acid, valine, and citrulline, or -EV-Cit- or -EVCit-. In some embodiments, the linker is an amino acid [ka] It is a peptide containing or derived from an amino acid. In some embodiments, the linker is an amino acid [ka] It is a peptide containing or derived from an amino acid. In some embodiments, the linker is an amino acid [ka] It is a peptide containing or derived from an amino acid. In some embodiments, the linker is an amino acid [ka] It is a peptide containing or derived from the amino acid-GG-. In some embodiments, the linker is a peptide containing or derived from the amino acid-GG-. In some embodiments, the linker is a peptide containing or derived from the amino acid-GG-. In some embodiments, the linker is an amino acid [ka] It is a peptide containing or derived from an amino acid. In some embodiments, the linker is an amino acid [ka] The linker is a peptide containing or comprising the amino acids lysine, valine, and citrulline, or -KVCit-. In some embodiments, the linker is a peptide containing or comprising the amino acid -KVA-. In some embodiments, the linker is a peptide containing or comprising the amino acid -VA-. In any of the embodiments described in this paragraph and throughout the disclosure, standard three-letter or one-letter amino acid names are used so as to be recognizable to those skilled in the art. Exemplary one-letter amino acid names include G for glycine, K for lysine, S for serine, V for valine, A for alanine, and F for phenylalanine.

[0137] In some embodiments, the linker includes a self-destructing group. This self-destructing group can be any such group known to those skilled in the art. In certain embodiments, the self-destructing group is p-aminobenzyl (PAB) or a derivative thereof. A useful derivative is p-aminobenzyloxycarbonyl (PABC). Those skilled in the art will recognize that the self-destructing group can undergo a chemical reaction that releases the remaining atoms of the linker from the payload.

[0138] In some embodiments, the linker is: [ka] That is (In the formula: SP 1 It is a spacer; SP 2 It is a spacer; [ka] is one or more bonds to the binder; [ka] is one or more bindings to the payload; Each AA is an amino acid residue; and p is an integer between 0 and 10. In one embodiment, each AA within the linker L herein can be characterized as a second amino acid residue, in contrast to a first amino acid residue within the payload or prodrug payload as described elsewhere in this specification. As will be recognized by those skilled in the art, in one embodiment, two or more AAs within the linker L herein can be characterized as second peptide residues, in contrast to a first peptide residue within the payload or prodrug payload as described elsewhere in this specification.

[0139] SP 1 The spacer is (AA) p This is a site that connects a site or residue to the binder (BA) or to a reactive group residue bound to BA. Preferred SP 1 Examples of spacers include, but are not limited to, alkylenes, polyethers, or both. The ends of the spacer, for example, the portion bound to BA or AA, may be sites derived from a reactive site used for coupling the antibody or AA to the spacer during the chemical synthesis of the conjugate. In some embodiments, p is 0, 1, 2, 3, or 4. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4.

[0140] In some embodiments, SP 1 The spacer contains alkylene. In some embodiments, SP 1 The spacer is C 5-7 Contains alkylene. In some embodiments, SP 1 The spacer contains polyether. In some embodiments, SP 1 The spacer contains an ethylene oxide polymer such as polyethylene glycol.

[0141] In some embodiments, SP 1Spacers are: [ka] That is (In the formula: RG' is a reactive group residue that results from the reaction of the reactive group RG with the binder; [ka] This is bonding to the binder; [ka] (AA) p It is a combination to (where p is an integer from 0 to 10); and b is an integer between 2 and 8.

[0142] The reactive group RG can be any reactive group known to those skilled in the art that it can form one or more bonds to the binder. The reactive group RG is a moiety within its structure that can react with the binder (for example, with an antibody and its cysteine ​​or lysine residues, or with an azide moiety, for example, with a PEG-N3 functionalized antibody and one or more glutamine residues) to form compounds of formula A, A', B, B', C, C', D, D', E, or E. After conjugation to the binder, the reactive group becomes the reactive group residue (RG'). Examples of reactive groups include, but are not limited to, those containing haloacetyl, isothiocyanate, succinimide, N-hydroxysuccinimide, or maleimide moieties that can react with the binder.

[0143] In some embodiments, the reactive group may be, but is not limited to, alkynes. In some embodiments, the alkyne is an alkyne that can undergo a 1,3-cycloaddition reaction with an azide in the absence of a copper catalyst, such as a strained alkyne. Strained alkynes are suitable for strain-enhanced alkyne-azide cycloaddition (SPAAC), and examples include cycloalkynes, such as cyclooctyne and aromatic cycloalkynes. Preferred alkynes include dibenzoazacyclooctyne or [ka] Dibenzocyclooctin or [ka] Biaryl azacyclooctinone or [ka] Difluorinated cyclooctin or [ka] Substituted, for example, fluorinated alkynes, aza-cycloalkynes, bicycle[6.1.0]nonyne or [ka] Examples include, but are not limited to, their derivatives. Particularly useful alkynes include, [ka] These are some examples.

[0144] In one version, the binder is directly bonded to RG'. In another version, the binder is a spacer, for example, [ka] SP located between and RG' 4is bound to RG′ via. In certain embodiments, the binding agent is SP 4 , for example, indirectly bound to RG′ via a PEG spacer. As described in detail below, in some embodiments, the binding agent is prepared by functionalization with one or more azide groups. Each azide group can react with RG to form RG′. In certain embodiments, the binding agent is derivatized using -PEG-N3 linked to a glutamine residue (e.g., a transglutaminse-modified binding agent). Exemplary -N3 derivatized binding agents, methods for their preparation, and methods for their use in reaction with RG are provided herein. In some embodiments, RG is an alkyne suitable for participating in 1,3-cycloaddition, and RG′ is a regioisomeric 1,2,3-triazolyl moiety formed by reaction of RG with an azide-functionalized binding agent. As a further example, in some embodiments, RG′ is

化

[0145] SP 2 A spacer, when present, is a moiety that connects the (AA) p moiety to the payload. Suitable spacers include, but are not limited to, those described above as SP 1 spacers. Further suitable SP 2 spacers include, but are not limited to, those comprising alkylene or polyether, or both. The end of the SP 2 spacer, for example, the portion of the spacer directly bound to the payload, prodrug payload, or AA, can be a moiety derived from a reactive site used for the purpose of coupling the payload, prodrug payload, or AA to the SP 2 spacer during chemical synthesis of the conjugate. In some examples, the SP 2The end of the spacer, for example, the SP 2 The spacer payload, prodrug payload, or portion directly bound to AA may be a reactive site residue used to couple the payload, prodrug payload, or AA to the spacer during the chemical synthesis of the conjugate.

[0146] In some embodiments, SP 2 Spacers, if present, are -NH-(p-C6H4)-CH2-, -NH-(p-C6H4)-CH2OC(O)-, amino acids, dipeptides, tripeptides, oligopeptides, -O-, -N(H)-, [ka] and selected from the group consisting of any combination thereof. In one embodiment, each [ka] This involves binding to the payload or prodrug payload, and each [ka] (AA) p It is a connection to.

[0147] In the above formula, each (AA) p is an amino acid, or optionally a p-aminobenzyloxycarbonyl residue (PABC), [ka] In certain embodiments, if PABCs are present, only one PABC is present. In some embodiments, if a PABC residue is present, it is (AA) closer to the payload or prodrug payload. p It is bound to the terminal AA in the base. [ka] However, if it exists, [ka] Only exists. In one embodiment, the [ka] If present, the residue is bound to the payload or prodrug payload via the benzyloxycarbonyl moiety, and AA is absent. In one embodiment, [ka] The residues, if present, are bound to the payload or prodrug payload via -O-. Suitable amino acids for each AA include natural, unnatural, standard, non-standard, protein-constitutive, non-protein-constitutive, and L- or D-α-amino acids. In some embodiments, the AA includes alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, their derivatives, or any combination thereof (e.g., dipeptides, tripeptides, and oligopeptides). In some embodiments, one or more side chains of the amino acid are linked to the side-chain groups described below. In some embodiments, p is 2. In some embodiments, (AA) p This is valine-citrulline. In some embodiments, (AA) p This is citrulline-valine. In some embodiments, (AA) p is valine-alanine. In some embodiments, (AA) p This is alanine-valine. In some embodiments, (AA) p It is valine-glycine. In some embodiments, (AA) p is glycine-valine. In some embodiments, p is 3. In some embodiments, (AA) pThis is valine-citrulline-PABC. In some embodiments, (AA) p This is citrulline-valine-PABC. In some embodiments, (AA) p This is glutamate-valine-citrulline. In some embodiments, (AA) p This is glutamine-valine-citrulline. In some embodiments, (AA) p This is lysine-valine-alanine. In some embodiments, (AA) p is lysine-valine-citrulline. In some embodiments, p is 4. In some embodiments, (AA) p This is glutamate-valine-citrulline-PAB. In some embodiments, (AA) p It is glutamine-valine-citrulline-PABC. Those skilled in the art will know that PABC has the following structure: [ka] It will be recognized as a residue of p-aminobenzyloxycarbonyl having -NH-(p-C6H4)-CH2-. The PABC residue has been shown to promote the cleavage of certain linkers in vitro and in vivo. Those skilled in the art will recognize PAB as a divalent residue of p-aminobenzyl, i.e., -NH-(p-C6H4)-CH2-.

[0148] In some embodiments, the linker is: [ka] TIFF0007912488000159.tif194170TIFF0007912488000160.tif119170 (In the formula: each [ka] This involves binding to a transglutaminase modification binder; each [ka] This is the coupling to the payload; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -S-, -NH-, [ka] (wherein ZZ is hydrogen or the side chain of an amino acid as described elsewhere herein). As a further example, in one embodiment, ZZ is C 1-6 It is alkyl. As a further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. In certain embodiments of this paragraph, A may be derived from a primary amine compound or a residue thereof, where X is -N3 as described elsewhere herein. In these embodiments, the 1,2,3-triazole residue is derived from the azide after involvement in a click chemistry reaction with the compounds described herein or the alkyne or terminal acetylene of the payload, as described elsewhere herein. Thus, in a non-limiting example, A is [ka] Or a mixture thereof. Alternatively, in another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. As described above, binding to the binder can be direct or via a spacer. In one embodiment, binding to the binder is via a PEG spacer to the glutamine residue of the binder.

[0149] In some embodiments, the linker is: [ka] That is (In the formula: each [ka] This involves binding to a transglutaminse-modifying binder; each [ka] This is the binding to the payload; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] (wherein ZZ is hydrogen or the side chain of an amino acid as described elsewhere herein). For example, in one embodiment, ZZ is C 1-6 It is alkyl. As a further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. In certain embodiments of this paragraph, A may be derived from a primary amine compound or a residue thereof, where X is -N3 as described elsewhere herein. In these embodiments, the 1,2,3-triazole residue is derived from the azide after involvement in a click chemistry reaction with the compounds described herein or the alkyne or terminal acetylene of the payload, as described elsewhere herein. Thus, in a non-limiting example, A is [ka] Or a mixture thereof. Alternatively, in another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. As described above, binding to the binder can be direct or via a spacer. In one embodiment, binding to the binder is via a PEG spacer to the glutamine residue of the binder.

[0150] In any of the above embodiments, (AA) p The group can be modified with one or more reinforcing groups. Advantageously, the reinforcing group can be (AA) pIt can be linked to the side chain of any amino acid within. Useful amino acids for linking the reinforcing group include lysine, asparagine, aspartic acid, glutamine, glutamic acid, and citrulline. Linking to the reinforcing group can be a direct link to the amino acid side chain, or it can be an indirect link via a spacer and / or reactive group. Useful spacers and reactive groups include any of the above. The reinforcing group can be any group that is considered useful by those skilled in the art. For example, the reinforcing group can be any group that imparts beneficial effects to a compound, payload, linker payload, or antibody conjugate, including but not limited to biological, biochemical, synthetic, solubilizing, imaging, detection, and reactive effects. In one embodiment, the reinforcing group is a hydrophilic group. In one embodiment, the reinforcing group is a cyclodextrin. In one embodiment, the reinforcing group is alkyl, heteroalkyl, alkylenyl, heteroalkylenylsulfonic acid, heteroalkylenyl taurine, heteroalkylenyl phosphate or phosphate, heteroalkylenylamine (e.g., quaternary amine), or heteroalkylenyl sugar. In one embodiment, the sugars are, but are not limited to, monosaccharides, disaccharides, and polysaccharides. Examples of monosaccharides include glucose, ribose, deoxyribose, xylose, arabinose, mannose, galactose, and fructose. In one embodiment, the sugars are sugar acids such as glucuronic acid, and further, conjugated forms such as glucuronides (i.e., those by glucuronidation). Examples of disaccharides include maltose, sucrose, lactose, lactulose, and trehalose. Examples of polysaccharides include amylose, amylopectin, glycogen, inulin, and cellulose. The cyclodextrin can be any cyclodextrin known to those skilled in the art.In some embodiments, the cyclodextrin is alpha-cyclodextrin, beta-cyclodextrin, or gamma-cyclodextrin, or a mixture thereof. In some embodiments, the cyclodextrin is alpha-cyclodextrin. In some embodiments, the cyclodextrin is beta-cyclodextrin. In some embodiments, the cyclodextrin is gamma-cyclodextrin. In some embodiments, the reinforcing group can improve the remaining solubility of the conjugate. In some embodiments, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenylsulfonic acid is substituted or unsubstituted. In some embodiments, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenylsulfonic acid is -(CH2). 1-5 SO3H, -(CH2) n -NH-(CH2) 1-5 SO3H, -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (wherein n is 1, 2, 3, 4, or 5, and m is 1, 2, 3, 4, or 5). In one embodiment, the alkyl or alkylenyl sulfonic acid is -(CH2) 1-5 In another embodiment, the heteroalkyl or heteroalkylenylsulfonic acid is -(CH2) n -NH-(CH2) 1-5SO3H (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H (wherein m is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (wherein m is 1, 2, 3, 4, or 5). In some embodiments, the linker is: [ka] That is (In the formula: SP 1 It is a spacer; SP 2 It is a spacer; SP 3 (AA) p It is a spacer connected to one of the AAs; [ka] is one or more bonds to the binder; [ka] This is the binding of one or more of the payload or prodrug payloads to the payload; [ka] is one or more bonds to the reinforcing group EG; Each AA is an amino acid; and (where p is an integer between 0 and 10). As described above, binding to the binder can be direct or via a spacer. In one embodiment, binding to the binder is via a PEG spacer to the glutamine residue of the binder.

[0151] SP 1 The spacer base is as described above. SP 2 The spacer base is as described above. Each (AA) p The basis is as described above.

[0152] SP 3 The spacer is (AA) p This is the part that connects the part to the reinforcing group (EG). Suitable SP 3 Examples of spacers include, but are not limited to, alkylenes, polyethers, or both. 3 The end of the spacer, i.e., the SP 3 The portion of the spacer directly bonded to the reinforcing group or AA during the chemical synthesis of the conjugate is the SP 3 These may be sites derived from reactive sites used for coupling with spacers. In some examples, SP 3The end of the spacer, i.e., the portion directly bonded to the reinforcing group or AA of the spacer, may be a reactive site residue used for coupling the reinforcing group or AA to the spacer during the chemical synthesis of the conjugate. In one embodiment, SP 3 (AA) p It is a spacer connected to only one of the AAs. In one embodiment, SP 3 The spacer is (AA) p It is linked to the side chain of the lysine residue.

[0153] In some embodiments, SP 3 Spacers are: [ka] That is (In the formula: RG′ is a reactive group residue that results from the reaction of the reactive group RG with the reinforcing agent EG; [ka] This is a binding to the reinforcing agent; [ka] (AA) p It is a coupling to; a is an integer between 2 and 8; and p is an integer between 0 and 4.

[0154] The reactive group RG can be any reactive group known to those skilled in the art that it can form one or more bonds with the reinforcing agent. The reactive group RG is a moiety in its structure that can react with the reinforcing group to form compounds of formulas LPa, LPb, LPc, LPd, LPe, LPa', LPb', LPc', LPd', LPa', A, B, C, D, E, A', B', C', D', or E'. After conjugation to the reinforcing group, the reactive group becomes a reactive group residue (RG'). The reactive group RG can be any of the reactive groups described above. Examples of reactive groups include, but are not limited to, those containing haloacetyl, isothiocyanate, succinimide, N-hydroxysuccinimide, or maleimide moieties that can react with the binder.

[0155] In one embodiment, the reactive group may be, but is not limited to, an alkyne. In one embodiment, the alkyne is an alkyne that can undergo a 1,3-cycloaddition reaction with an azide in the absence of a copper catalyst, such as a strained alkyne. Strained alkynes are suitable for strain-enhanced alkyne-azide cycloaddition (SPAAC) and include cycloalkynes, such as cyclooctyne, and aromatic cycloalkynes. Suitable alkynes include dibenzoazacyclooctyne or [ka] Dibenzocyclooctin or [ka] Biaryl azacyclooctinone or [ka] Difluorinated cyclooctin or [ka] Substituted, for example, fluorinated alkynes, aza-cycloalkynes, bicycle[6.1.0]nonyne or [ka] Examples include, but are not limited to, their derivatives. Particularly useful alkynes include, [ka] These are some examples.

[0156] In some embodiments, the linker is: [ka] That is (In the formula: RG' is a reactive group residue that results from the reaction of the reactive group RG with the binder; PEG is -NH-PEG4-C(O)-; SP 2 It is a spacer; SP 3 (AA) p It is a spacer attached to one of the AA residues; [ka] is one or more bonds to the binder; [ka] is one or more bindings to the payload; [ka] is one or more bonds to the reinforcing group EG; Each AA is an amino acid residue; and p is an integer between 0 and 10. As described above, binding to the binder can be direct or via a spacer. In one embodiment, binding to the binder is via a PEG spacer to the glutamine residue of the binder.

[0157] In one embodiment, the linker is: [ka] It is either a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a positional isomer thereof, or a mixture thereof. (In the formula: each [ka] This involves binding to a transglutaminase modification binder; each [ka] This is the binding to the payload; each [ka] This is a binding to the reinforcing agent; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] (wherein ZZ is hydrogen or the side chain of an amino acid as described elsewhere herein). For example, in one embodiment, ZZ is C 1-6 It is alkyl. As a further example, in one embodiment, ZZ is C 1-6It is heteroalkyl. In certain embodiments of this paragraph, A may be derived from a primary amine compound or a residue thereof, where X is -N3 as described elsewhere herein. In these embodiments, the 1,2,3-triazole residue is derived from the azide after involvement in a click chemistry reaction with the compounds described herein or the alkyne or terminal acetylene of the payload, as described elsewhere herein. Thus, in a non-limiting example, A is [ka] Or a mixture thereof. Alternatively, in another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. In one embodiment, a 1,3-cyclization or a positional isomer or mixture of positional isomers of SPAAC is derived from a PEG-N3 derivatized antibody treated with a suitable alkyne. For example, in one embodiment, the linker is: [ka] Or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a positional isomer thereof, or a mixture thereof. As a further example, in one embodiment, the linker is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a positional isomer thereof, or a mixture thereof. As a further example, a linker is: [ka] Or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a positional isomer thereof, or a mixture thereof. As a further example, in one embodiment, the linker is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a positional isomer thereof, or a mixture thereof. As described above, binding to the binder may be direct or via a spacer. In one embodiment, binding to the binder is via a PEG spacer to a glutamine residue of the binder. In one embodiment, the reinforcing agent is a hydrophilic group. In one embodiment, the reinforcing agent is a cyclodextrin. In one embodiment, the reinforcing group is an alkyl, heteroalkyl, alkylenyl, heteroalkylenylsulfonic acid, heteroalkylenyl taurine, heteroalkylenyl phosphate or phosphate, heteroalkylenylamine (e.g., a quaternary amine), or heteroalkylenyl sugar. In one embodiment, sugars include, but are not limited to, monosaccharides, disaccharides, and polysaccharides. Examples of monosaccharides include glucose, ribose, deoxyribose, xylose, arabinose, mannose, galactose, and fructose. In one embodiment, sugars include sugar acids such as glucuronic acid, and further, conjugated forms such as glucuronides (i.e., those obtained by glucuronidation). Exemplary disaccharides include maltose, sucrose, lactose, lactulose, and trehalose. Exemplary polysaccharides include amylose, amylopectin, glycogen, inulin, and cellulose. Cyclodextrin can be any cyclodextrin known to those skilled in the art. In one embodiment, cyclodextrin is alpha-cyclodextrin, beta-cyclodextrin, or gamma-cyclodextrin, or a mixture thereof. In one embodiment, cyclodextrin is alpha-cyclodextrin. In one embodiment, cyclodextrin is beta-cyclodextrin. In one embodiment, cyclodextrin is gamma-cyclodextrin. In one embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) 1-5 SO3H, -(CH2)n -NH-(CH2) 1-5 SO3H, -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (wherein n is 1, 2, 3, 4, or 5, and m is 1, 2, 3, 4, or 5). In one embodiment, the alkyl or alkylenyl sulfonic acid is -(CH2) 1-5 In another embodiment, the heteroalkyl or heteroalkylenylsulfonic acid is -(CH2) n -NH-(CH2) 1-5 SO3H (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H (wherein m is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5SO3H)2 (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (where m is 1, 2, 3, 4, or 5).

[0158] In some embodiments, the linker is: [ka] It is either a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a positional isomer thereof, or a mixture thereof. (In the formula: each [ka] This involves binding to a transglutaminase modification binder; each [ka] This is bonding to the reinforcing agent; each [ka] This is the coupling to the payload; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] (wherein ZZ is hydrogen or the side chain of an amino acid as described elsewhere herein). For example, in one embodiment, ZZ is C 1-6 It is alkyl. As a further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. In certain embodiments of this paragraph, A may be derived from a primary amine compound or a residue thereof, where X is -N3 as described elsewhere herein. In these embodiments, the 1,2,3-triazole residue is derived from the azide after involvement in a click chemistry reaction with the compounds described herein or the alkyne or terminal acetylene of the payload, as described elsewhere herein. Thus, in a non-limiting example, A is [ka] Or a mixture thereof. Alternatively, in another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. As described above, binding to the binder can be direct or via a spacer. In one embodiment, binding to the binder is via a PEG spacer to a glutamine residue of the binder. In one embodiment, the reinforcing agent is a hydrophilic group. In one embodiment, the reinforcing agent is a cyclodextrin. In one embodiment, the reinforcing group is an alkyl, heteroalkyl, alkylenyl, heteroalkylenyl sulfonic acid, heteroalkylenyl taurine, heteroalkylenyl phosphate or phosphate, heteroalkylenylamine (e.g., a quaternary amine), or heteroalkylenyl sugar. In one embodiment, sugars include, but are not limited to, monosaccharides, disaccharides, and polysaccharides. Examples of monosaccharides include glucose, ribose, deoxyribose, xylose, arabinose, mannose, galactose, and fructose. In one embodiment, sugars include sugar acids such as glucuronic acid, and further, conjugated forms such as glucuronides (i.e., those obtained by glucuronidation). Exemplary disaccharides include maltose, sucrose, lactose, lactulose, and trehalose. Exemplary polysaccharides include amylose, amylopectin, glycogen, inulin, and cellulose. Cyclodextrin can be any cyclodextrin known to those skilled in the art. In one embodiment, cyclodextrin is alpha-cyclodextrin, beta-cyclodextrin, or gamma-cyclodextrin, or a mixture thereof. In one embodiment, cyclodextrin is alpha-cyclodextrin. In one embodiment, cyclodextrin is beta-cyclodextrin. In one embodiment, cyclodextrin is gamma-cyclodextrin. In one embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) 1-5 SO3H, -(CH2) n -NH-(CH2) 1-5 SO3H, -(CH2)n -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (wherein n is 1, 2, 3, 4, or 5, and m is 1, 2, 3, 4, or 5). In one embodiment, the alkyl or alkylenyl sulfonic acid is -(CH2) 1-5 In another embodiment, the heteroalkyl or heteroalkylenylsulfonic acid is -(CH2) n -NH-(CH2) 1-5 SO3H (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H (wherein m is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n-C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (where m is 1, 2, 3, 4, or 5).

[0159] In some embodiments, the linker is: [ka] TIFF0007912488000216.tif230170, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a positional isomer thereof, or a mixture thereof. (In the formula: each [ka] This involves binding to a transglutaminse-modifying binder; each [ka] This is the coupling to the payload; R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and A is -O-, -N(H)-, [ka] (wherein ZZ is hydrogen or the side chain of an amino acid as described elsewhere herein). For example, in one embodiment, ZZ is C 1-6 It is alkyl. As a further example, in one embodiment, ZZ is C 1-6It is heteroalkyl. In certain embodiments of this paragraph, A may be derived from a primary amine compound or a residue thereof, where X is -N3 as described elsewhere herein. In these embodiments, the 1,2,3-triazole residue is derived from the azide after involvement in a click chemistry reaction with the compounds described herein or the alkyne or terminal acetylene of the payload, as described elsewhere herein. Thus, in a non-limiting example, A is [ka] Or a mixture thereof. Alternatively, in another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. As described above, binding to the binder can be direct or via a spacer. In one embodiment, binding to the binder is via a PEG spacer to the glutamine residue of the binder.

[0160] In some embodiments, the linker is: [ka] TIFF0007912488000225.tif217170, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a positional isomer thereof, or a mixture thereof. (In the formula: each [ka] This involves binding to a transglutaminse-modifying binder; each [ka] This is the binding to the payload; R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and A is -O-, -N(H)-, [ka] (wherein ZZ is hydrogen or the side chain of an amino acid as described elsewhere herein). For example, in one embodiment, ZZ is C 1-6 It is alkyl. As a further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. In certain embodiments of this paragraph, A may be derived from a primary amine compound or a residue thereof, where X is -N3 as described elsewhere herein. In these embodiments, the 1,2,3-triazole residue is derived from the azide after involvement in a click chemistry reaction with the compounds described herein or the alkyne or terminal acetylene of the payload, as described elsewhere herein. Thus, in a non-limiting example, A is [ka] Or a mixture thereof. Alternatively, in another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. As described above, binding to the binder can be direct or via a spacer. In one embodiment, binding to the binder is via a PEG spacer to the glutamine residue of the binder.

[0161] In some embodiments, the linker is: [ka] It is either a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a positional isomer thereof, or a mixture thereof. (In the formula: each [ka] This involves binding to a transglutaminse-modifying binder; each [ka] This is the binding to the payload; each [ka] This is a bond to a reinforcing group; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] (wherein ZZ is hydrogen or the side chain of an amino acid as described elsewhere herein). For example, in one embodiment, ZZ is C 1-6 It is alkyl. As a further example, in one embodiment, ZZ is C 1-6It is heteroalkyl. In certain embodiments of this paragraph, A may be derived from a primary amine compound or a residue thereof, where X is -N3 as described elsewhere herein. In these embodiments, the 1,2,3-triazole residue is derived from the azide after involvement in a click chemistry reaction with the compounds described herein or the alkyne or terminal acetylene of the payload, as described elsewhere herein. Thus, in a non-limiting example, A is [ka] Or a mixture thereof. Alternatively, in another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. As described above, binding to the binder can be direct or via a spacer. In one embodiment, binding to the binder is via a PEG spacer to a glutamine residue of the binder. In one embodiment, the reinforcing agent is a hydrophilic group. In one embodiment, the reinforcing agent is a cyclodextrin. In one embodiment, the reinforcing group is an alkyl, heteroalkyl, alkylenyl, heteroalkylenyl sulfonic acid, heteroalkylenyl taurine, heteroalkylenyl phosphate or phosphate, heteroalkylenylamine (e.g., a quaternary amine), or heteroalkylenyl sugar. In one embodiment, sugars include, but are not limited to, monosaccharides, disaccharides, and polysaccharides. Examples of monosaccharides include glucose, ribose, deoxyribose, xylose, arabinose, mannose, galactose, and fructose. In one embodiment, sugars include sugar acids such as glucuronic acid, and further, conjugated forms such as glucuronides (i.e., those obtained by glucuronidation). Exemplary disaccharides include maltose, sucrose, lactose, lactulose, and trehalose. Exemplary polysaccharides include amylose, amylopectin, glycogen, inulin, and cellulose. Cyclodextrin can be any cyclodextrin known to those skilled in the art. In one embodiment, cyclodextrin is alpha-cyclodextrin, beta-cyclodextrin, or gamma-cyclodextrin, or a mixture thereof. In one embodiment, cyclodextrin is alpha-cyclodextrin. In one embodiment, cyclodextrin is beta-cyclodextrin. In one embodiment, cyclodextrin is gamma-cyclodextrin. In one embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) 1-5 SO3H, -(CH2) n -NH-(CH2) 1-5 SO3H, -(CH2)n -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (wherein n is 1, 2, 3, 4, or 5, and m is 1, 2, 3, 4, or 5). In one embodiment, the alkyl or alkylenyl sulfonic acid is -(CH2) 1-5 In another embodiment, the heteroalkyl or heteroalkylenylsulfonic acid is -(CH2) n -NH-(CH2) 1-5 SO3H (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H (wherein m is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n-C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (where m is 1, 2, 3, 4, or 5).

[0162] In some embodiments, the linker is: [ka] It is either a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a positional isomer thereof, or a mixture thereof. (In the formula: each [ka] This involves binding to a transglutaminase modification binder; each [ka] This is the binding to the payload; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] (wherein ZZ is hydrogen or the side chain of an amino acid as described elsewhere herein). For example, in one embodiment, ZZ is C 1-6 It is alkyl. As a further example, in one embodiment, ZZ is C 1-6It is heteroalkyl. In certain embodiments of this paragraph, A may be derived from a primary amine compound or a residue thereof, where X is -N3 as described elsewhere herein. In these embodiments, the 1,2,3-triazole residue is derived from the azide after involvement in a click chemistry reaction with the compounds described herein or the alkyne or terminal acetylene of the payload, as described elsewhere herein. Thus, in a non-limiting example, A is [ka] Or a mixture thereof. Alternatively, in another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. As described above, binding to the binder can be direct or via a spacer. In one embodiment, binding to the binder is via a PEG spacer to a glutamine residue of the binder. In one embodiment, the reinforcing agent is a hydrophilic group. In one embodiment, the reinforcing agent is a cyclodextrin. In one embodiment, the reinforcing group is an alkyl, heteroalkyl, alkylenyl, heteroalkylenyl sulfonic acid, heteroalkylenyl taurine, heteroalkylenyl phosphate or phosphate, heteroalkylenylamine (e.g., a quaternary amine), or heteroalkylenyl sugar. In one embodiment, sugars include, but are not limited to, monosaccharides, disaccharides, and polysaccharides. Examples of monosaccharides include glucose, ribose, deoxyribose, xylose, arabinose, mannose, galactose, and fructose. In one embodiment, sugars include sugar acids such as glucuronic acid, and further, conjugated forms such as glucuronides (i.e., those obtained by glucuronidation). Exemplary disaccharides include maltose, sucrose, lactose, lactulose, and trehalose. Exemplary polysaccharides include amylose, amylopectin, glycogen, inulin, and cellulose. Cyclodextrin can be any cyclodextrin known to those skilled in the art. In one embodiment, cyclodextrin is alpha-cyclodextrin, beta-cyclodextrin, or gamma-cyclodextrin, or a mixture thereof. In one embodiment, cyclodextrin is alpha-cyclodextrin. In one embodiment, cyclodextrin is beta-cyclodextrin. In one embodiment, cyclodextrin is gamma-cyclodextrin. In one embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) 1-5 SO3H, -(CH2) n -NH-(CH2) 1-5 SO3H, -(CH2)n -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (wherein n is 1, 2, 3, 4, or 5, and m is 1, 2, 3, 4, or 5). In one embodiment, the alkyl or alkylenyl sulfonic acid is -(CH2) 1-5 In another embodiment, the heteroalkyl or heteroalkylenylsulfonic acid is -(CH2) n -NH-(CH2) 1-5 SO3H (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H (wherein m is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n-C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (wherein n is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (where m is 1, 2, 3, 4, or 5).

[0163] In some embodiments, the linker is: [ka] TIFF0007912488000251.tif70170, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a positional isomer thereof, or a mixture thereof. (In the formula: each [ka] This involves binding to a transglutaminanse-modifying binder; each [ka] This is the binding to the payload; R 9 is CH3 or -(CH2)3N(H)C(O)NH2; and A is -O-, -N(H)-, [ka] (wherein ZZ is hydrogen or the side chain of an amino acid as described elsewhere herein). For example, in one embodiment, ZZ is C 1-6 It is alkyl. As a further example, in one embodiment, ZZ is C 1-6It is heteroalkyl. In certain embodiments of this paragraph, A may be derived from a primary amine compound or a residue thereof, where X is -N3 as described elsewhere herein. In these embodiments, the 1,2,3-triazole residue is derived from the azide after involvement in a click chemistry reaction with the compounds described herein or the alkyne or terminal acetylene of the payload, as described elsewhere herein. Thus, in a non-limiting example, A is [ka] Or a mixture thereof. Alternatively, in another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. As described above, binding to the binder can be direct or via a spacer. In one embodiment, binding to the binder is via a PEG spacer to the glutamine residue of the binder.

[0164] In some embodiments, the linker is: [ka] TIFF0007912488000260.tif98170, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a positional isomer thereof, or a mixture thereof. (In the formula: each [ka] This involves binding to a transglutaminase modification binder; each [ka] This is the binding to the payload; R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and A is -O-, -N(H)-, [ka] (wherein ZZ is hydrogen or the side chain of an amino acid as described elsewhere herein). For example, in one embodiment, ZZ is C 1-6 It is alkyl. As a further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. In certain embodiments of this paragraph, A may be derived from a primary amine compound or a residue thereof, where X is -N3 as described elsewhere herein. In these embodiments, the 1,2,3-triazole residue is derived from the azide after involvement in a click chemistry reaction with the compounds described herein or the alkyne or terminal acetylene of the payload, as described elsewhere herein. Thus, in a non-limiting example, A is [ka] Or a mixture thereof. Alternatively, in another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. In another embodiment, A is [ka] or a mixture thereof. As described above, binding to the binder can be direct or via a spacer. In one embodiment, binding to the binder is via a PEG spacer to the glutamine residue of the binder.

[0165] In certain embodiments, the disclosed alkyne or terminal acetylene-containing compound, payload, or prodrug payload may be linked to a -PEG-N3 derivatized binder (i.e., a transglutaminase-modifying binder) linked to a glutamine residue. Exemplary -N3 derivatized binders (i.e., transglutaminase-modifying binders), methods for their preparation, and methods for their use are provided herein. In some embodiments, an alkyne-containing compound or payload described herein, suitable for involvement in 1,3-cyclization with a -PEG-N3 derivatized binder, gives rise to a positional isomer 1,2,3-triazolyl linkage site. For example, in some embodiments, the compound or payload linked to the binder is [ka] Alternatively, a mixture thereof may be used. (In the formula, each [ka] (This refers to binding to the binder.)

[0166] (Linker-payload) In some embodiments, the linker-payload or linker-prodrug payload (i.e., these terms are used interchangeably throughout) comprises any specific compound bound to the linker, which is encompassed by one or more of the above formulas I, Ia, II, III, IV, V, or VI, wherein the linker as described herein comprises a site that is reactive with the antibody or its antigen-binding fragment as described herein. In certain embodiments, the linker comprises one or more nitrogen atoms, R, from the above formulas I, Ia, II, III, IV, V, or VI. 1 , R 2 , R 3 , R 6 , or R 7 It is bonded to a heterocycle that includes [the specified element].

[0167] In one embodiment, the linker-payload has formula LPa, formula LPb, formula LPc, formula LPd, or formula LPa. [ka] TIFF0007912488000271.tif249170 (where L is the linker).

[0168] In one embodiment, the linker-payload is such that L is the linker; and R 7 However, in each case independently, hydrogen, -OH, -O-, halogen, or -NR 7a R 7b (In the formula, R 7a and R 7b Each of these independently comprises a bond, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, acyl, -C(O)CH2OH, -C(O)CH2O-, a first N-terminal amino acid residue, a first N-terminal peptide residue, -CH2CH2NH2, and -CH2CH2NH-, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted), and has the formulas LPa, LPb, LPc, LPd, or LPa.

[0169] In one embodiment, the linker-payload has the structure of formula LPa′: [ka] (In the formula, SP 1 , (AA) p SP 2 , R 1 Q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 (wherein r, and a are as described in any of the embodiments disclosed herein). In one embodiment, the linker-payload has the structure of formula LPb': [ka] (In the formula, SP 1 , (AA) p SP 2 , R 1 Q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 (wherein r, and a are as described in any of the embodiments disclosed herein). In one embodiment, the linker-payload has the structure of formula LPc': [ka] (In the formula, SP 1 , (AA) p SP 2 , R 1 Q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10(wherein r, and a are as described in any of the embodiments disclosed herein). In one embodiment, the linker-payload has the structure of formula LPd′: [ka] (In the formula, SP 1 , (AA) p SP 2 , R 1 Q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 (wherein r, and a are as described in any of the embodiments disclosed herein). In one embodiment, the linker-payload has the structure of formula LPe′: [ka] (In the formula, SP 1 , (AA) p SP 2 , R 1 Q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 ,r, and a are as described in any of the embodiments disclosed herein). In any of the embodiments of this paragraph, formula LPa', formula LPb', formula LPc', formula LPd', or formula LPa' may be a pharmaceutically acceptable salt or prodrug thereof. In any of the embodiments of this paragraph, p is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment, the linker-payload is the -SP 2 - If a spacer is present, [ka] and; the aforementioned second - (AA) p -but, [ka] and; the aforementioned -SP 1 -Spacer, [ka] (wherein RG is a reactive group); and b is an integer from 1 to 4, having the structure of LPa′, LPb′, LPc′, LPd′, or LPa′. In one embodiment, the linker-payload has the structure of LPa′, LPb′, LPc′, LPd′, or LPa′, where Q is -O-. In one embodiment, the linker-payload has Q is -CH2-;R 1 However, C1-C 10 Alkyl; R 2 However, it is alkyl; R 4 and R 5 However, it is a C1-C5 alkyl group; R 6 However, it is -OH; R 10 However, it does not exist; r is 4; and a is 1, having the structure of formula LPa', formula LPb', formula LPc', formula LPd', or formula LPe'. In one embodiment, the linker-payload has the structure of LPc' or a pharmaceutically acceptable salt thereof. In one embodiment, the linker-payload has R 7 However, it is -NH- and R 8 However, it has the structure of LPc' or a pharmaceutically acceptable salt thereof, which is hydrogen or fluoro. In one embodiment, the linker-payload is R 7 However, it is -NH- and R 8 However, it has the structure of hydrogen, LPc' or a pharmaceutically acceptable salt thereof. In one embodiment, the linker-payload is R 7 However, it is -NH- and R 8 However, it has the structure of LPc' or a pharmaceutically acceptable salt thereof, which is fluoro. In one embodiment, the linker-payload has the structure of LPe' or a pharmaceutically acceptable salt thereof. In one embodiment, the linker-payload is R 3However, it has the structure of LFe′ or a pharmaceutically acceptable salt thereof, which is -OC(O)N(H)CH2CH2NH- or -OC(O)N(H)CH2CH2OCH2CH2OCH2CH2OCH2CH2NH-. In one embodiment, the linker-payload is R 3 However, it has the structure of LPe′ or a pharmaceutically acceptable salt thereof, which is -OC(O)N(H)CH2CH2NH-. In one embodiment, the linker-payload is R 3 However, it has the structure of LPa' or a pharmaceutically acceptable salt thereof, which is -OC(O)N(H)CH2CH2OCH2CH2OCH2CH2OCH2CH2NH-. In one embodiment, the linker-payload is such that Q is -CH2-;R 1 However, hydrogen or C1-C 10 Alkyl; R 2 However, it is alkyl; R 4 and R 5 However, it is a C1-C5 alkyl group; R 6 but 、 The linker payload has the structure of LPa′, formula LPb′, formula LPc′, formula LPd′, or formula LPa′, where -OH; r is 3 or 4; and a is 1. In one embodiment, the linker payload has the structure of LPc′ or a pharmaceutically acceptable salt thereof. In one embodiment, the linker payload has the structure of R 7 However, it is -NH- and R 8 However, it has the structure of LPc' or a pharmaceutically acceptable salt thereof, which is hydrogen. In one embodiment, the linker-payload is such that Q is -CH2-;R 1 However, hydrogen or C1-C 10 Alkyl; R 2 However, it is alkyl; R 4 and R 5 However, it is a C1-C5 alkyl group; R 6 However, it is -OH; R 10 However, it does not exist; r is 4; and a is 1, having the structure of formula LPa', formula LPb', formula LPc', formula LPd', or formula LPe'. In one embodiment, the linker-payload has the structure of LPc' or a pharmaceutically acceptable salt thereof. In one embodiment, the linker-payload has R7 However, it is -NH- and R 8 However, it has the structure of LPc' or a pharmaceutically acceptable salt thereof, which is hydrogen. In one embodiment, the linker-payload is such that Q is -O- and R 1 However, hydrogen or C1-C 10 Alkyl; R 2 However, it is alkyl or alkynyl; R 3 However, it is hydroxyl or -OC(O)C1-C5 alkyl; R 4 and R 5 However, it is a C1-C5 alkyl group; R 6 However, it is -OH; R 10 However, if present, it is a C1-C5 alkyl; r is 3 or 4; and a is 1, having the structure of LPa′, formula LPb′, formula LPc′, formula LPd′, or formula LPa′. In one embodiment, the linker-payload has the structure of LPc′ or a pharmaceutically acceptable salt thereof. In one embodiment, the linker-payload is R 7 However, it is -NH- and R 8 However, it has the structure of hydrogen, LPc' or a pharmaceutically acceptable salt thereof. In one embodiment, the linker-payload is such that Q is -CH2- or -O-;R 1 However, C1-C 10 Alkyl; R 2 However, it is alkyl or alkynyl; R 4 and R 5 However, it is a C1-C5 alkyl group; R 6 However, -NHSO2(CH2) a1 -Aryl-(CH2) a2 NR 6a R 6b And; R 10 However, it does not exist; r is 4; and a, a1, and a2 are independently 0 or 1, having the structure of formula LPa', formula LPb', formula LPc', formula LPd', or formula LPe'. In one embodiment, the linker-payload has the structure of LPb' or a pharmaceutically acceptable salt thereof. In one embodiment, the linker-payload has R 6 but, [ka] It has the structure of LPb' or a pharmaceutically acceptable salt thereof. In one embodiment, the linker-payload is R 6 but, [ka] It has the structure of LPb' or a pharmaceutically acceptable salt thereof. In one embodiment, the linker-payload is R 6 but, [ka] It has the structure of LPb' or a pharmaceutically acceptable salt thereof. In one embodiment, the linker-payload is R 6 but, [ka] It has the structure of LPb' or a pharmaceutically acceptable salt thereof. In one embodiment, the linker-payload is such that a is zero; and R 6 but, [ka] It has the structure of LPb' or a pharmaceutically acceptable salt thereof. In one embodiment, the linker-payload is such that a is zero; and R 6 but, [ka] It has the structure of LPb' or a pharmaceutically acceptable salt thereof. In one embodiment, the linker-payload is such that a is zero; and R 6 but, [ka] It has the structure of LPb' or a pharmaceutically acceptable salt thereof. In one embodiment, the linker-payload is such that a is zero; and R 6 but, [ka] It has the structure of LPb' or a pharmaceutically acceptable salt thereof. In one embodiment, the linker-payload is such that a is 1 and R 6 but, [ka] It has the structure of LPb' or a pharmaceutically acceptable salt thereof. In one embodiment, the linker-payload is such that a is 1 and R 6 but, [ka] It has the structure of LPb' or a pharmaceutically acceptable salt thereof. In one embodiment, the linker-payload is such that a is 1 and R 6 but, [ka] It has the structure of LPb' or a pharmaceutically acceptable salt thereof. In one embodiment, the linker-payload is such that a is 1 and R 6 but, [ka] It has the structure of LPb' or a pharmaceutically acceptable salt thereof. In one embodiment, the linker-payload is R 7 However, it is -O- and R 8 However, it has the structure of hydrogen, LPc', or a pharmaceutically acceptable salt thereof.

[0170] In any of the embodiments described above, examples of aryls include phenyl, naphthyl, fluorenyl, azlenyl, anthryl, phenanthryl, and pyrenyl; examples of heteroaryls include furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pteridinyl, benzofuranyl, dibenzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, dibenzothiophenyl, indolyl, indolinyl, benzimidazolyl, indazolyl, and benztriazolyl; examples of nitrogen-containing heterocycles include azilidinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanil, and azokanil; and examples of acyls include R 3c -C(O)R, which includes alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl compounds. 3cExamples include: In one embodiment, the aryl is phenyl. In one embodiment, the aryl is naphthyl. In one embodiment, the aryl is fluorenyl. In one embodiment, the aryl is azlenyl. In one embodiment, the aryl is anthryl. In one embodiment, the aryl is phenanthryl. In one embodiment, the aryl is pyrenyl. In one embodiment, the heteroaryl is furanyl. In one embodiment, the heteroaryl is thiophenyl. In one embodiment, the heteroaryl is pyrrolyl. In one embodiment, the heteroaryl is oxazolyl. In one embodiment, the heteroaryl is thiazolyl. In one embodiment, the heteroaryl is imidazolyl. In one embodiment, the heteroaryl is pyrazolyl. In one embodiment, the heteroaryl is isoxazolyl. In one embodiment, the heteroaryl is isothiazolyl. In one embodiment, the heteroaryl is pyridyl. In one embodiment, the heteroaryl is pyrazinyl. In one embodiment, the heteroaryl is pyrimidinyl. In one embodiment, the heteroaryl is pyridazinyl. In one embodiment, the heteroaryl is quinolinyl. In one embodiment, the heteroaryl is isoquinolinyl. In one embodiment, the heteroaryl is synnolinyl. In one embodiment, the heteroaryl is quinazolinyl. In one embodiment, the heteroaryl is quinoxalinyl. In one embodiment, the heteroaryl is phthalazinyl. In one embodiment, the heteroaryl is pteridinyl. In one embodiment, the heteroaryl is benzofuranil. In one embodiment, the heteroaryl is dibenzofuranil. In one embodiment, the heteroaryl is benzothiophenyl. In one embodiment, the heteroaryl is benzoxazolyl. In one embodiment, the heteroaryl is benzthiazolyl. In one embodiment, the heteroaryl is dibenzothiophenyl. In one embodiment, the heteroaryl is indolyl.In one embodiment, the heteroaryl is indolinyl. In one embodiment, the heteroaryl is benzimidazolyl. In one embodiment, the heteroaryl is indazolyl. In one embodiment, the heteroaryl is benztriazolyl. In one embodiment, the nitrogen-containing heterocycle is azilidinyl. In one embodiment, the nitrogen-containing heterocycle is azetidinyl. In one embodiment, the nitrogen-containing heterocycle is pyrrolidinyl. In one embodiment, the nitrogen-containing heterocycle is piperidinyl. In one embodiment, the nitrogen-containing heterocycle is azepanyl. In one embodiment, the nitrogen-containing heterocycle is azokanyl. In one embodiment, the acyl is -C(O)R. 3c And R 3c is alkyl. In one embodiment, the acyl is -C(O)R 3c And R 3c is an alkenil. In one embodiment, the acyl is -C(O)R 3c And R 3c is alkinyl. In one embodiment, acyl is -C(O)R 3c And R 3c It is a cycloalkyl. In one embodiment, the acyl is -C(O)R 3c And R 3c is an aryl. In one embodiment, the acyl is -C(O)R 3c And R 3c It is a heteroaryl compound.

[0171] In any of the embodiments described in this section, R 7 -O- or -NR 7a R 7b (In the formula, R 7a and R 7bIn each case, R is independently a bond, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, acyl, a first N-terminal amino acid residue, or a first N-terminal peptide residue, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted. In one embodiment, R 7a is hydrogen, and R 7b This is a combination. For one reason, R 7 is -O-. In one embodiment, R 7a is hydrogen, and R 7b This is the first N-terminal amino acid residue.

[0172] (Conjugate / Antibody-drug conjugate (ADC)) Provided herein are antibodies or antigen-binding fragments thereof, wherein the antibody is conjugated to one or more compounds of formula I, formula Ia, formula II, formula III, formula IV, formula V, or formula VI as described herein.

[0173] Provided herein are conjugates having formula A, formula B, formula C, formula D, or formula E: [ka] TIFF0007912488000293.tif219170 (wherein L is a linker). In one embodiment, R 1 Q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 m, r, and a are as described above in the context of Formula I, and k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment, k is in the range of 1-2, 1-3, 2-3, 2-4, 3-4, or 1-4.

[0174] Provided herein is R7 However, in each case independently, hydrogen, -OH, -O-, halogen, or -NR 7a R 7b (In the formula, R 7a and R 7b In each case, independently, the elements are a bond, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, acyl, -C(O)CH2OH, -C(O)CH2O-, a first N-terminal amino acid residue, a first N-terminal peptide residue, -CH2CH2NH2, and -CH2CH2NH-, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted), formula: [ka] A conjugate of A, B, C, D, or E (wherein T is as described elsewhere herein), or a pharmaceutically acceptable salt, solvate, positional isomer, or stereoisomer thereof. In one embodiment, R 1 Q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 m, r, and a are as described above in the context of Formula I, and k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment, k is in the range of 1-2, 1-3, 2-3, 2-4, 3-4, or 1-4.

[0175] Provided herein are conjugates of A′, B′, C′, D′, or E′, or pharmaceutically acceptable salts, prodrugs, solvates, positional isomers, or stereoisomers thereof: [ka] TIFF0007912488000296.tif223170TIFF0007912488000297.tif79170 (in the formula, SP 1 and SP 2(where present is a spacer group; each AA is a second amino acid residue, where present; and p is an integer from 0 to 10). In one embodiment, R 1 Q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 m, r, and a are as described above in the context of Formula I, and k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment, k is in the range of 1-2, 1-3, 2-3, 2-4, 3-4, or 1-4. In one embodiment, -SP 2 -Spacers are used if present. [ka] and; the aforementioned second - (AA) p -teeth, [ka] and; the aforementioned -SP 1 - The spacer is, [ka] (In the formula, RG′ is a reactive group residue that is produced as a result of the reaction of the reactive group RG with the binder; [ka] (where is a direct or indirect bond to the binder; and b is an integer from 1 to 4). In one embodiment, p is as described above. In one embodiment, b is 1. In one embodiment, b is 2. In one embodiment, b is 3. In one embodiment, b is 4. In one embodiment, Q is -O-. In one embodiment, the conjugate is Q is -CH2-; R 1 However, C1-C 10 Alkyl; R 2 However, it is alkyl; R4 and R 5 However, it is a C1-C5 alkyl group; R 6 However, it is -OH; R 10 However, it does not exist; r is 4; and a is 1, having the structure of formula A', formula B', formula C', formula D', or formula E'. In one embodiment, the conjugate has the structure of formula C', or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate has R 7 However, it is -NH- and R 8 However, it has a structure of formula C′, or a pharmaceutically acceptable salt thereof, which is hydrogen or fluoro. In one embodiment, the conjugate is R 7 However, it is -NH- and R 8 However, it has the structure of formula C′, or a pharmaceutically acceptable salt thereof, which is hydrogen. In one embodiment, the conjugate is R 7 However, it is -NH- and R 8 However, the structure is fluoro, of formula C′, or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate has the structure of formula E′, or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate is R 3 However, it has the structure of formula E′, or a pharmaceutically acceptable salt thereof, which is -OC(O)N(H)CH2CH2NH- or -OC(O)N(H)CH2CH2OCH2CH2OCH2CH2OCH2CH2NH-. In one embodiment, the conjugate is R 3 However, it has the structure of formula E′, which is -OC(O)N(H)CH2CH2NH-, or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate is R 3 However, it has the structure of formula E′, or a pharmaceutically acceptable salt thereof, which is -OC(O)N(H)CH2CH2OCH2CH2OCH2CH2OCH2CH2NH-. In one embodiment, the conjugate is such that Q is -CH2-;R 1 However, hydrogen or C1-C 10 Alkyl; R 2 However, it is alkyl; R 4 and R 5 However, it is a C1-C5 alkyl group; R 6The structure of formula A', formula B', formula C', formula D', or formula E' is -OH; r is 3 or 4; and a is 1. In one embodiment, the conjugate has the structure of formula C', or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate has R 7 However, it is -NH- and R 8 However, it has the structure of formula C′, or a pharmaceutically acceptable salt thereof, where Q is hydrogen. In one embodiment, the conjugate is -CH2-;R 1 However, hydrogen or C1-C 10 Alkyl; R 2 However, it is alkyl; R 4 and R 5 However, it is a C1-C5 alkyl group; R 6 However, it is -OH; R 10 However, it does not exist; r is 4; and a is 1, having the structure of formula A', formula B', formula C', formula D', or formula E'. In one embodiment, the conjugate has the structure of formula C', or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate has R 7 However, it is -NH- and R 8 However, it has the structure of formula C′, or a pharmaceutically acceptable salt thereof, where Q is hydrogen. In one embodiment, the conjugate is such that Q is -O- and R 1 However, hydrogen or C1-C 10 Alkyl; R 2 However, it is alkyl or alkynyl; R 3 However, it is hydroxyl or -OC(O)C1-C5 alkyl; R 4 and R 5 However, it is a C1-C5 alkyl group; R 6 However, it is -OH; R 10 However, if present, it is a -C1-C5 alkyl; r is 3 or 4; and a is 1, having the structure of formula A', formula B', formula C', formula D', or formula E'. In one embodiment, the conjugate has the structure of formula C', or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate has R 7 However, it is -NH- and R 8However, it has the structure of formula C′, or a pharmaceutically acceptable salt thereof, where Q is hydrogen. In one embodiment, the conjugate is such that Q is -CH2- or -O-; R 1 However, C1-C 10 Alkyl; R 2 However, it is alkyl or alkynyl; R 4 and R 5 However, it is a C1-C5 alkyl group; R 6 However, -NHSO2(CH2) a1 -Aryl-(CH2) a2 NR 6a R 6b And; R 10 However, it does not exist; r is 4; and a, a1, and a2 are independently 0 or 1, having the structure of formula A', formula B', formula C', formula D', or formula E'. In one embodiment, the conjugate has the structure of formula B', or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate has R 6 but, [ka] It has the structure of formula B', or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate is R 6 but, [ka] It has the structure of formula B', or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate is R 6 but, [ka] It has the structure of formula B', or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate is R 6 but, [ka] The structure is of formula B', or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate is such that a is zero; and R 6 but, [ka] The structure is of formula B', or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate is such that a is zero; and R 6 but, [ka] The structure is of formula B', or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate is such that a is zero; and R 6 but, [ka] The structure is of formula B', or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate is such that a is zero; and R 6 but, [ka] The structure is of formula B', or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate is such that a is 1 and R 6 but, [ka] The structure is of formula B', or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate is such that a is 1 and R 6 but, [ka] The structure is of formula B', or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate is such that a is 1 and R 6 but, [ka] The structure is of formula B', or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate is such that a is 1 and R6 but, [ka] It has the structure of formula B', or a pharmaceutically acceptable salt thereof. In one embodiment, the conjugate is R 7 However, it is -O- and R 8 However, it has the structure of formula C′, which is hydrogen, or a pharmaceutically acceptable salt thereof.

[0176] Provided herein are conjugates of formula A. In some embodiments, the compound conjugated to -L-BA in formula A includes one or more compounds of the above-described formulas I, Ia, II, III, IV, V, and / or VI, where BA is a binder; L is a linker; and k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, k is in the range of 1-2, 1-3, 2-3, 2-4, 3-4, or 1-4. In any embodiment of this paragraph, BA is an antibody or an antigen-binding fragment thereof, where the antibody is conjugated to a compound of formula I as described above. In any embodiment of this paragraph, BA is an antibody or an antigen-binding fragment thereof, where the antibody is conjugated to a compound of formula Ia as described above. In any embodiment of this paragraph, BA is an antibody or an antigen-binding fragment thereof, where the antibody is conjugated to a compound of formula II as described above. In any embodiment of this paragraph, BA is an antibody or an antigen-binding fragment thereof, where the antibody is conjugated to a compound of formula III as described above. In any embodiment of this paragraph, BA is an antibody or an antigen-binding fragment thereof, where the antibody is conjugated to a compound of formula IV as described above. In any embodiment of this paragraph, BA is an antibody or an antigen-binding fragment thereof, where the antibody is conjugated to a compound of formula V as described above. In any embodiment of this paragraph, BA is an antibody or an antigen-binding fragment thereof, where the antibody is conjugated to a compound of formula VI as described above. In any of the embodiments of this paragraph, one or more compounds of formulas I, Ia, II, III, IV, V, and / or VI conjugated to -L-BA in formula A are conjugated via a nitrogen-containing heterocycle as described elsewhere in this specification. In one embodiment, if Q is -O-, then R 2 C1-C 10 Alkyl, C1-C 10 Alkinyl, triazole positional isomer, -C1-C 10Alkylene-(5-membered heteroaryl),-C1-C3 alkylene-Q 1 -(CH2) nn Aryl, C1-C3 hydroxyalkyl, or C1-C 10 It is an alkyl ether. In one embodiment of this paragraph, nn is 1. In one embodiment of this paragraph, nn is 2. In one embodiment of this paragraph, nn is 3. In one embodiment of this paragraph, nn is 4. In one embodiment of this paragraph, nn is 5. In one embodiment of this paragraph, nn is 6. In one embodiment of this paragraph, nn is 7. In one embodiment of this paragraph, nn is 8. In one embodiment of this paragraph, nn is 9. In one embodiment of this paragraph, nn is 10. In one embodiment of this paragraph, Q 1 is -CH2-. In one embodiment of this paragraph, Q 1 is -O-. In one embodiment, if Q is -CH2-, then R 2 C5-C 10 Alkyl, C1-C 10 Alkinyl, -C1-C 10 Alkylene-(5-membered heteroaryl),-C1-C3 alkylene-Q 1 -(CH2) nn Aryl, C1-C3 hydroxyalkyl, or C1-C 10 It is an alkyl ether. In one embodiment of this paragraph, nn is 1. In one embodiment of this paragraph, nn is 2. In one embodiment of this paragraph, nn is 3. In one embodiment of this paragraph, nn is 4. In one embodiment of this paragraph, nn is 5. In one embodiment of this paragraph, nn is 6. In one embodiment of this paragraph, nn is 7. In one embodiment of this paragraph, nn is 8. In one embodiment of this paragraph, nn is 9. In one embodiment of this paragraph, nn is 10. In one embodiment of this paragraph, Q 1 is -CH2-. In one embodiment of this paragraph, Q 1 It is -O-.

[0177] Provided herein are conjugates of formula B. In some embodiments, the compound conjugated to -L-BA in formula B includes one or more compounds of the above-described formulas I, Ia, II, III, IV, V, and / or VI, where BA is a binder; L is a linker; and k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, k is in the range of 1-2, 1-3, 2-3, 2-4, 3-4, or 1-4. In any embodiment of this paragraph, BA is an antibody or an antigen-binding fragment thereof, where the antibody is conjugated to a compound of formula I as described above. In any embodiment of this paragraph, BA is an antibody or an antigen-binding fragment thereof, where the antibody is conjugated to a compound of formula Ia as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula II as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula III as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula IV as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula V as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula VI as described above. In any embodiment of this paragraph, one or more compounds of formula I, formula Ia, formula II, formula III, formula IV, formula V, and / or formula VI conjugated to -L-BA in formula B is a divalent R 6 It is conjugated via. In one embodiment, if Q is -O-, then R 2 C1-C 10 Alkyl, C1-C 10 Alkinyl, triazole positional isomer, -C1-C 10Alkylene-(5-membered heteroaryl),-C1-C3 alkylene-Q 1 -(CH2) nn Aryl, C1-C3 hydroxyalkyl, or C1-C 10 It is an alkyl ether. In one embodiment of this paragraph, nn is 1. In one embodiment of this paragraph, nn is 2. In one embodiment of this paragraph, nn is 3. In one embodiment of this paragraph, nn is 4. In one embodiment of this paragraph, nn is 5. In one embodiment of this paragraph, nn is 6. In one embodiment of this paragraph, nn is 7. In one embodiment of this paragraph, nn is 8. In one embodiment of this paragraph, nn is 9. In one embodiment of this paragraph, nn is 10. In one embodiment of this paragraph, Q 1 is -CH2-. In one embodiment of this paragraph, Q 1 is -O-. In one embodiment, if Q is -CH2-, then R 2 C5-C 10 Alkyl, C1-C 10 Alkinyl, -C1-C 10 Alkylene-(5-membered heteroaryl),-C1-C3 alkylene-Q 1 -(CH2) nn Aryl, C1-C3 hydroxyalkyl, or C1-C 10 In one embodiment of this paragraph, which is an alkyl ether, nn is 1. In one embodiment of this paragraph, nn is 2. In one embodiment of this paragraph, nn is 3. In one embodiment of this paragraph, nn is 4. In one embodiment of this paragraph, nn is 5. In one embodiment of this paragraph, nn is 6. In one embodiment of this paragraph, nn is 7. In one embodiment of this paragraph, nn is 8. In one embodiment of this paragraph, nn is 9. In one embodiment of this paragraph, nn is 10. In one embodiment of this paragraph, Q 1 is -CH2-. In one embodiment of this paragraph, Q 1 It is -O-.

[0178] Provided herein are conjugates of formula C. In some embodiments, the compound conjugated to -L-BA in formula C includes one or more compounds of the above-described formulas I, Ia, II, III, IV, V, and / or VI, where BA is a binder; L is a linker; and k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, k is in the range of 1-2, 1-3, 2-3, 2-4, 3-4, or 1-4. In any embodiment of this paragraph, BA is an antibody or an antigen-binding fragment thereof, where the antibody is conjugated to a compound of formula I as described above. In any embodiment of this paragraph, BA is an antibody or an antigen-binding fragment thereof, where the antibody is conjugated to a compound of formula Ia as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula II as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula III as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula IV as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula V as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula VI as described above. In any embodiment of this paragraph, one or more compounds of formula I, formula Ia, formula II, formula III, formula IV, formula V, and / or formula VI conjugated to -L-BA in formula C is a divalent R 7 It is conjugated via. In one embodiment, if Q is -O-, then R 2 C1-C 10 Alkyl, C1-C 10 Alkinyl, triazole positional isomer, -C1-C 10Alkylene-(5-membered heteroaryl),-C1-C3 alkylene-Q 1 -(CH2) nn Aryl, C1-C3 hydroxyalkyl, or C1-C 10 It is an alkyl ether. In one embodiment of this paragraph, nn is 1. In one embodiment of this paragraph, nn is 2. In one embodiment of this paragraph, nn is 3. In one embodiment of this paragraph, nn is 4. In one embodiment of this paragraph, nn is 5. In one embodiment of this paragraph, nn is 6. In one embodiment of this paragraph, nn is 7. In one embodiment of this paragraph, nn is 8. In one embodiment of this paragraph, nn is 9. In one embodiment of this paragraph, nn is 10. In one embodiment of this paragraph, Q 1 is -CH2-. In one embodiment of this paragraph, Q 1 is -O-. In one embodiment, if Q is -CH2-, then R 2 C5-C 10 Alkyl, C1-C 10 Alkinyl, -C1-C 10 Alkylene-(5-membered heteroaryl),-C1-C3 alkylene-Q 1 -(CH2) nn Aryl, C1-C3 hydroxyalkyl, or C1-C 10 It is an alkyl ether. In one embodiment of this paragraph, nn is 1. In one embodiment of this paragraph, nn is 2. In one embodiment of this paragraph, nn is 3. In one embodiment of this paragraph, nn is 4. In one embodiment of this paragraph, nn is 5. In one embodiment of this paragraph, nn is 6. In one embodiment of this paragraph, nn is 7. In one embodiment of this paragraph, nn is 8. In one embodiment of this paragraph, nn is 9. In one embodiment of this paragraph, nn is 10. In one embodiment of this paragraph, Q 1 is -CH2-. In one embodiment of this paragraph, Q 1 It is -O-.

[0179] Provided herein are conjugates of formula D. In some embodiments, the compound conjugated to -L-BA in formula D includes one or more compounds of the above-described formulas I, Ia, II, III, IV, V, and / or VI, where BA is a binder; L is a linker; and k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, k is in the range of 1-2, 1-3, 2-3, 2-4, 3-4, or 1-4. In any embodiment of this paragraph, BA is an antibody or an antigen-binding fragment thereof, where the antibody is conjugated to a compound of formula I as described above. In any embodiment of this paragraph, BA is an antibody or an antigen-binding fragment thereof, where the antibody is conjugated to a compound of formula Ia as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula II as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula III as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula IV as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula V as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula VI as described above. In any embodiment of this paragraph, one or more compounds of formula I, formula Ia, formula II, formula III, formula IV, formula V, and / or formula VI conjugated to -L-BA in formula D is a divalent R 2 It is conjugated via. In one embodiment, if Q is -O-, then R 2 C1-C 10 Alkylene, C1-C 10 Alkynylene, positional isomer C1-C 10Triazolylene, positional isomer -C1-C 10 Alkylene-(5-membered heteroarylene), or -C1-C3 alkylene-Q 1 -(CH2) nn It is allirene. In one embodiment of this paragraph, nn is 1. In one embodiment of this paragraph, nn is 2. In one embodiment of this paragraph, nn is 3. In one embodiment of this paragraph, nn is 4. In one embodiment of this paragraph, nn is 5. In one embodiment of this paragraph, nn is 6. In one embodiment of this paragraph, nn is 7. In one embodiment of this paragraph, nn is 8. In one embodiment of this paragraph, nn is 9. In one embodiment of this paragraph, nn is 10. In one embodiment of this paragraph, Q 1 is -CH2-. In one embodiment of this paragraph, Q 1 is -O-. In one embodiment, if Q is -CH2-, then R 2 C5-C 10 Alkylene, C1-C 10 Alkynylene, positional isomer C1-C 10 Triazolylene, positional isomer -C1-C 10 Alkylene-(5-membered heteroarylene), or -C1-C3 alkylene-Q 1 -(CH2) nn It is allirene. In one embodiment of this paragraph, nn is 1. In one embodiment of this paragraph, nn is 2. In one embodiment of this paragraph, nn is 3. In one embodiment of this paragraph, nn is 4. In one embodiment of this paragraph, nn is 5. In one embodiment of this paragraph, nn is 6. In one embodiment of this paragraph, nn is 7. In one embodiment of this paragraph, nn is 8. In one embodiment of this paragraph, nn is 9. In one embodiment of this paragraph, nn is 10. In one embodiment of this paragraph, Q 1 is -CH2-. In one embodiment of this paragraph, Q 1 It is -O-.

[0180] Provided herein are conjugates of formula E. In some embodiments, the compound conjugated to -L-BA in formula E includes one or more compounds of the above-described formulas I, Ia, II, III, IV, V, and / or VI, where BA is a binder; L is a linker; and k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, k is in the range of 1-2, 1-3, 2-3, 2-4, 3-4, or 1-4. In any embodiment of this paragraph, BA is an antibody or an antigen-binding fragment thereof, where the antibody is conjugated to a compound of formula I as described above. In any embodiment of this paragraph, BA is an antibody or an antigen-binding fragment thereof, where the antibody is conjugated to a compound of formula Ia as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula II as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula III as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula IV as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula V as described above. In any embodiment of this paragraph, BA is an antibody or its antigen-binding fragment, wherein the antibody is conjugated to the compound of formula VI as described above. In any embodiment of this paragraph, one or more compounds of formula I, formula Ia, formula II, formula III, formula IV, formula V, and / or formula VI conjugated to -L-BA in formula E is a divalent R 3 It is conjugated via. In one embodiment, if Q is -O-, then R 2 C1-C 10 Alkyl, C1-C 10 Alkinyl, triazole positional isomer, -C1-C 10Alkylene-(5-membered heteroaryl),-C1-C3 alkylene-Q 1 -(CH2) nn Aryl, C1-C3 hydroxyalkyl, or C1-C 10 It is an alkyl ether. In one embodiment of this paragraph, nn is 1. In one embodiment of this paragraph, nn is 2. In one embodiment of this paragraph, nn is 3. In one embodiment of this paragraph, nn is 4. In one embodiment of this paragraph, nn is 5. In one embodiment of this paragraph, nn is 6. In one embodiment of this paragraph, nn is 7. In one embodiment of this paragraph, nn is 8. In one embodiment of this paragraph, nn is 9. In one embodiment of this paragraph, nn is 10. In one embodiment of this paragraph, Q 1 is -CH2-. In one embodiment of this paragraph, Q 1 is -O-. In one embodiment, if Q is -CH2-, then R 2 C5-C 10 Alkyl, C1-C 10 Alkinyl, -C1-C 10 Alkylene-(5-membered heteroaryl),-C1-C3 alkylene-Q 1 -(CH2) nn Aryl, C1-C3 hydroxyalkyl, or C1-C 10 In one embodiment of this paragraph, which is an alkyl ether, nn is 1. In one embodiment of this paragraph, nn is 2. In one embodiment of this paragraph, nn is 3. In one embodiment of this paragraph, nn is 4. In one embodiment of this paragraph, nn is 5. In one embodiment of this paragraph, nn is 6. In one embodiment of this paragraph, nn is 7. In one embodiment of this paragraph, nn is 8. In one embodiment of this paragraph, nn is 9. In one embodiment of this paragraph, nn is 10. In one embodiment of this paragraph, Q 1 is -CH2-. In one embodiment of this paragraph, Q 1 It is -O-.

[0181] In one embodiment, compounds of formula A', formula B', formula C', formula D', or formula E are [ka] TIFF0007912488000315.tif218170TIFF0007912488000316.tif159170TIFF0007912488000317.ti f170170TIFF0007912488000318.tif203170TIFF0007912488000319.tif174170TIFF000791248800 0320.tif224170TIFF0007912488000321.tif225170TIFF0007912488000322.tif242170TIFF00079 12488000323.tif121170TIFF0007912488000324.tif221170TIFF0007912488000325.tif203170TIF F0007912488000326.tif150170TIFF0007912488000327.tif164170TIFF0007912488000328.tif15 7170TIFF0007912488000329.tif138170TIFF0007912488000330.tif123170TIFF000791248800033 A salt selected from the group consisting of 1.tif224170TIFF0007912488000332.tif131170TIFF0007912488000333.tif229170TIFF0007912488000334.tif211170, or a pharmaceutically acceptable salt thereof (wherein BA is a binder; and k is 1, 2, 3, or 4).

[0182] In one embodiment, an antibody or its antigen-binding fragment can be conjugated directly or via a linker to one or more of the formulas I, Ia, II, III, IV, V, and / or VI described herein. In one embodiment, the antibody-drug conjugate may be: [ka] TIFF0007912488000336.tif223170TIFF0007912488000337.tif234170TIFF0007912488000338.tif221170TIFF0007912488000339.tif 226170TIFF0007912488000340.tif227170TIFF0007912488000341.tif223170TIFF0007912488000342.tif230170TIFF00079124880003 Examples include antibodies or antigen-binding fragments thereof conjugated to one or more of the formulas I, Ia, II, III, IV, V, and / or VI described herein, selected from the group consisting of 43.tif215170TIFF0007912488000344.tif188170TIFF0007912488000345.tif232170TIFF0007912488000346.tif205170TIFF0007912488000347.tif169170.

[0183] In any of the embodiments of the provided compound or conjugate, BA is an antibody that binds to PRLR, or an antigen-binding fragment thereof. In any of the embodiments of the provided compound or conjugate, BA is an antibody that binds to STEAP2, or an antigen-binding fragment thereof. In any of the embodiments of the provided compound or conjugate, BA is an antibody or an antigen-binding fragment thereof, and the conjugation is via at least one Q295 residue. In any of the embodiments of the provided compound or conjugate, BA is an antibody or an antigen-binding fragment thereof, and the conjugation is via two Q295 residues. In any of the embodiments of the provided compound or conjugate, BA is an N297Q antibody or an antigen-binding fragment thereof. In any of the embodiments of the provided compound or conjugate, BA is an N297Q antibody or an antigen-binding fragment thereof, and the conjugation is via at least one Q295 and at least one Q297 residue. In any of the provided embodiments of the compound or conjugate, BA is an N297Q antibody or its antigen-binding fragment, and the conjugation is via two Q295 residues and two Q297 residues. In certain embodiments, the numbering is according to the EU numbering system.

[0184] In any of the above embodiments, BA is an anti-STEAP2 antibody. In one embodiment, BA is the anti-STEAP2 antibody H1H7814N described in the following example. In one embodiment, BA is the anti-STEAP2 antibody H1H7814N N297Q described in the following example. In one embodiment, BA is an anti-STEAP2 antibody containing HCVR according to SEQ ID NO: 1 and LCVR according to SEQ ID NO: 5. In one embodiment, BA is an N297Q antibody containing HCVR according to SEQ ID NO: 1 and LCVR according to SEQ ID NO: 5. In one embodiment, BA is an anti-STEAP2 antibody containing one, two, three, four, five, or six of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively, according to SEQ ID NOs: 2, 3, 4, 6, 7, and 8. In one embodiment, BA is an N297Q antibody containing one, two, three, four, five, or six of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively, as indicated by SEQ ID NOs: 2, 3, 4, 6, 7, and 8. N297Q indicates that one or more residues 297 are mutated from asparagine (N) to glutamine (Q). In one embodiment, each residue 297 is mutated to Q. In one embodiment, the numbering is according to the EU numbering system. In one embodiment of this paragraph, k is 1 to 4. In one embodiment, k is 1, 2, 3, or 4. In one embodiment, k is 4.

[0185] In any of the above embodiments, BA is an anti-PRLR antibody. In one embodiment, BA is the anti-PRLR antibody H1H6958N2 described in the following example. In one embodiment, BA is the anti-PRLR antibody H1H6958N2 N297Q described in the following example. In one embodiment, BA is an anti-PRLR antibody containing HCVR according to SEQ ID NO: 9 and LCVR according to SEQ ID NO: 13. In one embodiment, BA is an N297Q antibody containing HCVR according to SEQ ID NO: 9 and LCVR according to SEQ ID NO: 13. In one embodiment, BA is an anti-PRLR antibody containing one, two, three, four, five, or six of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively, according to SEQ ID NOs: 10, 11, 12, 14, 15, and 16. In one embodiment, BA is an N297Q antibody containing one, two, three, four, five, or six of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively, as indicated by SEQ ID NOs: 10, 11, 12, 14, 15, and 16. N297Q indicates that one or more residues 297 are mutated from asparagine (N) to glutamine (Q). In one embodiment, each residue 297 is mutated to Q. In one embodiment, the numbering is according to the EU numbering system. In one embodiment of this paragraph, k is 1 to 4. In one embodiment, k is 1, 2, 3, or 4. In one embodiment, k is 4.

[0186] In any of the embodiments described in this section, R 7 -NR 7a R 7b (In the formula, R 7a and R 7b In each case, R is independently a hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, acyl, and amino acid residue, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted. In one embodiment, R 7a is hydrogen, and R 7bThis is an amino acid residue.

[0187] (Method for preparing compounds or payloads, and linker-payloads) The compounds provided herein can be prepared, isolated, or obtained by any method obvious to those skilled in the art. Exemplary preparation methods are described in detail in the following examples.

[0188] In one embodiment, the following is provided herein: [ka] A compound selected from the group consisting of TIFF0007912488000349.tif192170TIFF0007912488000350.tif197170TIFF0007912488000351.tif211170TIFF0007912488000352.tif204170TIFF0007912488000353.tif228170 (e.g., a linker-payload or linker-prodrug payload), or a pharmaceutically acceptable salt thereof. In some embodiments of this paragraph, all diastereomers are assumed. For example, in one embodiment, [ka] The internal stereochemistry is indeterminate or racemic. As a further example, in one embodiment, [ka] The internal stereochemistry is (R)-. As a further example, in one embodiment, [ka] The internal stereochemistry is (S)-. As a further example, in one embodiment, [ka] The internal stereochemistry is such that (R)- is in excess of (S)-. As a further example, in one embodiment, [ka] The internal stereochemistry is such that there is an excess of (S)- relative to (R)-.

[0189] The conjugates described herein can be synthesized by coupling the linker-payload or linker-prodrug payload described herein with a binder, such as an antibody, under standard conjugation conditions (see, for example, Doronina et al., Nature Biotechnology 2003, 21, 778, which is incorporated herein by reference in its entirety). If the binder is an antibody, the antibody may be linked to the linker-payload via one or more cysteine ​​or lysine residues of the antibody. The linker-payload can be linked to cysteine ​​residues, for example, by exposing the antibody to a reducing agent, such as dithiotheritol, to cleave the disulfide bonds of the antibody, purifying the reduced antibody, for example by gel filtration, and subsequently treating the antibody with a linker-payload containing a suitable reactive site, such as a maleimide group. Suitable solvents include, but are not limited to, water, DMA, DMF, and DMSO. A linker-payload or linker-prodrug payload containing a reactive group, such as an activated ester or acid halide group, can be linked to the lysine residue of an antibody. Suitable solvents include, but are not limited to, water, DMA, DMF, and DMSO. The conjugate can be purified using known protein techniques, such as size exclusion chromatography, dialysis, and ultrafiltration / dialysis filtration.

[0190] A binder, such as an antibody, can also be conjugated by a click chemistry reaction. In some embodiments of the click chemistry reaction, the linker-payload comprises a reactive group, such as an alkyne, that can undergo a positional isomeric 1,3-cycloaddition reaction with an azide. Such suitable reactive groups are described above. The antibody comprises one or more azide groups. Examples of such antibodies include antibodies functionalized with an azide-polyethylene glycol group. In some embodiments, such a functionalized antibody is induced by treating an antibody having at least one glutamine residue, such as a heavy chain Gln295, with a primary amine compound in the presence of the enzyme transglutaminase (e.g., a transglutaminase-modified antibody or its antigen-binding fragment). In some embodiments, such a functionalized or transglutaminase-modified antibody is induced by treating an antibody having at least one glutamine residue, such as a heavy chain Gln297, with a primary amine compound in the presence of the enzyme transglutaminase. Examples of such antibodies include the Asn297Gln(N297Q) variant. In one embodiment, such a functionalized antibody is induced by treating an antibody having at least two glutamine residues, for example, heavy chain Gln295 and heavy chain Gln297, with a primary amine compound in the presence of the enzyme transglutaminase. Examples of such antibodies include the Asn297Gln(N297Q) variant. In one embodiment, the antibody has two heavy chains as described in this paragraph for a total of two or a total of four glutamine residues.

[0191] In one embodiment, the antibody contains two glutamine residues, one in each heavy chain. In a particular embodiment, the antibody contains a Q295 residue in each heavy chain. In a further embodiment, the antibody contains one, two, three, four, five, six, seven, eight, or more glutamine residues. These glutamine residues may be present in the heavy chain, the light chain, or both. These glutamine residues may be wild-type residues or modified residues. The antibody can be prepared by standard techniques.

[0192] Those skilled in the art will recognize that antibodies are often glycosylated at residue N297, near residue Q295 in the heavy chain sequence. Glycosylation at residue N297 can interfere with transglutaminase at residue Q295 (Dennler et al., see above). Therefore, in advantageous embodiments, the antibody is not glycosylated. In some embodiments, the antibody is either deglycosylated or aglycosylated. In certain embodiments, the antibody heavy chain has an N297 mutation. In other words, the antibody is mutated so that it no longer has an asparagine residue at position 297. In certain embodiments, the antibody heavy chain has an N297Q mutation. Such antibodies can be prepared by site-directed mutagenesis to remove or inactivate the glycosylated sequence, or by site-directed mutagenesis to insert a glutamine residue into a site other than the glycosylated site that interferes with the sequence or any other interfering structure. Such antibodies can also be isolated from natural or artificial sources.

[0193] Subsequently, an antibody that does not interfere with glycosylation is reacted with or treated with a primary amine compound. In one embodiment, an aglycosylated antibody is reacted with or treated with a primary amine compound to produce a glutaminyl-modified antibody or a transglutaminase-modified antibody. In another embodiment, a deglycosylated antibody is reacted with or treated with a primary amine compound to produce a glutaminyl-modified antibody or a transglutaminase-modified antibody.

[0194] The primary amine can be any primary amine capable of forming a covalent bond with a glutamine residue in the presence of transglutaminase. Useful primary amines are described herein. The transglutaminase can be any transglutaminase deemed suitable by those skilled in the art. In some embodiments, the transglutaminase is an enzyme that catalyzes the formation of an isopeptide bond between a free amine group on a primary amine compound and an acyl group on the side chain of a glutamine residue. Transglutaminase is also known as protein-glutamine-γ-glutamyltransferase. In certain embodiments, the transglutaminase is classified as EC 2.3.2.13. The transglutaminase can be of any origin deemed suitable. In some embodiments, the transglutaminase is from a microorganism. Useful transglutaminases have been isolated from Streptomyces mobaraense, Streptomyces cinnamoneum, Streptomyces griseo-carneum, Streptomyces lavendulae, and Bacillus subtilis. Non-microbial transglutaminases, including mammalian transglutaminases, can also be used. In some embodiments, transglutaminases can be produced by any technique deemed appropriate by a skilled professional, or can be obtained from any source. In certain embodiments, transglutaminases are obtained from commercial sources.

[0195] In certain embodiments, the primary amine compound includes a reactive group that can undergo further reactions after transglutamation. In these embodiments, a glutaminyl-modified antibody or a transglutaminase-modified antibody can be reacted with or treated with a reactive payload or prodrug payload compound or a reactive linker-payload or linker-prodrug compound to produce an antibody-payload conjugate or an antibody-linker-payload conjugate. In some embodiments, the primary amine compound includes an azide.

[0196] In one embodiment, a glutaminyl-modified antibody or a transglutaminase-modified antibody is reacted with or treated with a reactive linker-payload to generate an antibody-linker-payload conjugate. The reaction may proceed under conditions deemed suitable by those skilled in the art. In one embodiment, a glutaminyl-modified antibody or a transglutaminase-modified antibody is contacted with a reactive linker-payload or linker-prodrug payload compound under conditions suitable for forming a conjugate between the glutaminyl-modified antibody or the transglutaminase-modified antibody and the linker-payload or linker-prodrug payload compound. Suitable reaction conditions are well known to those skilled in the art. Exemplary reactions are provided in the examples below.

[0197] (Pharmaceutical compositions and methods of treatment) Provided herein are methods for treating and preventing a disease, condition, or disorder, comprising administering a therapeutically or prophylactically effective amount of one or more of the compounds disclosed herein, for example, one or more of the compounds of the formulas provided herein. Diseases, disorders, and / or conditions include, but are not limited to, those related to antigens listed herein.

[0198] The compounds described herein may be administered alone or in combination with one or more additional therapeutic agents. One or more additional therapeutic agents may be administered immediately before, simultaneously with, or immediately after the administration of the compounds described herein. The disclosure also includes pharmaceutical compositions comprising any of the compounds described herein in combination with one or more additional therapeutic agents, and methods of treatment comprising administering such combination to a subject in need thereof.

[0199] Suitable additional therapeutic agents include, but are not limited to, a second tubulicin, an autoimmune therapeutic agent, a hormone, a biologic, or a monoclonal antibody. Also, suitable therapeutic agents include, but are not limited to, any pharmaceutically acceptable salts, acids, or derivatives of the compounds described herein.

[0200] In some embodiments of the methods described herein, multiple doses of the compounds described herein (or a pharmaceutical composition comprising a combination of the compounds described herein and any additional therapeutic agents mentioned herein) may be administered to a subject over a specified period of time. Methods according to this embodiment of the Disclosure include sequential administration of multiple doses of the compounds described herein to a subject. As used herein, “sequential administration” means that each dose of the compound is administered to the subject at different times, for example, on different days separated by a predetermined interval (e.g., several hours, several days, several weeks, or several months). The Disclosure includes methods that include sequentially administering to a patient a single initial dose of the compounds described herein, followed by one or more second doses of the compounds, and optionally, one or more subsequent third doses of the compounds.

[0201] The terms “initial dose,” “second dose,” and “third dose” refer to the time series of administrations of the compounds described herein. Thus, the “initial dose” is the dose administered at the start of the treatment regimen (also known as the “baseline dose”); the “second dose” is the dose administered after the initial dose; and the “third dose” is the dose administered after the second dose. The initial, second, and third doses may all contain the same amount of the compound described herein, but they may differ from each other in terms of the frequency of administration. In some embodiments, the amounts of the compound in the initial, second, and / or third doses may differ from each other during the course of treatment (e.g., adjusted by increasing or decreasing the doses as needed). In some embodiments, two or more doses (e.g., two, three, four, or five) may be administered as a “loading dose” at the beginning of the treatment regimen, followed by subsequent doses administered at a lower frequency (e.g., “maintenance doses”).

[0202] In some exemplary embodiments of this disclosure, each second and / or third dose is 1 to 26 weeks (e.g., 1, 1) of the preceding dose. 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, 4 1 / 2, 5, 5 1 / 2, 6, 6 1 / 2, 7, 7 1 / 2, 8, 8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2, 13, 13 1 / 2, 14, 14 1 / 2, 15, 15 1 / 2, 16, 16 1 / 2, 17, 17 1 / 2, 18, 18 1 / 2, 19, 19 1 / 2, 20, 20 1 / 2, 21, 21 1 / 2, 22, 22 1 / 2, 23, 23 1 / 2, 24, 24 1 / 2, 25, 25 1 / 2, 26, 261 It is administered after two weeks or longer. As used herein, the term “immediate dose” means the dose of the compound administered to the patient in a sequence of doses, without any other doses in between, immediately preceding the next dose.

[0203] The methods according to this embodiment of the Disclosure may involve administering to a patient any number of second and / or third doses of the compound. For example, in one embodiment, only a single second dose is administered to the patient. In another embodiment, two or more (e.g., two, three, four, five, six, seven, eight, or more) second doses are administered to the patient. Similarly, in one embodiment, only a single third dose is administered to the patient. In another embodiment, two or more (e.g., two, three, four, five, six, seven, eight, or more) third doses are administered to the patient. The administration regimen may be carried out indefinitely for the lifetime of a particular subject, or until such treatment is no longer therapeutically necessary or beneficial.

[0204] In embodiments including multiple second doses, each second dose may be administered at the same frequency as the other second doses. For example, each second dose may be administered to the patient 1 to 2 weeks or 1 to 2 months after the previous dose. Similarly, in embodiments including multiple third doses, each third dose may be administered at the same frequency as the other third doses. For example, each third dose may be administered to the patient 2 to 12 weeks after the previous dose. In some embodiments of this disclosure, the frequency at which the second and / or third doses are administered to the patient may vary within the duration of the treatment regimen. The frequency of administration may also be adjusted by the physician during the course of treatment according to the individual patient's needs after clinical examinations.

[0205] This disclosure includes a dosing regimen in which 2 to 6 loading doses are administered to the patient at a first frequency (e.g., once a week, once every two weeks, once every three weeks, once a month, once every two months, etc.), followed by two or more maintenance doses administered to the patient at a lower frequency. For example, according to this embodiment of the disclosure, if the loading dose is administered at a frequency of once a month, the maintenance dose may be administered to the patient at a frequency of once every six weeks, once every two months, once every three months, etc.

[0206] This disclosure includes pharmaceutical compositions comprising the compounds and / or conjugates described herein, e.g., compounds of formulas I, Ia, II, III, IV, V, and VI, e.g., compounds described herein, their salts, stereoisomers, positional isomers, polymorphs, and pharmaceutically acceptable carriers, diluents, and / or excipients. Examples of suitable carriers, diluents, and excipients include, but are not limited to, buffers for maintaining a suitable composition pH (e.g., citrate buffer, succinate buffer, acetate buffer, phosphate buffer, lactate buffer, oxalate buffer, etc.), carrier proteins (e.g., human serum albumin), physiological saline, polyols (e.g., trehalose, sucrose, xylitol, sorbitol, etc.), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxolate, etc.), antimicrobial agents, and antioxidants.

[0207] In some examples, the methods described herein are for treating cancer, comprising administering to a patient suffering from the cancer a therapeutically effective amount of a compound of formula I, formula Ia, formula II, formula III, formula IV, formula V, and formula VI, or a pharmaceutical composition thereof. In some embodiments, the methods provided herein are for treating cancer, comprising administering to a patient suffering from the cancer a therapeutically effective amount of an antibody-tubulisin conjugate described herein or a pharmaceutical composition thereof. In some embodiments, the conjugate, for example, the binder of the antibody-drug conjugate described herein, for example, the antibody, interacts with or binds to a tumor antigen, which includes an antigen specific to a type of tumor or antigen that is common, overexpressed, or modified on a particular type of tumor. Examples include, but are not limited to, alpha-actinin-4 in lung cancer, ARTC1 in melanoma, BCR-ABL fusion protein in chronic myeloid leukemia, B-RAF, CLPP, or Cdc27 in melanoma, CASP-8 in squamous cell carcinoma, and hsp70-2 in renal cell carcinoma, as well as the following common tumor-specific antigens, e.g., BAGE-1, GAGE, GnTV, KK-LC-1, MAGE-A2, NA88-A, and TRP2-INT2. Further examples of tumor antigens include, but are not limited to, PSMA, PRLR, MUC16, HER2, EGFRvIII, and anti-STEAP2, and MET.

[0208] The compounds disclosed herein can be used to treat primary and / or metastatic tumors occurring in the brain and meninges, oropharynx, lungs and bronchial tree, gastrointestinal tract, male and female reproductive systems, muscles, bones, skin and appendages, connective tissue, spleen, immune system, hematopoietic cells and bone marrow, liver and urinary tract, and special sensory organs such as the eyes. In some embodiments, the compounds provided herein can be used to treat the following cancers: renal cell carcinoma, pancreatic cancer, head and neck cancer (e.g., head and neck squamous cell carcinoma [HNSCC]), prostate cancer, castration-resistant prostate cancer (prostrate It is used to treat one or more of the following: cancer, malignant glioma, osteosarcoma, colorectal cancer, gastric cancer (e.g., gastric cancer with MET amplification), mesothelioma, malignant mesothelioma, multiple myeloma, ovarian cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, synovial sarcoma, thyroid cancer, breast cancer, PRLR-positive (PRLR+) breast cancer, melanoma, acute myeloid leukemia, adult T-cell leukemia, astrocytoma, bladder cancer, cervical cancer, cholangiocarcinoma, endometrial cancer, esophageal cancer, glioblastoma, Kaposi's sarcoma, kidney cancer, leiomyosarcoma, liver cancer, lymphoma, MFH / fibrosarcoma, nasopharyngeal cancer, rhabdomyosarcoma, colon cancer, gastric cancer, uterine cancer, residual cancer (where "residual cancer" means the presence or persistence of one or more cancerous cells in a subject after treatment with anticancer therapy), and Wilms' tumor. In some embodiments, cancer is breast cancer. In some embodiments, cancer is prostate cancer.

[0209] In some examples, the methods described herein for preventing prostate cancer include administering to a patient having the disorder a prophylactically effective amount of a compound of formula I, formula Ia, formula II, formula III, formula IV, formula V, and formula VI, or a pharmaceutical composition thereof. [Examples]

[0210] (Examples) Provided herein are novel tubulsin, its protein conjugate, and methods for treating diseases, disorders, and conditions comprising administering the tubulsin and conjugate.

[0211] Some embodiments of this disclosure are illustrated by the following non-limiting examples. Where used herein, the symbols and conventions used in these processes, schemes, and examples are consistent with those used in contemporary scientific literature, e.g., the Journal of the American Chemical Society or the Journal of Biological Chemistry, whether or not specific abbreviations are specifically defined. Specifically, the following abbreviations may be used throughout the examples and specification, without limitation: [Table 4] TIFF0007912488000360.tif233170TIFF0007912488000361.tif233170TIFF0007912488000362.tif66170

[0212] Unless otherwise explicitly stated, reagents and solvents may be obtained from commercial sources such as Sinopharm Chemical Reagent Co. (SCRC), Sigma-Aldrich, Alfa, or other suppliers. 1 1H NMR and other NMR spectra can be recorded with a Bruker AVIII 400 or Bruker AVIII 500. The data can be processed with Nuts or MestReNova software, and proton shifts can be measured in parts per million (ppm) on the low-field side from an internal standard of tetramethylsilane (TMS).

[0213] HPLC-MS measurements can be performed on an Agilent 1200 HPLC / 6100 SQ system under the following conditions: Method A for HPLC-MS measurement uses the following mobile phases: A: water (0.01% trifluoroacetic acid (TFA)), B: acetonitrile (0.01% TFA); gradient phase: 5% B increasing to 95% B within 15 minutes; flow rate: 1.0 mL / min; column: SunFire C18, 4.6 × 50 mm, 3.5 μm; column temperature: 50°C. Detectors include analog-to-digital converter (ADC) evaporative light scattering detector (ELSD), diode array detector (DAD) (214 nm and 254 nm), and electrospray ionization-air ionization (ES-API). Method B for HPLC-MS measurement includes: mobile phase: A: water (10 mM NH4HCO3), B: acetonitrile; gradient phase: 5% to 95% of B within 15 minutes; flow rate: 1.0 mL / min; column: XBridge C18, 4.6 × 50 mm, 3.5 μm; column temperature: 50 °C. Detector: ADC ELSD, DAD (214 nm and 254 nm), mass selective detector (MSD) (ES-API).

[0214] LC-MS measurements can be performed using an Agilent 1200 HPLC / 6100 SQ system under the following conditions: Method A for LC-MS measurement includes: Instrument: WATERS 2767; Column: Shimadzu Shim-Pack, PRC-ODS, 20×250 mm, 15 μm, two connected in series; Mobile phase: A: Water (0.01% TFA), B: Acetonitrile (0.01% TFA); Gradient phase: 5% B increasing to 95% B within 3 minutes; Flow rate: 1.8~2.3 mL / min; Column: SunFire C18, 4.6×50 mm, 3.5 μm; Column temperature: 50°C; Detector: ADC ELSD, DAD (214 nm and 254 nm), ES-API. Method B for LC-MS measurement includes the following: Instrument: Gilson GX-281; ​​Column: Xbridge Prep C18 10μm OBD, 19×250mm; Mobile phase: A: Water (10mM NH4HCO3), B: Acetonitrile; Gradient phase: 5% to 95% of B within 3 minutes; Flow rate: 1.8 to 2.3 mL / min; Column: XBridge C18, 4.6×50mm, 3.5μm; Column temperature: 50℃; Detector: ADC ELSD, DAD (214nm and 254nm), MSD (ES-API).

[0215] Preparative high-pressure liquid chromatography (preparative HPLC) in acidic or basic solvent systems can be used with the Gilson GX-281 instrument. The acidic solvent system includes a Waters SunFire 10 μm C18 column (100 Å, 250 × 19 mm), with solvent A being water / 0.05% TFA and solvent B being acetonitrile. Elution conditions can be a linear gradient increase of solvent B from 5% to 100% over 20 minutes at a flow rate of 30 mL / min. The basic solvent system includes a Waters Xbridge 10 μm C18 column (100 Å, 250 × 19 mm), with solvent A used for preparative HPLC being water / 10 mM ammonium bicarbonate (NH4HCO3) and solvent B being acetonitrile. Elution conditions can be a linear gradient increase of solvent B from 5% to 100% over 20 minutes at a flow rate of 30 mL / min.

[0216] Flash chromatography can be performed on a Biotage instrument using an Agela flash column silica-CS cartridge; reverse-phase flash chromatography can be performed on a Biotage instrument using a Boston ODS or Agela C18 cartridge.

[0217] Chiral HPLC for Analytical Applications - SFC Conditions a) Equipment: SFC Method Station (Thar, Waters) b) Column: CHIRALPAK AD-H / AS-H / OJ-H / OD-H 4.6×100mm, 5μm (Daicel) c) Column temperature: 40℃ d) Mobile phase: CO2 / IPA(0.1% DEA)=55 / 45 e) Flow rate: 4.0mL / min f) Back pressure: 120 bar (12 MPa) g) Injection volume: 2 μL

[0218] Preparative Chiral HPLC Method - SFC Conditions a) Equipment: SFC-80 (Thar, Waters) b) Column: CHIRALPAK AD-H / AS-H / OJ-H / OD-H 20×250mm, 10μm (Daicel) c) Column temperature: 35℃ d) Mobile phase: CO2 / IPA (0.2% methanol ammonia) = 30 / 70 e) Flow rate: 80g / min f) Back pressure: 100 bar (10 MPa) g) Detection wavelength: 214nm h) Cycle time: 6.0 minutes i) Sample solution: Dissolve 1500 mg in 70 mL of methanol. j) Injection volume: 2 mL (Loading: 42.86 mg / injection)

[0219] (Preparation method) Intermediate 1A was synthesized as shown in Figure 1.

[0220] Compound 1A-1 (Figure 1) was synthesized according to Organic & Biomolecular Chemistry, (2013), 11(14), 2273-2287, and compound 1A-7 (Figure 1) was synthesized according to WO 2008 / 138561 A1. Stereospecific reduction of ketone 1A-1 using a (R,R)-Ru catalyst yielded the (R,R)-isomer 1A-2 (Figure 1). Stereospecific reduction of ketone 1A-1 using a (S,S)-Ru catalyst yielded the (S,R)-isomer 1C-2 (Figure 3).

[0221] (Ethyl 2-[(1R,3R)-3-{[(tert-butoxy)carbonyl]amino}-1-hydroxy-4-methylpentyl]-1,3-thiazole-4-carboxylate(1A-2)) [ka]

[0222] To a solution of compound 1A-1 (0.30 kg, 0.81 mol) in ethanol (4.5 L), R,R-Ru catalyst (CAS: 192139-92-7, 26 g, 41 mmol) and potassium hydroxide (4.5 g, 81 mmol) were added. After stirring at room temperature for 3 hours and monitoring by LC-MS, the reaction mixture was quenched with saturated ammonium chloride solution (1.5 L). Volatile substances were removed under vacuum, and the residue was diluted with water (1.2 L). The aqueous mixture was extracted with ethyl acetate (2.0 L x 2), and the combined organic extract was washed with brine (0.50 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (9-15% ethyl acetate in petroleum ether) to obtain compound 1A-2 (0.13 kg, yield 42%) as a white solid. ESI m / z: 373 (M+H) + , 395(M+Na) + TLC (silica gel): R f = 0.4 (33% ethyl acetate in petroleum ether; the other diastereoisomer R)f The value was 0.2. [ka] >99.9% ee after chromatography using AS, AD, OD, and OJ columns.

[0223] (Ethyl 2-[(1R,3R)-3-{[(tert-butoxy)carbonyl]amino}-1-[(tert-butyldimethylsilyl)oxy]-4-methylpentyl]-1,3-thiazole-4-carboxylate(1A-3)) [ka]

[0224] Subsequently, to a solution of compound 1A-2 (0.11 kg, 0.30 mol) in DCM (1.1 L) under nitrogen, imidazole (0.12 kg, 1.8 mol) was added in fractional amounts, and tert-butyldimethylsilyl chloride (TBSCl) (0.14 kg, 0.90 mol) was added dropwise over 15 minutes. The reaction mixture was refluxed for 4 hours (35°C) according to LC-MS until 1A-2 was completely consumed. After cooling to room temperature, the reaction mixture was quenched with saturated ammonium chloride solution (0.40 L) and extracted with DCM (0.40 L x 2). The combined organic solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was dissolved in ethyl acetate (0.40 L), concentrated under vacuum, and this process was repeated 10 times to obtain crude 1A-3 (0.14 kg, crude) as a yellow oil. Crude material 1A-3 was used in the next process without further purification. ESI m / z: 487 (M+H) + , 509(M+Na) + . [ka]

[0225] (Ethyl 2-[(1R,3R)-3-amino-1-[(tert-butyldimethylsilyl)oxy]-4-methylpentyl]-1,3-thiazole-4-carboxylate(1A-4)) [ka]

[0226] A solution of crude compound 1A-3 (0.14 kg, 0.29 mol) in DCM (1.4 L) was cooled to 0°C. TFA (0.24 L) was added dropwise to this cooled solution over 30 minutes. The resulting mixture was stirred at room temperature for 16 hours according to LC-MS until all of 1A-3 was consumed. The mixture was then cooled to 0°C and quenched with saturated sodium bicarbonate solution (2.8 L). The organic layer was washed with water (0.28 L x 2) and brine (0.28 L), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain crude compound 1A-4 (0.14 kg, crude) as a semi-solid. Crude compound 1A-4 was used in the next step without further purification. ESI m / z: 387 (M+H) + . [ka]

[0227] (Ethyl 2-[(1R,3R)-1-[(tert-butyldimethylsilyl)oxy]-3-(hexylamino)-4-methylpentyl]-1,3-thiazole-4-carboxylate(1A-6)) [ka]

[0228] To a solution of crude compound 1A-4 (90 g, 0.23 mol) in DCM (0.12 L), hexanal (1A-5, 20 g, 0.20 mol) was added dropwise over 10 minutes under nitrogen. The reaction mixture was stirred at room temperature for 3 hours, and then sodium triacetoxyborohydride (0.15 kg, 0.70 mol) was added in portions to the reaction mixture under nitrogen at 0°C. The reaction mixture was then stirred at room temperature for 1 hour and monitored by LC-MS. The resulting mixture was quenched with saturated sodium bicarbonate solution (0.20 L) and diluted with water (0.20 L). The organic layer was washed with water (0.20 L) and brine (0.20 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (9-50% ethyl acetate in petroleum ether) to obtain compound 1A-6 (45 g, 41% yield in 3 steps) as a white solid. ESI m / z:471(M+H) + . [ka]

[0229] (Ethyl 2-[(1R,3R)-3-[(2S,3S)-2-azido-N-hexyl-3-methylpentanamide]-1-[(tert-butyldimethylsilyl)oxy]-4-methylpentyl]-1,3-thiazole-4-carboxylate (1A-8)) [ka]

[0230] Subsequently, under nitrogen, DIPEA (8.2 g, 64 mmol) was added dropwise over 2 minutes to a chilled solution of compound 1A-6 (6.0 g, 13 mmol) in 0°C DCM (60 mL), and compound 1A-7 (7.9 g, 45 mmol) was added dropwise over 5 minutes. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour according to LC-MS until all of 1A-6 was consumed. Brine (12 mL) was added to the resulting mixture. The aqueous layer was extracted with DCM (18 mL), and the combined DCM solution was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to obtain compound 1A-8 (5.0 g, yield 64%) as a yellow oil. ESI m / z: 610 (M+H) + , 632(M+Na) + . [ka] Optical rotation: +99.5° (temperature: 19.8°C, concentration: 1.25mg / mL in methanol).

[0231] (Ethyl 2-[(1R,3R)-3-[(2S,3S)-2-amino-N-hexyl-3-methylpentanamide]-1-[(tert-butyldimethylsilyl)oxy]-4-methylpentyl]-1,3-thiazole-4-carboxylate (1A)) [ka]

[0232] Under nitrogen at room temperature, triphenylphosphine (15 g, 57 mmol) was added dropwise over 5 minutes to a solution of compound 1A-8 (5.0 g, 8.2 mmol) in THF (50 mL) and water (2.5 mL). The reaction mixture was stirred at 35°C for 16 hours and monitored by LC-MS. Volatile substances were then removed under vacuum, and the residue was dissolved in ethyl acetate (10 mL). Zinc chloride (3.3 g, 25 mmol) was added to this mixture, and the suspension was stirred at room temperature for 2 hours. The resulting suspension was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (50% ethyl acetate in petroleum ether) to obtain intermediate 1A (3.0 g, yield 63%) as a yellow solid. ESI m / z: 584 (M+H) + . [ka] Optical rotation: +41.3° (Temperature: 19.8°C, Concentration: 1.16 mg / mL in methanol).

[0233] Intermediate 1B was synthesized as shown in Figure 2.

[0234] Compound 1B-1 was synthesized according to WO 2008 / 138561 A1.

[0235] (Ethyl 2-(3-{[(tert-butoxy)carbonyl](hexa-5-in-1-yl)amino}-4-methylpentanoyl)-1,3-thiazole-4-carboxylate(1B-3)) [ka]

[0236] Next, to a solution of compound 1B-2 (73 g, 0.37 mol) in dry THF (1.2 L) at -65°C, KHMDS (1 M, 0.37 L, 0.37 mol in THF) was added dropwise over 30 minutes. Subsequently, a solution of compound 1B-1 (62 g, 0.25 mol) in THF (0.20 L) was added dropwise over 30 minutes while maintaining the temperature below -60°C. The reaction mixture was stirred at -65°C for 4 hours until 1B-1 was completely consumed by TLC. The resulting mixture was quenched with saturated ammonium chloride solution (0.30 L). The aqueous layer was extracted with ethyl acetate (0.5 L x 3). All organic layers were combined, washed with brine (0.5 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to obtain compound 1B-3 (55 g, 50% yield) as a yellow oil. ESI m / z: 351 (M-Boc+H) + . [ka]

[0237] (Ethyl 2-[(1R,3R)-3-{[(tert-butoxy)carbonyl](hexa-5-in-1-yl)amino}-1-hydroxy-4-methylpentyl]-1,3-thiazole-4-carboxylate(1B-4)) [ka]

[0238] To a solution of compound 1B-3 (54 g, 0.12 mol) in isopropanol (0.60 L), R,R-Ru catalyst (CAS: 192139-92-7, 3.9 g, 6.0 mmol) and potassium hydroxide (0.73 g, 12 mmol) were added. The mixture was stirred at room temperature for 6 hours until 1B-3 was completely consumed by TLC. The reaction mixture was then quenched with saturated ammonium chloride solution (0.3 L). The mixture was extracted with ethyl acetate (0.5 L x 3), the combined organic extract was washed with brine (0.5 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (10-20% ethyl acetate in petroleum ether) to obtain compound 1B-4 (15 g, yield 28%) as a yellow oil. ESI m / z: 453 (M+H) + , 475(M+Na) + .

[0239] (Ethyl 2-[(1R,3R)-3-{[(tert-butoxy)carbonyl](hexyl)amino}-1-hydroxy-4-methylpentyl]-1,3-thiazole-4-carboxylate(1B-5)) [ka]

[0240] Under nitrogen, 10% palladium-carbon (50 mg, 11 wt%) was added to a solution of compound 1B-4 (0.45 g, 1.0 mmol) in methanol (10 mL). The suspension was degassed, purged three times with hydrogen, and then stirred at room temperature for 1 hour under a hydrogen balloon. The reaction was monitored by LC-MS. The resulting suspension was filtered through Celite, and the filtrate was concentrated under vacuum to obtain crude product 1B-5 (0.45 g, crude) as a white solid. Crude product 1B-5 was used in the next step without further purification. ESI m / z: 457 (M+H) + , 479(M+Na) + .

[0241] (Ethyl 2-[(1R,3R)-3-{[(tert-butoxy)carbonyl](hexyl)amino}-1-ethoxy-4-methylpentyl]-1,3-thiazole-4-carboxylate(1B-6)) [ka]

[0242] Under nitrogen at -78°C, a solution of compound 1B-5 (0.44 g, 1.0 mmol) and 18-crown-6 (0.53 g, 2.0 mmol) in THF (10 mL) was added dropwise over 5 minutes to a solution of KHMDS in THF (1.0 M, 2.0 mL, 2.0 mmol). The reaction mixture was stirred at -78°C for 30 minutes, after which ethyl iodide (0.78 g, 5.0 mmol) was added. The mixture was then slowly warmed to room temperature, stirred for 1 hour, and monitored by LC-MS. After cooling to -10°C, the resulting mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic solution was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by preparative HPLC (5-95% acetonitrile in 10 mM ammonium bicarbonate solution) to obtain compound 1B-6 (0.29 g, 60% yield in 2 steps) as a white solid. ESI m / z: 485 (M+H), 507 (M+Na) + .

[0243] (Ethyl 2-[(1R,3R)-1-ethoxy-3-(hexylamino)-4-methylpentyl]-1,3-thiazole-4-carboxylate(1B-7)) [ka]

[0244] To a solution of compound 1B-6 (0.20 g, 0.41 mmol) in DCM (5.0 mL), TFA (1.0 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 hours according to LC-MS until Boc was completely removed. After removing volatile substances under vacuum, crude product 1B-7 (0.12 g, crude) was obtained as a white solid. Crude product 1B-7 was used in the next step without further purification. ESI m / z: 385 (M+H) + .

[0245] (Ethyl 2-[(1R,3R)-3-[(2S,3S)-2-azido-N-hexyl-3-methylpentanamide]-1-ethoxy-4-methylpentyl]-1,3-thiazole-4-carboxylate (1B-8)) [ka]

[0246] Compound 1B-8 (0.12 g, 60% yield) was obtained as a white solid by following a procedure similar to that for 1A-8, except that 1B-6 (0.15 g, 0.39 mmol) was used instead of 1A-6. ESI m / z: 520 (M+H) + , 542(M+Na) + .

[0247] (Ethyl 2-[(1R,3R)-3-[(2S,3S)-2-amino-N-hexyl-3-methylpentanamide]-1-ethoxy-4-methylpentyl]-1,3-thiazole-4-carboxylate (1B)) [ka]

[0248] Under nitrogen, 10% palladium-carbon (50 mg, 50 wt%) was added to a solution of compound 1B-8 (0.10 g, 0.19 mmol) in methanol (10 mL). The suspension was degassed and purged three times with hydrogen. The reaction was then stirred at room temperature for 1 hour under a hydrogen balloon and monitored by LC-MS. The resulting suspension was filtered through Celite, and the filtrate was concentrated under vacuum to obtain intermediate 1B (0.16 g, yield 85%) as a white solid. Intermediate 1B was used in the next step without purification. ESI m / z: 498 (M+H) + .

[0249] Intermediate 1C was synthesized as shown in Figure 3.

[0250] (Ethyl 2-[(1S,3R)-3-{[(tert-butoxy)carbonyl]amino}-1-hydroxy-4-methylpentyl]-1,3-thiazole-4-carboxylate(1C-2)) [ka]

[0251] Compound 1C-2 (1.7g, 45% yield, 80 e.e%) was obtained as a colorless oil following a procedure similar to that of 1A-2, except that an S,S-Ru catalyst (CAS: 192139-90-5) was used instead of an R,R-Ru catalyst. ESI m / z: 373 (M+H) + TLC (silica gel): R f = 0.3 (33% ethyl acetate in petroleum ether; the other diastereoisomer R) f The value was 0.4.

[0252] A small amount of product was separated by chiral HPLC (column: R'R WHELK 20*250 mm, 10 μm (Daicel), mobile phase: CO2 / MeOH (0.2% methanol ammonia) = 90 / 10) to obtain enantiomerically pure product 1C-2 (>99.9% ee). Chiral HPLC using AS, AD, OD, and OJ columns: >99.9%. [ka]

[0253] (Ethyl 2-[(1S,3R)-3-{[(tert-butoxy)carbonyl]amino}-1-(methanesulfonyloxy)-4-methylpentyl]-1,3-thiazole-4-carboxylate(1C-3)) [ka]

[0254] Subsequently, triethylamine (0.60 g, 6.0 mmol) and methanesulfonyl chloride (0.55 g, 4.8 mmol) were added dropwise to a suspension of compound 1C-2 (1.4 g, 4.0 mmol, 80% ee) in DCM (50 mL) at 0°C. After the reaction mixture became clear, the reaction mixture was stirred at 0°C for 1 hour, then at room temperature for 30 minutes, and monitored by TLC. The solution was sequentially washed with aqueous hydrochloride (aq. hydrochloride) (1 N, 50 mL), water (50 mL), aqueous sodium carbonate (10%, 50 mL), and brine (50 mL). The resulting organic solution was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude compound 1C-3 (1.6 g, crude) as a yellow oil. Crude 1C-3 was used in the next step without further purification. ESI m / z: 451 (M+H) + .

[0255] (Ethyl 2-[(1R,3R)-1-azido-3-{[(tert-butoxy)carbonyl]amino}-4-methylpentyl]-1,3-thiazole-4-carboxylate(1C-4)) [ka]

[0256] Sodium azide (1.2 g, 18 mmol) was added to a stirred mixture of compound 1C-3 (1.6 g, crude) in DMF (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour and monitored by LC-MS. The mixture was then diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic solution was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain crude compound 1C-4 (1.3 g, crude) as a yellow oil. ESI m / z: 398 (M+H) + .

[0257] (Ethyl 2-[(1R,3R)-1-amino-3-{[(tert-butoxy)carbonyl]amino}-4-methylpentyl]-1,3-thiazole-4-carboxylate(1C-5)) [ka]

[0258] To a solution of compound 1C-4 (1.3 g, crude) in methanol (50 mL), 10% palladium-carbon (0.12 g, 10 wt%) was added under nitrogen. The suspension was degassed and purged three times with hydrogen. The reaction was then stirred at room temperature for 1 hour under a hydrogen balloon and monitored by LC-MS. The resulting suspension was filtered through Celite, and the filtrate was concentrated under vacuum to obtain crude compound 1C-5 (1.0 g, crude) as a yellow oil. Crude 1C-5 was used in the next step without further purification. ESI m / z: 371 (M+H) + .

[0259] (Ethyl 2-[(1R,3R)-3-{[(tert-butoxy)carbonyl]amino}-1-acetamido-4-methylpentyl]-1,3-thiazole-4-carboxylate(1C-6)) [ka]

[0260] Subsequently, triethylamine (0.45 g, 4.5 mmol) and acetyl chloride (0.28 g, 3.6 mmol) were added at 0°C to a stirred suspension of compound 1C-5 (1.0 g, crude) in DCM (50 mL). After the reaction mixture cleared, the reaction mixture was stirred at room temperature for 1.5 hours and monitored by LC-MS. The resulting solution was then washed with hydrochloride solution (1N, 50 mL), water (50 mL), sodium carbonate solution (10%, 50 mL), and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (15-20% ethyl acetate in petroleum ether) to obtain compound 1C-6 (1.0 g, 66% yield in 4 steps) as a yellow oil. ESI m / z: 413 (M+H) + .

[0261] (Ethyl 2-[(1R,3R)-3-amino-1-acetamido-4-methylpentyl]-1,3-thiazole-4-carboxylate(1C-7)) [ka]

[0262] To a solution of compound 1C-6 (1.3 g, 3.0 mmol) in DCM (20 mL), TFA (4 mL) was added at 0°C. The mixture was stirred at room temperature for 1 hour and monitored by LC-MS. Volatile substances were removed under vacuum to obtain crude compound 1C-7 (1.0 g, crude) as a yellow solid. Crude 1C-7 was used in the next step without further purification. ESI m / z: 314 (M+H) + .

[0263] (Ethyl 2-[(1R,3R)-1-acetamido-3-(hexylamino)-4-methylpentyl]-1,3-thiazole-4-carboxylate(1C-8)) [ka]

[0264] Subsequently, hexanal (1A-5, 0.26 g, 2.6 mmol) was added dropwise over 5 minutes to a solution of crude compound 1C-7 (0.70 g, 2.2 mmol) in DCM (30 mL) under nitrogen, and sodium triacetoxyborohydride (0.70 g, 3.3 mmol) and 2 drops of TFA were added. The reaction mixture was stirred at room temperature for 1 hour and monitored by LC-MS. The resulting mixture was washed with water (20 mL), sodium carbonate solution (10%, 20 mL), and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by chiral HPLC (column: IG 20*250 mm, 10 μm, mobile phase: CO2 / methanol (0.2% methanol ammonia) = 80 / 20) to obtain compound 1C-8 (0.52 g, 60% yield in 2 steps) as a colorless oil. ESI m / z:398(M+H) + . [ka] Using the IG column, >99.9% ee.

[0265] (Ethyl 2-[(1R,3R)-3-[(2S,3S)-2-azido-N-hexyl-3-methylpentanamide]-1-acetamido-4-methylpentyl]-1,3-thiazole-4-carboxylate(1C-9)) [ka]

[0266] Subsequently, DIPEA (0.13 g, 1.0 mmol) and compound 1A-7 (0.18 g, 1.0 mmol) were added to a mixture of compound 1C-8 (0.20 g, 0.50 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 2 hours and monitored by LC-MS. Volatile substances were removed under vacuum, and the residue was purified by silica gel column chromatography (15-20% ethyl acetate in petroleum ether) to obtain compound 1C-9 (0.19 g, 70% yield) as a yellow oil. ESI m / z: 537 (M+H) + .

[0267] (Ethyl 2-[(1R,3R)-3-[(2S,3S)-2-amino-N-hexyl-3-methylpentanamide]-1-acetamido-4-methylpentyl]-1,3-thiazole-4-carboxylate(1C)) [ka]

[0268] To a solution of compound 1C-9 (0.19 g, 0.35 mmol) in methanol (10 mL), 10% palladium-carbon (20 mg, 10 wt%) was added under nitrogen. The suspension was degassed and purged three times with hydrogen. The reaction was then stirred at room temperature for 2 hours under a hydrogen balloon and monitored by LC-MS. The resulting suspension was filtered through Celite, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (50% ethyl acetate in petroleum ether) to obtain intermediate 1C (0.15 g, 90% yield) as a yellow oil. ESI m / z: 511 (M+H) + .

[0269] Intermediate 1G was synthesized as shown in Figure 4 and as described in U.S. Patent Application No. 16 / 724,164, filed December 20, 2019. The synthesis of the corresponding compound in U.S. Patent Application No. 16 / 724,164 is incorporated herein by reference.

[0270] (Intermediate: MEP)

[0271] The intermediate MEPa~MEPe was commercially available. Its CAS number and structure are shown below. [ka]

[0272] (Intermediate: TUP)

[0273] Intermediate TUPa-l was synthesized as shown in Figure 5. Intermediate TUPa~TUPe was synthesized as described in U.S. Patent Application No. 16 / 724,164, filed December 20, 2019. The synthesis of the corresponding compound in U.S. Patent Application No. 16 / 724,164 is incorporated herein by reference. Intermediate TUPf-l was synthesized according to the following procedure.

[0274] ((4S)-4-amino-5-[4-(2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}acetamide)-3-fluorophenyl]-2,2-dimethylpentanoic acid (TUPf)) [ka]

[0275] To a solution of Fmoc-Gly-OH (0.25 g, 0.85 mmol) in DCM (10 mL), oxalyl chloride (0.16 g, 1.3 mmol) and one drop of DMF were added. The reaction mixture was stirred at room temperature for 1 hour and monitored by LC-MS. Volatile substances were removed under vacuum, and the residue was dissolved in DMF (4 mL). To this solution, TUP-6a (30 mg, 85 μmol) and DIPEA (0.11 g, 0.85 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour and monitored by LC-MS. The resulting mixture was directly purified by reverse-phase flash chromatography (0-100% acetonitrile in TFA water (0.01%)) to obtain compound TUP-8aa (45 mg, yield 84%) as a white solid. ESI m / z: 656 (M+Na) + , 534(M-Boc+H) + .

[0276] To a solution of compound TUP-8aa (45 mg, 71 μmol) in DCM (0.6 mL), TFA (0.2 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and monitored by LC-MS. Volatile substances were removed under vacuum, and the residue was purified by reverse-phase flash chromatography (0-30% acetonitrile in ammonium bicarbonate aqueous solution (10 mM)) to obtain TUPf (36 mg, 94% yield) as a white solid. ESI m / z: 534 (M+H) + . [ka]

[0277] ((4S)-4-amino-5-[4-(2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}acetamide)phenyl]-2,2-dimethylpentanoic acid (TUPg)) [ka]

[0278] To a solution of TUP-6b (0.34 g, 1.0 mmol) in DCM (5.0 mL), 2,6-lutidine (21 mg, 2.0 mmol), DMAP (12 mg, 0.10 mmol), and Fmoc-Gly-Cl (TUP-7a) (0.38 g, 1.2 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours and monitored by LC-MS. The resulting mixture was diluted with ethyl acetate (50 mL), washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by reverse-phase flash chromatography (0-100% acetonitrile in TFA water (0.3%)) to obtain compound TUP-8ba (0.28 g, yield 45%) as a white solid. ESI m / z 516 (M-Boc+H) + .

[0279] To a solution of TUP-8ba (61 mg, 0.10 mmol) in DCM (5 mL), TFA (1.0 mL) was added. The mixture was stirred at room temperature for 2 hours under vacuum according to LC-MS until Boc was completely removed. Volatile substances were removed under vacuum to obtain the crude product TUPg (51 mg, >100% crude yield) as a white solid. ESI m / z 516 (M+H) + .

[0280] ((4S)-4-amino-5-{4-[2-(2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}acetamide)acetamide]phenyl}-2,2-dimethylpentanoic acid (TUPh)) [ka]

[0281] To a solution of Fmoc-Gly-Gly-OH (0.30 g, 0.85 mmol) in dry DCM (10 mL), oxalyl chloride (0.17 g, 1.3 mmol) and DMF (3 mg, 43 μmol) were added. The reaction mixture was stirred at room temperature for 30 minutes and monitored by LC-MS and TLC (10% methanol in DCM). Volatile substances were removed under vacuum, and the residue was added to a solution of TUP-6b (0.34 g, 1.0 mmol) in dry DMF (5 mL). DIPEA (0.33 g, 2.6 mmol) was added dropwise to the stirred reaction mixture. The mixture was stirred at room temperature for 3 hours and monitored by LC-MS. The resulting mixture was directly purified by reverse-phase flash chromatography (0-30% acetonitrile in ammonium bicarbonate aqueous solution (10 mM)) to obtain TUP-8bb (0.15 g) as a white solid. ESI m / z: 695 (M+Na) + .

[0282] To a solution of TUP-8bb (0.15 g) in DCM (6...

Claims

1. Compounds having the following formula or pharmaceutically acceptable salts thereof: 【Chemistry 1】 (In the formula, BA is a binder; L is a linker covalently bonded to BA and T; T is 【Chemistry 2】 And here, R 1 is a bond, hydrogen, C 1 -C 10 alkyl, a first N-terminal amino acid residue, a first amino acid residue, -C 1 -C 10 alkyl-NR 3a R 3b , or -C 1 -C 10 alkyl-OH; R 3 is hydroxyl, -O-, -OC 1 -C 5 Alkyl, -OC(O)C 1 -C 5 Alkyl, -OC(O)N(H)C 1 -C 10 Alkyl, -OC(O)N(H)C 1 -C 10 Alkyl-NR 3a R 3b ,-NHC(O)C 1 -C 5 Alkyl, or -OC(O)N(H)(CH 2 CH 2 O) n C 1 -C 10 Alkyl-NR 3a R 3b And, Here, R 3a and R 3b In each case, independently, are a bond, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl; where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted; R 4 and R 5 C 1 -C 5 It is alkyl; R 6 -OH, -O-, -NHNH 2 -NHNH-, -NHSO 2 (CH 2 ) a1 -Aryl-(CH 2 ) a2 NR 6a R 6b And, Here, aryl is either substituted or not substituted; and R 6a and R 6b In each case, independently, are a bond, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl; where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted; R 7 In each case, independently, hydrogen, -OH, -O-, halogen, or -NR 7a R 7b And, Here, R 7a and R 7b In each case, independently, the bonds are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, acyl, and -C(O)CH 2 OH, -C(O)CH 2 O-, first N-terminal amino acid residue, first amino acid residue, first N-terminal peptide residue, first peptide residue, -CH 2 CH 2 NH 2 , and -CH 2 CH 2 It is NH-; where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted; R 8 In each case, independently, hydrogen, -NHR 9 , or halogen, Here, R 9 is hydrogen, -C 1 -C 5 Alkyl, or -C(O)C 1 -C 5 It is alkyl; and m is either 1 or 2; R 10 If present, -C 1 -C 5 It is alkyl; Q is -CH 2 - or -O-, where Q is -CH 2 -If R 2 C 5 -C 20 Alkyl, C 5 -C 20 Alkylene, Alkinyl, C 5 -C 20 Alkynylene, the positional isomer triazole, or the positional isomer triazolylene; and If Q is -O-, then R 2 C 3 -C 20 Alkyl, C 3 -C 20 Alkylene, C 3 -C 20 Alkinyl, C 3 -C 20 Alkynylene, the positional isomer triazole, or the positional isomer triazolylene; Here, the positional isomer triazole or positional isomer triazolylene is either unsubstituted or substituted with alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or acyl; n is an integer between 1 and 10; r is an integer between 1 and 6; a, a1, and a2 are independently 0 or 1; and k is an integer between 1 and 30; T is covalently bonded to L, and is one of the following compounds: 【Transformation 3】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 (or salts that are not acceptable as medicines.)

2. A compound according to claim 1, having formula A: 【Chemistry 4】 (In the formula, L is the linker).

3. R 7 However, in each case independently, hydrogen, -OH, -O-, halogen, or -NR 7a R 7b And, Here, R 7a and R 7b are each independently in each instance a bond, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, acyl, -C(O)CH 2 OH, -C(O)CH 2 O-, a first N-terminal amino acid residue, a first N-terminal peptide residue, -CH 2 CH 2 NH 2 , and -CH 2 CH 2 NH-, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and acyl are optionally substituted, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 2, which is of formula A': 【Transformation 5】 (In the formula, SP 1 and SP 2 If present, it is a spacer base; Each AA is the second amino acid residue, if present; and p is an integer between 0 and 10; or The aforementioned SP 2 - If a spacer is present, 【Transformation 6】 and; The aforementioned second - (AA) p -but, 【Transformation 7】 and; The aforementioned SP 1 -Spacer, 【Transformation 8】 (In the formula, RG′ is a reactive group residue that is produced as a result of the reaction of the reactive group RG with the binder; 【Chemistry 9】 is a direct or indirect bond to the binder; and b is an integer between 1 and 4. (That is.)

5. The aforementioned binder is, Formula H 2 N-LL-X (wherein LL is: Divalent polyethylene glycol (PEG) group; -(CH 2 ) n -; -(CH 2 CH 2 O) n -(CH 2 ) p -; -(CH 2 ) n -N(H)C(O)-(CH 2 ) m -; -(CH 2 CH 2 O) n -N(H)C(O)-(CH 2 CH 2 O) m -(CH 2 ) p -; -(CH 2 ) n -C(O)N(H)-(CH 2 ) m -; -(CH 2 CH 2 O) n -C(O)N(H)-(CH 2 CH 2 O) m -(CH 2 ) p -; -(CH 2 ) n -N(H)C(O)-(CH 2 CH 2 O) m -(CH 2 ) p -; -(CH 2 CH 2 O) n -N(H)C(O)-(CH 2 ) m -; -(CH 2 ) n -C(O)N(H)-(CH 2 CH 2 O) m -(CH 2 ) p -; and -(CH 2 CH 2 O) n -C(O)N(H)-(CH 2 ) m But (In the formula, n is an integer selected from 1 to 12; m is an integer selected from 0 to 12; p is an integer selected from 0 to 2. A divalent linker selected from the group consisting of; and X is -SH, -N 3 -C≡CH, -C(O)H, tetrazole, 【Chemistry 10】 (Selected from the group consisting of) It is an antibody modified with a primary amine compound, or The aforementioned binder has the following formula: 【Chemistry 11】 The compound according to claim 4, which is an antibody modified with a primary amine.

6. The compound according to claim 4, wherein Q is -O-.

7. Q is -CH 2 -and; R 1 However, C 1 -C 10 It is alkyl; R 2 However, C 5 -C 20 It is alkyl; R 6 However, it is -OH; R 10 However, it does not exist; r is 4; and a is 1, The compound according to claim 4.

8. Q is -CH 2 -and; R 1 However, hydrogen or C 1 -C 10 It is alkyl; R 2 However, C 5 -C 20 It is alkyl; R 6 However, it is -OH; r is 3 or 4; and a is 1, The compound according to claim 4.

9. Q is -CH 2 -and; R 1 However, hydrogen or C 1 -C 10 It is alkyl; R 2 However, C 5 -C 20 It is alkyl; R 6 However, it is -OH; R 10 However, it does not exist; r is 4; and a is 1, The compound according to claim 4.

10. Q is -O-; R 1 However, hydrogen or C 1 -C 10 It is alkyl; R 2 However, C 5 -C 20 Alkyl or C 5 -C 20 It is alkinyl; R 3 However, hydroxyl or -OC(O)C 1 -C 5 It is alkyl; R 6 However, it is -OH; R 10 However, if it exists, -C 1 -C 5 It is alkyl; r is 3 or 4; and a is 1, The compound according to claim 4.

11. Q is -CH 2 -or -O-; R 1 However, C 1 -C 10 It is alkyl; R 2 However, C 5 -C 20 Alkyl or C 5 -C 20 It is alkinyl; R 6 However, -NHSO 2 (CH 2 ) a1 -Aryl-(CH 2 ) a2 NR 6a R 6b and; R 10 However, it does not exist; r is 4; and a, a1, and a2 are independently either 0 or 1. The compound according to claim 4.

12. below: 【Chemistry 12】 【change】 【change】 【change】 The compound according to claim 1, which is an antibody-drug conjugate comprising an antibody or an antigen-binding fragment thereof conjugated to a compound selected from the group consisting of the above.

13. Compounds having the structure of formula I, or pharmaceutically acceptable salts thereof: 【Chemistry 13】 (In the formula, R 1 is hydrogen, C 1 -C 10 Alkyl, first N-terminal amino acid residue, -C 1 -C 10 Alkyl-NR 3a R 3b , or -C 1 -C 10 It is alkyl-OH; R 3 is hydroxyl, -OC 1 -C 5 Alkyl, -OC(O)C 1 -C 5 Alkyl, -OC(O)N(H)C 1 -C 10 Alkyl, -OC(O)N(H)C 1 -C 10 Alkyl-NR 3a R 3b ,-NHC(O)C 1 -C 5 Alkyl, or -OC(O)N(H)(CH 2 CH 2 O) n C 1 -C 10 Alkyl-NR 3a R 3b And, Here, R 3a and R 3b In each case, independently, are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl; where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted; R 4 and R 5 C 1 -C 5 It is alkyl; R 6 -OH, -NHNH 2 , -NHSO 2 (CH 2 ) a1 -Aryl-(CH 2 ) a2 NR 6a R 6b And, Here, aryl is either substituted or not substituted; and R 6a and R 6b In each case, independently, are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl; where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted; R 7 In each case, independently, hydrogen, -OH, halogen, or -NR 7a R 7b And, Here, R 7a and R 7b In each case, independently, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, acyl, -C(O)CH 2 OH, the first N-terminal amino acid residue, the first N-terminal peptide residue, and -CH 2 CH 2 NH 2 Herein, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted; R 8 In each case, independently, hydrogen, -NHR 9 , or halogen, Here, R 9 is hydrogen, -C 1 -C 5 Alkyl, or -C(O)C 1 -C 5 It is alkyl; and m is either 1 or 2; R 10 If present, -C 1 -C 5 It is alkyl; Q is -CH 2 - or -O-, where Q is -CH 2 -If R 2 C 5 -C 20 Alkyl, C 5 -C 20 Alkylene, C 5 -C 20 Alkinyl, C 5 -C 20 Alkynylene, the positional isomer triazole, or the positional isomer triazolylene; and If Q is -O-, then R 2 C 3 -C 20 Alkyl, C 3 -C 20 It is an alkynyl or a positional isomer triazole; Here, the triazole of the positional isomer is either unsubstituted or substituted with alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl; n is an integer between 1 and 10; r is an integer between 1 and 6; a, a1, and a2 are independently 0 or 1; and T is the following compound: 【Chemistry 14】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 Tubricin A-I, U-X, or Z, pretubbricin D, or N 14 (Not desacetoxytublicin H)

14. Q is -CH 2 -and; R 1 However, C 1 -C 10 It is alkyl; R 2 However, C 5 -C 20 It is alkyl; R 6 However, it is -OH; R 10 However, it does not exist; r is 4; and a is 1, The compound according to claim 13.

15. Formula II: 【Chemistry 15】 The compound according to claim 13, or a pharmaceutically acceptable salt thereof, which is due to the structure of the compound according to claim 13.

16. R 3 However, hydroxyl, -OEt, -OC(O)N(H)CH 2 CH 2 NH 2 -NHC(O)Me, or -OC(O)N(H)CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 NH 2 is or The aforementioned compound is as follows: 【Chemistry 16】 【change】 A compound according to claim 15, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

17. Q is -CH 2 -and; R 1 However, hydrogen or C 1 -C 10 It is alkyl; R 2 However, C 5 -C 20 It is alkyl; R 6 However, it is -OH; r is 3 or 4; and a is 1, The compound according to claim 13.

18. Formula III: 【Chemistry 17】 The compound according to claim 17, or a pharmaceutically acceptable salt thereof, which is due to the structure of the compound according to claim 17.

19. R 1 but is hydrogen or methyl; and R 10 However, is it methyl, or The aforementioned compound is as follows: 【Chemistry 18】 【change】 【change】 A compound according to claim 18, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

20. Q is -CH 2 -and; R 1 However, hydrogen or C 1 -C 10 It is alkyl; R 2 However, C 5 -C 20 It is alkyl; R 6 However, it is -OH; R 10 However, it does not exist; r is 4; and a is 1, The compound according to claim 13.

21. Formula II: 【Chemistry 19】 The compound according to claim 20, or a pharmaceutically acceptable salt thereof, which is due to the structure of the compound according to claim 20.

22. R 7 However, hydrogen, -N(H)C(O)CH 2 NH 2 ,-N(H)C(O)CH 2 OH, or -N(H)CH 2 CH 2 NH 2 And R 8 However, it is hydrogen or fluoro, or The aforementioned compound is as follows: 【Chemistry 20】 【change】 【change】 A compound according to claim 21, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

23. Q is -O-; R 1 However, hydrogen or C 1 -C 10 It is alkyl; R 2 However, C 5 -C 20 Alkyl or C 5 -C 20 It is alkinyl; R 3 However, hydroxyl or -OC(O)C 1 -C 5 It is alkyl; R 6 However, it is -OH; R 10 However, if it exists, -C 1 -C 5 It is alkyl; r is 3 or 4; and a is 1, The compound according to claim 13.

24. Formula IV: 【Chemistry 21】 The compound according to claim 23, or a pharmaceutically acceptable salt thereof, which is due to the structure of the compound according to claim 23.

25. R 7 However, hydrogen or -NH 2 And R 8 However, it is hydrogen or fluoro, or The aforementioned compound is as follows: 【Chemistry 22】 A compound according to claim 23, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

26. Q is -O-; R 1 However, C 1 -C 10 It is alkyl; R 2 However, C 5 -C 20 It is alkinyl; R 3 However, -OC(O)C 1 -C 5 It is alkyl; R 6 However, it is -OH; R 10 However, it does not exist; r is 4; and a is 1, The compound according to claim 13.

27. Formula V: 【Chemistry 23】 The compound according to claim 26, or a pharmaceutically acceptable salt thereof, which is due to the structure of the compound according to claim 26.

28. R 7 However, hydrogen or -N(H)C(O)CH 2 OH, -N(H)C(O)CH 2 NHC(O)CH 2 NH 2 ,or 【Chemistry 24】 And R 8 However, is it hydrogen, or The aforementioned compound is as follows: 【Chemistry 25】 A compound according to claim 27, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

29. Q is -CH 2 -or -O-; R 1 However, C 1 -C 10 It is alkyl; R 2 However, C 5 -C 20 Alkyl or C 5 -C 20 It is alkinyl; R 6 However, -NHSO 2 (CH 2 ) a1 -Aryl-(CH 2 ) a2 NR 6a R 6b and; R 10 However, it does not exist; r is 4; and a, a1, and a2 are independently either 0 or 1. The compound according to claim 13.

30. Equation VI: 【Chemistry 26】 The compound according to claim 29, or a pharmaceutically acceptable salt thereof, which is due to the structure of the compound according to claim 29.

31. R 6 but, 【Chemistry 27】 is or a is zero; and R 6 but, 【Chemistry 28】 is or a is 1; and R 6 but, 【Chemistry 29】 is or The aforementioned compound is as follows: 【Transformation 30】 【change】 A compound according to claim 30, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

32. A pharmaceutical composition comprising the compound described in claim 1.

33. For treating cancer, or For the treatment of cancers selected from the group consisting of renal cell carcinoma, pancreatic cancer, head and neck cancer, prostate cancer, castration-resistant prostate cancer, malignant glioma, osteosarcoma, colorectal cancer, gastric cancer, mesothelioma, malignant mesothelioma, multiple myeloma, ovarian cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, synovial sarcoma, thyroid cancer, breast cancer, PRLR-positive (PRLR+) breast cancer, melanoma, acute myeloid leukemia, adult T-cell leukemia, astrocytoma, bladder cancer, cervical cancer, cholangiocarcinoma, endometrial cancer, esophageal cancer, glioblastoma, Kaposi's sarcoma, kidney cancer, leiomyosarcoma, liver cancer, lymphoma, MFH / fibrosarcoma, nasopharyngeal cancer, rhabdomyosarcoma, colon cancer, gastric cancer, uterine cancer, residual cancer, and Wilms' tumor, or For treating tumors expressing antigens selected from the group consisting of PRLR and STEAP2, Use of the compound according to claim 1 in the manufacture of pharmaceuticals.

34. For treating cancer, or For the treatment of cancers selected from the group consisting of renal cell carcinoma, pancreatic cancer, head and neck cancer, prostate cancer, castration-resistant prostate cancer, malignant glioma, osteosarcoma, colorectal cancer, gastric cancer, mesothelioma, malignant mesothelioma, multiple myeloma, ovarian cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, synovial sarcoma, thyroid cancer, breast cancer, PRLR-positive (PRLR+) breast cancer, melanoma, acute myeloid leukemia, adult T-cell leukemia, astrocytoma, bladder cancer, cervical cancer, cholangiocarcinoma, endometrial cancer, esophageal cancer, glioblastoma, Kaposi's sarcoma, kidney cancer, leiomyosarcoma, liver cancer, lymphoma, MFH / fibrosarcoma, nasopharyngeal cancer, rhabdomyosarcoma, colon cancer, gastric cancer, uterine cancer, residual cancer, and Wilms' tumor, or For treating tumors expressing antigens selected from the group consisting of PRLR and STEAP2, Use of the compound according to claim 13 in the manufacture of a pharmaceutical product.

35. formula: 【Chemistry 31】 (In the formula, L is a linker covalently bonded to T; T is 【Chemistry 32】 And here, R 1 is a bond, hydrogen, C 1 -C 10 Alkyl, first N-terminal amino acid residue, first amino acid residue, -C 1 -C 10 Alkyl-NR 3a R 3b , or -C 1 -C 10 It is alkyl-OH; R 3 is hydroxyl, -O-, -OC 1 -C 5 Alkyl, -OC(O)C 1 -C 5 Alkyl, -OC(O)N(H)C 1 -C 10 Alkyl, -OC(O)N(H)C 1 -C 10 Alkyl-NR 3a R 3b ,-NHC(O)C 1 -C 5 Alkyl, or -OC(O)N(H)(CH 2 CH 2 O) n C 1 -C 10 Alkyl-NR 3a R 3b And, Here, R 3a and R 3b In each case, independently, are a bond, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl; where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted; R 4 and R 5 C 1 -C 5 It is alkyl; R 6 -OH, -O-, -NHNH 2 -NHNH-, -NHSO 2 (CH 2 ) a1 -Aryl-(CH 2 ) a2 NR 6a R 6b And, Here, aryl is either substituted or not substituted; and R 6a and R 6b In each case, independently, are a bond, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl; where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted; R 7 In each case, independently, hydrogen, -OH, -O-, halogen, or -NR 7a R 7b And, Here, R 7a and R 7b In each case, independently, the bonds are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, acyl, and -C(O)CH 2 OH, -C(O)CH 2 O-, first N-terminal amino acid residue, first amino acid residue, first N-terminal peptide residue, first peptide residue, -CH 2 CH 2 NH 2 , and -CH 2 CH 2 It is NH-; where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted; R 8 In each case, independently, hydrogen, -NHR 9 , or halogen, Here, R 9 is hydrogen, -C 1 -C 5 Alkyl, or -C(O)C 1 -C 5 It is alkyl; and m is either 1 or 2; R 10 If present, -C 1 -C 5 It is alkyl; Q is -CH 2 - or -O-, where Q is -CH 2 -If R 2 C 5 -C 20 Alkyl, C 5 -C 20 Alkylene, C 5 -C 20 Alkinyl, C 5 -C 20 Alkynylene, the positional isomer triazole, or the positional isomer triazolylene; and If Q is -O-, then R 2 C 3 -C 20 Alkyl, C 3 -C 20 Alkylene, C 3 -C 20 Alkinyl, C 3 -C 20 Alkynylene, the positional isomer triazole, or the positional isomer triazolylene; Here, the positional isomer triazole or positional isomer triazolylene is either unsubstituted or substituted with alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or acyl; n is an integer between 1 and 10; r is an integer between 1 and 6; a, a1, and a2 are independently either 0 or 1. A linker-payload having, or a pharmaceutically acceptable salt thereof; The linker-payload is composed of the following compounds: 【Transformation 33】 【change】 【change】 【change】 【change】 【change】 The linker-payload, or a pharmaceutically acceptable salt thereof, that is not a pharmaceutically acceptable salt thereof.

36. Linker-payload according to claim 35, having formula LPa: 【Transformation 34】 (In the formula, L is the linker).

37. R 7 However, in each case independently, hydrogen, -OH, -O-, halogen, or -NR 7a R 7b And, Here, R 7a and R 7b However, in each case independently, the bond, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, acyl, -C(O)CH 2 OH, -C(O)CH 2 O-, first N-terminal amino acid residue, first N-terminal peptide residue, -CH 2 CH 2 NH 2 , and -CH 2 CH 2 The linker-payload according to claim 36, wherein the payload is NH-, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and acyl are optionally substituted.

38. Linker-payload according to claim 37, having formula LPa': 【Chemistry 35】 (In the formula, SP 1 and SP 2 If present, it is a spacer base; Each AA is the second amino acid residue, if present; and p is an integer between 0 and 10, or The aforementioned SP 2 - If a spacer is present, 【Transformation 36】 and; The aforementioned second - (AA) p -but, 【Chemistry 37】 and; The aforementioned SP 1 -Spacer, 【Transformation 38】 (In the formula, RG is a reactive group; and b is an integer from 1 to 4.

39. The linker-payload according to claim 38, wherein Q is -O-.

40. Q is -CH 2 -and; R 1 However, C 1 -C 10 It is alkyl; R 2 However, C 5 -C 20 It is alkyl; R 6 However, it is -OH; R 10 However, it does not exist; r is 4; and a is 1, Linker-payload according to claim 38.

41. Q is -CH 2 -and; R 1 However, hydrogen or C 1 -C 10 It is alkyl; R 2 However, C 5 -C 20 It is alkyl; R 6 However, it is -OH; r is 3 or 4; and a is 1, Linker-payload according to claim 38.

42. Q is -CH 2 -and; R 1 However, hydrogen or C 1 -C 10 It is alkyl; R 2 However, C 5 -C 20 It is alkyl; R 6 However, it is -OH; R 10 However, it does not exist; r is 4; and a is 1, Linker-payload according to claim 38.

43. Q is -O-; R 1 However, hydrogen or C 1 -C 10 It is alkyl; R 2 However, C 5 -C 20 Alkyl or C 5 -C 20 It is alkinyl; R 3 However, hydroxyl or -OC(O)C 1 -C 5 It is alkyl; R 6 However, it is -OH; R 10 However, if it exists, -C 1 -C 5 It is alkyl; r is 3 or 4; and a is 1, Linker-payload according to claim 38.

44. Q is -CH 2 -or -O-; R 1 However, C 1 -C 10 It is alkyl; R 2 However, C 5 -C 20 Alkyl or C 5 -C 20 It is alkinyl; R 6 However, -NHSO 2 (CH 2 ) a1 -Aryl-(CH 2 ) a2 NR 6a R 6b and; R 10 However, it does not exist; r is 4; and a, a1, and a2 are independently either 0 or 1. Linker-payload according to claim 38.

45. For use in treating cancer, or For use in treating cancers selected from the group consisting of renal cell carcinoma, pancreatic cancer, head and neck cancer, prostate cancer, castration-resistant prostate cancer, malignant glioma, osteosarcoma, colorectal cancer, gastric cancer, mesothelioma, malignant mesothelioma, multiple myeloma, ovarian cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, synovial sarcoma, thyroid cancer, breast cancer, PRLR-positive (PRLR+) breast cancer, melanoma, acute myeloid leukemia, adult T-cell leukemia, astrocytoma, bladder cancer, cervical cancer, cholangiocarcinoma, endometrial cancer, esophageal cancer, glioblastoma, Kaposi's sarcoma, kidney cancer, leiomyosarcoma, liver cancer, lymphoma, MFH / fibrosarcoma, nasopharyngeal cancer, rhabdomyosarcoma, colon cancer, gastric cancer, uterine cancer, residual cancer, and Wilms' tumor, or The pharmaceutical composition according to claim 32, for use in treating a tumor expressing an antigen selected from the group consisting of PRLR and STEAP2.

46. A pharmaceutical composition comprising the compound described in claim 13.

47. For use in treating cancer, or For use in treating cancers selected from the group consisting of renal cell carcinoma, pancreatic cancer, head and neck cancer, prostate cancer, castration-resistant prostate cancer, malignant glioma, osteosarcoma, colorectal cancer, gastric cancer, mesothelioma, malignant mesothelioma, multiple myeloma, ovarian cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, synovial sarcoma, thyroid cancer, breast cancer, PRLR-positive (PRLR+) breast cancer, melanoma, acute myeloid leukemia, adult T-cell leukemia, astrocytoma, bladder cancer, cervical cancer, cholangiocarcinoma, endometrial cancer, esophageal cancer, glioblastoma, Kaposi's sarcoma, kidney cancer, leiomyosarcoma, liver cancer, lymphoma, MFH / fibrosarcoma, nasopharyngeal cancer, rhabdomyosarcoma, colon cancer, gastric cancer, uterine cancer, residual cancer, and Wilms' tumor, or The pharmaceutical composition according to claim 46, for use in treating a tumor expressing an antigen selected from the group consisting of PRLR and STEAP2.

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