Bis-octahydrophenanthrene carboxamide derivatives and protein conjugates thereof for use as lxr agonists

Abstract

To provide compounds useful for effective treatments of, e.g., metabolic diseases using small molecule antibody-drug conjugates of liver X receptor modulators.SOLUTION: Provided herein are compounds or payloads, linker-payloads, antibody-drug conjugates, and compositions, and methods for the treatment of diseases and disorders associated with the liver X receptor, including bis-octahydrophenanthrene carboxamides and protein (e.g., antibody) drug conjugates thereof.SELECTED DRAWING: Figure 13

Description

[Technical Field]

[0001] (Field) Provided herein are novel bis-octahydrophenanthrenecarboxamides and and protein conjugates thereof, as well as the bis-octahydrophenanthrene carboxylate Various diseases, disorders, and It is a method for treating a condition. [Background technology]

[0002] (background) Antibody-drug conjugates (ADCs) are bioactive small molecule drugs linked to antibodies. ADCs are antibodies that combine the target specificity of small molecule drugs with the mode of action and efficacy of small molecule drugs. Therapeutic benefits have been confirmed in the treatment of cancer, which is the primary focus of ongoing trials. ADCETRIS® (brentuximab vedotin) and KADCYLA® (ad- Rastuzumab emtansine is one of two ADCs approved for the treatment of certain types of cancer. At least 40 ADCs are currently in clinical development.

[0003] Liver X receptors (LXRs) are involved in cholesterol, lipid, and glucose homeostasis, inflammation, and LXRα and LXR are ligand-dependent transcription factors that regulate the expression of genes involved in innate immunity. LXRα is highly expressed in the liver, intestine, adipose tissue, and differentiated macrophages. LXRs are expressed as (i) cholesterol transporters, e.g. , stimulates the expression of ABCA1 and ABCG1, both of which mediate cellular cholesterol efflux and (ii) negatively affecting macrophage inflammatory gene expression through the suppression of NF-kB activation. LXRs have a variety of biological functions, including regulating atherosclerosis, Proliferative disorders, neurodegenerative disorders, and inflammation have also been implicated. These include bladder cancer, lung cancer, oral squamous cell carcinoma, and prostate cancer (Pencheva et al., 200 4; Wu et al., 2015; Kaneko et al., 2015; Chuu et al., 2006). Neurodegenerative disorders include: Alzheimer's disease and myelin gene expression (Terwel et al., 2011; Sandoval- Hernandez et al., 2016; Meffre et al., 2014). Inflammation includes inflammatory bowel disease, ulcerative colitis, and Enteritis, Crohn's disease, and arthritis (Anderson et al., 2011; Huang et al., 201 5; Cui et al., 2012). Macrophage LXRs are known to contain anti-atherogenic activity. LXR agonists have been shown to (i) inhibit the initiation of atherosclerosis and slow its progression; (ii) attenuating atherosclerosis and improving established atherosclerotic lesions; and (iii) can reduce lesional macrophage content by apoptosis. It is believed that

[0004] The therapeutic efficacy of small molecule LXR modulators may be enhanced by, for example, undesired modulation of LXRs in non-target cells. Regulation of LXRs in non-target cells is limited by their limited activity and / or low bioavailability. However, poor bioavailability can lead to undesirable side effects, including but not limited to: However, this appears to be due to a number of reasons, including low solubility, which exacerbates the inadequate therapeutic window of treatment. If ADCs containing LXR modulators are developed, target-specific LXR regulation will become possible. This would avoid side effects due to off-target regulation of LXR. Furthermore, such ADCs may offer benefits such as improved modulation of biological targets, increased bioavailability, and Therefore, small molecule ADCs of LXR modulators may be useful. There is a continuing need for effective treatment of, for example, metabolic disorders. Summary of the Invention

[0005] (overview) Provided herein are metabolic disorders, including, but not limited to, dyslipidemia. These compounds are useful in the treatment of neurological disorders, e.g., inflammation or neurodegenerative disorders. Also provided herein are compounds such as

[0006] In one embodiment, provided herein is a compound of Formula I, or a pharmaceutical thereof Acceptable salts, solvates, or stereoisomeric forms of: [ka] (In the formula, Q 1 and Q 2 each independently represents -CH2-, -C(O)-, -C(H)(OH)-, -C(OH)2-, -SO2-, -SO- , -PO(OR 3 )-, -PO(NR 3 NR 4 )-, -NR 3 - or -N =; W is -CH2-, -N(H)-, or -O-; R 1 is -N(H)R 4 or -N(R 5 )2; R 2 is -N(H)R4 and; Each R 4 is in each case independently hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, group, biodegradable moiety, alkyl, substituted alkyl, acyl, or substituted acyl; R 5 is alkyl, aryl, arylalkyl, heterocycloalkyl, or substituted heterocyclic alkyl. wherein each heterocycloalkyl or substituted heterocycloalkyl The alkyl group contains 1, 2, or 3 heteroatoms selected from nitrogen and oxygen and is substituted. If present, at least one of -OH and -CH2OH, or at least one primary or secondary Contains nitrogen; Each R 6 are independently halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O-amino O-PEG or O-acid residue n1 where each n is an integer from 0 to 14, and each n1 is an integer from 1 to 12. is an integer; and Each R 3 are independently hydrogen, alkyl, or aryl).

[0007] In one embodiment, provided herein is a compound according to Formula I, or a medicament thereof. and its acceptable salts, solvates, or stereoisomeric forms: [ka] (In the formula, Q 1 and Q 2 each independently represents -CH2-, -C(O)-, -C(H)(OH)-, -C(OH)2-, -SO2-, -SO- , -PO(OR 3 )-, -PO(NR 3 NR 4 )-, -NR 3- or -N =; W is -CH2-, -N(H)-, or -O-; R 1 is -N(H)R 4 or -N(R 5 )2; R 2 is -N(H)R 4 and; Each R 4 is in each case independently hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, group, a biodegradable moiety, or an alkyl; R 5 is alkyl, aryl, arylalkyl, heterocycloalkyl, or substituted heterocyclic alkyl. wherein each heterocycloalkyl or substituted heterocycloalkyl The alkyl group contains 1, 2, or 3 heteroatoms selected from nitrogen and oxygen and is substituted. If present, at least one of -OH and -CH2OH, or at least one primary or secondary Contains nitrogen; Each R 6 are independently halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O-amino O-PEG or O-acid residue n1 where each n is an integer from 0 to 14, and each n1 is an integer from 1 to 12. is an integer; and Each R 3 are independently hydrogen, alkyl, or aryl).

[0008] In another embodiment, described herein is a compound of formula I above attached to a linker. The compound is a linker-payload having a

[0009] In another embodiment, the present invention provides a method for treating a pulmonary arthritis (PTA) infection by administering to a subject an antibody or antigen-binding fragment thereof. or an antibody-drug conjugate having a compound of formula I above combined with a linker-payload. do.

[0010] In one embodiment, described herein is a compound according to Formula A, Formula B, Formula C, or Formula D. or a pharmaceutically acceptable salt or stereoisomeric form thereof: [ka] (In the formula, L is a linker; BA is a binder; k is an integer from 1 to 30; Q 1 and Q 2 each independently represents -CH2-, -C(O)-, -C(H)(OH)-, -C(OH)2-, -SO2-, -SO- , -PO(OR 3 )-, -PO(NR 3 NR 4 )-, -NR 3 - or -N =; W is -CH2-, -N(H)-, or -O-; R 1 is -N(H)R 4 , -N(H)R 4 -, -N(H)-, -N(R 5 )2, or -N(R 5 )2- and; R 2 is -N(H)R 4 , -N(H)R 4 - or -N(H)-; Each R 4 is in each case independently hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, group, biodegradable moiety, alkyl, substituted alkyl, acyl, substituted acyl, or -alkylene- can be; R 5 is alkyl, aryl, arylalkyl, heterocycloalkyl, or substituted heterocyclic alkyl. wherein each heterocycloalkyl or substituted heterocycloalkyl The alkyl group contains 1, 2, or 3 heteroatoms selected from nitrogen and oxygen and is substituted. If present, at least one of -OH and -CH2OH, or at least one primary or secondary Contains nitrogen; Each R 6 are independently halo, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Alkoxy, -CN, O-g glucose, O-amino acid residue, or O-PEG n1 (wherein each n is an integer from 0 to 14, and and each n1 is an integer from 1 to 12; and Each R 3 are independently hydrogen, alkyl, or aryl).

[0011] In another embodiment, described herein is a compound according to Formula A, Formula B, Formula C, or Formula D. or a pharmaceutically acceptable salt or stereoisomeric form thereof: [ka] (In the formula, L is a linker; BA is a binder; k is an integer from 1 to 30; Q 1 and Q 2 each independently represents -CH2-, -C(O)-, -C(H)(OH)-, -C(OH)2-, -SO2-, -SO- , -PO(OR 3 )-, -PO(NR 3 NR 4 )-, -NR 3 - or -N =; W is -CH2-, -N(H)-, or -O-; R 1 is -N(H)R 4 , -N(H)R4 -, -N(H)-, -N(R 5 )2, or -N(R 5 )2- and; R 2 is -N(H)R 4 , -N(H)R 4 - or -N(H)-; Each R 4 is in each case independently hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, group, a biodegradable moiety, an alkyl, or an -alkylene-; R 5 is alkyl, aryl, arylalkyl, heterocycloalkyl, or substituted heterocyclic alkyl. wherein each heterocycloalkyl or substituted heterocycloalkyl The alkyl group contains 1, 2, or 3 heteroatoms selected from nitrogen and oxygen and is substituted. If present, at least one of -OH and -CH2OH, or at least one primary or secondary Contains nitrogen; Each R 6 are independently halo, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Alkoxy, -CN, O-g glucose, O-amino acid residue, or O-PEG n1 (wherein each n is an integer from 0 to 14, and and each n1 is an integer from 1 to 12; and Each R 3 are independently hydrogen, alkyl, or aryl).

[0012] In another embodiment, described herein is a compound described herein, Linker-payload or antibody-drug conjugate, and a pharmaceutically acceptable excipient , a carrier, or a diluent.

[0013] In another embodiment, the present disclosure provides a method for treating dyslipidemia, metabolic syndrome, and other conditions in a subject. 20. A method for treating a sexual, inflammatory, or neurodegenerative disease, comprising administering to said subject an effective therapeutic amount of The compounds, linker-payload, or antibody-drug conjugates described herein or the method comprising administering a pharmaceutical composition.

[0014] In another embodiment, described herein is a compound described herein, Methods for making linker-payload or antibody-drug conjugates and compositions do. [Brief explanation of the drawings]

[0015] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] FIG. 1 shows the payload, the compound, and the synthetic chemical scheme of bis-octahydrophenanthrenecarboxamide. [Figure 2] FIG. 2 shows the payload, the compound, and the synthetic chemical scheme of bis-octahydrophenanthrenecarboxamide.

[0016] [Figure 3] FIG. 3 shows the synthetic chemistry schemes for the linker-payload, cyclodextrin-based linker-payload, PEG4-taurine-based linker-payload, and maltose-based linker-payload. [Figure 4] FIG. 4 shows the synthetic chemistry schemes for the linker-payload, cyclodextrin-based linker-payload, PEG4-taurine-based linker-payload, and maltose-based linker-payload. [Figure 5] FIG. 5 shows the synthetic chemistry schemes for the linker-payload, cyclodextrin-based linker-payload, PEG4-taurine-based linker-payload, and maltose-based linker-payload. [Figure 6]FIG. 6 shows the synthetic chemistry schemes for the linker-payload, cyclodextrin-based linker-payload, PEG4-taurine-based linker-payload, and maltose-based linker-payload. [Figure 7] FIG. 7 shows the synthetic chemistry schemes for the linker-payload, cyclodextrin-based linker-payload, PEG4-taurine-based linker-payload, and maltose-based linker-payload. [Figure 8] FIG. 8 shows the synthetic chemistry schemes for the linker-payload, cyclodextrin-based linker-payload, PEG4-taurine-based linker-payload, and maltose-based linker-payload. [Figure 9] FIG. 9 shows the synthetic chemistry schemes for linker-payload, cyclodextrin-based linker-payload, PEG4-taurine-based linker-payload, and maltose-based linker-payload.

[0017] [Figure 10] FIG. 10 shows the synthetic chemical schemes for cyclodextrin-azide, azide-PEG4-taurine, and maltose-azide. [Figure 11] FIG. 11 shows the synthetic chemical schemes for cyclodextrin-azide, azide-PEG4-taurine, and maltose-azide. [Figure 12] FIG. 12 shows the synthetic chemical schemes for cyclodextrin-azide, azide-PEG4-taurine, and maltose-azide.

[0018] [Figure 13] FIG. 13 shows an EC50 plot of activation of cholesterol efflux by anti-MSR1 ADCs with P2 payloads. DETAILED DESCRIPTION OF THE INVENTION

[0019] DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS Provided herein are compounds or payloads, linker-payload, antibody-drug Conjugates, compositions, and subjects may be used to treat, for example, dyslipidemia, metabolic disorders, inflammation, Or a method useful for treating a neurodegenerative disease.

[0020] Unless otherwise defined, all technical and scientific terms used herein refer to the The terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. When used, the term "about" is used in reference to a specific stated numerical value. means that the value may differ from the stated value by 1% or less. When used in the present specification, the expression "about 100" includes values ​​between 99 and 101 and all values ​​therebetween (e.g., , 99.1, 99.2, 99.3, 99.4, etc.).

[0021] Any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. Although various methods and materials can be used in the present study, preferred methods and materials are now described. All patents, applications, and non-patent publications mentioned in this document are hereby fully incorporated by reference. be absorbed.

[0022] (definition) The compounds or payloads provided herein, linker-payload (LP), or antigen When referring to a drug-drug conjugate, the following terms have the following meanings unless otherwise indicated: Unless otherwise defined, all technical and scientific terms used herein are , have the same meaning as commonly understood by one of ordinary skill in the art. In the event that there is a plurality of definitions for , those definitions prevail unless stated otherwise. .

[0023] As used herein, "alkyl" refers to a monovalent saturated hydrocarbon radical moiety. Alkyl is optionally substituted and may be linear, branched, or cyclic, i.e., cycloalkenyl. Alkyl may be a radical having 1 to 20 carbon atoms, i.e., C, C 1-20 Alkyl; a radical having 1 to 12 carbon atoms, i.e., C 1-12 Alkyl; 1~ Radicals with 8 carbon atoms, i.e., C 1-8 Alkyl; alkyl having 1 to 6 carbon atoms Dical, i.e., C 1-6 alkyl; and radicals having 1 to 3 carbon atoms, i.e., C 1-3 Examples of alkyl moieties include, but are not limited to, methyl ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, i-butyl, pentyl The cyclopropyl, cyclobutyl, cyclohexyl moieties and their structural isomers are Examples include, but are not limited to, cyclopentyl, and cyclohexyl.

[0024] As used herein, "structural isomers" are isomers that have the same molecular formula but differ in the arrangement of atoms. Structural isomers refer to compounds that have different chemical structures due to the way they are synthesized. Exemplary structural isomers include: n-Propyl and isopropyl; n-butyl, sec-butyl, and tert-butyl; and n-butyl Examples include pentyl, isopentyl, and neopentyl.

[0025] As used herein, "alkylene" refers to a divalent alkyl group. Unless otherwise specified, alkylene includes, but is not limited to, 1 to 20 carbon atoms. The olefin group is optionally substituted as described herein for alkyl. In some embodiments, the alkylene is unsubstituted.

[0026] As used herein, the term "O-amino acid" or "HO-amino acid" refers to an amino acid. The amino acid or the natural amino group at the N-terminus of the amino acid sequence is converted to an oxygen or a hydroxyl group, respectively. represents the amino acid that has been replaced. For example, "O-AAAA" or "HO-AAAA" represents the amino acid The sequence (AAAA) in which the N-terminal natural amino group is replaced with an oxygen or a hydroxyl group, respectively. replaced (e.g., [ka] where each R is intended to represent an amino acid side chain. The terms "acid residue" or "HO-amino acid residue" refer to the chemical moiety in a compound that remains after a chemical reaction. For example, "O-amino acid residue" or "HO-amino acid residue" refers to an O-amino acid or HO- Amide or peptide coupling of amino acids with suitable coupling partners where, for example, a water molecule is present in the amino acid of the O-amino acid or the HO-amino acid. After peptide coupling, the O-amino acid residue or the HO- A product is generated into which the amino acid residue is incorporated.

[0027] The designation of an amino acid or amino acid residue without specifying its stereochemistry refers to the L-form of that amino acid, the D-form or a racemic mixture thereof.

[0028] As used herein, "haloalkyl" refers to an alkyl group as defined above. wherein the alkyl is a halogen, such as fluorine (F), chlorine (Cl), bromine (Br), or iodine. haloalkyl refers to said alkyl containing at least one substituent selected from iodine(I). Examples of alkyl groups include, but are not limited to, -CF3, -CH2CF3, -CCl2F, and -CCl3. do not have.

[0029] As used herein, "alkenyl" refers to an alkyl group having at least two carbon atoms and one or more alkyl groups. Alkenyl refers to a monovalent hydrocarbon radical moiety containing a non-aromatic carbon-carbon double bond. is optionally substituted and can be linear, branched, or cyclic. The radicals are those with 2 to 20 carbon atoms, i.e., C 2-20 Alkenyl; 2 to 12 carbon atoms Radicals with elementary atoms, i.e., C 2-12 Alkenyl; Radicals containing 2 to 8 carbon atoms le, i.e., C 2-8 Alkenyl; a radical having 2 to 6 carbon atoms, i.e., C 2-6 a alkenyl; and radicals having 2 to 4 carbon atoms, i.e., C 2-4 Alkenyl is an example. Examples of alkenyl moieties include, but are not limited to, vinyl, propenyl, butyl, and butyl. Examples include, but are not limited to, thenyl and cyclohexenyl.

[0030] As used herein, "alkynyl" refers to a group having at least two carbon atoms and one or more alkyl groups. Alkynyl refers to a monovalent hydrocarbon radical moiety containing a carbon-carbon triple bond of any Alkynyl is substituted with, and can be linear, branched, or cyclic. Radicals with 2 to 20 carbon atoms, i.e., C 2-20 Alkynyl; 2 to 12 carbon atoms radicals, i.e., C 2-12 Alkynyl; a radical having 2 to 8 carbon atoms, i.e. Wachi, C 2-8 Alkynyl; a radical having 2 to 6 carbon atoms, i.e., C 2-6 Alkynyl; and radicals having 2 to 4 carbon atoms, i.e., C 2-4 Alkynyl is an example of this. Examples of alkynyl moieties include, but are not limited to, ethynyl, propynyl, and butynyl. Examples include, but are not limited to:

[0031] As used herein, "alkoxy" refers to a monovalent saturated hydrocarbon radical moiety. wherein the hydrocarbon contains a single bond to an oxygen atom and the radical is positioned on the oxygen atom. For example, ethoxy is CH3CH2-O·. An alkoxy substituent is The alkoxy is optionally bonded to the compound through this oxygen atom of the alkoxy substituent. It can be substituted and linear, branched, or cyclic, i.e., cycloalkoxy. The alkoxy includes those having 1 to 20 carbon atoms, i.e., C 1-20 Alcoki C; those having 1 to 12 carbon atoms, i.e., C 1-12 Alkoxy; 1 to 8 carbon atoms That is, 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 Alkoxy is an example. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, n-propyl, and propyl. propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, i-butoxy, pentoxy cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy (i.e., respectively [ka] ), but are not limited to these.

[0032] As used herein, "haloalkoxy" refers to an alkoxy group as defined above. alkoxy, wherein the alkoxy is at least one selected from halogen, for example, F, Cl, Br, or I. "alkoxy" refers to any of the above alkoxy groups containing at least one substituent.

[0033] As used herein, "aryl" refers to an aromatic compound in which the ring atoms are carbon atoms. Aryl refers to a monovalent moiety that is a radical. Aryl is optionally substituted and may be monocyclic or polycyclic. The aryl moiety can be of the formula, for example, bicyclic or tricyclic. those with up to 20 ring carbon atoms, i.e., C 6-20 Aryl; having 6 to 15 ring carbon atoms That is, C 6-15 Aryl, 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, azulenyl, anthryl, phenanthryl, and pyridine Examples of suitable amines include, but are not limited to, renyl.

[0034] As used herein, "arylalkyl" refers to the radical of an alkyl compound. where the alkyl compound is substituted with an aromatic substituent, i.e., That is, the aromatic compound contains a single bond to an alkyl group, and the radical is bonded to the alkyl group. The arylalkyl group is linked to the chemical structure shown through the alkyl group. Arylalkyl has the structure, for example: [ka] where B is an aromatic moiety, e.g., phenyl. The aryl alkyl is optionally substituted, i.e., the aryl and / or alkyl group is and arylalkyl, which may be substituted as disclosed herein. Examples of arylalkyl include benzyl. These include, but are not limited to:

[0035] As used herein, "alkylaryl" is a radical of an aryl compound. where the aryl compound is substituted with alkyl substituents. That is, the aryl compound contains a single bond to an alkyl group, and the radical is The alkylaryl group is connected to the illustrated chemical structure via the aryl group. The alkylaryl is bonded to the structure, e.g. [ka] where B is an aromatic moiety, e.g., phenyl. The aryl is optionally substituted, i.e., the aryl and / or alkyl groups are Examples of alkylaryl include toluyl, methyl ... These include, but are not limited to:

[0036] As used herein, "aryloxy" refers to an aryl group in which the ring atoms are carbon atoms and the A monovalent moiety that is a radical of an aromatic compound in which the ring is substituted with an oxygen radical. That is, the aromatic compound contains a single bond to an oxygen atom and the radical is attached to the oxygen atom. For example, in the case of phenoxy, [ka] The aryloxy substituent is bonded to the compound it substitutes through this oxygen atom. The aryloxy is optionally substituted. The aryloxy is preferably a substituted aryl having 6 to 20 carbon atoms. Radicals with ring carbon atoms, i.e., C 6-20 Aryloxy; 6 to 15 ring carbon atoms What has, i.e., C 6-15 aryloxy and those having 6 to 10 ring carbon atoms; That is, C 6-10 Examples include, but are not limited to, aryloxy. Examples of aryl moieties include phenoxy, naphthoxy, and anthroxy. Not limited to:

[0037] As used herein, "R a R b "N-aryloxy" means that the ring atoms are carbon atoms, and the ring is at least one R a R b substituted with an N-substituent and at least one oxygen radical refers to a monovalent moiety that is a radical of an aromatic compound that is a R b It contains a single bond to the N-substituent and a single bond to the oxygen atom, and the radical is Located, for example, [ka] R a R b N-aryloxy substituents are substituted by oxygen atoms that bind to the compound they substitute. Combine. Ra R b N-aryloxy is optionally substituted. a R b N-aryloxy For example, those having 6 to 20 ring carbon atoms, such as C 6-20 (R a R b N) nn -aryloxy, 6 those with up to 15 ring carbon atoms, e.g., C 6-15 (R a R b N) nn -aryloxy, and 6-10 having ring carbon atoms, e.g., C 6-10 (R a R b N) nn -aryloxy (wherein nn is R a R b N- represents the number of substituents), but is not limited to these. a R b N-aryloxy Examples of the aryl moiety include 4-(dimethylamino)-phenoxy, [ka] These include, but are not limited to:

[0038] As used herein, "arylene" refers to an aromatic ring in which the ring atoms are only carbon atoms. Arylene refers to a divalent moiety of an optionally substituted, monocyclic or polycyclic, e.g. For example, it can be a bicyclic or tricyclic ring. Examples of the arylene moiety include 6 to 20 having ring carbon atoms, i.e., C 6-20 Arylene; having 6 to 15 ring carbon atoms That is, C 6-15 arylene, and those having 6 to 10 ring carbon atoms, i.e. , C 6-10Examples include, but are not limited to, arylene.

[0039] As used herein, "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced by a heteroatom. As used herein, "heteroalkenyl" refers to an alkyl substituted by "Alkenyl" refers to an alkenyl in which one or more carbon atoms are replaced by a heteroatom. As used herein, "heteroalkynyl" refers to an alkyl group in which one or more carbon atoms are bonded to a heteroatom. Suitable heteroatoms include nitrogen, oxygen, and Heteroalkyl groups include, but are not limited to, sulfur atoms. Examples of heteroalkyl moieties include aminoalkyl, sulfonylalkyl, and sulfonylalkyl. Examples of heteroalkyl moieties include, but are not limited to, phenylalanyl. Examples include methylamino, methylsulfonyl, and methylsulfinyl. As used herein, "heteroalkylene," "heteroalk ... "Heteroalkynylene" and "heteroalkynylene" are heteroalkyl and heteroalkynylene, respectively. Heteroalkynyl is a divalent form of alkyl, alkynyl, and heteroalkynyl.

[0040] As used herein, "heteroaryl" refers to a group of ring atoms in which the ring atoms are carbon atoms and at least one heteroaryl. A monovalent radical of an aromatic compound containing one oxygen, sulfur, nitrogen, or phosphorus atom Examples of heteroaryl moieties include those having 5 to 20 ring atoms; 5 to 15 ring atoms; and Examples include, but are not limited to, those having 5 to 10 ring atoms. is optionally substituted.

[0041] As used herein, "heteroarylene" refers to a heteroaryl group in which one or more ring atoms of the aromatic ring are substituted or unsubstituted. Heteroarylene refers to an arylene substituted with a hydrogen, sulfur, nitrogen, or phosphorus atom. , optionally substituted.

[0042] As used herein, "heterocycloalkyl" refers to a group in which one or more carbon atoms are heterocyclic. The preferred heteroatoms are nitrogen and cycloalkyl. Heterocycloalkyl includes, but is not limited to, , oxygen, and sulfur atoms. , optionally substituted. Heterocycloalkyl is optionally substituted. Examples of alkyl moieties include morpholinyl, piperidinyl, tetrahydropyranyl, pyridinyl, and pyridinyl. rolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, dioxolanyl, Examples include, but are not limited to, dithiolanyl, oxanyl, or thianyl.

[0043] As used herein, a "Lewis acid" is a molecule or ion that accepts a lone pair of electrons. The Lewis acids used in the methods described herein are other than protons. Lewis acids include non-metallic acids, metallic acids, hard Lewis acids, and soft Lewis acids. Lewis acids include, but are not limited to, aluminum, boron, iron, tin, and titanium. Tungsten, magnesium, copper, antimony, phosphorus, silver, ytterbium, scandium, nickel Exemplary Lewis acids include, but are not limited to, Lewis acids of zinc, zinc ions, and zinc. Examples include AlBr3, AlCl3, BCl3, boron trichloride methyl sulfide, BF3, boron trifluoride methyl 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, CuB r2, zinc chloride, alkylaluminum halide (R n AlX 3-n wherein R is a hydrocarbyl Zn(OTf)2, ZnCl2, Yb(OTf)3, Sc(OTf)3, MgBr2, NiCl2, Sn(OTf)2, Ni(OTf)2 and Mg(OTf)2.

[0044] As used herein, "N-containing heterocycloalkyl" refers to an N-containing heterocycloalkyl group in which one or more carbon atoms are heterocyclic. substituted by heteroatoms, and at least one heteroatom is a nitrogen atom; Suitable heteroatoms other than nitrogen include oxygen and sulfur atoms. Examples include, but are not limited to, N-containing heterocycloalkyls, which are optionally substituted. Examples of N-containing heterocycloalkyl moieties include morpholinyl, piperidinyl, and pyrrolidinyl. Examples of the alkyl groups include aryl, imidazolidinyl, oxazolidinyl, and thiazolidinyl. Not limited to.

[0045] As used herein, "O-glucose" refers to a glucose molecule attached via the exocyclic glucose oxygen atom. Suitable O-glucose moieties include, but are not limited to: [ka] These include:

[0046] As used herein, "O-PEG" n1 " is a monovalent atom attached via a terminal oxygen atom where n1 is 1 to 100. For example, when n1 is 1, O-PEG n1 -O -CH2CH2OH; when n1 is 2, O-PEG n1 is -O-CH2CH2O-CH2CH2OH; n1 is 3 If O-PEG n1 is —O—CH2CH2O—CH2CH2O—CH2CH2OH.

[0047] As used herein, the term "optionally substituted" is used to describe a radical moiety. For example, optionally substituted alkyl means that such moiety is optionally substituted with one or more substituents. Examples of such substituents include halo, cyano, nitro, and the like. b) optionally substituted haloalkyl, azido, epoxy, optionally substituted heteroaryl cycloalkyl, optionally substituted heterocycloalkyl, [ka] (In the formula, R A , R B , and R C independently at each occurrence, represent a hydrogen atom, an alkyl, an alkenyl, an alkynyl , aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, or R A and R B are the atoms to which they are bonded. together form a saturated or unsaturated carbocyclic ring, which ring is optionally substituted and one or more ring atoms are optionally substituted with a heteroatom), In some embodiments, the radical moiety is not limited to an optionally substituted heteroaryl. alkyl, optionally substituted heterocycloalkyl, or optionally substituted saturated or unsaturated alkyl. When the optionally substituted carbocyclic ring is an optionally substituted heteroaryl, the optionally substituted heteroaryl is substituted heterocycloalkyl, or optionally substituted saturated or unsaturated carbocyclic The substituents, when substituted, are optionally further substituted with further substituents. In some embodiments, the hydroxyl groups described herein are not substituted with any substituent. When a group is optionally substituted, the substituents attached to that group may be any group, unless otherwise specified. , unsubstituted.

[0048] As used herein, "acyl" means [ka] (In the formula, R A is alkyl or optionally substituted alkyl Also, as used herein, "optionally substituted acyl" refers to R A But, optional This refers to the case where the .

[0049] As used herein, a "binding agent" refers to a molecule that specifically binds to a given binding partner, e.g., an antigen. It refers to any molecule, such as a protein, that is capable of isomeric bonding.

[0050] As used herein, a "linker" refers to a linker that connects a binder to one or more of the molecules described herein. Bivalent groups covalently linked to the compounds above, e.g., payload compounds and enhancers. , trivalent, or multivalent moieties.

[0051] As used herein, "amide synthesis conditions" refers to, for example, carboxylic acids, activated carboxylic acids, to achieve amide formation by reaction of carboxylic acids or acyl halides with amines. In some instances, amide synthesis conditions refer to suitable reaction conditions for the reaction of a carboxylic acid with an amine. Some of these examples refer to reaction conditions suitable for achieving the formation of an amide bond between In this method, the carboxylic acid is first converted to an activated carboxylic acid, and then the activated carboxylic acid is reacted with the activated carboxylic acid. The carboxylic acid reacts with the amine to form an amide. Suitable conditions for achieving amide formation are: Examples include, but are not limited to, dicyclohexylcarbodiimide (DCC), diisopropyl Carbodiimide (DIC), (benzotriazol-1-yloxy)tris(dimethylamino)phos Benzonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy) tripitrium Lolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazole -1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), Mototripyrrolidinophosphonium hexafluorophosphate (PyBrOP), O-(benzotriazol-2-yl) (1-isopropyl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU ), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoride TBTU, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pi Lysinium 3-oxide hexafluorophosphate (HATU), N-ethoxycarbonyl-2- Ethoxy-1,2-dihydroquinoline (EEDQ), N-ethyl-N'-(3-dimethylaminopropyl) carbamazepine 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (EDC) phosphate (CIP), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), and carbonyldiimide Utilizing reagents to effect the reaction of carboxylic acids with amines, including tetrahydrofuran (CDI), In some examples, the carboxylic acid is first , converted to an activated carboxylic acid ester, and then reacted with an amine to form the activated carboxylic acid ester. In some embodiments, the carboxylic acid is treated with a reagent to form an amide bond. The reagent deprotonates the carboxylic acid, and then the deprotonated carboxylic acid is As a result of nucleophilic attack on the protonated reagent by The carboxylic acid is activated by forming a product complex with the acid. Activation of carboxylic acids The carboxylic acid ester is more soluble in amines than before the carboxylic acid is activated. This results in amide bond formation. Thus, the carboxylic acid is said to be activated. Exemplary reagents include DCC and DIC. Examples include:

[0052] As used herein, "positional isomer," "positional isomers," or "positional isomers" refers to a group of isomers that are heterocyclic or heterocyclic. A "mixture of isomers" can be obtained by treating an appropriate azide (e.g., -N3, or PE) with an appropriate alkyne. 1,3-cycloaddition or strain-promoted alkyne-azide cycloaddition (S-G-N3 derivatized antibody) derived from In one embodiment, the term "PAAC" refers to the product of a click reaction. For example, positional isomers and mixtures of positional isomers can be synthesized by the click reaction products shown below. It is characterized by: [ka] In some embodiments, two or more suitable azides and two or more suitable alkynes are combined in a azide-based Each pair of do-alkynes participates in one or more independent click reactions to form regioisomeric clicks. Utilized within a synthetic scheme en route to a product that can give rise to a mixture of reaction products For example, one skilled in the art can independently catalyze the first suitable azide on the way to the product. and a second suitable azide can react independently with a second suitable alkyne. There are four possible Click reaction regioisomers that can be reacted and are included in the samples of ADCs described herein: or the production of a mixture of the four possible click reaction regioisomers. As a further example, one skilled in the art may independently select a first suitable azide on the way to the product. and a suitable azide can be reacted with a first suitable alkyne and a second suitable azide can be reacted with a second suitable azide independently. There are four possible click reaction sites in the samples of LP described herein that can react with alkynes. It is recognized that this results in the production of a mixture of isomers, or the four possible click reaction regioisomers. You will be aware of this.

[0053] As used herein, the term "residue" refers to a chemical residue in a compound that remains after a chemical reaction. For example, the term "amino acid residue" or "N-alkyl amino acid residue" The amide coupling of an amino acid or N-alkyl amino acid to a suitable coupling partner is carried out. refers to the product of coupling or peptide coupling; After peptide coupling of the amino acid amide, for example, a water molecule is expelled to form the amide. This results in a product having an N-acid residue or an N-alkyl amino acid residue incorporated therein.

[0054] As used herein, a "therapeutically effective amount" refers to a dose or amount of a compound administered in the treatment or management of a disease or disorder. sufficient to provide a therapeutic benefit to the patient or to suppress one or more symptoms associated with the disease or disorder an amount sufficient to delay or minimize the effects of the compound or payload This refers to something.

[0055] Certain groups, moieties, substituents, and atoms are depicted with wavy lines intersecting the bond(s). and indicates the atom through which the group, moiety, substituent, or atom is bonded. For example: [ka] A phenyl group substituted with a propyl group, depicted as, has the following structure: [ka] As used herein, a cyclic group (e.g., aromatic, heterocyclic, etc.) is formed through a bond between the ring atoms. (aromatic, fused ring, and saturated or unsaturated cycloalkyl or heterocycloalkyl) Diagrams showing bonded substituents are not intended to be limiting unless otherwise specified, and are not intended to be limiting unless otherwise specified. According to techniques known in the art to which the disclosure pertains, the cyclic group may be selected from any of the cyclic groups or fused ring groups. is meant to indicate that the substituent may be substituted at any ring position on any ring. For example, the following group [ka] (wherein the subscript q is an integer from 0 to 4, and the substituent R 1 The location of , i.e., directly bonded to any vertex of the bond line structure, i.e., to a specific ring carbon atom. (not shown) is the substituent R 1 The following non-limiting examples of groups are attached to specific ring carbon atoms: include [ka] .

[0056] As used herein, the phrase "reactive linker" or the abbreviation "RL" refers to, e.g., For example, [ka] where RG is a reactive group and SP is a spacer group. The term "reactive group" refers to a monovalent group comprising a reactive group and a spacer group, as depicted in the figure. The reactive linker may contain two or more reactive groups and two or more spacer groups. A sir group is any divalent moiety that crosslinks the reactive group to another group, such as a payload. The reactive linker (RL), together with the payload to which it is attached, is described herein. Intermediates useful as synthetic precursors for the preparation of antibody conjugates ("linker-payload"). The reactive linker provides a linker to another group, e.g., an antibody, a modified antibody, or A functional group or functional site that can react with the reactive portion of an antigen-binding fragment or enhancing group. The antibody, modified antibody, or antigen-binding fragment thereof contains a reactive group ("RG") that reacts with the reactive group. The resulting moiety, together with the linking group, constitutes the "binding agent phosphorus" of the conjugates described herein. In one embodiment, the "reactive group" comprises a carboxyl group ("BL") moiety. A functional group or moiety (e.g., maleimide) that reacts with a cysteine ​​or lysine residue of the binding fragment. In one embodiment, the "reaction A "reactive group" is a functional group or moiety that can undergo a click chemistry reaction. (See, e.g., click chemistry, Huisgen, Proc. Chem. Soc. 1999). 61, Wang et al., J. Am. Chem. Soc. 2003, and Agard et al., J. Am. Chem. Soc. 2004 In some embodiments of the click chemistry reaction, the reactivity The group is an alkyne that can undergo a 1,3-cycloaddition reaction with an azide. Suitable reactive groups include strained alkynes, e.g., strain-promoted alkyne-azide cycloaddition (SPAAC) Suitable for the above, cycloalkynes, e.g., cyclooctyne, aromatic alkynes (benzannul ated alkyne), and an aryl group capable of 1,3-cycloaddition with alkynes in the absence of a copper catalyst. Suitable alkynes include, but are not limited to, dibenzoaza Cyclooctyne or [ka] Dibenzocyclooctyne or [ka] Biarylazacyclooctynone or [ka] Difluorinated cyclooctyne or [ka] Substituted alkynes, e.g., fluorinated alkynes, aza-cycloalkynes, bicycles [6. 1.0] Nonin or [ka] (BCN (wherein R is alkyl, alkoxy, or acyl) and derivatives thereof are also included. Particularly useful alkynes include, but are not limited to: [ka] Such a linker-payload containing a reactive group may be functionalized with an azide group. Such functionalized antibodies are useful for conjugating azido-poly(2-hydroxybenzoates) to antibodies. In some embodiments, such antibodies are functionalized with ethylene glycol groups. Such functionalized antibodies are synthesized by cleaving at least one glutamine in the presence of the enzyme transglutaminase. An antibody having a residue, for example, Gln295 in the heavy chain, is treated with a compound having an amino group and an azide group. It is induced by

[0057] In some instances, the reactive group is an alkyne, e.g., [ka] which can be converted by click chemistry to azides, e.g. [ka] to produce a click chemistry product, e.g., [ka] In some instances, the group can form a modified antibody or antigen-binding fragment thereof. In some instances, the reactive group is an alkyne, e.g., [ka] which can be converted by click chemistry to azides, e.g. [ka] to produce a click chemistry product, e.g., [ka] In some instances, the reactive group can be an alkyne, e.g., [ka] which can be converted by click chemistry to azides, e.g. [ka] to produce a click chemistry product, e.g., [ka] In some instances, the reactive group can be a functional group, such as [ka] which reacts with and binds to cysteine ​​residues on an antibody or antigen-binding fragment thereof. For example, [ka] (wherein Ab represents an antibody or an antigen-binding fragment thereof, and S represents the group through which the functional group binds to Ab.) (Indicates the S atom on the corresponding cysteine ​​residue) In some instances, the reactive group is a functional group, such as [ka] which reacts with and binds to lysine residues on an antibody or antigen-binding fragment thereof; for example, [ka] (wherein Ab represents an antibody or an antigen-binding fragment thereof, and NH represents the functional group via which the Ab binds.) (The NH atom on the corresponding lysine side chain residue is shown.) Form.

[0058] As used herein, the phrase "biodegradable moiety" refers to a moiety that degrades in vivo, typically non-toxic, biocompatible components that can be removed from the body by biological processes In certain embodiments, the biodegradable portion is a portion that remains biodegradable for about 90 days or less, about 60 days or less, or is completely or substantially degraded in vivo in about 30 days or less, wherein the extent of degradation is determined by the Based on percent mass loss of degradable sites, and complete degradation is 100% mass loss. Exemplary biodegradable moieties include, but are not limited to, poly(ε-caproic acid). rolactone) (PCL), poly(3-hydroxybutyrate) (PHB), poly(glycolic acid) (PGA), poly( Lactic acid) (PLA) and its copolymer with glycolic acid (i.e., poly(D,L-lactide-co-glycol) and aliphatic polyesters such as polypropylene glycol arsenate (PLGA) (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 Shakesh Eff KM, (1999) Chemical Reviews 99(11):3181-3198; and Park TG, (199 5) Biomaterials 16(15):1123-1130 (each of which is incorporated herein by reference in its entirety). It is built into

[0059] As used herein, an "effective amount," "physiologically effective amount," or "prophylactically effective amount" The phrase "is a compound that, when administered to a subject in need of treatment, is effective in effecting such treatment" means A "physiologically effective amount" of an active agent refers to an amount of a compound sufficient to provide a physiologically effective dose of the active agent to a patient. It refers to an efficacious amount that has a significant externally observable effect. A physiologically effective amount is a dose that can be measured in a patient without the need for special equipment to measure the effect. For example, the present invention may affect one or more of the characteristics (e.g., phenotype) of a gene disclosed herein. A physiologically effective amount of a compound administered is one that reduces one or more of the symptoms of the condition being treated. Thus, the active ingredient has a significant externally observable effect on patient behavior. and monitoring the patient to determine whether an effective amount of the active ingredient is being administered and whether the active ingredient is being administered to the patient. This can be determined by observing whether changes caused by the substance have occurred. do.

[0060] As used herein, the phrase "binder linker" or "BL" refers to a binder (e.g., For example, an antibody or antigen-binding fragment thereof) can be coupled to a payload compound (e.g., a bis(amino acid) or a bis(amino acid)) described herein. -octahydrophenanthrenecarboxamide) and, optionally, one or more side chain compounds It refers to any divalent, trivalent, or polyvalent group or moiety that bonds, connects, or joins. Suitable binder linkers for the antibody conjugates described herein are those that increase the circulating half-life of the antibody. and at the same time, the conjugate is stable enough to utilize the antigen-mediated internalization of the conjugate. It is capable of releasing its payload after antigen-mediated internalization. The linker may be cleavable or non-cleavable. The linker may be cleaved by intracellular metabolism after internalization, e.g., by hydrolysis, reduction, or enzymatic reaction. A non-cleavable linker is a linker that is cleaved by cleavage. It is a linker that releases the attached payload upon lysosomal degradation of the Suitable linkers include acid-labile linkers, hydrolytically unstable linkers, and enzymatically cleavable linkers. Cleavable, reduction-labile, self-immolative, and non-cleavable linkers Suitable linkers include, but are not limited to, peptides, glycosaminoglycans, and the like. Ronide, succinimide-thioether, polyethylene glycol (PEG) unit, hydrazone , mal-caproyl unit, dipeptide unit, valine-citrulline unit, and para-aminobenzyl (PAB) units or containing them, In one embodiment, the binder linker (BL) is a reactive linker (RL). The reactive group (RG) and the reactive portion of the binding agent, e.g., an antibody, modified antibody, or antigen-binding fragment thereof, Includes sites formed by the reaction.

[0061] In some examples, the BL comprises the following site: [ka] (In the formula, [ka] is the bond to the binding agent), or triazolyl positional isomers. BL is the following parts: [ka] (In the formula, [ka] is the bond to the binding agent) In some examples, the BL comprises the following moiety: [ka] (In the formula, [ka] is the bond to the binding agent), or triazolyl positional isomers. In this case, BL is the following part: [ka] (In the formula, [ka] In some examples, the cysteine ​​bond is a bond to a cysteine ​​of an antibody or antigen-binding fragment thereof. BL is the following part: [ka] (In the formula, [ka] is the attachment to a lysine of the antibody or antigen-binding fragment thereof).

[0062] (compound or payload) In certain embodiments, described herein is a compound having the structure of Formula (I): or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof: [ka] (In the formula, Q 1 and Q 2 each is independently —CH—, —C(O)—, —C(H)(OH)—, or —C(OH)—; W is -CH2-, -N(H)-, or -O-; R 1is -N(H)R 4 or -N(R 5 )2; R 2 is -N(H)R 4 and; Each R 4 is in each case independently hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, group, biodegradable moiety, alkyl, substituted alkyl, acyl, or substituted acyl; R 5 is alkyl, aryl, arylalkyl, heterocycloalkyl, or substituted heterocyclic alkyl. wherein each heterocycloalkyl or substituted heterocycloalkyl The alkyl group contains 1, 2, or 3 heteroatoms selected from nitrogen and oxygen and is substituted. If present, at least one of -OH and -CH2OH, or at least one primary or secondary Contains nitrogen; and Each R 6 are independently halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O-amino O-PEG or O-acid residue n1 (wherein each n is an integer from 0 to 14, and each n1 is an integer from 1 to 12) is an integer).

[0063] In one embodiment of Formula I, Q 1 is -CH2- and Q 2 is -C(O)- and W is -CH2- In one embodiment of Formula I, Q 1 is -CH2- and Q 2 is -C(O)- and W is In one embodiment of formula I, Q 1 is -CH2- and Q 2 is -C(O)-, or and W is -NH-. In any of the embodiments of this paragraph, R 1 is -N(H)R4 or -N(R 5 )2 and R 2 is -N(H)R 4 In any of the embodiments of this paragraph, R 1 is -N(H) R 4 and R 2 is -N(H)R 4 In any of the embodiments of this paragraph, R 1 is -N( R 5 )2 and R 2 is -N(H)R 4 In any of the embodiments of this paragraph, each R 4 teeth , independently in each case, hydrogen, amino acid residue, N-alkyl amino acid residue, peptide residue, biosynthetic The degradable moiety is alkyl, substituted alkyl, acyl, or substituted acyl. In either of the above, each R 4 is independently in each occurrence hydrogen, an amino acid residue, an N-alkylamino Any of the embodiments of this paragraph may be an acid residue, a peptide residue, a biodegradable moiety, or an alkyl. In each R 4 is hydrogen. In any of the embodiments of this paragraph, each R 4 is at each venue In any of the embodiments of this paragraph, each R 4 is at each venue and independently in each case, an N-alkyl amino acid residue. R 4 is, independently in each occurrence, a peptide residue. In any of the embodiments of this paragraph, each R 4 is, independently in each occurrence, a biodegradable moiety. In any of the embodiments of this paragraph, each R 4 is, independently in each occurrence, alkyl. In any of the embodiments of this paragraph, each R 4 teeth and, independently in each occurrence, substituted alkyl. In any of the embodiments of this paragraph, each R 4 teeth and, independently in each occurrence, acyl. In any of the embodiments of this paragraph, each R 4 is at each venue and independently when R 4 is hydrogen Yes, and the other R 4 is an amino acid residue. R 4 is hydrogen and the other R 4 is a peptide residue. And one R 4 is hydrogen and the other R 4 is substituted alkyl. In one embodiment, one R 4 is hydrogen and the other R 4 is acyl. In any embodiment, one R 4 is hydrogen and the other R 4 is a substituted acyl In any of the embodiments of this paragraph, R 5 is alkyl, aryl, arylalkyl , heterocycloalkyl, or substituted heterocycloalkyl, wherein each heterocyclo The heterocycloalkyl or substituted heterocycloalkyl is 1, 2, or 3 selected from nitrogen and oxygen. heteroatoms and, if substituted, at least one of -OH and -CHOH, or at least one primary or secondary nitrogen. Te, R 5 is alkyl. In any of the embodiments of this paragraph, R 5 is an aryl In any of the embodiments of this paragraph, R 5 is arylalkyl. In any of the embodiments, R 5 is heterocycloalkyl. In either case, R 5 is a substituted heterocycloalkyl. In R 5 is heterocycloalkyl, which is a heterocycloalkyl group containing nitrogen and oxygen In any of the embodiments of this paragraph, R 5 teeth, Heterocycloalkyl, where the heterocycloalkyl contains one nitrogen. In any of the embodiments, R 5 is heterocycloalkyl, In any of the embodiments of this paragraph, R 5 is a heterocycloalkenyl group Heterocycloalkyl is a group containing two heteroatoms selected from nitrogen and oxygen. In any of the embodiments of this paragraph, R 5 is heterocycloalkyl, In any of the embodiments of this paragraph, R 5 is a heterocycloalkyl, which contains two oxygen atoms. In any of the embodiments of the paragraph, R 5 is heterocycloalkyl, Alkyl contains one nitrogen and one oxygen. In any of the embodiments of this paragraph, R 5 is heterocycloalkyl, wherein heterocycloalkyl is selected from nitrogen and oxygen; In any of the embodiments of this paragraph, R 5 is a heterocyclo The heterocycloalkyl contains three nitrogen atoms. In either case, R 5 is a heterocycloalkyl, and a heterocycloalkyl is a and one oxygen atom. In any of the embodiments of this paragraph, R 5 is placed substituted heterocycloalkyl and containing one heteroatom selected from nitrogen and oxygen; In any of the embodiments of this paragraph, R 5 is a substituted heterocycloalkyl, In any of the embodiments of this paragraph, R 5 is a substituted heterocyclo In any of the embodiments of this paragraph, R 5 is placed substituted heterocycloalkyl and containing two heteroatoms selected from nitrogen and oxygen; In any of the embodiments of this paragraph, R 5 is a substituted heterocycloalkyl, In any of the embodiments of this paragraph, R 5 is a substituted heterocyclic In any of the embodiments of this paragraph, R 5 is a substituted heterocycloalkyl and contains one nitrogen and one oxygen. In any of the embodiments, R 5 is a substituted heterocycloalkyl and is selected from nitrogen and oxygen In any of the embodiments of this paragraph, R 5 teeth, substituted heterocycloalkyl and contains three nitrogen atoms. In either case, R 5 is a substituted heterocycloalkyl and has two nitrogen atoms and one acid In any of the embodiments of this paragraph, R 5 is a substituted heterocycloalkyl and contains one heteroatom selected from nitrogen and oxygen as described above, and at least In any of the embodiments of this paragraph, R 5 is replaced Heterocycloalkyl and having two heteroatoms selected from nitrogen and oxygen as described above. Any of the embodiments of this paragraph contains a 2 atom and at least one of —OH and —CHOH. In R 5 is a substituted heterocycloalkyl and is selected from nitrogen and oxygen as described above. This paragraph contains three selected heteroatoms and at least one of -OH and -CHOH. In any of the embodiments, R 5 is a substituted heterocycloalkyl and is as defined above and at least one primary nitrogen atom, In any of the embodiments of this paragraph, R 5 is a substituted heterocycloalkyl and as defined above, contains two heteroatoms selected from nitrogen and oxygen, and at least In any of the embodiments of this paragraph, R 5 is a substituted heterocyclic and contains three heteroatoms selected from nitrogen and oxygen as defined above. and contains at least one primary nitrogen. In any of the embodiments of this paragraph, R 5 teeth , substituted heterocycloalkyl, and one nitrogen atom selected from nitrogen and oxygen as defined above; and at least one secondary nitrogen. In either case, R 5 is a substituted heterocycloalkyl and is selected from nitrogen and oxygen as described above. and at least one secondary nitrogen. In any of the embodiments, R 5 is a substituted heterocycloalkyl and is as defined above Contains three heteroatoms selected from nitrogen and oxygen and at least one secondary nitrogen. In any of the embodiments of this paragraph, each R 6 are independently halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O-amino acid residue, or O-PEG n1 (where each n is (n1 is an integer from 0 to 14, and each n1 is an integer from 1 to 12). In each R 6 is independently halo. In any of the embodiments of this paragraph, each R 6 teeth, Independently, C 1-6 In any of the embodiments of this paragraph, each R 6 are, independently, C 1-6 In any of the embodiments of this paragraph, each R 6 is -CN. In any of the embodiments of the paragraph, each R 6 are independently O-glucose. In any of the embodiments, each R 6 are independently O-amino acid residues. In the embodiment, each R 6 are independently O-PEG n1 (wherein each n1 is an integer from 1 to 12). In any embodiment of this paragraph, each R 6 are independently O-PEG n1 (wherein each n1 is 1) In any embodiment of this paragraph, each R 6 are independently O-PEG n1 (wherein each n1 is 2 In any embodiment of this paragraph, each R 6 are independently O-PEG n1 (In the formula, each n1 is 3). In any embodiment of this paragraph, each R 6 are independently O-PEG n1 (In the ceremony and each n1 is 4. In any embodiment of this paragraph, each R 6 are independently O-PEG n 1, wherein each n1 is 5. In any embodiment of this paragraph, each R 6 are, independently, O-PEG n1 wherein each n1 is 6. In any embodiment of this paragraph, each R 6 is German First, O-PEG n1 wherein each n1 is 7. In any embodiment of this paragraph, each R 6 are independently O-PEG n1 wherein each n1 is 8. In any embodiment of this paragraph, , each R 6 are independently O-PEG n1 wherein each n1 is 9. In each R 6 are independently O-PEG n1 where each n1 is 10. In the embodiment, each R 6 are independently O-PEG n1 (wherein each n1 is 11). In any embodiment, each R 6 are independently O-PEG n1 (wherein each n1 is 12). In any of the embodiments of this paragraph, each R 6 are independently halo, C 1-6 Alkyl, C 1-6 Al O-glucose, O-amino acid residue, or O-PEG n1 (where each n is between 0 and 1 4, and each n1 is an integer from 1 to 12), and any combination thereof. For example, in one embodiment, one R 6 is a halo and the other R 6 is C 1-6 Al As will be appreciated by those skilled in the art, another exemplary R 6 Combination embodiment of Any of the embodiments of this paragraph is contemplated. In the above, the amino acid residues are preferably combined as amino acids or peptide residues. Suitable amino acids to be used include alanine, Isoleucine, leucine, methionine, phenylalanine, tryptophan, tyrosine, Valine, serine, threonine, asparagine, glutamine, cysteine, selenocysteine glycine, proline, arginine, histidine, lysine, aspartic acid, and glutamic acid and thiamin, ... means that the amino acid residues can be achiral or chiral, e.g., L-amino acid residues or Those skilled in the art will recognize that the peptide residue may be a D-amino acid residue, e.g. For example, racemic DL-amino acids or non-racemic D- or L-amino acids and their diastereomeric forms. It will be recognized that the compounds may be achiral or chiral, including stereoisomeric mixtures. In any of the embodiments of this paragraph, suitable arylalkyl moieties include benzoyl, ... diethyl, phenethyl, phenylpropyl, α-methylbenzyl and their respective stereoisomers, and 2-phenylpropyl and its respective stereoisomers. In any of the embodiments of this paragraph, arylalkyl is benzyl. In any of the embodiments of this paragraph, arylalkyl is phenethyl. In any of the embodiments of this paragraph, arylalkyl is phenylpropyl. The alkyl group is α-methylbenzyl and its stereoisomers. In either case, arylalkyl is (R)-α-methylbenzyl. In any of the embodiments, arylalkyl is (S)-α-methylbenzyl. In any of the embodiments, arylalkyl is 2-phenylpropyl (i.e., C HCH(Ph)CH—) and each stereoisomer thereof. In any of the embodiments of this paragraph, arylalkyl is (R)-2-phenylpropyl. In any of the embodiments of this paragraph, arylalkyl is (S)-2-phenylpropyl. wherein halo is selected from the group consisting of fluoro, chloro, bromo, and iodo. In any of the embodiments of this paragraph, halo is fluoro. In any of the embodiments of this paragraph, halo is chloro. In any of the embodiments of this paragraph, halo is iodo. In any of the embodiments, C 1-6 Alkyl is methyl, ethyl, propyl, butyl, pentyl, and hexyl, and structural isomers thereof. In any of the embodiments, C 1-6 Alkyl is methyl or -CH3. In any of the embodiments, C 1-6 Alkyl is ethyl or -CH2CH3. In either case, C 1-6 Alkyl is propyl or a structural isomer thereof. In any of the embodiments, C 1-6 The alkyl is butyl or a structural isomer thereof. In any of the above embodiments, C 1-6 Alkyl is pentyl or a structural isomer thereof In any of the embodiments of this paragraph, C 1-6 Alkyl is hexyl or its structural isomer. In any of the embodiments of this paragraph, C 1-6 Alkoxy includes methoxy and ethoxy. , propyloxy, butyloxy, pentyloxy, and hexyloxy, and the structures thereof In any of the embodiments of this paragraph, C is selected from the group consisting of: 1-6 Archi In any of the embodiments of this paragraph, C is methoxy or —OCH3. 1-6 Alkyl is ethoxy or —OCH2CH3. In any of the embodiments of this paragraph, C 1-6 Alkyl is propyloxy or a structural isomer thereof. In any of the embodiments of this paragraph, C 1-6 Alkyl is butyloxy or a structural isomer thereof. In C 1-6 The alkyl is pentyloxy or a structural isomer thereof. In either case, C 1-6 The alkyl is hexyloxy or a structural isomer thereof.

[0064] In one embodiment of Formula I, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- and W is In one embodiment of Formula I, Q is —CH—. 1 is -C(H)(OH)- and Q 2 is -C(O)- and W is —O—. In one embodiment of Formula I, Q 1 is -C(H)(OH)- and Q 2 is -C( In any of the embodiments of this paragraph, R 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with Formula I.

[0065] In one embodiment of Formula I, Q 1 is -C(O)- and Q 2 is -C(O)- and W is -CH2 In one embodiment of formula I, Q 1 is -C(O)- and Q 2 is -C(O)- and W In one embodiment of Formula I, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is -NH-. In any of the embodiments of this paragraph, R 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with Formula I.

[0066] In one embodiment of Formula I, Q 1 is -C(O)- and Q 2 is -CH2- and W is -CH2- In one embodiment of Formula I, Q 1 is -C(O)- and Q 2 is -CH2- and W is In one embodiment of formula I, Q 1 is -C(O)- and Q 2 is -CH2-, or and W is -NH-. In any of the embodiments of this paragraph, R 1 , R 2 , R 4 , R 5 , and R 6 teeth , as described above in connection with Formula I.

[0067] In one embodiment of Formula I, Q 1 is -C(O)- and Q 2 is —C(H)(OH)— and W is In one embodiment of Formula I, Q is —CH—. 1 is -C(O)- and Q 2 is -C(H)(OH)- and W is —O—. In one embodiment of Formula I, Q 1 is -C(O)- and Q 2 is -C(H)(O In any of the embodiments of this paragraph, R 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with Formula I.

[0068] In certain embodiments, described herein also provides a compound having the structure of Formula (II): or a payload, or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof Is: [ka] In any of the embodiments of this paragraph, R 1 , R 2 , R 4 , R 5 , and R 6 In relation to Formula I As mentioned above.

[0069] In certain embodiments, described herein is a compound having the structure of Formula (III): or a payload, or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof It is: [ka] In any of the embodiments of this paragraph, R 1 , R 2 , R 4 , R 5 , and R 6 In relation to Formula I As mentioned above.

[0070] In some embodiments, those described herein include R 1 But -N(H)R 4 Formula I, Formula II or a compound or payload of Formula III. What can be done is R 1 But -N(R 5 )2 is a compound or payload of Formula I, Formula II, or Formula III In any of the embodiments of this paragraph, R 2 , R 4 , R 5 , and R 6 is in the context of formula I As stated above.

[0071] In some embodiments, those described herein include R 1 is -NH; and R 4 but, Amino acid residue, N-alkyl amino acid residue, peptide residue, biodegradable site, alkyl, substitution A compound or payload of Formula I, Formula II, or Formula III that is alkyl, acyl, or substituted acyl In one embodiment, described herein is R1 is -NH; and R 4 is an amino acid residue. In the manner described herein, R 1 is -NH; and R 4 However, N-alkyl In one embodiment, the compound or payload of Formula I, Formula II, or Formula III is an amino acid residue. In this specification, R 1 is -NH; and R 4 is a peptide residue In one embodiment, the compound or payload described herein is of Formula I, Formula II, or Formula III. The items listed are R 1 is -NH; and R 4 is a biodegradable moiety, In one embodiment, the compounds or payloads described herein are , R 1 is -NH; and R 4 is an alkyl group of the compound of formula I, formula II, or formula III or In one embodiment, described herein is R 1 is -NH2; And R 4 is a compound or payload of Formula I, Formula II, or Formula III, wherein is a substituted alkyl. In embodiments, those described herein include R 1 is -NH; and R 4 But Acyl In one embodiment, the compound or payload of the present invention is a compound or payload of Formula I, Formula II, or Formula III, Those described in the fine print are R 1 is -NH; and R 4 is a substituted acyl group of formula I, formula II, or is a compound or payload of formula III. In any of the embodiments of this paragraph, suitable The amino acid residues are as described above in connection with Formula I. Any of the embodiments of this paragraph wherein suitable peptide residues are as described above in connection with Formula I. In the present specification, R 1 is -NH; and R 4 But the amino acid residue and the amino acid residue is alanine, isoleucine, leucine, methionine, phenyl alanine, tryptophan, tyrosine, valine, serine, threonine, asparagine, Glutamine, cysteine, selenocysteine, glycine, proline, arginine, histidine a compound selected from the group consisting of gin, lysine, aspartic acid, and glutamic acid; In one embodiment, described herein is a payload. 1 But -NH2 Ri;katsu R 4 is a peptide residue, wherein the peptide residue is alanine, isoleucine, leucine, methionine, phenylalanine, tryptophan, tyrosine, valine, Phosphorus, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine arginine, proline, histidine, lysine, aspartic acid, and glutamic acid In accordance with the implementation of this paragraph, the compound or payload comprises an amino acid residue selected from the group consisting of: In any of the embodiments, R 6 is as described above in connection with Formula I.

[0072] In some embodiments, those described herein include R 1 and R 2 But -N(H)R 4 The In one embodiment, described herein is a compound or payload comprising R 1 and R 2 But -N(H)R 4 and R 4 is, independently in each occurrence, an amino acid residue; and The residues are alanine, isoleucine, leucine, methionine, phenylalanine, tryptophan, Fattening, tyrosine, valine, serine, threonine, asparagine, glutamine, cysteine Selenocysteine, glycine, proline, arginine, histidine, lysine, aspartate The compound or payload is selected from the group consisting of glutamic acid, glutamic acid, and glutamic acid.

[0073] In some embodiments, provided herein is a method for treating a psoriasis comprising administering to a subject a therapeutically effective amount of: [ka] a compound or payload selected from the group consisting of: TIFF2025138724000055.tif240170TIFF2025138724000056.tif233170TIFF2025138724000057.tif57170; or a pharmaceutically acceptable salt thereof It is often a solvate.

[0074] In one embodiment, provided herein is a compound having the structure: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0075] Further provided herein are: [ka] TIFF2025138724000060.tif110170.

[0076] (binder) Suitable binding agents for any of the conjugates provided in this disclosure include antibodies, lymphocytes, and the like. kine, hormone, growth factor, viral receptor, interleukin, or any other cellular These include, but are not limited to, binding or peptide-binding molecules or substances. stomach.

[0077] In certain embodiments, the binding agent is an antibody or an antigen-binding fragment thereof. Antibodies can be used in the art. The term "antibody" as used herein refers to an antibody that is capable of binding to a target molecule. At least one complementary molecule that specifically binds to or interacts with a particular antigen The term "antibody" refers to any antigen-binding molecule or molecular complex containing a CDR. The term refers to four amino acid sequences: two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Immunoglobulin molecules containing one polypeptide chain and multimers thereof (e.g., IgM) are included. Each heavy chain comprises a heavy chain variable region (referred to herein as HCVR or V H and heavy chain constant region. The constant region consists of three domains: C H 1. C H 2, and C H Each light chain comprises a light chain variable region ( In the details, LCVR or V L The light chain constant region comprises one domain (C L 1) V H and V L The regions are separated by more conserved regions called framework regions (FR). They can be further subdivided into interspersed hypervariable regions called complementarity-determining regions (CDRs). Each V H and V L consists of three CDRs and four FRs, and is located from the amino terminus to the carboxy terminus. The CDRs are arranged in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In various embodiments of the disclosure, an antibody (or antibodies thereof) suitable for the compounds or payloads herein is The FRs of the antigen-binding portion of the The amino acid consensus sequence may be a sequence of two or more CDRs. The term "antibody" as used herein can be defined based on the complete It also includes antigen-binding fragments of antibody molecules. As used herein, the term "antigen-binding portion" of an antibody, antibody The term "antigen-binding fragment" and the like refers to any antigen-binding fragment that specifically binds to an antigen to form a complex. Naturally occurring, enzymatically obtained, synthetic, or genetically modified polypeptides or Antigen-binding fragments of antibodies can be obtained using any suitable standard technique, e.g., protein glycoproteins. lytic digestion or manipulation of DNA encoding antibody variable domains and optionally constant domains and It can be derived from whole antibody molecules using recombinant genetic engineering techniques involving expression. Such DNA is known and / or can be obtained, for example, from commercial sources, DNA libraries (e.g., These antibodies are readily available from libraries (including phage-antibody libraries) or can be synthesized. DNA can be sequenced and manipulated chemically or using molecular biology techniques. For example, by arranging one or more variable and / or constant domains in a suitable arrangement; introduces codons, generates cysteine ​​residues, modifies, adds, or deletes amino acids Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab) fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) antibody superfamily. A minimal recognition unit consisting of amino acid residues that mimics the variable region (e.g., a single CDR3 peptide) Other modified molecules include, for example, Domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies , diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, small modular immune medicines (SMIPs), and shark variable IgN The AR domain is also encompassed by the expression "antigen-binding fragment" as used herein. An antigen-binding fragment typically contains at least one variable domain. It may be of any size or amino acid composition and is usually comprised of one or more framework sequences. V. Contains at least one CDR that is contiguous with or in-frame with it. H Do The main is V L In the antigen-binding fragment associated with the domain, V H Domains and V L The domain is They may be in any suitable configuration relative to each other, for example, the variable regions are dimeric, and V H -V H , V H -V L , or V L -V L Alternatively, the antigen-binding fragment of an antibody may comprise a dimer. , monomeric V H or V L In one embodiment, the antigen of the antibody may contain a domain. The binding fragment comprises at least one variable domain covalently linked to at least one constant domain. The variable and constant domains that may be found within the antigen-binding fragments of the antibodies of the present invention may also contain Non-limiting exemplary configurations of common domains 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)V H -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 L is raised Any of the variable and constant domains, including any of the exemplary configurations above, may be used. In the configuration, the variable and constant domains may be directly linked to each other, or They may be linked by a complete or partial hinge or linker region. Range regions are regions between adjacent variable and / or constant domains in a single polypeptide molecule. At least two (e.g., five, ten, fifteen, twenty) flexible or semi-flexible linkages are provided. The complete antibody molecule may consist of 1, 40, 60 or more amino acids. Similarly, antigen-binding fragments may be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies typically contain at least two different variable domains. where each variable domain is specific for a separate antigen or a different epitope on the same antigen. Exemplary bispecific antibody formats disclosed herein Any multispecific antibody format, including can be used in conjunction with antigen-binding fragments of the antibodies of the present disclosure. In certain embodiments described herein, the antibodies described herein are human antibodies. As used herein, the term "human antibody" refers to an antibody that is based on human germline immunoglobulin sequences. The human antibodies of the present disclosure are intended to include antibodies having variable and constant regions derived therefrom. The antibody may, for example, have a CDR encoded by human germline immunoglobulin sequences, particularly CDR3. amino acid residues that have not been modified (e.g., by random or site-specific mutation in vitro) Mutations introduced by allogeneic or in vivo somatic mutations may be included. However, the term "human antibody" as used herein may refer to antibodies derived from other mammals, such as mice. Antibodies in which CDR sequences derived from the germline of a species are grafted onto human framework sequences The term "human antibody" refers to an antibody that is humanized in a naturally occurring, unmodified organism. does not include naturally occurring molecules that normally exist without modification or human intervention / manipulation. The antibodies of the present disclosure may, in certain embodiments, be recombinant human antibodies. As used, the term "recombinant human antibody" refers to an antibody that is prepared and expressed by recombinant means and All human antibodies produced or isolated, e.g., transfected into host cells, antibodies expressed using recombinant expression vectors (described further below); antibodies isolated from a human antibody library (discussed further below); isolated from animals (e.g., mice) that are transgenic for the globulin gene Antibodies (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or any other sequence involving splicing of the human immunoglobulin gene sequence to other DNA sequences. and antibodies, etc., prepared, expressed, produced, or isolated by means of Such recombinant human antibodies are contemplated. However, in some embodiments, such recombinant Human antibodies can be produced by in vitro mutagenesis (or by transgenic mice with human Ig sequences). When using a recombinant antibody, the recombinant antibody is subjected to in vivo somatic mutagenesis (VMU). H and V L The amino acid sequence of the region is human germline V H and V L Derived from and related to the sequence sequences that may not naturally occur within the human antibody germline repertoire in vivo Human antibodies can exist in two forms related to hinge heterogeneity. In some forms, immunoglobulin molecules are composed of dimers held together by interchain heavy chain disulfide bonds. In the second form, the dimer contains a stable four-chain structure of approximately 150-160 kDa, with interchain dissociation. from covalently linked light and heavy chains (half antibodies) not linked by sulfide bonds These forms are composed of approximately 75-80 kDa molecules, even after affinity purification. , which are extremely difficult to separate. Secondary forms in various intact IgG isotypes The frequency of occurrence of isotypes includes, but is not limited to, structural differences associated with antibody hinge region isotypes. A single amino acid substitution in the hinge region of the human IgG4 hinge is The use of hinges can significantly reduce the appearance of the second form to levels normally observed. (Angal et al. (1993) Molecular Immunology 30:105). The present disclosure provides a method for determining the structure of a hinge region, C H 2nd area or C H In three areas, for example, it is suitable for manufacturing and can improve the yield of the desired antibody form. The antibodies described herein include antibodies having one or more mutations that are As used herein, an "isolated antibody" refers to an antibody that has been identified and isolated from the body. It refers to an antibody that has been separated and / or recovered from at least one component of its natural environment. For example, , from at least one component of an organism, or from which the antibody is naturally occurring or naturally produced. An antibody that has been separated or removed from the tissue or cells from which it is derived is referred to as an "isolated" antibody for the purposes of this disclosure. An isolated antibody also includes an antibody in situ within a recombinant cell. The antibody is an antibody that has been subjected to at least one purification or isolation step. According to the present invention, an isolated antibody is one that is substantially free of other cellular material and / or chemicals. As used herein, an antibody may be a polypeptide having the corresponding germline sequence from which it is derived. in the framework and / or CDR regions of the heavy and light chain variable domains, compared to Such mutations may include amino acid substitutions, insertions, and / or deletions of the amino acids of the present invention. The amino acid sequences disclosed in the document may be compared with those available from, for example, public antibody sequence databases. This can be readily confirmed by comparison with the breeding sequence. and antibodies and antigen-binding fragments thereof derived from any of the disclosed amino acid sequences, In some cases, one or more amino acids in one or more framework and / or CDR regions may be present in the same or similar sequence as the amino acid sequence from which the antibody is derived. or to the corresponding residue(s) in another human germline sequence. or a conservative amino acid substitution of the corresponding germline residue(s). Such sequence variations are collectively referred to herein as "germline mutations." Starting with the heavy and light chain variable region sequences disclosed herein, one or more individual recombinant A large number of antibodies and antigen-binding fragments can be generated, including variants containing either a single variant or a combination thereof. In one embodiment, V H and / or V L All frameworks and / or CDR residues are mutated back to those found in the germline sequence from which the antibody was derived. In another embodiment, only certain residues, e.g., the first eight amino acids of FR1 or FR Mutant residues found in the last eight amino acids of 4 Only the mutated residues found in CDR1, CDR2, or CDR3 are mutated to obtain the original In another embodiment, one or more of the framework and / or CDR residues are reverted to the germline sequence. The above is a comparison of different germline sequences (i.e., a different germline sequence from the one from which the antibody was originally derived). The antibodies of the present disclosure are further mutated to the corresponding residues in the framework and germline sequences. and / or within the CDR regions, e.g., certain individual residues may be matched to corresponding residues in particular germline sequences. While mutated, certain other residues that differ from the original germline sequence are maintained. Two or more germline mutations that are either mutated to the same or different germline sequence and mutated to corresponding residues in different germline sequences. Once acquired, a gene containing one or more germline mutations may contain any combination of Antibodies and antigen-binding fragments having, for example, improved binding specificity, increased binding affinity, Improved or enhanced antagonistic or agonistic biological properties (as the case may be), and reduced immunogenicity, etc. The resulting anti-cancer drug can be tested for one or more of the desired properties. Antibodies and antigen-binding fragments thereof are encompassed within the scope of the present disclosure. Antibodies useful for loading include those containing one or more conservative substitutions of the HCV variants disclosed herein. Also included are antibodies containing variants of any of the R, LCVR, and / or CDR amino acid sequences. The term "epitope" refers to a specific region in the variable region of an antibody molecule known as a paratope. A single antigen can consist of two or more epitopes. Thus, different antibodies may bind to different parts of the antigen and have different binding domains. Epitopes can be either conformational or linear. Conformational epitopes are spatially juxtaposed antigens derived from different segments of a linear polypeptide chain. A linear epitope is formed by adjacent amino acid residues in a polypeptide chain. In some embodiments, the epitope is a saccharide, phosphatase, or phospholipase C on the antigen. It may contain sulfonyl or sulfonyl moieties.

[0078] In certain embodiments, the antibody comprises a light chain. In certain embodiments, the light chain is a kappa In some embodiments, the light chain is a lambda light chain. In some embodiments, the antibody comprises 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.

[0079] In some embodiments, the antibody is an antibody fragment. In some embodiments, the antibody fragment is In some embodiments, the antibody fragment is a Fab fragment. In one embodiment, the antibody fragment is a F(ab')2 fragment. In some embodiments, the antibody fragment is an scFv (sFv) fragment. In the above, the antibody fragment is an scFv-Fc fragment.

[0080] In certain embodiments, the antibody is a monoclonal antibody. The antibody is a polyclonal antibody.

[0081] In certain embodiments, the antibody is a chimeric antibody. Humanized Antibodies In certain embodiments, the antibodies are human antibodies.

[0082] The antibody may have a binding specificity for any antigen deemed suitable by one of skill in the art. In certain embodiments, the antigen is a transmembrane molecule (e.g., a receptor) or a growth factor. Exemplary antigens include scavenger receptor A (SR-A, or MSR1), collagen Macrophage receptor with a C-type lectin-like structure (MARCO), a scavenger with a C-type lectin Class A scavenger receptors, including scavenger receptor A-5 (SCARA5), and scavenger receptor SRCL (SRCL). Class B macrophage scavengers including COLEC12, CD36, LIMPII, SRBI, and SRBII receptor, class D scavenger receptor CD68, and lysosomal membrane glycoprotein (LAMP), Class E scavenger receptors, including cutin-like oxidized low-density lipoprotein receptor 1 (LOX-1) and dectin-1 scavenger receptors, endothelial cell-expressed scavenger receptor-I (SREC-I) and SREC-II , and multiple epidermal growth factor (EGF)-like domain (MEGF) 10 (multiple epidermal growth factor (EG Class F scavenger receptors containing MEGF-like domains (MEGF)10), and class G scavenger receptors -Receptor CXC chemokine ligand 16 (CXCL16), fasciclin, EGF-like, lamin-type EGF-like and Class H scavenger receptors, including link domain-containing scavenger receptor-1 (FEEL-1) and -2 (FEEL-2), scavenger receptor, class I scavenger receptor CD163, and receptor for advanced glycation end products (RAGE) Class J scavenger receptor, DEC205, CD206, Dectin-2, Mincle, DC-SIG N, and other C-type lectin superfamily members, including DNGR-1, as well as V-set and Colony-stimulating factor 1 receptor (CS1), a B7 family-related member containing Ig domain 4 (VSIG4) F1R), asialoglycoprotein receptor (ASGPR), and amyloid beta precursor-like protein These include, but are not limited to, other membrane proteins such as APLP-2 (APLP-2). In some embodiments, the antigen is PRLR or HER2. In some embodiments, the antibody , anti-PRLR, or anti-HER2 antibody. In certain embodiments, the antibody is an anti-MSR1 antibody. Exemplary anti-MSR1 antibodies are described herein.

[0083] A binder linker is attached to a binder, e.g., an antibody or antigen-binding molecule, The conjugation can be achieved by attachment at specific amino acids within the functional molecule. Exemplary amino acid attachments that can be used in conjunction with See, for example, US 5,208,020; US 2010 / 0129314; Hollander et al., Bioconjugate Chem., 2008, 19:358-361; WO 2005 / 089808; US 5,714,586; US 2013 / 0101546; and US 2012 / 0585592 cysteine ​​(see, e.g., US 2007 / 0258987; WO 2013 / 055993; WO 2013 / 05599 0; WO 2013 / 053873; WO 2013 / 053872; WO 2011 / 130598; US 2013 / 0101546; and US 7,750, 116), selenocysteine ​​(see, e.g., WO 2008 / 122039; and Hofer et al., Proc. Natl. Acad. Sci., USA, 2008, 105:12451-12456), formylglycerol Singh (e.g., 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. Protoco ls, 2012, 10:1052-1067), unnatural amino acids (see, e.g., WO 2013 / 068874, and and WO 2012 / 166559), as well as acidic amino acids (see, e.g., WO 2012 / 05982 The linker is attached to the antigen-binding protein via attachment to the carbohydrate. Conjugation is also possible (see, for example, US 2008 / 0305497, WO 2014 / 065661, and Ry (See, e.g., Wan et al., Food & Agriculture Immunol., 2001, 13:127-130).

[0084] In some instances, the binding agent is an antibody or an antigen-binding molecule, and the antibody is In one embodiment, the antibody or antigen-binding The molecule is attached to the linker via a cysteine ​​residue.

[0085] Alternatively, the linker can be conjugated by transglutaminase-based chemoenzymatic conjugation. Alternatively, the conjugated nucleotides can be conjugated to one or more glutamine residues via a nucleotide sequence (e.g., Dennle (See, for example, R. et al., Bioconjugate Chem. 2014, 25, 569-578 and WO 2017 / 147542) For example, in the presence of transglutaminase, one or more glutamine residues of the antibody can be cleaved. can be coupled to a primary amine compound. In an embodiment, an antibody having a glutamine residue (e.g., Gln295 residue) is ligated to the antibody by enzyme transfection. Treatment with a primary amine compound, as described in more detail below, in the presence of glutaminase Primary amine compounds can be, for example, coupled via transglutaminase-mediated coupling. to directly provide an antibody drug conjugate, The primary amine compounds include those that are subsequently further reacted with the primary amine compounds for the synthesis of antibody drug conjugates. Also included are linkers and spacers that are functionalized with reactive groups that can be treated with compounds. Antibodies containing glutamine residues may be isolated from natural sources or may be modified with one or more glutamines. The antibody polypeptide chain can be modified to contain glutamine residues (glutamine residues). Techniques for artificially producing tamoxifen-modified antibodies or antigen-binding molecules are within the skill of those in the art. In certain embodiments, the antibody is aglycosylated.

[0086] In certain embodiments, the antibody is numbered 295 in the EU numbering system. In this disclosure, this position contains a glutamine residue. , glutamine 295, or Gln295, or Q295. Those skilled in the art will recognize this as the amino acid sequence of many antibodies. It will be recognized that this is the glutamine residue that is conserved in the wild-type sequence. In one embodiment, the antibody can be modified to include glutamine residues. Techniques for modifying an amino acid sequence to include glutamine residues are within the skill of one in the art. (See, for example, Ausubel et al., Current Protoc. Mol. Biol.).

[0087] In one embodiment, the antibody or glutaminyl-modified antibody or antigen-binding molecule , containing at least one glutamine residue in at least one polypeptide chain sequence. In embodiments, the antibody or glutaminyl-modified antibody or antigen-binding molecule each comprises one Gln In a further embodiment, the antibody or The glutaminyl-modified antibody or antigen-binding molecule has one or more glutaminyl groups at a site other than 295 of the heavy chain. Included herein are the Asn297Gln (N297Q) mutations described herein. Antibodies in this section having mutation(s) at Gln55 (Q5 5) An antibody of this section having residues. As described herein, residue numbering is based on EU numbering. This is based on a numbering system.

[0088] (Primary amine compounds) In certain embodiments, transglutaminase of an antibody (or antigen-binding compound) containing glutamine is Primary amine compounds useful for amine-mediated coupling are those deemed useful by those skilled in the art. The primary amine compound can be any primary amine compound that can be prepared by the method of formula H2. It has the formula NR, where R can be any group that is compatible with the antibody and reaction conditions. In embodiments, R is alkyl, substituted alkyl, heteroalkyl, or substituted heteroaromatic alkyl. It's Rukiru.

[0089] In certain embodiments, the primary amine compound contains a reactive group or a protected reactive group. Useful reactive groups include azides, alkynes, cycloalkynes, thiols, and alcohols. , ketones, aldehydes, acids, esters, hydrazides, anilines, and amines In some embodiments, the reactive group is an azide, alkyne, sulfhydryl, cycloalkenyl, or cycloalkenyl. The alkyl group is selected from the group consisting of alkynyl, aldehyde, and carboxyl.

[0090] In certain embodiments, the primary amine compound is according to the formula HN-LL-X, where LL is a divalent spacer, and X is a reactive group or a protected reactive group. In one embodiment, LL is a divalent polyethylene glycol (PEG) group. In the above formula, X is selected from the group consisting of -SH, -N3, alkyne, aldehyde, and tetrazole. In certain embodiments, X is -N3.

[0091] In certain embodiments, the primary amine compound is according to 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)-(CH2CHO) 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)-(CH2CHO) 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:

[0092] In the above, any alkyl (i.e., -CH2-) group may be replaced by, for example, C 1-8 Al It can be optionally substituted with alkyl, methylformyl, or -SO3H. Thus, the alkyl group is unsubstituted.

[0093] In some embodiments, the primary amine compound is: [ka] is selected from the group consisting of:

[0094] In certain embodiments, the primary amine compound is [ka] is. Exemplary conditions for the above reactions are provided in the Examples below.

[0095] (Linker) In certain embodiments, the linker L portion of the conjugates described herein is A moiety that covalently links the combination to a payload compound described herein, e.g., For example, it is a bivalent moiety. In another example, the linker L couples the binder to a A trivalent or multivalent moiety that covalently links to a payload compound. Carr, for example, in Antibody-Drug Interactions, the contents of each of which are incorporated herein by reference in their entireties. Antibody-Drug Conjugates and Immunotoxins; Phillips, Edited by GL; Springer Verlag: New York, 2013; Antibody-Drug Conjugates Conjugates); edited by Ducry, L.; Humana Press, 2013; Antibody-Drug Conjugates ug Conjugates); Wang, J., Shen, W.-C., and Zaro, J.L. (eds.); Springer International Publishing, 2015. Payload compounds include those represented by the above formula I, formula II, and compounds of formula III, and their residues after attachment to or incorporation of a linker L. , where the combination of linker L and compound or payload is a linker-payload (LP). Those skilled in the art will appreciate that particular functional groups on the compound or payload moiety may be linked to linkers and / or binders. These groups include amines, hydroxy groups, and the like. Examples include hydroxyl, phosphates, and sugars.

[0096] In some embodiments, the linker is stable under physiological conditions. The linker may be cleavable, for example, in the presence of an enzyme or at a particular pH range or value. At least the payload portion can be released. The car contains an enzymatically cleavable site. Exemplary enzymatically cleavable sites include peptide These include, but are not limited to, amide bonds, ester linkages, hydrazones, and disulfide linkages. In some embodiments, the linker is a cathepsin-cleavable linker. Includes.

[0097] In some embodiments, the linker comprises a non-cleavable moiety. , the non-cleavable linker is [ka] or a residue thereof. In one embodiment, the non-cleavable linker-payload Do is [ka] or a positional isomer thereof. In some embodiments, the non-cleavable linker is [ka] or a residue thereof. In one embodiment, the non-cleavable linker-payload Do is [ka] or a positional isomer thereof. In one embodiment, the linker is maleimidocyclohexa carboxylate or 4-(N-maleimidomethyl)cyclohexanecarboxylic acid (MCC) In this structure, [ka] indicates attachment to a binding agent. In this structure, in some instances, [ka] is, for example, a click chemistry product resulting from the reaction of a binder with a linker payload. The residues are shown.

[0098] In some embodiments, suitable linkers include a single binding agent, e.g., an antibody. These include, but are not limited to, those chemically linked to two cysteine ​​residues in Such linkers do not bind to antibodies that are destroyed as a result of the conjugation process. The disulfide bonds in the hydroxylase may act to mimic the disulfide bonds in the hydroxylase.

[0099] In some embodiments, the linker comprises one or more amino acids. Acids include natural, unnatural, standard, non-standard, proteinogenic, and non-proteinogenic. and L- or D-α-amino acids. In some embodiments, the linker is Alanine, valine, glycine, leucine, isoleucine, methionine, tryptophan, Phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagus glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, a derivative thereof, or a combination thereof. One or more side chains of the amino acid are linked to a side chain group, as described below. In some embodiments, the linker comprises valine and citrulline. In some embodiments, the linker comprises lysine, valine, and citrulline. In some embodiments, the linker comprises valine and alanine. and alanine.

[0100] In some embodiments, the linker comprises a self-immolative group. In certain embodiments, the self-immolative group is a p-amino group. Useful derivatives include p-aminobenzyloxybenzoates (PAB) and their derivatives. Those skilled in the art will appreciate that the self-immolative group can separate the remainder of the linker from the payload. You will be aware that chemical reactions can be carried out that release atoms.

[0101] In some embodiments, the linker is: [ka] is (In the formula: SP 1 is a spacer; SP 2 is a spacer; [ka] is one or more bonds to the binding agent; [ka] is one or more bindings to the payload; each AA is an amino acid; and p1 is an integer from 0 to 10).

[0102] SP 1 The spacer is (AA) p1 The site is attached to the binding agent (BA) or to a reactive group residue attached to the BA. This is the connecting part. 1 The spacer may be alkylene or polyether. or both. For example, the portion of the spacer attached to the binding agent or AA may be selected during chemical synthesis of the conjugate. A reactive site-derived site used to couple an antibody or AA to the spacer In certain embodiments, p1 is 0, 1, 2, 3, or 4. In certain embodiments, p1 is 0. In certain embodiments, p1 is 2. In certain embodiments, p1 is 3. In certain embodiments, p1 is 4.

[0103] In some embodiments, SP 1 The spacer comprises an alkylene. In one embodiment, SP 1 The spacer is C 5-7 In some embodiments, the alkylene , SP 1 The spacer comprises a polyether. In some embodiments, SP 1 Spacer includes polymers of ethylene oxide such as polyethylene glycol.

[0104] In one embodiment, SP 1 Spacers are: [ka] is (In the formula, RG′ is the reactive group residue resulting from reaction of the reactive group RG with the binder; [ka] is the binding to the binding agent; [ka] is (AA) p1 is a bond to; b is an integer from 2 to 8; and p1 is an integer from 0 to 4).

[0105] It will be appreciated by those skilled in the art that the reactive group RG is capable of forming one or more bonds to a binding agent. The reactive group RG can be any known reactive group. The reactive group RG has a structure that allows it to bond with the binder. reacting (e.g., with an antibody at its cysteine ​​or lysine residues, or at an azide site, e.g., For example, a PEG-N3 functionalized antibody is reacted with one or more glutamine residues to form a compound of Formula A, Formula B, Formula C, Formula D, Formula E, Formula F, Formula G, Formula H, Formula I, Formula I, Formula J, Formula J, Formula J, Formula K, Formula J ... A moiety that can form a compound of formula A′, formula B′, formula C′, formula D′, or formula A″ After conjugation to a binding agent, the reactive group becomes a reactive group residue (RG′). Exemplary reactive groups include haloacetyl, isothiocyanate, and the like, which can react with the linking agent. containing an anate, succinimide, N-hydroxysuccinimide, or maleimide moiety Examples include, but are not limited to:

[0106] In certain embodiments, reactive groups include, but are not limited to, alkynes. In some embodiments, the alkyne can be converted to an azide in the absence of a copper catalyst, such as a strained alkyne. Strained alkynes are alkynes that can undergo 1,3-cycloaddition reactions with strain-promoting alkynes. Suitable for cycloalkyne-azide cycloaddition (SPAAC) and cycloalkynes, e.g., cyclooctyne and aromatic alkynes. Suitable alkynes include dibenzoazacyclooctynes. or [ka] Dibenzocyclooctyne or [ka] Biarylazacyclooctynone or [ka] Difluorinated cyclooctyne or [ka] Substituted, e.g., fluorinated alkynes, aza-cycloalkynes, bicycles [6.1. 0] Nonin or [ka] and derivatives thereof. Particularly useful alkynes include, but are not limited to, teeth, [ka] Examples include:

[0107] In some embodiments, the binding agent is directly bound to RG'. The binder may include a spacer, such as SP 4 Specific embodiments are shown below. In the formula (I), the binding agent is attached to RG′ via a PEG spacer. Thus, in certain embodiments, the binding agent is functionalized with one or more azide groups. Each azide group can react with RG to form RG′. In this embodiment, the binding agent is derivatized with -PEG-N3 linked to a glutamine residue. Exemplary -N3 derivatized binders, methods for their preparation, and their use in reaction with RG In certain embodiments, RG is a 1,3-ring RG′ is an alkyne suitable for participating in hydroxyaddition, and RG′ is formed by reaction of RG with an azide-functionalized linking agent. As a further example, in some embodiments, RG 'teeth, [ka] or a mixture of each positional isomer. As described in the details.

[0108] SP 2 The spacer is (AA) p1 A moiety that connects the moiety to the payload. As for SP 1 Spacers include, but are not limited to, those mentioned above. More suitable SP 2 The spacer may be alkylene or polyether, or both. Examples include, but are not limited to: SP 2 The end of the spacer, for example, The moiety directly attached to the payload or AA of the pacer is attached to the payload or AA during the chemical synthesis of the conjugate. Payload or AA to the SP 2 A reactive site used for coupling to a spacer In some instances, the SP 2 The end of the spacer, for example, the SP 2 vinegar The moiety directly attached to the payload or AA of the pacer is attached to the payload or AA during the chemical synthesis of the conjugate. The residue of a reactive site used to couple a payload or AA to the spacer. It can be a group.

[0109] In one embodiment, SP 2 The spacer is -O-, -N(R 6 ′)-, -R 4 ′-, -R 5 ′-, -OR 5 ′- , and -OP(O)(OR 6 ')O- is selected from the group consisting of: (In the formula, R 4 ′ is -Z′-YX-; X is selected from the group consisting of -O- and -N(H)-; Y is alkylene, substituted alkylene (including but not limited to, oxo-substituted, i.e., ═O), heteroalkylene, and substituted heteroalkylene; Z' is selected from the group consisting of -O- and -N(H)-; R 5 ' is heterocycloalkylene or substituted heterocycloalkylene, where each The heterocycloalkylene or substituted heterocycloalkylene is useful for attachment to the remainder of the molecule. -O-, -N(H)-, and [ka] and at least two moieties selected from the group consisting of nitrogen and oxygen. , 2, or 3 heteroatoms; and Each R 6 ' is -H, an amino acid residue, a peptide, or an alkyl).

[0110] In one embodiment, SP 2 The spacer is -O-, -N(H)-, [ka] In some embodiments, each [ka] is a binding to the payload, and each [ka] is (AA) p1 is a bond to

[0111] In the above formula, each AA is an amino acid or, optionally, p-aminobenzyloxy carbonyl residue (PABC) or [ka] where c is 1, 2, 3, 4, 5, or 6. When PABC is present, it is preferably Preferably, only one PABC residue is present. If present, the PABC residue is (AA) p1 It is attached to the terminal AA in the group. [ka] When present, preferably c is 2. Preferably, [ka] If present and c is 2, the residue is (AA) farthest from the payload. p1 Motonaka The amino acids suitable for each AA are natural, unnatural, standard, and non-standard. These include quasi-, proteinogenic, non-proteinogenic, and L- or D-α-amino acids. In some embodiments, the linker AA is selected from the group consisting of alanine, valine, leucine, isoleucine, and the like. Synthin, methionine, tryptophan, phenylalanine, proline, serine, threonine , cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, Lysine, arginine, histidine, or citrulline, derivatives thereof, or combinations thereof In certain embodiments, one or more side chains of the amino acid are linked to a side chain group as described below. In some embodiments, p1 is zero. is 2. In some embodiments, (AA) p1is valine-citrulline. In some embodiments, (AA) p1 is citrulline-valine. (AA) p1 is valine-alanine. In some embodiments, (AA) p1 teeth, In some embodiments, (AA) p1 is valine-glycine In some embodiments, (AA) p1 is glycine-valine. In some embodiments, p1 is 3. In some embodiments, (AA) p1 Is Balin-Shitl In some embodiments, (AA) p1 is citrulline-valine-PABC In some embodiments, (AA) p1 is lysine-valine-citrulline-PABC In some embodiments, (AA) p1 is glutamic acid-valine-citrulline. In some embodiments, (AA) p1 is glutamine-valine-citrulline. In the embodiment of (AA) p1 is lysine-valine-alanine. (AA) p1 is lysine-valine-citrulline. In some embodiments, p1 is 4. In some embodiments, (AA) p1 is glutamic acid-valine-citrulline In some embodiments, (AA) p1 Glutamine-Valine-Citrulline Those skilled in the art will recognize PABCs by the following exemplary structures: [ka] The residue will be recognized as p-aminobenzyloxycarbonyl. PABC residues have been shown to promote cleavage of certain linkers in vitro and in vivo. It is being done.

[0112] In some embodiments, the linker is: [ka] TIFF2025138724000092.tif173170 (In the formula: each [ka] is the binding to the binding agent; each [ka] is the binding to the payload; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 As noted above, the bond to the binding agent is This can be direct or via a spacer. In the method, the binding to the binder is via a PEG spacer to the glutamine residue of the binder. It is something.

[0113] In some embodiments, the linker is: [ka] is (In the formula: each [ka] is the binding to the binding agent; each [ka] is the binding to the payload; Each R 9 is -CH3, -CH(CH3)2, or -(CH2)3N(H)C(O)NH2; q is an integer from 1 to 3; and Each A is -O-, -N(H)-, [ka] wherein ZZ is hydrogen or the side chain of an amino acid described elsewhere herein; q1 is and H is -O- or -NH-). For example, in one embodiment, , ZZ, C 1-6 By way of further example, in one embodiment, ZZ is C 1-6 Haitai In one embodiment, H is -O-. In one embodiment, H is - As mentioned above, the bond to the binding agent can be direct or can be spaced. In some embodiments, the attachment to the binding agent can be via a PEG-spe The binding agent is attached to a glutamine residue via a hydroxyl group.

[0114] In some embodiments, the linker is: [ka] is (In the formula: each [ka] is the binding to the binding agent; each [ka] is the binding to the payload; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 As noted above, the bond to the binding agent is This can be direct or via a spacer. In the method, the binding to the binder is via a PEG spacer to the glutamine residue of the binder. It is something.

[0115] In some embodiments, the linker is: [ka] is (In the formula: each [ka] is the binding to the binding agent; each [ka] is the binding to the payload; Each R 9 is -CH3, -CH(CH3)2, or -(CH2)3N(H)C(O)NH2; q is an integer from 1 to 3; and Each A is -O-, -N(H)-, [ka] wherein ZZ is hydrogen or the side chain of an amino acid described elsewhere herein; q1 is and H is -O- or -NH-). For example, in one embodiment, , ZZ, C 1-6 By way of further example, in one embodiment, ZZ is C 1-6 Haitai In one embodiment, H is -O-. In one embodiment, H is - As mentioned above, the bond to the binding agent can be direct or can be spaced. In some embodiments, the attachment to the binding agent can be via a PEG-spe The binding agent is attached to a glutamine residue via a hydroxyl group.

[0116] In any of the above embodiments, (AA) p1 The group can be modified with one or more reinforcing groups. Advantageously, the reinforcing group can be (AA) p1 can be linked to the side chain of any amino acid in Amino acids useful for attaching strengthening groups include lysine, asparagine, and asparagine. Examples of such reinforcing groups include carboxylic acids, glutamine, glutamic acid, and citrulline. The linkage can be a direct bond to the amino acid side chain, or the linkage can be mediated by a spacer and / or a reaction Useful spacers and reactive groups include: The reinforcing group may be any group deemed useful by one of skill in the art. For example, the enhancing group may be any group that enhances, but is not limited to, a biological activity. , biochemical, synthetic, solubilizing, imaging, detecting, and reactive functions and the like, by combining the compound, payload, linker-payload, or antibody conjugate. The enhancing group can be any group that is added to the gate. In one embodiment, the enhancing group is hydrophilic. In some embodiments, the reinforcing group is a cyclodextrin. In such embodiments, the reinforcing group is an alkyl, heteroalkyl, alkylenyl, or heteroalkylene. The cyclodextrin may be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin may be an alpha cyclodextrin. cyclodextrin, beta cyclodextrin, or gamma cyclodextrin, or 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 enhancing group enhances the remaining solubility of the conjugate. In some embodiments, alkyl, heteroalkyl, aralkyl, The alkylenyl or heteroalkylenyl sulfonic acid may be substituted or unsubstituted. In embodiments, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulphur Phobic acid is -(CH2) 1-5 SO3H, -(CH2) n2 -NH-(CH2) 1-5 SO3H, -(CH2) n2-C(O)NH-(CH2) 1-5 SO3H , -(CH2CH2O) m2 -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n2 -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(C H2) n2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m2 -C(O)N((CH2) 1-5 C(O)NH( CH2) 1-5 SO3H2 (wherein n2 is 1, 2, 3, 4, or 5 and m2 is 1, 2, 3, 4, or 5) In one embodiment, the alkyl or alkylenyl sulfonic acid is —(CH) 1-5 In another embodiment, the heteroalkyl or heteroalkylenyl sulfonic acid is -(CH2) n2 -NH-(CH2) 1-5 SO3H (where n2 is 1, 2, 3, 4, or 5). In some embodiments, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyls may be used. Sulfonic acid is -(CH2) n2 -C(O)NH-(CH2) 1-5 SO3H (wherein n2 is 1, 2, 3, 4, or 5) In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroaromatic groups are Alkylenylsulfonic acid is -(CH2CH2O) m2 -C(O)NH-(CH2) 1-5 SO3H (where m2 is 1, 2, 3, 4 In another embodiment, alkyl, heteroalkyl, alkylenyl, The alkyl or heteroalkylenyl sulfonic acid is -(CH2) n2-N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2( wherein n2 is 1, 2, 3, 4, or 5. In another embodiment, The alkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n2 -C(O)N((CH 2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where n2 is 1, 2, 3, 4, or 5. In the above, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Phosphoric acid is -(CH2CH2O) m2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2 (wherein m2 is 1, 2, 3, 4, or 5). In some embodiments, the linker is: [ka] is (In the formula: SP 1 is a spacer; SP 2 is a spacer; SP 3 is (AA) p1 a spacer linked to one AA of [ka] is one or more bonds to the binding agent; [ka] is one or more bindings to the payload; [ka] is one or more bonds to the strengthening group EG; each AA is an amino acid; and p1 is an integer from 1 to 10. As mentioned above, the bond to the binder should be direct. In some embodiments, the binding agent may be attached to the hydroxyl group of the hydroxyl group or via a spacer. The attachment is to a glutamine residue of the binding agent via a PEG spacer.

[0117] SP 1 The spacer group is as described above. SP 2 The spacer group is as described above. A) p1 The groups are as defined above.

[0118] SP 3 The spacer is (AA) p1 A moiety that connects the moiety to the reinforcing group (EG). 3 Spacer Examples of the alkylene include those containing alkylene or polyether, or both. Not limited to these. SP 3 The end of the spacer, i.e., the SP 3 Spacer reinforcement group or AA The moiety directly attached to SP is the one that attaches the reinforcing group or AA to the SP during chemical synthesis of the conjugate. 3 Space The moiety may be derived from a reactive site used for coupling to the hydroxyl group. In the example, SP 3 The end of the spacer, i.e., the reinforcing group or AA of the spacer, is directly bonded to the The conjugated moiety couples the reinforcing group or AA to the spacer during chemical synthesis of the conjugate. In one embodiment, SP 3 is (AA) p1 In one embodiment, the spacer is linked to only one AA of , SP 3 The spacer is (AA) p1is linked to the side chain of a lysine residue of

[0119] In one embodiment, SP 3 Spacers are: [ka] is (In the formula: RG′ is the reactive group residue resulting from reaction of the reactive group RG with the toughening agent EG; [ka] is the bond to the enhancer; [ka] is (AA) p1 is a bond to; a is an integer from 2 to 8; and p1 is an integer from 1 to 4).

[0120] It will be appreciated by those skilled in the art that the reactive group RG is capable of forming one or more bonds to the toughening agent. The reactive group RG can be any reactive group known in the art. The reactive group RG reacts with the reinforcing group to form a compound of the formula LPa , formula LPb, formula LPc, formula LPd, formula LPa', formula LPb', formula LPc', formula LPd', formula A, formula B, formula C, formula D, The moiety capable of forming a compound of formula A', formula B', formula C', formula D', or formula A'' is After conjugation to the reinforcing group, the reactive group is a reactive group residue. (RG′). The reactive group RG can be any of the reactive groups described above. Exemplary Reactions The functional groups include haloacetyl, isothiocyanate, succinate, etc., which can react with the binder. and those containing an N-hydroxysuccinimide, N-hydroxysuccinimide, or maleimide moiety. However, the present invention is not limited to these.

[0121] In certain embodiments, reactive groups include, but are not limited to, alkynes. In certain embodiments, the alkyne can be substituted by azido in the absence of a copper catalyst, such as a strained alkyne. Strained alkynes are alkynes that can undergo 1,3-cycloaddition with aldehydes. Suitable for alkyne-azide cycloaddition (SPAAC) and cycloalkynes, e.g., cyclooctyl Suitable alkynes include dibenzoazacyclooctyl alkynes, dibenzoazacyclooctyl alkynes, and aromatic alkynes. or [ka] Dibenzocyclooctyne or [ka] Biarylazacyclooctynone or [ka] Difluorinated cyclooctyne or [ka] Substituted, e.g., fluorinated alkynes, aza-cycloalkynes, bicycle[6.1.0]nonyls or [ka] and derivatives thereof. Particularly useful alkynes include, but are not limited to, teeth, [ka] Examples include:

[0122] In some embodiments, the linker is: [ka] is (In the formula: RG′ is the reactive group residue resulting from reaction of the reactive group RG with the binder; PEG is -NH-PEG4-C(O)-; SP 2 is a spacer; SP 3 is (AA) p1 a spacer linked to one AA residue of [ka] is one or more bonds to the binding agent; [ka] is one or more bindings to the payload; [ka] is one or more bonds to the strengthening group EG; each AA is an amino acid residue; and p1 is an integer from 1 to 10. As mentioned above, the bond to the binder should be direct. In some embodiments, the binding agent may be attached to the hydroxyl group of the hydroxyl group or via a spacer. Conjugation is via a PEG spacer to a glutamine residue of the binding agent.

[0123] In some embodiments, the linker is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof isomer or a mixture of its positional isomers (In the formula: each [ka] is the binding to the binding agent; each [ka] is the binding to the payload; each [ka] is the bond to the enhancer; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 In some embodiments, the 1,3-annulated alkyl is heteroalkyl. The positional isomer or mixture of positional isomers of SPAAC can be synthesized by treating P For example, in one embodiment, the linker is derived from an EG-N3 derivatized antibody: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof As a further example, in one embodiment, The linker: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof isomer or a mixture of its positional isomers. As a further example, the linker: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof As a further example, in one embodiment, The linker: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof As mentioned above, the binding to the binding agent can be performed by direct In some embodiments, the hydroxyl group may be a hydroxyl group or a spacer. The binding to the binder is via a PEG spacer to the glutamine residue of the binder. In some embodiments, the strengthening agent is a hydrophilic group. In some embodiments, the enhancing group is alkyl, hetero The cyclodex is an alkyl, alkylenyl, or heteroalkylenyl sulfonic acid. The cyclodextrin can be any cyclodextrin known to those of skill in the art. In the present invention, the cyclodextrin is alpha cyclodextrin, beta cyclodextrin, In some embodiments, the cyclodextrin is cyclohexyl phosphate, cyclohexyl phosphate, or gamma cyclodextrin, or a mixture thereof. In some embodiments, the cyclodextrin is alpha cyclodextrin. In some embodiments, the cyclodextrin is a beta cyclodextrin. In some embodiments, the cyclodextrin is gamma cyclodextrin. The alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) 1-5 SO3H, -(CH2) n2 -NH-(CH2) 1-5SO3H, -(CH2) n2 -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m2 -C( O)NH-(CH2) 1-5 SO3H, -(CH2) n2 -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2) n2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2(formula wherein n2 is 1, 2, 3, 4, or 5, and m2 is 1, 2, 3, 4, or 5. In embodiments, the alkyl or alkylenyl sulfonic acid is —(CH) 1-5 It is SO3H. In one embodiment, the heteroalkyl or heteroalkylenyl sulfonic acid is —(CH) n2 -N H-(CH2) 1-5 SO3H, wherein n2 is 1, 2, 3, 4, or 5. In another embodiment , alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acids are -( CH2) n2 -C(O)NH-(CH2) 1-5 SO3H, where n2 is 1, 2, 3, 4, or 5. In embodiments, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulphur Phobic acid is -(CH2CH2O) m2 -C(O)NH-(CH2) 1-5 SO3H (wherein m2 is 1, 2, 3, 4, or 5) In another embodiment, alkyl, heteroalkyl, alkylenyl, or hetero Alkylenylsulfonic acids are -(CH2) n2 -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2 (where n2 is 1 In another embodiment, alkyl, heteroalkyl, Alkylenyl or heteroalkylenyl sulfonic acids are —(CH2) n2 -C(O)N((CH2) 1-5 C(O)NH( CH2) 1-5 SO3H2, where n2 is 1, 2, 3, 4, or 5. In another embodiment, The alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH 2CH2O) m2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where m2 is 1, 2, 3, 4, or 5. is.

[0124] In some embodiments, the linker is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof isomer or a mixture of its positional isomers (In the formula: each [ka] is the binding to the binding agent; each [ka] is the bond to the enhancer; each [ka] is the binding to the payload; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 As noted above, the bond to the binding agent is This can be direct or via a spacer. In the method, the binding to the binder is via a PEG spacer to the glutamine residue of the binder. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancing group is alkyl, Heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acids. The cyclodextrin can be any cyclodextrin known to those of skill in the art. In this regard, cyclodextrins include alpha cyclodextrin, beta cyclodextrin, cyclodextrin, or gamma cyclodextrin, or a mixture thereof. In one embodiment, the cyclodextrin is alpha cyclodextrin. In some embodiments, the cyclodextrin is a beta cyclodextrin. In one embodiment, the cyclodextrin is gamma cyclodextrin. The alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH 2) 1-5SO3H, -(CH2) n2 -NH-(CH2) 1-5 SO3H, -(CH2) n2 -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m2 - C(O)NH-(CH2) 1-5 SO3H, -(CH2) n2 -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2) n2 -C(O)N((CH 2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2( wherein n2 is 1, 2, 3, 4, or 5, and m2 is 1, 2, 3, 4, or 5). In one embodiment, the alkyl or alkylenyl sulfonic acid is —(CH) 1-5 It is SO3H. In another embodiment, the heteroalkyl or heteroalkylenyl sulfonic acid is —(CH) n2 -NH-(CH2) 1-5 SO3H, where n2 is 1, 2, 3, 4, or 5. and the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n2 -C(O)NH-(CH2) 1-5 SO3H (where n2 is 1, 2, 3, 4, or 5). In some embodiments, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyls may be used. Sulfonic acid is -(CH2CH2O) m2 -C(O)NH-(CH2) 1-5 SO3H (wherein m2 is 1, 2, 3, 4, or 5) In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkyl is Alkylenyl sulfonic acid is -(CH2) n2 -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where n2 is In another embodiment, alkyl, heteroalkyl, Alkylenyl or heteroalkylenyl sulfonic acids are —(CH2) n2 -C(O)N((CH2) 1-5 C(O)NH( CH2) 1-5 SO3H2, where n2 is 1, 2, 3, 4, or 5. In another embodiment, The alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH 2CH2O) m2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where m2 is 1, 2, 3, 4, or 5. is.

[0125] In some embodiments, the linker is: [ka] TIFF2025138724000140.tif135170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof isomer or a mixture of its positional isomers (In the formula: each [ka] is the binding to the binding agent; each [ka] is the binding to the payload; R9 is —CH or —(CH)N(H)C(O)NH; and A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 As noted above, the bond to the binding agent is This can be direct or via a spacer. In the method, the binding to the binder is via a PEG spacer to the glutamine residue of the binder. It is something.

[0126] In some embodiments, the linker is: [ka] TIFF2025138724000145.tif221170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof isomer or a mixture of its positional isomers (In the formula: each [ka] is the binding to the binding agent; each [ka] is the binding to the payload; R 9 is —CH or —(CH)N(H)C(O)NH; and A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 As noted above, the bond to the binding agent is This can be direct or via a spacer. In the method, the binding to the binder is via a PEG spacer to the glutamine residue of the binder. It is something.

[0127] In some embodiments, the linker is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof isomer or a mixture of its positional isomers (In the formula: each [ka] is the binding to the binding agent; each [ka] is the binding to the payload; each [ka] is the bond to the reinforcing group; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 As noted above, the bond to the binding agent is This can be direct or via a spacer. In the method, the binding to the binder is via a PEG spacer to the glutamine residue of the binder. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancing group is alkyl, Heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acids. The cyclodextrin can be any cyclodextrin known to those of skill in the art. In this regard, cyclodextrins include alpha cyclodextrin, beta cyclodextrin, cyclodextrin, or gamma cyclodextrin, or a mixture thereof. In one embodiment, the cyclodextrin is alpha cyclodextrin. In some embodiments, the cyclodextrin is a beta cyclodextrin. In one embodiment, the cyclodextrin is gamma cyclodextrin. The alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH 2) 1-5 SO3H, -(CH2) n2 -NH-(CH2) 1-5 SO3H, -(CH2) n2 -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m2 - C(O)NH-(CH2)1-5 SO3H, -(CH2) n2 -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2) n2 -C(O)N((CH 2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2( wherein n2 is 1, 2, 3, 4, or 5, and m2 is 1, 2, 3, 4, or 5). In one embodiment, the alkyl or alkylenyl sulfonic acid is —(CH) 1-5 It is SO3H. In another embodiment, the heteroalkyl or heteroalkylenyl sulfonic acid is —(CH) n2 -NH-(CH2) 1-5 SO3H, where n2 is 1, 2, 3, 4, or 5. and the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n2 -C(O)NH-(CH2) 1-5 SO3H (where n2 is 1, 2, 3, 4, or 5). In some embodiments, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyls are used. Sulfonic acid is -(CH2CH2O) m2 -C(O)NH-(CH2) 1-5 SO3H (wherein m2 is 1, 2, 3, 4, or 5) In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkyl is Alkyl sulfonic acid is -(CH2) n2 -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where n2 is In another embodiment, alkyl, heteroalkyl, Alkylenyl or heteroalkylenyl sulfonic acids are —(CH2) n2 -C(O)N((CH2) 1-5 C(O)NH( CH2) 1-5 SO3H2, where n2 is 1, 2, 3, 4, or 5. In another embodiment, The alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH 2CH2O) m2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where m2 is 1, 2, 3, 4, or 5. is.

[0128] In some embodiments, the linker is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof isomer or a mixture of its positional isomers (In the formula: each [ka] is the binding to the binding agent; each [ka] is the binding to the payload; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 As noted above, the bond to the binding agent is This can be direct or via a spacer. In the method, the binding to the binder is via a PEG spacer to the glutamine residue of the binder. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancing group is alkyl, Heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acids. The cyclodextrin can be any cyclodextrin known to those of skill in the art. In this regard, cyclodextrins include alpha cyclodextrin, beta cyclodextrin, cyclodextrin, or gamma cyclodextrin, or a mixture thereof. In one embodiment, the cyclodextrin is alpha cyclodextrin. In some embodiments, the cyclodextrin is a beta cyclodextrin. In one embodiment, the cyclodextrin is gamma cyclodextrin. The alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH 2) 1-5 SO3H, -(CH2) n2 -NH-(CH2) 1-5 SO3H, -(CH2) n2 -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m2 - C(O)NH-(CH2) 1-5 SO3H, -(CH2) n2 -N((CH2)1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2) n2 -C(O)N((CH 2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2( wherein n2 is 1, 2, 3, 4, or 5, and m2 is 1, 2, 3, 4, or 5). In one embodiment, the alkyl or alkylenyl sulfonic acid is —(CH) 1-5 It is SO3H. In another embodiment, the heteroalkyl or heteroalkylenyl sulfonic acid is —(CH) n2 -NH-(CH2) 1-5 SO3H, where n2 is 1, 2, 3, 4, or 5. and the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n2 -C(O)NH-(CH2) 1-5 SO3H (where n2 is 1, 2, 3, 4, or 5). In some embodiments, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyls are used. Sulfonic acid is -(CH2CH2O) m2 -C(O)NH-(CH2) 1-5 SO3H (wherein m2 is 1, 2, 3, 4, or 5) In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkyl is Alkyl sulfonic acid is -(CH2) n2 -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where n2 is In another embodiment, alkyl, heteroalkyl, Alkylenyl or heteroalkylenyl sulfonic acids are —(CH2) n2 -C(O)N((CH2) 1-5 C(O)NH( CH2) 1-5 SO3H2, where n2 is 1, 2, 3, 4, or 5. In another embodiment, The alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH 2CH2O) m2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where m2 is 1, 2, 3, 4, or 5. is.

[0129] In some embodiments, the linker is: [ka] TIFF2025138724000159.tif171170; or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or or a mixture of the positional isomers (In the formula: each [ka] is the binding to the binding agent; each [ka] is the binding to the payload; and H is —O— or —NH—).

[0130] In some embodiments, the linker is: [ka] is (In the formula: each [ka] is the binding to the binding agent; each [ka] is the binding to the payload; and H is —O— or —NH—).

[0131] In some embodiments, the linker is: [ka] TIFF2025138724000166.tif74170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof isomer or a mixture of its positional isomers (In the formula: each [ka] is the binding to the binding agent; each [ka] is the binding to the payload; R 9 is —CH or —(CH)N(H)C(O)NH; and A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 As noted above, the bond to the binding agent is This can be direct or via a spacer. In the method, the binding to the binder is via a PEG spacer to the glutamine residue of the binder. It is something.

[0132] In some embodiments, the linker is: [ka] TIFF2025138724000171.tif104170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof isomer or a mixture of its positional isomers (In the formula: each [ka] is the binding to the binding agent; each [ka] is the binding to the payload; R 9 is —CH or —(CH)N(H)C(O)NH; and A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 As noted above, the bond to the binding agent is This can be direct or via a spacer. In the method, the binding to the binder is via a PEG spacer to the glutamine residue of the binder. It is something.

[0133] (Linker-Payload or Reactive Linker-Payload) Provided are compounds or payloads described herein (e.g., Formula I, Formula II, or a compound of Formula III or a payload) and a linker-pair derived from either In certain embodiments described below, Thus, the conjugates provided herein may comprise a linker having a reactive group RG as described above. -payload or reactive linker-payload. The load or reactive linker-payload is linked to a reinforcing group and / or It can be linked to a binding agent.

[0134] In certain embodiments, the linker-payload comprises a compound of formula I above attached to a linker(s). Any particular payload encompassed by any one or more of Formula II, Formula III, or Formula III. wherein the linker(s) described herein are linked to a binding agent described herein. , an antibody or antigen-binding fragment thereof, and / or a site reactive with the enhancing group. In embodiments, the linker is any one of Formula I, Formula II, or Formula III of the payloads above. As in the above case, R 1 , R 2 , or R 6 , or R 1 , R 2 , or R 6 bound to the divalent form of In one embodiment, the linker-payload has the structure of formula LPa: [ka] wherein L is a linker as described above, and Q 1 , Q 2 , W, -R 1 -, R2 , R 4 , R 5 , and R 6 is as described above in connection with Formula I). ​​In one embodiment, the linker-payload is , having the structure of formula LPb: [ka] wherein L is a linker as described above, and Q 1 , Q 2 , W, R 1 , -R 2 -, R 4 , R 5 , and R 6 is as described above in connection with Formula I). ​​In one embodiment, the linker-payload is , having the structure of formula LPc: [ka] wherein L is a linker as described above, and Q 1 , Q 2 , W., R. 1 , R 2 , R 4 , R 5 , and -R 6 - is as described above in connection with Formula I). ​​In one embodiment, the linker-payload is , having the structure of formula LPd: [ka] wherein L is a linker as described above, and Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and -R 6 - is as described above in connection with Formula I). ​​In one embodiment, the linker-payload is , having the structure of formula LPa′: [ka] (In the formula, SP 1 and SP 2 is a spacer as defined above, and each AA is an amino acid as defined above. residue, Q 1 , Q 2 , W, -R 1 -, R 2 , R 4 , R 5 , and R 6 is as described above in connection with Formula I and p1 is an integer of 1 to 10. In one embodiment, has a structure of formula LPb′: [ka] (In the formula, SP 1 and SP 2 is a spacer as defined above, and each AA is an amino acid as defined above. residue, Q 1 , Q 2 , W, R 1 , -R 2 -, R 4 , R 5 , and R 6 is as described above in connection with Formula I and p1 is an integer of 1 to 10. In one embodiment, has a structure of formula LPc′: [ka] (In the formula, SP 1 and SP 2 is a spacer as defined above, and each AA is an amino acid as defined above. residue, Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and -R 6 - is as described above in connection with formula I and p1 is an integer of 1 to 10. In one embodiment, has a structure of formula LPd′: [ka] (In the formula, SP 1 and SP 2 is a spacer as defined above, and each AA is an amino acid as defined above. residue, Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and -R 6 - is as described above in connection with formula I and p1 is an integer from 1 to 10. In any of the embodiments of this paragraph, p1 is , 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In any of the embodiments of this paragraph, Linker L or spacer SP 2 is an aryl nitrogen or an amino acid, alone or within a peptide In any of the embodiments of this paragraph, each R 4 is independently , hydrogen, amino acid residue, N-alkyl amino acid residue, peptide residue, biodegradable site, alkyl In any of the embodiments of this paragraph, the alkyl group is substituted alkyl, acyl, or substituted acyl. And each R 4 is, independently in each occurrence, hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, biodegradable moiety, or alkyl.

[0135] In some embodiments, the linker-payload or reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof (In the formula: each RG is a reactive group as described herein; Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 It is heteroalkyl.

[0136] In some embodiments, the linker-payload or reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof (In the formula: each RG is a reactive group as described herein; Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 It is heteroalkyl.

[0137] In some embodiments, the linker-payload or reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof (In the formula: Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)- [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 It is heteroalkyl.

[0138] In some embodiments, the linker-payload or reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof (In the formula: Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 It is heteroalkyl.

[0139] In some embodiments, the reactive linker-payload is: [ka] TIFF2025138724000192.tif156170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof Body (In the formula: Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 It is heteroalkyl.

[0140] In some embodiments, the reactive linker-payload is: [ka] TIFF2025138724000195.tif156170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof Body (In the formula: Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 It is heteroalkyl.

[0141] In some embodiments, the linker-payload or reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof (In the formula: Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 It is heteroalkyl.

[0142] In some embodiments, the linker-payload or reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof (In the formula: Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 It is heteroalkyl.

[0143] In some embodiments, the linker-payload or reactive linker-payload is: [ka] TIFF2025138724000202.tif87170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof Body (In the formula: Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 It is heteroalkyl.

[0144] In some embodiments, the linker-payload or reactive linker-payload is: [ka] TIFF2025138724000205.tif89170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof Body (In the formula: Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 It is heteroalkyl.

[0145] In some embodiments, the linker-payload or reactive linker-payload is: [ka] TIFF2025138724000208.tif247170TIFF2025138724000209.tif240170TIFF2025138724000210.tif220170TIFF2025138724000211.tif217170TIFF2025138724000212.tif108170; or a pharmaceutically acceptable salt or solvate thereof.

[0146] Further provided herein are: [ka] TIFF2025138724000214.tif158170 and a pharmaceutically acceptable salt or solvate thereof. It's a load.

[0147] The linker, linker-payload, or reactive linker-payload may be: These compounds are useful for providing conjugates.

[0148] (Conjugates / Antibody Drug Conjugates (ADCs) Provided herein is an antibody, or antigen-binding fragment thereof, wherein the antibody is conjugated to one or more compounds of Formula I, Formula II, or Formula III described herein There are.

[0149] Provided herein are compounds or conjugates of formula A, or pharmaceuticals thereof and its corresponding acceptable salts or stereoisomeric forms: [ka] where BA is a binder, L is a linker, and Q 1 , Q 2 , W, -R 1 -, R 2 , R 4 , R 5 , and BiR 6 is as described above in connection with Formula I, and k is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10). In one embodiment, the -L-BA conjugated in Formula A is The compound or payload may include one or more compounds of Formula I, Formula II, and / or Formula III above. where BA is a binding agent; L is a linker; and k is 1, 2, 3, 4, 5, 6, 7, 8 , 9, or 10. In any embodiment of this paragraph, the BA is an antibody, or an antigen-binding fragment, wherein the antibody is conjugated to a compound of formula I, as described above. In any embodiment of this paragraph, the BA is an antibody, or an antigen-binding fragment thereof, wherein wherein the antibody is conjugated to a compound of formula II, as described above. In an embodiment, the BA is an antibody, or an antigen-binding fragment thereof, wherein the antibody is an antibody as described above. In any of the embodiments of this paragraph, wherein k ranges from 1 to 2, 1 to 3, 2 to 3, 2 to 4, 3 to 4, or 1 to 4. In any of the embodiments of this paragraph, k is 1. In any of the embodiments of this paragraph, k is 2. In any of the embodiments of this paragraph, k is 3. In any of the embodiments of this paragraph, each R 4 are independent in each case hydrogen, amino acid residues, N-alkyl amino acid residues, peptide residues, biodegradable sites, and alkyl groups. In any of the embodiments of this paragraph, the alkyl is substituted alkyl, substituted alkyl, acyl, or substituted acyl. And each R 4 is independently in each case hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide The moiety may be a hydroxyl group, a biodegradable moiety, or an alkyl group.

[0150] Provided herein are compounds or conjugates of formula B, or pharmaceuticals thereof and its corresponding acceptable salts or stereoisomeric forms: [ka] where BA is a binder, L is a linker, and Q 1 , Q 2, W, R 1 , -R 2 -, R 4 , R 5 , and BiR 6 is as described above in connection with Formula I, and k is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10). In one embodiment, the -L-BA in Formula B is conjugated to The compound or payload may include one or more compounds of Formula I, Formula II, and / or Formula III above. where BA is a binding agent; L is a linker; and k is 1, 2, 3, 4, 5, 6, 7, 8 , 9, or 10. In any embodiment of this paragraph, the BA is an antibody, or an antigen-binding fragment, wherein the antibody is conjugated to a compound of formula I, as described above. In any embodiment of this paragraph, the BA is an antibody, or an antigen-binding fragment thereof, wherein wherein the antibody is conjugated to a compound of formula II, as described above. In an embodiment, the BA is an antibody, or an antigen-binding fragment thereof, wherein the antibody is an antibody as described above. In any of the embodiments of this paragraph, wherein k ranges from 1 to 2, 1 to 3, 2 to 3, 2 to 4, 3 to 4, or 1 to 4. In any of the embodiments of this paragraph, k is 1. In any of the embodiments of this paragraph, k is 2. In any of the embodiments of this paragraph, k is 3. In any of the embodiments of this paragraph, each R 4 are independent in each case hydrogen, amino acid residues, N-alkyl amino acid residues, peptide residues, biodegradable sites, and alkyl groups. In any of the embodiments of this paragraph, the alkyl is substituted alkyl, substituted alkyl, acyl, or substituted acyl. And each R4 is independently in each case hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide The moiety may be a hydroxyl group, a biodegradable moiety, or an alkyl group.

[0151] Provided herein are compounds or conjugates of formula C, or pharmaceuticals thereof and its corresponding acceptable salts or stereoisomeric forms: [ka] where BA is a binder, L is a linker, and Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and - R 6 - is as described above in connection with Formula I, and k is 1, 2, 3, 4, 5, 6, 7, 8, 9 In some embodiments, the -L-BA in Formula C is conjugated to The compound or payload may include one or more compounds of Formula I, Formula II, and / or Formula III above. where BA is a binding agent; L is a linker; and k is 1, 2, 3, 4, 5, 6, 7, 8 , 9, or 10. In any embodiment of this paragraph, the BA is an antibody, or an antigen-binding fragment, wherein the antibody is conjugated to a compound of formula I, as described above. In any embodiment of this paragraph, the BA is an antibody, or an antigen-binding fragment thereof, wherein wherein the antibody is conjugated to a compound of formula II, as described above. In an embodiment, the BA is an antibody, or an antigen-binding fragment thereof, wherein the antibody is an antibody as described above. In any of the embodiments of this paragraph, wherein k ranges from 1 to 2, 1 to 3, 2 to 3, 2 to 4, 3 to 4, or 1 to 4. In any of the embodiments of this paragraph, k is 1. In any of the embodiments of this paragraph, k is 2. In any of the embodiments of this paragraph, k is 3. In any of the embodiments of this paragraph, each R 4 are independent in each case hydrogen, amino acid residues, N-alkyl amino acid residues, peptide residues, biodegradable sites, and alkyl groups. In any of the embodiments of this paragraph, the alkyl is substituted alkyl, substituted alkyl, acyl, or substituted acyl. And each R 4 is independently in each case hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide The moiety may be a hydroxyl group, a biodegradable moiety, or an alkyl group.

[0152] Provided herein are compounds or conjugates of formula D, or pharmaceuticals thereof and its corresponding acceptable salts or stereoisomeric forms: [ka] where BA is a binder, L is a linker, and Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and - R 6 - is as described above in connection with Formula I, and k is 1, 2, 3, 4, 5, 6, 7, 8, 9 In some embodiments, the -L-BA in formula D is conjugated to The compound or payload may include one or more compounds of Formula I, Formula II, and / or Formula III above. where BA is a binding agent; L is a linker; and k is 1, 2, 3, 4, 5, 6, 7, 8 , 9, or 10. In any embodiment of this paragraph, the BA is an antibody, or an antigen-binding fragment, wherein the antibody is conjugated to a compound of formula I, as described above. In any embodiment of this paragraph, the BA is an antibody, or an antigen-binding fragment thereof, wherein wherein the antibody is conjugated to a compound of formula II, as described above. In an embodiment, the BA is an antibody, or an antigen-binding fragment thereof, wherein the antibody is an antibody as described above. In any of the embodiments of this paragraph, wherein k ranges from 1 to 2, 1 to 3, 2 to 3, 2 to 4, 3 to 4, or 1 to 4. In any of the embodiments of this paragraph, k is 1. In any of the embodiments of this paragraph, k is 2. In any of the embodiments of this paragraph, k is 3. In any of the embodiments of this paragraph, each R 4 are independent in each case hydrogen, amino acid residues, N-alkyl amino acid residues, peptide residues, biodegradable sites, and alkyl groups. In any of the embodiments of this paragraph, the alkyl is substituted alkyl, substituted alkyl, acyl, or substituted acyl. And each R 4 is independently in each case hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide The moiety may be a hydroxyl group, a biodegradable moiety, or an alkyl group.

[0153] In any of the embodiments in the four paragraphs immediately preceding, L is a linker or XYZ (wherein X is -NH- or -O-; Y is an enzymatically cleavable moiety, a self-immolative group, an acid-labile moiety, PEG n1 , a sugar moiety, or a reinforcing group; and Z is a binder linker (BL), where Z is a BA Exemplary enzymatically cleavable sites include any di- or Tri-peptides (e.g., VC-PAB and VA, as described elsewhere herein) are included. Exemplary self-immolative groups include, but are not limited to, those described elsewhere herein. Exemplary acid-labile moieties include alkoxamines, ketoxamines, and the like. Examples include, but are not limited to, amines, carbonates, or phosphonates. Exemplary reinforcing groups are described elsewhere herein. Exemplary reactive sites are described elsewhere herein. In some embodiments, Y is a PEG group in which n1 is 1, 2, 3, 4, or 5. n In some embodiments, amino acids are used to form the amino acids described elsewhere herein. As will become apparent, the payload, enhancing group, and antibody (each of which is described elsewhere herein) may be used in combination. The payload via the amino acid, The connection of the reinforcing group and the antibody may be achieved by amide coupling, as will be appreciated by those skilled in the art. This can be carried out by a thio-Michael addition, or an aniline-NH-alkylation. For example, the amino acid connecting the payload, the enhancing group, and the antibody is lysine. In one embodiment, the amino acid connecting the payload, the enhancing group, and the antibody is D-lysine. By way of further example, in one embodiment, the payload, enhancing group, and antibody are The connecting amino acid is aspartic acid. The amino acid connecting the payload, the enhancing group, and the antibody is glutamic acid. In one embodiment, the amino acid connecting the payload, the enhancing group, and the antibody is By way of further example, in one embodiment, the payload, enhancing group, and antibody are The connecting amino acid is cysteine. The amino acid connecting the load, the strengthening group, and the antibody is tyrosine.

[0154] Provided herein are compounds having Formula A', Formula B', Formula C', or Formula D' or or a pharmaceutically acceptable salt or stereoisomeric form thereof: [ka] (Where BA is a binder, Q 1 , Q 2 , W, R 1 , -R 1 -, R 2 , R 2 -, R 4 , R 5 , and R 6 or -R 6 - is as described above in connection with formula I, and SP 1 and SP 2 If present, each AA is an amino acid residue, and p1 is an integer from 1 to 10. In embodiments, the compound or conjugate is such that BA is a binding agent and Q 1 , Q 2 , W, -R 1 -, R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I, and SP 1 and SP 2 But there is In the case where p1 is a spacer group, each AA is an amino acid residue, and p1 is an integer from 1 to 10. or a pharmaceutically acceptable salt or stereoisomeric form thereof. In embodiments, the compound or conjugate has a structure in which BA is a binding agent and Q 1 , Q 2 , W, R 1 ,- R 2 -, R 4 , R 5 , and R 6 is as described above in connection with formula I, and SP 1 and SP 2 But, existence In this case, each AA is a spacer group, each AA is an amino acid residue, and p1 is 1 to 10. or a pharmaceutically acceptable salt or stereoisomeric form thereof of formula B', wherein R is an integer. In an embodiment, the compound or conjugate is such that BA is a binding agent and Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and -R 6 is as described above in relation to formula I, and SP 1 and SP 2 but, If present, it is a spacer group, each AA is an amino acid residue, and p1 is 1 to 1 0, or a pharmaceutically acceptable salt or stereoisomeric form thereof. In one embodiment, the compound or conjugate is 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and -R 6 is as described above in relation to formula I, and SP 1 and SP 2 but, If present, it is a spacer group, each AA is an amino acid residue, and p1 is 1 to 1 0, or a pharmaceutically acceptable salt or stereoisomeric form thereof. In any of the embodiments of this paragraph, the BA is an antibody, or an antigen-binding fragment thereof, wherein: The antibody is conjugated to a compound of Formula I, as described above. In an embodiment, the BA is an antibody, or an antigen-binding fragment thereof, wherein the antibody is an antibody as described above. In any embodiment of this paragraph, BA is an antibody, or antigen-binding fragment thereof, wherein the antibody is a compound of formula III, as described above. In any of the embodiments of this paragraph, p1 is conjugated to 1, 2, 3 In any of the embodiments of this paragraph, k is 1, 2, 3, 4, 5, 6, 7, In any of the embodiments of this paragraph, k is 1 to 2, 1 to 3, 2 to 3, 2 In any of the embodiments of this paragraph, k is 1. In any of the embodiments of this paragraph, k is 2. In any of the embodiments of this paragraph, k is 4.

[0155] In certain embodiments, the compound or conjugate has the formula A″, or a pharmaceutical thereof An acceptable salt or stereoisomeric form, or positional isomer thereof: [ka] (In the formula: BA is a binder; Each SP 1 , SP 2 , and SP 3 is a spacer group as described above, where SP 3 is (AA) p1 brain linked to one amino acid residue AA of the p1 is an integer from 1 to 10; EG is a fortifying agent; k is an integer from 1 to 30; Q 1 , Q 2 , W, -R 1 -, R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I) .

[0156] As mentioned above, the attachment to the binding agent can be direct or via a spacer. In some embodiments, the linkage to the binding agent is via a PEG spacer. In some embodiments, the enhancer is a glutamine residue of the parent In some embodiments, the enhancer is a cyclodextrin. In embodiments, the reinforcing group is an alkyl, heteroalkyl, alkylenyl, or heteroalkyl. The cyclodextrin may be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin may be alphacyclodextrin. cyclodextrin, beta cyclodextrin, or gamma cyclodextrin, or In some embodiments, the cyclodextrin is an alpha cyclodextrin. In some embodiments, the cyclodextrin is beta cyclodextrin. In some embodiments, the cyclodextrin is a gamma cyclodextrin. In some embodiments, alkyl, heteroalkyl, alkylenyl, or heteroaryl is substituted or unsubstituted. Tetraalkylenylsulfonic acid is -(CH2) 1-5 SO3H, -(CH2) n2 -NH-(CH2) 1-5 SO3H, -(CH2)n2 - C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m2 -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n2 -N((CH2) 1-5 C(O)NH (CH2) 1-5 SO3H)2, -(CH2) n2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m2 -C( O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n2 is 1, 2, 3, 4, or 5, and m2 is In one embodiment, alkyl or alkylenyl sulphur is 1, 2, 3, 4, or 5. Phobic acid is -(CH2) 1-5 In another embodiment, heteroalkyl or heteroaromatic Alkylenylsulfonic acid is -(CH2) n2 -NH-(CH2) 1-5 SO3H (wherein n2 is 1, 2, 3, 4, or 5) In another embodiment, alkyl, heteroalkyl, alkylenyl, or Heteroalkylenyl sulfonic acids are -(CH2) n2 -C(O)NH-(CH2) 1-5 SO3H (where n2 is 1, 2, 3 In another embodiment, the alkyl, heteroalkyl, alkyl Heteroalkylenyl or heteroalkylenyl sulfonic acids are -(CH2CH2O) m2 -C(O)NH-(CH2) 1-5 SO3H(formula wherein m2 is 1, 2, 3, 4, or 5. In another embodiment, alkyl, hetero The alkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH)n2 -N((CH2) 1-5 C (O)NH(CH2) 1-5 SO3H2, where n2 is 1, 2, 3, 4, or 5. In this case, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acids are , -(CH2) n2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2 (where n2 is 1, 2, 3, 4, or 5) In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroaryl is Tetraalkylenyl sulfonic acid is -(CH2CH2O) m2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2(formula wherein m2 is 1, 2, 3, 4, or 5. In one embodiment, SP 1 Spacers are: [ka] and (wherein RG′ is the reactive group residue resulting from reaction of the reactive group RG with the coupling agent; [ka] is a direct or indirect bond to the binder; and b is an integer from 1 to 4; (AA) p1 -SP 2 - is -NH-lysine-valine-alanine-, -NH-lysine-valine-citrulline-, or -NH-lysine- Valine-Citrulline-PABC-;SP 3 Spacers are: [ka] is where RG′ is the reactive group residue resulting from reaction of the reactive group RG with the toughening agent EG; [ka] is the bond to the enhancer; and [ka] is (AA) p1 In any embodiment of this paragraph, the BA is an antibody or its an antigen-binding fragment, wherein the antibody is conjugated to a compound of formula I, as described above. In any of the embodiments of this paragraph, the BA is an antibody, or an antigen-binding fragment thereof. wherein the antibody is conjugated to a compound of formula II, as described above. In any of the embodiments, the BA is an antibody, or an antigen-binding fragment thereof, wherein the antibody is conjugated to a compound of formula III, as described above. In any of the embodiments of this paragraph, p1 is 1, 2, 3, 4, or 5. , k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In any of the embodiments of this paragraph and k ranges from 1 to 2, 1 to 3, 2 to 3, 2 to 4, 3 to 4, or 1 to 4. In any of the embodiments of this paragraph, k is 1. In any of the embodiments of this paragraph, k is 2. In any of the embodiments of this paragraph, k is 3. In this case, k is 4.

[0157] In certain embodiments, the compound or conjugate comprises: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof Body (In the formula: BA is a binder; each RG′ is a residue of a reactive group as described herein; EG is a fortifying agent; k is an integer from 1 to 30; Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 As noted above, the bond to the binding agent is This can be direct or via a spacer. In the method, the binding to the binder is via a PEG spacer to the glutamine residue of the binder. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancing group is alkyl, Heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acids. The cyclodextrin can be any cyclodextrin known to those of skill in the art. In this regard, cyclodextrins include alpha cyclodextrin, beta cyclodextrin, cyclodextrin, or gamma cyclodextrin, or a mixture thereof. In one embodiment, the cyclodextrin is alpha cyclodextrin. In some embodiments, the cyclodextrin is a beta cyclodextrin. In one embodiment, the cyclodextrin is gamma cyclodextrin. The alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH 2) 1-5 SO3H, -(CH2) n2 -NH-(CH2) 1-5 SO3H, -(CH2) n2 -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m2 - C(O)NH-(CH2) 1-5 SO3H, -(CH2) n2 -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2) n2 -C(O)N((CH 2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2( wherein n2 is 1, 2, 3, 4, or 5, and m2 is 1, 2, 3, 4, or 5). In one embodiment, the alkyl or alkylenyl sulfonic acid is —(CH) 1-5 It is SO3H. In another embodiment, the heteroalkyl or heteroalkylenyl sulfonic acid is —(CH) n2 -NH-(CH2) 1-5 SO3H, where n2 is 1, 2, 3, 4, or 5. and the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n2 -C(O)NH-(CH2) 1-5 SO3H (where n2 is 1, 2, 3, 4, or 5). In some embodiments, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyls are used. Sulfonic acid is -(CH2CH2O) m2 -C(O)NH-(CH2) 1-5 SO3H (wherein m2 is 1, 2, 3, 4, or 5) In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkyl is Alkyl sulfonic acid is -(CH2) n2 -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where n2 is In another embodiment, alkyl, heteroalkyl, Alkylenyl or heteroalkylenyl sulfonic acids are —(CH2) n2 -C(O)N((CH2) 1-5 C(O)NH( CH2) 1-5 SO3H2, where n2 is 1, 2, 3, 4, or 5. In another embodiment, The alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH 2CH2O) m2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where m2 is 1, 2, 3, 4, or 5. is.

[0158] In certain embodiments, the compound or conjugate comprises: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof Body (In the formula: BA is a binder; each RG′ is a residue of a reactive group as described herein; EG is a fortifying agent; k is an integer from 1 to 30; Q 1 , Q 2 , W., R. 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 As noted above, the bond to the binding agent is This can be direct or via a spacer. In the method, the binding to the binder is via a PEG spacer to the glutamine residue of the binder. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancing group is alkyl, Heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acids. The cyclodextrin can be any cyclodextrin known to those of skill in the art. In this regard, cyclodextrins include alpha cyclodextrin, beta cyclodextrin, cyclodextrin, or gamma cyclodextrin, or a mixture thereof. In one embodiment, the cyclodextrin is alpha cyclodextrin. In some embodiments, the cyclodextrin is a beta cyclodextrin. In one embodiment, the cyclodextrin is gamma cyclodextrin. The alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH 2) 1-5 SO3H, -(CH2) n2 -NH-(CH2) 1-5 SO3H, -(CH2) n2 -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m2 - C(O)NH-(CH2) 1-5 SO3H, -(CH2) n2 -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2) n2 -C(O)N((CH 2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2( wherein n2 is 1, 2, 3, 4, or 5, and m2 is 1, 2, 3, 4, or 5). In one embodiment, the alkyl or alkylenyl sulfonic acid is —(CH) 1-5 It is SO3H. In another embodiment, the heteroalkyl or heteroalkylenyl sulfonic acid is —(CH) n2 -NH-(CH2) 1-5SO3H, where n2 is 1, 2, 3, 4, or 5. and the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n2 -C(O)NH-(CH2) 1-5 SO3H (where n2 is 1, 2, 3, 4, or 5). In some embodiments, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyls may be used. Sulfonic acid is -(CH2CH2O) m2 -C(O)NH-(CH2) 1-5 SO3H (wherein m2 is 1, 2, 3, 4, or 5) In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkyl is Alkylenyl sulfonic acid is -(CH2) n2 -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where n2 is In another embodiment, alkyl, heteroalkyl, Alkylenyl or heteroalkylenyl sulfonic acids are —(CH2) n2 -C(O)N((CH2) 1-5 C(O)NH( CH2) 1-5 SO3H2, where n2 is 1, 2, 3, 4, or 5. In another embodiment, The alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH 2CH2O) m2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where m2 is 1, 2, 3, 4, or 5. is.

[0159] In certain embodiments, the compound or conjugate comprises: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof Body (In the formula: BA is a binder; k is an integer from 1 to 30; Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I; each [ka] is the bond to the reinforcing group; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 In some embodiments, the enhancer is In some embodiments, the enhancer is a cyclodextrin. In embodiments, the reinforcing group is alkyl, heteroalkyl, alkylenyl, or heteroalkenyl. The cyclodextrin may be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin can be alpha cyclodextrin. cyclodextrin, beta cyclodextrin, or gamma cyclodextrin, or and mixtures thereof. In some embodiments, the cyclodextrin is alphacyclodextrin. In some embodiments, the cyclodextrin is a beta cyclodextrin. In some embodiments, the cyclodextrin is gamma cyclodextrin. In some embodiments, alkyl, heteroalkyl, alkylenyl, or Heteroalkylenyl sulfonic acids are -(CH2) 1-5 SO3H, -(CH2) n2 -NH-(CH2) 1-5 SO3H, -(CH2) n 2-C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m2 -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n2 -N((CH2) 1-5 C(O) NH(CH2) 1-5 SO3H)2, -(CH2) n2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m2 - C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n2 is 1, 2, 3, 4, or 5, and m2 is In one embodiment, alkyl or alkylenyl Sulfonic acid is -(CH2) 1-5 In another embodiment, heteroalkyl or hetero Alkylenylsulfonic acids are -(CH2) n2 -NH-(CH2) 1-5 SO3H (wherein n2 is 1, 2, 3, 4, or 5) In another embodiment, alkyl, heteroalkyl, alkylenyl, or Heteroalkylenyl sulfonic acids are -(CH2)n2 -C(O)NH-(CH2) 1-5 SO3H (where n2 is 1, 2 In another embodiment, alkyl, heteroalkyl, aralkyl, aryl ... Alkylenyl or heteroalkylenyl sulfonic acids are -(CH2CH2O) m2 -C(O)NH-(CH2) 1-5 SO3H( wherein m2 is 1, 2, 3, 4, or 5. In another embodiment, The alkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n2 -N((CH2) 1- 5C(O)NH(CH2) 1-5 SO3H2, where n2 is 1, 2, 3, 4, or 5. In the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2 (wherein n2 is 1, 2, 3, 4, or 5) In another embodiment, alkyl, heteroalkyl, alkylenyl, or Heteroalkylenyl sulfonic acids are -(CH2CH2O) m2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2( wherein m2 is 1, 2, 3, 4, or 5).

[0160] In one embodiment, the conjugate comprises: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof Body (In the formula: BA is a binder; k is an integer from 1 to 30; Q 1 , Q 2 , W., R. 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I; each [ka] is the bond to the reinforcing group; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 It is heteroalkyl.

[0161] In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the reinforcing group is alkyl, heteroalkyl, or cyclodextrin. alkyl, alkylenyl, or heteroalkylenyl sulfonic acids. can be any cyclodextrin known to those of skill in the art. Cyclodextrins include alpha cyclodextrin, beta cyclodextrin, or gamma cyclodextrin, or a mixture thereof. The cyclodextrin is alpha cyclodextrin. The cyclodextrin is a beta cyclodextrin. The dextrin is gamma cyclodextrin. In some embodiments, the alkyl Heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acids are —(CH) 1-5 SO3H , -(CH2) n2 -NH-(CH2) 1-5 SO3H, -(CH2) n2 -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m2 -C(O)NH-(C H2) 1-5 SO3H, -(CH2) n2 -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2) n2 -C(O)N((CH2) 1-5 C(O) NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 (where n2 is , 1, 2, 3, 4, or 5, and m2 is 1, 2, 3, 4, or 5. In the formula, the alkyl or alkylenyl sulfonic acid is —(CH2) 1-5 SO3H. In the above, the heteroalkyl or heteroalkylenyl sulfonic acid is —(CH) n2 -NH-(CH2)1 -5 SO3H, where n2 is 1, 2, 3, 4, or 5. In another embodiment, The alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n2 -C (O)NH-(CH2) 1-5SO3H, where n2 is 1, 2, 3, 4, or 5. In this case, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acids are , -(CH2CH2O) m2 -C(O)NH-(CH2) 1-5 SO3H (wherein m2 is 1, 2, 3, 4, or 5). In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylene Nilsulfonic acid is -(CH2) n2 -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2 (where n2 is 1, 2, 3, 4 In another embodiment, alkyl, heteroalkyl, alkylenyl, The alkyl or heteroalkylenyl sulfonic acid is -(CH2) n2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3 H)2, wherein n2 is 1, 2, 3, 4, or 5. In another embodiment, alkyl, Heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acids are —(CH2CH2O) m2 -C (O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where m2 is 1, 2, 3, 4, or 5.

[0162] In certain embodiments, the compound or conjugate comprises: [ka] TIFF2025138724000237.tif189170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof Body (In the formula: BA is a binder; k is an integer from 1 to 30; Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 It is heteroalkyl.

[0163] In certain embodiments, the compound or conjugate comprises: [ka] TIFF2025138724000240.tif211170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof Body (In the formula: BA is a binder; k is an integer from 1 to 30; Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 It is heteroalkyl.

[0164] In certain embodiments, the compound or conjugate comprises: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof Body (In the formula: BA is a binder; k is an integer from 1 to 30; Q 1 , Q 2 , W., R. 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I; each [ka] is the bond to the reinforcing group; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C1-6 In some embodiments, the enhancer is In some embodiments, the enhancer is a cyclodextrin. In embodiments, the reinforcing group is alkyl, heteroalkyl, alkylenyl, or heteroalkenyl. The cyclodextrin may be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin can be alpha cyclodextrin. cyclodextrin, beta cyclodextrin, or gamma cyclodextrin, or and mixtures thereof. In some embodiments, the cyclodextrin is alphacyclodextrin. In some embodiments, the cyclodextrin is a beta cyclodextrin. In some embodiments, the cyclodextrin is gamma cyclodextrin. In some embodiments, alkyl, heteroalkyl, alkylenyl, or Heteroalkylenyl sulfonic acids are -(CH2) 1-5 SO3H, -(CH2) n2 -NH-(CH2) 1-5 SO3H, -(CH2) n 2-C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m2 -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n2 -N((CH2) 1-5 C(O) NH(CH2) 1-5 SO3H)2, -(CH2) n2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m2 - C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5SO3H)2, where n2 is 1, 2, 3, 4, or 5, and m2 is In one embodiment, alkyl or alkylenyl Sulfonic acid is -(CH2) 1-5 In another embodiment, heteroalkyl or hetero Alkylenylsulfonic acids are -(CH2) n2 -NH-(CH2) 1-5 SO3H (wherein n2 is 1, 2, 3, 4, or 5) In another embodiment, alkyl, heteroalkyl, alkylenyl, or Heteroalkylenyl sulfonic acids are -(CH2) n2 -C(O)NH-(CH2) 1-5 SO3H (where n2 is 1, 2 In another embodiment, alkyl, heteroalkyl, aralkyl, aryl ... Alkylenyl or heteroalkylenyl sulfonic acids are -(CH2CH2O) m2 -C(O)NH-(CH2) 1-5 SO3H( wherein m2 is 1, 2, 3, 4, or 5. In another embodiment, The alkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n2 -N((CH2) 1- 5C(O)NH(CH2) 1-5 SO3H2, where n2 is 1, 2, 3, 4, or 5. In the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2 (wherein n2 is 1, 2, 3, 4, or 5) In another embodiment, alkyl, heteroalkyl, alkylenyl, or Heteroalkylenyl sulfonic acids are -(CH2CH2O) m2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2( wherein m2 is 1, 2, 3, 4, or 5).

[0165] In certain embodiments, the compound or conjugate comprises: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof Body (In the formula: BA is a binder; k is an integer from 1 to 30; Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I; each [ka] is the bond to the reinforcing group; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 In some embodiments, the enhancer is In some embodiments, the enhancer is a cyclodextrin. In embodiments, the reinforcing group is alkyl, heteroalkyl, alkylenyl, or heteroalkenyl. The cyclodextrin may be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin can be alpha cyclodextrin. cyclodextrin, beta cyclodextrin, or gamma cyclodextrin, or and mixtures thereof. In some embodiments, the cyclodextrin is alphacyclodextrin. In some embodiments, the cyclodextrin is a beta cyclodextrin. In some embodiments, the cyclodextrin is gamma cyclodextrin. In some embodiments, alkyl, heteroalkyl, alkylenyl, or Heteroalkylenyl sulfonic acids are -(CH2) 1-5 SO3H, -(CH2) n2 -NH-(CH2) 1-5 SO3H, -(CH2) n 2-C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m2 -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n2 -N((CH2) 1-5 C(O) NH(CH2) 1-5 SO3H)2, -(CH2) n2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m2 - C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n2 is 1, 2, 3, 4, or 5, and m2 is In one embodiment, alkyl or alkylenyl Sulfonic acid is -(CH2) 1-5 In another embodiment, heteroalkyl or hetero Alkylenylsulfonic acids are -(CH2) n2 -NH-(CH2) 1-5 SO3H (wherein n2 is 1, 2, 3, 4, or 5) In another embodiment, alkyl, heteroalkyl, alkylenyl, or Heteroalkylenyl sulfonic acids are -(CH2) n2 -C(O)NH-(CH2) 1-5 SO3H (where n2 is 1, 2 In another embodiment, alkyl, heteroalkyl, aralkyl, aryl ... Alkylenyl or heteroalkylenyl sulfonic acids are -(CH2CH2O) m2 -C(O)NH-(CH2) 1-5 SO3H( wherein m2 is 1, 2, 3, 4, or 5. In another embodiment, The alkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n2 -N((CH2) 1- 5C(O)NH(CH2) 1-5 SO3H2, where n2 is 1, 2, 3, 4, or 5. In the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n2 -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2 (wherein n2 is 1, 2, 3, 4, or 5) In another embodiment, alkyl, heteroalkyl, alkylenyl, or Heteroalkylenyl sulfonic acids are -(CH2CH2O) m2 -C(O)N((CH2) 1-5C(O)NH(CH2) 1-5 SO3H)2( wherein m2 is 1, 2, 3, 4, or 5).

[0166] In certain embodiments, the compound or conjugate comprises: [ka] TIFF2025138724000249.tif95170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof Body (In the formula: BA is a binder; k is an integer from 1 to 30; Q 1 , Q 2 , W., R. 1 , R 2 , R 4 , R 5 , and R 6 is as described above in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 It is heteroalkyl.

[0167] In certain embodiments, the compound or conjugate comprises: [ka] TIFF2025138724000252.tif149170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof Body (In the formula: BA is a binder; k is an integer from 1 to 30; Q 1 , Q 2 , W, R 1 , R 2 , R 4 , R 5 , R 6 is as described above in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid described elsewhere herein. For example, in one embodiment, ZZ is C 1-6 As a further example, In an embodiment, ZZ is C 1-6 It is heteroalkyl.

[0168] In each of the above embodiments, the conjugate may be any of the conjugates described in the following sections. As such, it can be prepared from a linking agent functionalized with an azide group, and its residue. The triazole moiety in some of the structures above is shown in parentheses. The riazole is linked to the azide group of the azide-derivatized binder and the alkyne of the linker-payload LP. You will be aware that it can be formed from

[0169] In certain embodiments, the compound or conjugate is: [ka] TIFF2025138724000255.tif247170TIFF2025138724000256.tif156170TIFF2025138724000257.tif179170TIFF2025 138724000258.tif214170TIFF2025138724000259.tif243170TIFF2025138724000260.tif242170TIFF202513872400 TIFF2025138724000262.tif186170TIFF2025138724000263.tif223170TIFF2025138724000264.tif248170TIFF2025138724000265.tif180170TIFF2025138724000266.tif197170; or a positional or stereoisomeric form thereof. In embodiments, the BA is a binding agent. In any of the embodiments of this paragraph, the BA is an antibody, or an antigen-binding fragment thereof. In any of the embodiments of this paragraph, k is an integer from 1 to 30. In any of the embodiments of this paragraph, k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or In any of the embodiments of this paragraph, k is 1 to 2, 1 to 3, 2 to 3, 2 to 4, 3 to 4 or in the range of 1 to 4. In any of the embodiments of this paragraph, k is 1. In any of the embodiments of this paragraph, k is 2. In any of the embodiments of this paragraph, k is 3. In any of the embodiments of this paragraph, k is 4.

[0170] Further provided herein are: [ka] TIFF2025138724000268.tif217170TIFF2025138724000269.tif184170TIFF2025138724000270.tif86170.

[0171] In any of the embodiments of the compounds or conjugates provided, the BA binds to HER2. An embodiment of the compound or conjugate is an antibody or antigen-binding fragment thereof that binds to the antibody. In any of the above, the BA is an antibody or antigen-binding fragment thereof that binds to PRLR. In any of the embodiments of the compound or conjugate described above, BA is an antibody or its antigen. binding fragment, and the conjugation is via at least one Q295 residue. In any of the embodiments of the compounds or conjugates provided, the BA is an antibody. or an antigen-binding fragment thereof, and wherein the conjugation is via the two Q295 residues. In any of the embodiments of the compounds or conjugates provided, BA is N2 97Q antibody or an antigen-binding fragment thereof. In any one of the above, the BA is the N297Q antibody or an antigen-binding fragment thereof, and the conjugate The coupling is via at least one Q295 and at least one Q297 residue. In any of the embodiments of the compound or conjugate described above, the BA is an N297Q antibody or and the conjugation is via two Q295 residues and two Q297 residues. In certain embodiments, the numbering is according to the EU numbering system.

[0172] In any of the above embodiments, the BA is an anti-MSR1 antibody. BA is the anti-MSR1 antibody H1H21234N described in the Examples below. A is the anti-MSR1 antibody H1H21234N N297Q described in the Examples below. BA is an anti-MSR1 antibody comprising an HCVR according to SEQ ID NO:2 and an LCVR according to SEQ ID NO:10. In certain embodiments, the BA comprises an HCDR according to SEQ ID NOs: 4, 6, 8, 12, 14, and 16, respectively. 1, 2, 3, 4, 5, or 6 of HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 In one embodiment, the HCVR is an anti-MSR1 antibody comprising: In certain embodiments, the LCVR is encoded by SEQ ID NO:9. In the above, one, two, three, or four of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 , five, or six of the polynucleotide sequences SEQ ID NOs: 3, 5, 7, 11, 13, and N297Q is encoded by the amino acid sequence N297Q, where one or more residues 297 are asparagine (N) to glutamine (G). Preferably, each residue 297 is mutated to Q. In a preferred embodiment, the numbering is according to the EU numbering system. In some embodiments, k is 1 to 4. In some embodiments, k is 1, 2, 3, or 4. In some embodiments, k is 4. In some embodiments, BA is WO 2019 / 217591 filed May 8, 2019, which is incorporated herein by reference. The anti-MSR1 antibody is described in

[0173] (Method of Preparing the Compound) The compounds provided herein may be prepared, isolated, or purified by any method apparent to one skilled in the art. Exemplary preparation methods are described in detail in the examples below. In certain embodiments, the compounds provided herein can be prepared according to Schemes A and B. It is possible.

[0174] (Scheme A: Exemplary Preparation Scheme) [ka] In exemplary preparation scheme A, Q 1 , Q 2 , W, R 1 , R 2 , R 6 and n in the context of formula (I) After the initial esterification, R 1 Protection of and / or R 2 P R 1 R 1 After protection of the carboxylic acid moiety, for example, After denitrification and activation, Q 1 Amination Subsequent saponification and amidation of the carboxylic acid moiety, for example, gives Q 2 A second cup having Ring partners are created. Each Q 1 and Q 2 Integrates a coupling partner with followed by R 1 and R 2 Deprotection of each of these compounds yields compounds of formula I. The preparation method is described in detail in the Examples below.

[0175] In certain embodiments, one or more protection or deprotection steps are performed as described in Scheme A above. It may be included in the preparation method.

[0176] The linker-payloads described herein are synthesized by a series of coupling steps. For example, the payload on the right can be coupled to the carboxyl group via one or more standard coupling reactions. By SP 2 In a preferred embodiment, the Payload compounds are available for coupling via the amide synthesis conditions described herein. Contains a free amino group capable of being cleaved. (AA) p1 The amino acid is synthesized under amide synthesis conditions, e.g., peptide synthesis. Spacer SP can be added depending on synthesis conditions. 2 is one or more standard couples By the ing reaction (AA) p1 In a preferred embodiment, the SP to be described 2 and (AA) p1 The groups are coupled by the amide synthesis conditions described herein. If present, the spacer SP 3 can be converted to (AA) by one or more standard coupling reactions. p1 It can be connected to In certain embodiments, the SPs described herein 3 and (AA) p1 The groups are described herein. Contains a free amino or carboxyl group available for coupling under amide synthesis conditions. nothing.

[0177] (Scheme B1 Exemplary Preparation Scheme) [ka] In exemplary preparation scheme B1, B1 is oxidatively decarboxylated to give B2, followed by B2 is replaced with a payload (HO-payload or H2N-payload) to give B3 or B4 Alternatively, B5 may be used with a payload (HO-payload or H2N-payload, respectively). Esterification or peptide coupling can give B6 or B7.

[0178] (Scheme B2 Exemplary Preparation Scheme) [ka] In exemplary preparation scheme B2, B3, B4, B6, or B7 is a peptide coupling with BB. and then deprotected to give B8, B9, B10, or B11. B8 to B11 are independently B12 to B19 are peptide-coupled with either enantiomer of protected glutamic acid. Activation of B20 or B21 carboxylates gives B22 or B23, which are then Each of these is independently linked to one of B12 to B19 to obtain B24 to B27.

[0179] Spacer SP 3 When present, the reactive group RG terminates. The compound is coupled to the strengthener EG under coupling conditions deemed suitable by the user. In one embodiment, the spacer SP 3 is enhanced by amide synthesis conditions In some embodiments, the spacer SP 3 Click Chemistry Thus, the spacer SP is linked to the enhancer EG. 3 Click The toughener EG is terminated with a suitable reactive group, e.g., azide or alkyne, for the click reaction. In a preferred embodiment, the compound comprises a suitable complementary reactive group, such as an alkyne or an azide. SP 3 terminates in a strained alkyne and EG contains an azide; or SP 3 terminates in a carboxylic acid However, EG contains an amine. When EG is a cyclodextrin moiety, the cyclodextrin The phosphorus may contain azide. Azidocyclodextrins can be prepared synthetically. or obtained from a commercial source. When EG is a sulfonic acid moiety, The (s) are terminated with sulfonic acid group(s) and the other end with a primary or secondary amine. do.

[0180] The conjugates described herein may comprise a linker-payload as described herein. is coupled to a binding agent, e.g., an antibody, under standard conjugation conditions. and (e.g., the entire contents of which are incorporated herein by reference) (See Doronina et al., Nature Biotechnology 2003, 21, 7, 778 for a review.) When the combination is an antibody, the antibody is fused to the antibody via one or more cysteine ​​or lysine residues of the antibody. The linker-payload may be linked to a linker-payload, for example, to bind the antibody. Disulfide bonds of the antibody are broken down by exposure to a disulfide-binding agent, such as dithiotheritol. The cleaved and reduced antibody is purified, for example, by gel filtration, and then the antibody is By treating the linker-payload with a suitable reactive moiety, e.g., a maleimide group, Suitable solvents include water, DMA, and DMF. and DMSO. Reactive groups, such as activated esters or linking a linker-payload containing an acid halide group to a lysine residue of an antibody Suitable solvents include water, DMA, DMF, and DMSO. Conjugates can be purified by, but not limited to, methods such as size exclusion chromatography, dialysis, and Purification can be achieved using known protein techniques including ultrafiltration / diafiltration.

[0181] Conjugating a binding agent, e.g., an antibody, by a click chemistry reaction In some embodiments of the click chemistry reaction, a linker-pay The load contains a reactive group, e.g., an alkyl group, that can undergo a 1,3-cycloaddition reaction with an azide. Suitable such reactive groups are described above. The antibody may comprise one or more azines. Such antibodies include, for example, antibodies functionalized with an azido-polyethylene glycol group. In some embodiments, such functionalized antibodies are enzyme-transferase-activated antibodies. In the presence of transglutaminase, at least one glutamine residue, e.g., heavy chain Gln29 It is induced by treating an antibody having Gln5 or Gln55 with a primary amine compound. In an embodiment, such functionalized antibodies are prepared by the procedure of: An antibody having at least one glutamine residue, e.g., heavy chain Gln297, is ligated to a primary amine compound. Such antibodies are induced by treatment with the Asn297Gln (N297Q) mutation. In some embodiments, such functionalized antibodies are capable of binding to the enzyme transglutaminase. In the presence of glutamine, at least two glutamine residues, e.g., heavy chain Gln295 and heavy chain Gln 297-containing antibody is induced by treating it with a primary amine compound. The antibody includes the Asn297Gln (N297Q) mutant. Two glutamine residues in total, or two glutamine residues in total, as described in this paragraph. It has a heavy chain.

[0182] In certain embodiments, the antibody contains two glutamine residues, one in each heavy chain. In one embodiment, the antibody comprises a Q295 residue in each heavy chain. The body may contain one, two, three, four, five, six, seven, eight, or more glutamine residues. These glutamine residues can be present in the heavy chain, the light chain, or both the heavy and light chains. Exemplary glutamine residues include Q55. These glutamine residues The residues may be wild-type or modified. The antibody may be purified by standard techniques. It can be prepared more easily.

[0183] Those skilled in the art will appreciate that antibodies often contain a glycosylated residue at residue N297, which is near residue Q295 in the heavy chain sequence. It will be recognized that the glycosylation at residue N297 is sylated at residue Q295. can interfere with transglutaminase (Dennler et al., supra). In a preferred embodiment, the antibody is aglycosylated. In certain embodiments, the antibody complex is deglycosylated or aglycosylated. The chain has an N297 mutation. In other words, the antibody no longer has an asparagine residue at position 297. In certain embodiments, the antibody heavy chain has a N297Q mutation. Such antibodies can be generated by site-directed mutagenesis to remove or disable glycosylation sequences. or by inserting a glutamine residue at a site that does not abolish antibody function or binding. In one embodiment, the Q295 residue can be prepared by site-directed mutagenesis. and / or the antibody with the N297Q mutation can access transglutaminase and therefore and one or more linkers or linker-payloads that can be conjugated to the linker or linker-payload. They contain additional native glutamine residues in their variable regions. Exemplary native glutamine residues are: The group can be found, for example, at Q55 of the light chain. Antibodies conjugated with tamoxifen have a higher than expected drug:antibody ratio (DA). Any such antibody may have a DAR of greater than 4. It can be isolated from industrial sources.

[0184] The antibody, which does not interfere with glycosylation, is then reacted with a primary amine compound. In embodiments, the aglycosylated antibody is reacted with a primary amine compound to form a glycosylated antibody. In one embodiment, the deglycosylated antibody is prepared by the primary Reaction with an amine compound results in the formation of a glutaminyl-modified antibody.

[0185] Kabat et al. ("Kabat" numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948 ("Chothia" numbering scheme); MacCallum et al., 1996, J. Mol. Biol. 262 :732-745 ("Contact" numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27 :55-77 ("IMGT" numbering scheme); and Honegge and Pluckthun, J. Mol. Biol., 20 01, 309:657-70 ("AHo" numbering scheme) A scheme can be used to number the amino acid sequence of an antibody. To the extent possible, the numbering scheme used herein is the Kabat numbering scheme. , the choice of numbering scheme is not intended to imply sequence differences where they do not exist. Those skilled in the art can readily ascertain the sequence location by examining the amino acid sequence of one or more antibodies. When referring to residues in an antibody heavy chain constant region, unless otherwise specified, The "EU numbering scheme" is commonly used (e.g., as reported in Kabat et al., supra). ).

[0186] The term "aglycosylated antibody" refers to an antibody that may interfere with the transglutamination reaction. Antibodies that do not contain a glycosylation sequence that may be glycosylated, e.g., antibodies that do not contain a glycosylation site at N297 of one or more heavy chains. In certain embodiments, the antibody heavy chain has an N297 mutation. In other words, the antibody is numbered 297 according to the EU numbering system as disclosed in Kabat et al. In certain embodiments, the antibody heavy chain is mutated to no longer have an asparagine residue. The chain has the N297Q or N297D mutation. Such antibodies have a glycosylation sequence removed or eliminated. by site-directed mutagenesis to enhance the activity of the nucleotide sequence, or by removing interfering glycosylation sites or other interfering structures. The nucleotide sequence can be prepared by site-directed mutagenesis to insert a glutamine residue at the site of Such antibodies may also be isolated from natural or artificial sources.

[0187] The term "deglycosylated antibody" refers to an antibody in which the saccharide group at N297 has been removed, thereby refers to an antibody in which Q295 is released for transglutamation. In accordance with the present invention, provided herein are additional methods for deglycosylating antibodies, e.g., N297 antibodies. It is a process that includes steps.

[0188] The primary amine forms a covalent bond with a glutamine residue in the presence of transglutaminase. The primary amine can be any primary amine that can be synthesized. Useful primary amines are those described above. The transglutaminase may be any suitable enzyme as deemed suitable by one skilled in the art. In one embodiment, the transglutaminase Aminoase reacts with the free amine group on the primary amine compound and the acyl group on the side chain of the glutamine residue. Transglutaminase is an enzyme that catalyzes the formation of isopeptide bonds between glutamic acid and glutamic acid. Also known as protein-glutamine-γ-glutamyltransferase. In embodiments, the transglutaminase is classified as EC 2.3.2.13. The glutaminase may be from any source deemed suitable. In some embodiments, the transglutaminase is microbial. Glutaminase was found in Streptomyces mobaraense, Streptomyces cinnamoneum, Streptomyces g Streptomyces griseo-carneum, Streptomyces lavendula Isolated from Streptomyces lavendulae and Bacillus subtilis Non-microbial transglutaminase, including mammalian transglutaminase, has been reported. In one embodiment, transglutaminase can be used. May be produced by any technique deemed appropriate by a skilled artisan In certain embodiments, transglutaminase may be obtained from any source. The minase is obtained from commercial sources.

[0189] In certain embodiments, the primary amine compound is In these embodiments, glutamic acid is a hydroxy group that contains a reactive group that can undergo further reaction. The hydroxyl-modified antibody can be coupled to a reactive payload compound, a linker-payload, or a reactive linker- Reacting or treating with a payload compound to produce an antibody-payload conjugate. In some embodiments, the primary amine compound comprises an azide.

[0190] In some embodiments, the glutaminyl-modified antibody is linked to a linker-payload or reactive linker. reacting or treating with an anchor-payload to produce an antibody-payload conjugate; The reaction can proceed under conditions deemed appropriate by one skilled in the art. In some embodiments, the glutaminyl-modified antibody and the linker-payload compound can be The glutaminyl-modified antibody is attached to the linker-peiro under conditions suitable for forming a bond between them. The appropriate reaction conditions are known to those skilled in the art. It is well known.

[0191] Exemplary reactions are provided in the Examples below.

[0192] Pharmaceutical Compositions and Methods of Treatment Provided herein are therapeutically or prophylactically effective amounts of the compounds disclosed herein. or one or more of the payloads, for example, one of the compounds of the formula provided herein and a method for treating and preventing a disease, condition, or disorder comprising administering the above. The diseases, disorders, and / or conditions include those associated with the antigens listed herein. However, it is not limited to these.

[0193] The compounds described herein may be administered alone or in combination with one or more additional therapeutic agents. The one or more additional therapeutic agents may be administered immediately following administration of the compounds described herein. The present disclosure also provides the A pharmaceutical composition comprising any of the compounds described above in combination with one or more additional therapeutic agents. and methods of treatment comprising administering such combinations to a subject in need thereof. The method includes:

[0194] Suitable additional therapeutic agents include: a second glucocorticoid, an autoimmune agent, a hormone These include, but are not limited to, monoclonal antibodies, biologics, or monoclonal antibodies. Suitable therapeutic agents include any pharmaceutically acceptable salts of the compounds described herein. This includes, but is not limited to, salts, acids, or derivatives.

[0195] In some embodiments of the methods described herein, multiple doses of the methods described herein are administered. The compounds described herein (or the compounds described herein and the additional therapeutic agents mentioned therein) a pharmaceutical composition containing a combination of any of the therapeutic agents of the present invention over a specified time period The method according to this aspect of the disclosure may involve administering to the subject multiple doses of the compounds described herein. As used herein, "sequential administration" includes administering compounds sequentially. " means that each dose of the compound is administered at different time points, e.g., at predetermined intervals (e.g., hours, days, This means that the compounds are administered to a subject on different days separated by a period of time (weeks or months). The present invention provides a method for treating a patient with a single initial dose of a compound described herein, followed by one or more subsequent doses of the compound. a second dose of the compound, and optionally, one or more subsequent third doses of the compound. The present invention also includes a method comprising:

[0196] The terms "initial dose," "second dose," and "third dose" refer to the compounds described herein. Thus, an "initial dose" refers to the time sequence of administration of a compound administered at the beginning of a treatment regimen. the first dose (also known as the "baseline dose"); the "second dose" is the dose administered after the initial dose. The "third dose" is the dose administered after the second dose. The doses may all contain the same amount of a compound described herein, but typically vary depending on the frequency of administration. In some embodiments, the initial, second, and / or third doses may differ from one another in terms of intensity. The amounts of the compounds contained in the In some embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered in a single dose. Administered as a "loading dose" at the beginning of a treatment regimen, followed by less frequent Subsequent doses (e.g., "maintenance doses") are administered at 100 mg / kg / day.

[0197] In certain exemplary embodiments of the present disclosure, each second and / or third dose is 1 to 3 times the dose immediately preceding it. 26 weeks (e.g., 1, 1 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, 26 1 / 2 weeks or longer) As used herein, the phrase "the most recent dose" refers to a dose administered in a series of multiple doses. administered to a patient prior to administration of the very next dose in the sequence without any intervening doses. It refers to the dose of compound given.

[0198] The method according to this aspect of the disclosure may further comprise administering to the patient any number of second and / or third doses of the compound. For example, in some embodiments, only a single second dose is administered to the patient. In another embodiment, the compound is administered two or more times (e.g., 2, 3, 4, 5, 6, 7, 8, or more times). Similarly, in some embodiments, a single third dose (or more) is administered to the patient. In another embodiment, two or more (e.g., 2, 3, 4, 5, 6) doses are administered to the patient. A third dose (one, two, three, or more) is administered to the patient. indefinitely for the life of the elephant, or until such treatment is no longer therapeutically necessary. It may be carried out for a period of time or until it is no longer beneficial.

[0199] In embodiments comprising multiple second doses, each second dose is administered at the same frequency as the other second doses. For example, each second dose may be administered to the patient 1-2 weeks or 1-2 months after the immediately preceding dose. Similarly, in embodiments comprising multiple third doses, each third dose may be administered at a time. Each third dose may be administered at the same frequency as the other third doses. For example, each third dose may be administered immediately to the patient. In some embodiments of the present disclosure, the second and third doses may be administered 2 to 12 weeks after the previous dose. and / or the frequency with which the third dose is administered to the patient may vary between treatment regimens. It is also adjusted by the doctor during the course of treatment according to the individual patient's needs after clinical examination. Good too.

[0200] The present disclosure provides that 2 to 6 loading doses are administered at a first frequency (e.g., once weekly, once every two weeks, once every three weeks, once a month, once every two months, etc.), followed by two or more For example, dosing regimens include those in which the patient receives a maintenance dose less frequently than the doses described herein. According to this aspect of the invention, if the loading dose is administered monthly, the maintenance dose may be administered to the patient once every six weeks, once every two months, once every three months, etc.

[0201] The present disclosure relates to compounds, payloads, linker-payloads, and / or are conjugates, e.g., pharmaceutical compositions of compounds of Formula I, Formula II, and / or Formula III, e.g., The compounds described herein, their salts, stereoisomers, polymorphs, and pharmaceutically acceptable salts thereof, Suitable carriers, diluents, and excipients are also included in the compositions. Examples of agents include buffers for maintaining the appropriate composition pH (e.g., citrate buffer, -, succinate buffer, acetate buffer, phosphate buffer, lactate buffer, oxalate acid buffer, etc.), carrier protein (e.g., human serum albumin), saline, Polyols (e.g., trehalose, sucrose, xylitol, sorbitol, etc.), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxolate, etc.), antimicrobials These include, but are not limited to, biological agents, and antioxidants.

[0202] In some instances, those described herein are used to treat a disease, disorder, or condition. a therapeutically effective amount of a compound of Formula I, Formula II, and / or Formula II to a patient having the disorder; The method comprises administering a compound of formula I or a pharmaceutical composition thereof.

[0203] In some instances, those described herein are used to prevent a disease, disorder, or condition. a prophylactically effective amount of a compound of Formula I, Formula II, and / or Formula II to a patient having the disorder; The method comprises administering a compound of formula I or a pharmaceutical composition thereof.

[0204] In some instances, described herein are antibodies that are responsive to modulation of LXR signaling. In some examples, the present invention is a method for treating or preventing any disease, disorder, or condition of the present invention. wherein the disease or disorder is related to LXR function, LXR polymorphisms, LXR agonist activity, or LXR antagonist activity. In some instances, the methods described herein are associated with proliferative disorders, neurodegenerative disorders, and the like. Degenerative disorders, immunological disorders, autoimmune diseases, inflammatory disorders, skin diseases, metabolic diseases, cardiovascular and gastrointestinal disorders. This is a method.

[0205] The proliferative disorder can be any proliferative disorder known to those of skill in the art. In this regard, proliferative disorders include, but are not limited to, oncology disorders wherein the oncological disorder can be any cancer disorder known to those skilled in the art. In certain embodiments, provided herein are methods for treating or preventing melanoma. In certain embodiments, provided herein are methods for treating metastatic melanoma. In one embodiment, provided herein are methods for treating or preventing lung cancer. In some embodiments, provided herein are methods for treating or preventing EG A method for treating or preventing FR-tyrosine kinase inhibitor-resistant lung cancer. In accordance with the present invention, provided herein are methods for treating or preventing oral cancer. In embodiments, provided herein are methods for treating or preventing oral squamous cell carcinoma. In certain embodiments, provided herein are methods for treating or preventing prostate cancer. In some embodiments, provided herein are methods for preventing Hodgkin's lymphoma. In one embodiment, provided herein is a method for treating or preventing a tumor, comprising: A method for treating or preventing breast cancer.

[0206] The neurodegenerative disorder can be any neurodegenerative disorder known to those of skill in the art. In accordance with the present invention, provided herein are methods for treating or preventing Alzheimer's disease. In certain embodiments, provided herein are methods for treating or preventing Parkinson's disease. In some embodiments, provided herein are methods for treating Huntington's disease. In one embodiment, provided herein are methods for treating or preventing muscle atrophy. In one embodiment, the method comprises administering to a subject a compound provided herein, the compound being administered to a subject ... Provided are methods for treating or preventing myelin gene expression. Provided herein are methods for treating myelination and remyelination conditions, diseases, or disorders. A method of treatment or prevention.

[0207] The immunological disorder can be any immunological disorder known to those of skill in the art. In accordance with the present invention, provided herein are methods for treating or preventing inflammatory bowel disease. In certain embodiments, provided herein are methods for treating or preventing ulcerative colitis. In certain embodiments, provided herein are methods for treating or preventing Crohn's disease. It is a way to prevent this.

[0208] The inflammatory disorder can be any inflammatory disorder known to those of skill in the art. In one embodiment, provided herein is a method for treating or preventing arthritis. In accordance with the present invention, provided herein are methods for treating or preventing rheumatoid arthritis.

[0209] The metabolic disorder can be any metabolic disorder known to those of skill in the art. In the present invention, the metabolic disorder is dyslipidemia. Dyslipidemia can be any lipid abnormality known to those skilled in the art. In some embodiments, the dyslipidemia can be hyperlipidemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia, HDL deficiency, ApoA-I deficiency, and Cardiovascular diseases, such as coronary artery disease (e.g., angina pectoris, myocardial infarction, and sudden cardiac death) including the treatment and prevention of atherosclerosis; and prevention); and restenosis (e.g., as a result of medical procedures such as balloon angioplasty). and (including the treatment or prevention of atherosclerotic plaques resulting from the In certain embodiments, provided herein are methods for treating or preventing diabetes. It is the law.

[0210] The cardiovascular disease can be any cardiovascular disease known to those of skill in the art. In the present specification, there is provided a method for treating or preventing atherosclerosis. In one embodiment, provided herein is a method for treating abnormal macrophage proliferation. A method for treating or preventing atherosclerosis resulting from vasoconstriction. In an embodiment, provided herein is a method for treating oxLDL in macrophages. Atherosclerosis results from the formation of oxidized low-density lipoprotein (oxLDL) that cannot be removed. In one embodiment, provided herein are methods for treating or preventing a rheumatoid arthritis. In one embodiment, the present invention provides a method for treating or preventing ischemic heart disease. Contemplated is a method for treating or preventing stroke. Provided are methods for treating or preventing hypertensive heart disease. In certain embodiments, Provided herein are methods for treating or preventing aortic aneurysms. In one embodiment, provided herein is a method for treating or preventing endocarditis. In accordance with the present invention, provided herein are methods for treating or preventing peripheral arterial disease. In certain embodiments, provided herein is a method for treating a disease as presented in this paragraph. The present invention is a method for treating or preventing any combination of these.

[0211] In some instances, described herein are methods for modulating the function of nuclear receptors. By way of non-limiting example, the function may be to inhibit inflammatory mediators (e.g., cytokines, Expression / secretion of kines and chemokines, cholesterol regulation, cholesterol uptake, cholesterol cholesterol efflux, cholesterol oxidation, migration, chemotaxis, apoptosis and necrosis, inflammatory activity, lipid Selected from quality control, apoptosis, migration, chemotaxis, gene transcription, and protein expression obtain. [Example]

[0212] (Example) Provided herein are novel bis-octahydrophenanthrenecarboxamides, Protein conjugates thereof, and the bis-octahydrophenanthrene carboxamide Methods for treating diseases, disorders, and conditions comprising administering amides and conjugates It is the law.

[0213] In some instances, the compound of formula (I) is a compound identified in Table 1. (Table 1. Payload list) [Table 1] TIFF2025138724000275.tif227170TIFF2025138724000276.tif246170

[0214] Examples of linker-payloads of the present disclosure include those listed in Table 2 below. However, the present invention is not limited to these. (Table 2. Linker-payload list) [Table 2] TIFF2025138724000278.tif235170TIFF2025138724000279.tif156170

[0215] Certain embodiments of the invention are illustrated by the following non-limiting examples.

[0216] Unless otherwise expressly stated, reagents and solvents were purchased from Sinopharm Chemical Reagent Co. (S CRC), Sigma-Aldrich, Alfa, or other suppliers.

[0217] 1 H NMR and other NMR spectra were recorded on a Bruker AVIII 400 or Bruker AVIII 500. The data were processed using Nuts software or MestReNova software, and the proton shifts were calculated. Measurements were made in parts per million (ppm) downfield from the internal standard tetramethylsilane.

[0218] HPLC-MS measurements were performed on an Agilent 1200 HPLC / 6100 SQ system using the following conditions:

[0219] Method A for HPLC-MS measurement included the following mobile phases: A: water (0.01% TFA) and B: acetonitrile The gradient phase consisted of 5% B to 95% B over 15 minutes (min) at 1.0 mL / min. The column used was a SunFire C18, 4.6 x 50 mm, 3.5 μm. The column temperature was 50 °C. The detector was an analog-to-digital converter (ADC). Light scattering detector (hereinafter referred to as "ADC ELSD"), diode array detector (DAD, 214 nm and 254 nm), and electrospray ionization-atmospheric pressure ionization (ES-API).

[0220] Method B for HPLC-MS determination used the following mobile phases: A: water (10 mM NH4HCO3) and B: acetonitrile The gradient phase consisted of 5% B increasing to 95% B over 15 min at 1.0 mL / min. The column used was an XBridge C18, 4.6 x 50 mm, 3.5 μm. The system temperature was 50° C. The detectors included an ADC ELSD, a DAD (214 nm and 254 nm), and a mass selective A detector (MSD ES-API) was included.

[0221] LC-MS measurements were performed on an Agilent 1200 HPLC / 6100 SQ system using the following conditions:

[0222] Method A for LC-MS measurements was performed on a WATERS 2767 instrument. The column was a Shimadzu Shim-Pac The column was a PRC-ODS column, 20 x 250 mm, 15 μm (two columns connected in series). The mobile phase was A: water (0.01% TFA A: acetonitrile (0.01% TFA) and B: acetonitrile (0.01% TFA). The gradient phase was 1.8–2.3 mL / min for 3 min. The column used was a SunFire C18 column. The column temperature was 50°C. The detectors were ADC ELSD, D AD (214 nm and 254 nm), and MSD ES-API were included.

[0223] Method B for LC-MS measurements was performed on a Gilson GX-281 instrument. The column was an Xbridge Prep C1 The column was 8 10 μm OBD, 19 × 250 mm. The mobile phase was A: water (10 mM NH4HCO3) B: acetonitrile. The gradient phase was 5% B increasing to 95% B over 3 min at 1.8–2.3 mL / min. The column used was an XBridge C18, 4.6 x 50 mm, 3.5 μm. The temperature was 50° C. The detectors were ADC ELSD, DAD (214 nm and 254 nm), and MSD ES-API. Including.

[0224] Preparative high pressure liquid chromatography (preparative HPLC) was performed on a Gilson GX-281 instrument. Two solvent systems were used, one acidic and the other basic. For the acidic solvent system (Method A), Waters Sun A fire 10 μm C18 column (100 Å, 250 × 19 mm) was included. Solvent A for preparative HPLC was 0.05% in water. The solvent A was TFA, and solvent B was acetonitrile. The elution conditions were 30 mL / min for 20 min. A linear gradient was used, increasing solvent B from 5% to 100%. Basic Solvent System (Method B) The solvents used for preparative HPLC included a Waters Xbridge 10 μm C18 column (100 Å, 250 × 19 mm). Solvent A was 10 mM ammonium bicarbonate (NH4HCO3) in water and solvent B was acetonitrile. The elution conditions were a linear gradient of increasing solvent B from 5% to 100% over 20 minutes at 30 mL / min. It was Zient.

[0225] Flash chromatography was performed using Agela Flash columns silica-CS on a Biotage system. Reversed-phase flash chromatography was performed unless otherwise explicitly indicated. Except where noted, analyses were performed on a Biotage instrument using Boston ODS or Agela C18.

[0226] As used herein, the terms used in these processes, schemes, and examples are The symbols and conventions are based on modern scientific notation, regardless of whether a particular abbreviation is specifically defined. Literature, e.g., the Journal of the American Chemical Society or the Journal of Bio Consistent with those used in logical chemistry. The following abbreviations may be used in the examples and throughout the specification: [Table 3] TIFF2025138724000281.tif241170

[0227] (Preparation method) Example 1 This example illustrates a method for the synthesis of podocarpic acid derivatives P1, P15, and P2 in Table 1 above. In this example, the numbers 1 to 12a-b and P1, P15, and P2 in FIG. This refers to compounds that have been

[0228] (Methyl (1S,4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydro phenanthrene-1-carboxylate (2) [ka] A solution of podocarpic acid (1, 90 g, 0.33 mol) in methanol (200 mL) and toluene (600 mL) To the reaction mixture was added (trimethylsilyl)diazomethane (2M in hexane, 200 mL). The mixture was stirred at room temperature for 2 hours. LCMS showed that the podocarpic acid was completely consumed. The solids were removed in vacuo and the residue was triturated from petroleum ether (2 L) to give compound 2 (91 g). , 96% yield) was obtained as a white solid. ESI m / z: 289 (M + H) + . [ka]

[0229] (Methyl (1S,4aS,10aR)-1,4a-dimethyl-6-(trifluoromethanesulfonyloxy)-1,2,3 ,4,4a,9,10,10a-Octahydrophenanthrene-1-carboxylate (3) [ka] A solution of compound 2 (10 g, 35 mmol) in methylene chloride (200 mL) was added with pyridine (3.3 g, 42 mmol) and DMA. P (0.84 g, 6.9 mmol) was added under nitrogen. The mixture was cooled to -78°C and trifluoromethane Sulfonic anhydride (12 g, 42 mmol) was added. The resulting mixture was warmed to 25° C. The reaction mixture was stirred at 0 C for an additional 4 hours. The reaction mixture was diluted with DCM (500 mL) and diluted with water (100 mL), aqueous hydrochloric acid (1N, 150 mL) and brine (100 mL), dried over sodium sulfate and concentrated in vacuo. This gave crude compound 3 (14 g, 97% crude yield) as a viscous oil, which was suitable for the next step. The crude compound 3 was purified by flash chromatography (0.05% ethanol in petroleum ether). Purification by elution with 10% ethyl acetate afforded pure 3 as a viscous oil. ESI m / z: 421.2 (M + 1) + . [ka]

[0230] (Methyl (1S,4aS,10aR)-6-((tert-butoxycarbonyl)amino)-1,4a-dimethyl-1,2,3,4, 4a,9,10,10a-Octahydrophenanthrene-1-carboxylate (4) [ka] Compound 3 (14 g, 34 mmol) and tert-butyl carbamate (BocNH2, 7.9 g, 68 mmol) In a solution of butanol (100 mL), cesium carbonate (22 g, 68 mmol), tris(dibenzylidene acetone) Dipalladium(0) (Pd2(dba)3, 1.8 g, 2.0 mmol) and X-Phos (1.8 g, 4.0 mmol) were added to the solution at room temperature. The mixture was degassed and purged with argon three times, then monitored by TLC. The mixture was stirred overnight at 80°C under an argon balloon until compound 3 was completely consumed. After cooling, the reaction mixture was diluted with ethyl acetate and filtered through Celite. The combined filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography. Purification by chromatography (0-6.25% ethyl acetate in petroleum ether) gave compound 4 (1 1 g, 80% yield, was obtained as a white solid. ESI m / z: 410 (M + 23) + . [ka]

[0231] ((1S,4aS,10aR)-6-{[(tert-butoxy)carbonyl]amino}-1,4a-dimethyl-1,2,3,4,4a,9, 10,10a-Octahydrophenanthrene-1-carboxylic acid (5) [ka] To a DMSO solution of compound 4 (4.9 g, 13 mmol), potassium tert-butoxide (15 g, 0.13 mol) was added at room temperature. The reaction mixture was stirred under argon for 60 minutes until the reaction was complete by LCMS. After cooling to room temperature, the reaction mixture was poured onto ice and added with aqueous hydrochloride (0.5 M). The mixture was slowly acidified to pH 5 with 500 ml of water, while the temperature was not allowed to exceed 25°C. The crude product was collected by filtration and washed several times with water. Further purification by filtration (0-20% ethyl acetate in petroleum ether) gave compound 5 (4.5 g (93% yield) was obtained as a white solid. ESI m / z: 318 (M - 55) + . [ka]

[0232] (tert-butyl N-[(4bS,8S,8aR)-8-carbamoyl-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-o octahydrophenanthrene-3-yl]carbamate (6) [ka] A solution of 5 (4.5 g, 12 mmol) and HATU (4.9 g, 13 mmol) in DMF (50 mL) was added with diisopropyl ethyl acetate. Methylamine (20 mL, 0.12 mol) was added and the mixture was stirred at 25° C. for 1 hour. Ammonium chloride (16 g, 0.30 mol) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography (0-20% ethyl acetate in petroleum ether). Purification by HCl afforded compound 6 (4.2 g, 94% yield) as a white solid. m / z: 373.3 (M + 1) + . [ka]

[0233] (Methyl (1S,4aS,10aR)-6-amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrofuran Phenanthrene-1-carboxylate trifluoroacetate (7) [ka] To a solution of compound 4 (6.0 g, 15 mmol) in DCM (60 mL) was added TFA (12 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours until Boc was completely removed. The reaction mixture was concentrated in vacuo to give crude compound 7 as a TFA salt, which was further purified. Used in the next step without further purification. ESI m / z: 288 (M+1) + .

[0234] (Methyl (1S,4aS,10aR)-6-(benzyloxy)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octyl) Trihydrophenanthrene-1-carboxylate (8a) [ka] A mixture of compound 2 (12 g, 40 mmol) and cesium carbonate (14 g, 44 mmol) in DMF (100 mL) was The mixture was stirred for 15 minutes at 25° C. To the mixture was added benzyl bromide (7.1 mL, 60 mmol) at room temperature. After stirring at room temperature for 4 hours, the resulting mixture was poured into cold water and extracted with ethyl acetate. The combined organic solution was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (0-10% ethyl acetate in petroleum ether). Purification by ESI m gave the title compound 8a (13 g, 89% yield) as a white solid. / z: 379 (M + H) + . [ka]

[0235] (Methyl (1S,4aS,10aR)-6-(dibenzoylamino)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a- Octahydrophenanthrene-1-carboxylate (8b) [ka] To a solution of crude compound 7 (calculated amount 15 mmol) obtained above in DMF (60 mL) was added potassium carbonate (6.4 g, 46 mmol). 1) and benzyl bromide (5.8 g, 34 mmol) were added at room temperature. The reaction was monitored by TLC. The reaction mixture was stirred at 80°C overnight until the reaction was complete. After cooling to room temperature, the mixture was The combined organic solution was poured into water (300 mL) and extracted with ethyl acetate (x3). Washing with ethanol, drying over sodium sulfate and concentration in vacuo gave crude product 8b, which was used in the next step without further purification. ESI m / z: 468 (M + 1) + .

[0236] ((1S,4aS,10aR)-6-(benzyloxy)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydro Phenanthrene-1-carboxylic acid (9a) [ka] DMSO (0.19 L) was added until the ester was completely consumed as monitored by LCMS and TLC. A mixture of compound 8a (11 g, 29 mmol) and potassium tert-butoxide (33 g, 0.29 mol) in The mixture was stirred for 1 hour at 0° C. After cooling to 25° C., the mixture was quenched with aqueous hydrochloride (1N) and ethyl acetate. The combined organic solution was washed with brine, dried over sodium sulfate, and The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (0-24% petroleum ether). Purification by hexane (ethyl acetate) gave compound 9a (7.5 g, 71% yield) as a white solid. ESI m / z: 365 (M + H) + . [ka]

[0237] ((1S,4aS,10aR)-6-(dibenzoylamino)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydroxybenzoate phenanthrene-1-carboxylic acid (9b) [ka] A solution of crude compound 8b (calculated amount 15 mmol) obtained above in DMSO (100 mL) was added with potassium tert-butoxide. The reaction mixture was stirred until the reaction was complete by LCMS. The mixture was stirred under argon at 100° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured onto ice. and slowly acidify with aqueous hydrochloride (4M) to pH 5, while ensuring that the temperature does not exceed 25°C. The mixture was extracted with ethyl acetate and the combined organic solution was washed with water and brine. The crude product was purified by silica gel column chromatography. Purification by chromatography (0–20% ethyl acetate in petroleum ether) gave compound 9b (6. 8g, 99% yield in 3 steps from compound 4) was obtained as a white solid. ESI m / z: 454 (M + 1) + .

[0238] (pentafluorophenyl (1S,4aS,10aR)-6-(benzyloxy)-1,4a-dimethyl-1,2,3,4,4 a,9,10,10a-Octahydrophenanthrene-1-carboxylate (10a) [ka] A solution of 9a (9.6 g, 26 mmol) in DMF (100 mL) was added with DIPEA (14 mL, 79 mmol) and perfluorophenyl To the mixture was added 2,2,2-trifluoroacetate (15 g, 53 mmol). The mixture was allowed to stand at room temperature overnight. The reaction mixture was stirred and monitored by LCMS. The reaction mixture was then diluted with ether (200 mL). The organic solution was dried over sodium sulfate and washed with water (300 mL) and brine (200 mL). The residue was purified by flash chromatography (0-10% acetic acid in petroleum ether). Purification by ethyl acetate afforded compound 10a (12 g, 88% yield) as a white solid. ESI m / z: 531 (M + H) + . [ka]

[0239] (pentafluorophenyl (1S,4aS,10aR)-6-(dibenzoylamino)-1,4a-dimethyl-1,2,3 ,4,4a,9,10,10a-Octahydrophenanthrene-1-carboxylate (10b) [ka] A solution of 9b (6.8 g, 15 mmol) in DMF (100 mL) was added with DIPEA (10 mL, 0.61 mol) and perfluorophenyl To this mixture was added 2,2,2-trifluoroacetate (10 mL, 58 mmol). The mixture was stirred at 5°C overnight and then diluted with ether. The organics were washed with water and brine, and the sulfuric acid The residue was purified by silica gel column chromatography. Purification by HCl (0–10% ethyl acetate in petroleum ether) gave compound 10b (7.5 g, 81% yield). %) was obtained as a white solid. ESI m / z: 620 (M + 1) + . [ka]

[0240] (tert-butyl N-[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-(benzyloxy)-1,4a-dimethyl -1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-yl]formamide}carbonyl)- 4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]carbamate ( 11a)) [ka] To a solution of compound 6 (2.3 g, 6.2 mmol) in THF (20 mL) was added n-BuLi (2.5 M in hexane, 5.5 mL, 14 mmol). was added dropwise at −78° C. The reaction was stirred at −78° C. for 1 h. To the mixture was added 10a (3.0 g, 5.6 mmol) of T A solution of HF (20 mL) is added, after which compound 10a is consumed as monitored by LCMS. The resulting mixture was stirred overnight at 10 to 20°C until the reaction mixture was dissolved in water. The combined organic solution was washed with water and brine, and diluted with sulfuric acid. The residue was purified by flash chromatography (petroleum Purification by 0-30% ethyl acetate in ether gave compound 11a (1.59 g, 51% yield). Obtained as a colored solid. ESI m / z: 719 (M + 1) + .

[0241] (Compared to procedure 11b below, n-BuLi was used here instead of LiHMDS. 6 is completely Although not consumed, this procedure gave rise to fewer by-products and the yield of 11a was The reaction yield increased from approximately 40% to 51%. Unreacted compound 6 was recovered (recovered yield 10-20%).

[0242] (tert-butyl N-[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-(dibenzoylamino)-1,4a-dimethylamino] methyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-yl]formamide}carbonyl (4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl)carbamate (11b) [ka] A solution of compound 6 (1 g, 2.7 mmol) in THF (15 mL) was added with lithium bis(trimethylsilyl)amide (H2SO4). A solution of 1M in xanthenes (8.0 mL) was added dropwise at 0° C. The reaction was stirred at 0° C. for 1 hour. The mixture was added with Compound 1 A solution of 0b (2.5 g, 4.0 mmol) in THF (10 mL) was added, and the resulting mixture was then stirred at room temperature overnight. The reaction was then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic solution was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (0-35% ethyl acetate in petroleum ether). Compound 11b (0.95 g, 44% yield) was obtained as a white solid; The desired compound 6 (recovery yield 37%) was obtained. ESI m / z: 808 (M + 1) + . [ka]

[0243] (tert-butyl N-[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2,3 ,4,4a,9,10,10a-octahydrophenanthrene-1-yl]formamide}carbonyl)-4b,8- Dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]carbamate (12a) ( P15)) [ka] A solution of 11a (2.0 g, 2.78 mmol) in ethyl acetate (40 mL) was added to wet palladium-carbon (10% Pd, 0.9 g ) was added under nitrogen. The mixture was degassed, purged with hydrogen and monitored by LCMS. The mixture was stirred overnight at room temperature under a hydrogen balloon until 11a was completely consumed. The residue was purified by silica gel column chromatography ( Purification by 0–55% ethyl acetate in petroleum ether gave 12a (P15; 1.06 g, 61% yield). Obtained as a white solid. ESI m / z: 629 (M + H) + . [ka]

[0244] (tert-butyl N-[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-amino-1,4a-dimethyl-1,2,3,4,4 a,9,10,10a-octahydrophenanthrene-1-yl]formamido}carbonyl)-4b,8-dimethyl ethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]carbamate (12b) [ka] A solution of 11b (0.45 g, 0.56 mmol) in ethyl acetate (5 mL) was added to wet palladium on carbon (10% Pd, 50 mg). was added under nitrogen. The mixture was degassed and purged with hydrogen three times and stirred under a hydrogen balloon at room temperature overnight. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give compound 12b (0.33 g). , 94% yield) was obtained as a white solid. ESI m / z: 628 (M + 1) + .

[0245] ((1S,4aS,10aR)-N-[(1S,4aS,10aR)-6-amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octyl [0.014]-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10, 10a-Octahydrophenanthrene-1-carboxamide (P1) [ka] To a solution of compound 12a (0.17 g, 0.27 mmol) in DCM (10 mL) was added TFA (3 mL) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour until the Boc was removed by illumination. The volatiles were removed in vacuo. The residue was purified by preparative HPLC (Method B) to give P1 (0.10 g, 70% yield) as a white solid. ESI m / z: 529.3 (M + 1) + . Optical rotation (α): +2.53 ° (1.7g / 100mL TH F, 25°C).

[0246] [ka]

[0247] [ka]

[0248] [ka]

[0249] HPLC (Method B): Retention time: 8.92 min, Purity: 99.4%. Chiral HPLC: >99.9% (Columns AD, AS, OD) , and in OJ).

[0250] ((1S,4aS,10aR)-6-amino-N-((1S,4aS,10aR)-6-amino-1,4a-dimethyl-1,2,3,4,4a,9,10, 10a-Octahydrophenanthrene-1-carbonyl)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a- Octahydrophenanthrene-1-carboxamide (P2) [ka] To a solution of compound 12b (0.63 g, 1.0 mmol) in DCM (10 mL) was added TFA (3 mL) dropwise at room temperature. The reaction mixture was stirred at room temperature for 4 hours until Boc was removed by evaporation. The mixture was analyzed by preparative HPLC. Direct purification by (Method B) gave P2 (0.42 g, 79% yield) as a white solid. I m / z: 528.2 (M + 1) + . [ka]

[0251] Example 2 This example illustrates a general method for the synthesis of podocarpic acid derivative P3 in Table 1 above. This example refers to compounds numbered 11b through P3 in Figure 2A.

[0252] ((3S,8R,9S,10R,13S,14S)-17-imino-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,1 6,17-Tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol, trifluoroacetic acid acid salt (P3)) [ka] To a solution of compound 11b (10 mg, 12 μmol) in DCM (2 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 2 hours until the c was removed. The volatiles were removed in vacuo. The residue was dissolved in 5% acetonitrile in water. The solution was lyophilized to give compound P3 ( 7 mg (80%) was obtained as a pale yellow solid. ESI m / z: 354.8 (M / 2 + H) + . [ka]

[0253] Example 3 This example describes a general method for the synthesis of podocarpic acid derivatives P4 to P8 in Table 1 above. This example shows the method of manufacturing the semiconductor device shown in FIG. 2A. This refers to compounds that have been

[0254] Example 3a (Intermediates 13a-e) [ka] A DMF or DCM solution of compound 12b (1.0 equivalent) was added with Fmoc-amino acid (1.1 to 1.2 equivalents), HATU (1.2 to 1. 0.5 equivalents) and DIPEA (2.0-3.0 equivalents) were added sequentially. The reaction mixture was stirred at room temperature for 4 hours. This was monitored by LCMS. The mixture was concentrated in vacuo (if DCM was the solvent) The residue was purified by silica gel column chromatography (0-90% ethyl acetate in petroleum ether). or the reaction mixture (if DMF is the solvent) was purified by reverse phase flash chromatography. Directly by chromatography (50-90% acetonitrile in 10 mM aqueous ammonium bicarbonate). Purification gave compound 13 as a white solid. [Table 4]

[0255] (9H-Fluoren-9-ylmethyl N-({[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-{[(tert-butanoyl) (oxy)carbonyl]amino}-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene 4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrobenzoyl (13a)) [ka] Compound 13a (0.14 g, 78% yield) was obtained as a white solid by following the general procedure for intermediates 13a-e. ESI m / z: 907 (M + H) + .

[0256] (9H-fluoren-9-ylmethyl N-[(1S)-1-{[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-{[(ter t-Butoxy)carbonyl]amino}-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophen 4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octanol {(2-hydroxyethyl)-4-(4-hydroxyphenanthren-3-yl)carbamoyl}-2-hydroxyethylcarbamate (13b) ) [ka] Compound 13b (0.39 g, 83% yield) was obtained as a white solid by following the general procedure for intermediates 13a-e. ESI m / z: 938 (M + H) + .

[0257] (9H-fluoren-9-ylmethyl N-[(5S)-5-{[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-{[(ter t-Butoxy)carbonyl]amino}-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophen 4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octanol 5-{[(9H-fluoren-9-ylmethoxy)-(4-hydroxyphenanthrene-3-yl)carbamoyl}-5-{[(9H-fluoren-9-ylmethoxy ... [Carbonyl]amino}pentyl]carbamate (13c) [ka] Following the general procedure for intermediates 13a-e, compound 13c (0.30 g, 78% yield) was obtained as a white solid. ESI m / z: 1201 (M + H) + .

[0258] ((S)-tert-butyl 3-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-((4bS,8S ,8aR)-8-((1S,4aS,10aR)-6-(tert-butoxycarbonylamino)-1,4a-dimethyl-1,2,3,4,4 a,9,10,10a-Octahydrophenanthrene-1-carbonylcarbamoyl)-4b,8-dimethyl-4b ,5,6,7,8,8a,9,10-octahydrophenanthrene-3-ylamino)-4-oxobutanoate (1 3d)) [ka] Compound 13d (0.43 g, 85% yield) was obtained as a white solid by following the general procedure for intermediates 13a-e. ESI m / z: 1021 (M + H) + .

[0259] ((S)-tert-butyl 4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-((4bS,8S ,8aR)-8-((1S,4aS,10aR)-6-(tert-butoxycarbonylamino)-1,4a-dimethyl-1,2,3,4,4 a,9,10,10a-Octahydrophenanthrene-1-carbonylcarbamoyl)-4b,8-dimethyl-4b ,5,6,7,8,8a,9,10-Octahydrophenanthrene-3-ylamino)-5-oxopentanoate (13e)) [ka] Following the general procedure for intermediates 13a-e, compound 13e (0.42 g, 82% yield) was obtained as a white solid. ESI m / z: 1036 (M + H) + .

[0260] Example 3b (Intermediates 14a-e) [ka] To a solution of compound 13 (1.0 equivalent) in DCM was added TFA at room temperature. The reaction mixture was stirred at room temperature for 1 hour. Concentration in vacuo gave crude product 14 as a colorless oil, which was further purified. It was used in the next step without further purification. [Table 5]

[0261] (9H-fluoren-9-ylmethyl N-({[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-amino-1,4a- Dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-yl]formamide} (4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl)carbohydrate (bamoyl)methyl)carbamate, trifluoroacetate (14a) [ka] Following the general procedure for intermediates 14a-e, crude compound 14a (0.14 g, 99% yield, TFA salt) was purified by HPLC using Obtained as a colored oil. ESI m / z: 807 (M + 1) + .

[0262] (9H-fluoren-9-ylmethyl (S)-1-((4bS,8S,8aR)-8-((1S,4aS,10aR)-6-amino-1,4a- Dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonylcarbamoyl )-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-ylamino)-3-hydroxybenzoate Hydroxy-1-oxopropan-2-ylcarbamate, trifluoroacetate (14b) [ka] Following the general procedure for intermediates 14a-e, crude compound 14b (0.14 g, 99% yield, TFA salt) was purified by free radical spectroscopy. Obtained as a colored oil. ESI m / z: 837 (M + 1) + .

[0263] (9H-fluoren-9-ylmethyl N-[(5S)-5-{[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-amino -1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-yl]formamido (do}carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl phenyl]carbamoyl}-5-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}pentyl] Carbamate, trifluoroacetate (14c) [ka] Following the general procedure for intermediates 14a-e, crude compound 14c (0.22 g, 92% yield, TFA salt) was purified by free radical spectroscopy. Obtained as a colored oil. ESI m / z: 1101 (M + 1) + .

[0264] ((S)-3-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-((4bS,8S,8aR)-8-((1S ,4aS,10aR)-6-amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene (1-carbonylcarbamoyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenane Tren-3-ylamino)-4-oxobutanoic acid, trifluoroacetate (14d) [ka] Following the general procedure for intermediates 14a-e, crude compound 14d (0.10 g, 87% yield, TFA salt) was purified by free radical spectroscopy. Obtained as a colored oil. ESI m / z: 866 (M + 1) + .

[0265] ((S)-4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-((4bS,8S,8aR)-8-((1S ,4aS,10aR)-6-amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene (1-carbonylcarbamoyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenane Tren-3-ylamino)-5-oxopentanoic acid, trifluoroacetate (14e) [ka] Following the general procedure for intermediates 14a-e, crude compound 14e (84 mg, 86% yield, TFA salt) was obtained from the colorless ESI m / z: 880 (M + 1) + .

[0266] Example 3c (Payloads P4-9, 13, 14, and 17) [ka] To a solution of the crude product 14 obtained above in DMF was added piperidine. The mixture was stirred at room temperature for 30 minutes. The mixture was stirred and monitored by LCMS. Direct purification afforded payloads P4-8 as white solids. [Table 6]

[0267] ((1S,4aS,10aR)-N-[(1S,4aS,10aR)-6-(2-aminoacetamido)-1,4a-dimethyl-1,2,3,4,4 a,9,10,10a-octahydrophenanthrene-1-carbonyl]-6-amino-1,4a-dimethyl-1,2,3 ,4,4a,9,10,10a-Octahydrophenanthrene-1-carboxamide (P4) [ka] Following the general procedure for payloads P4-8, compound P4 (12 mg, 28% yield) was obtained as a white solid ESI m / z: 585 (M + 1) + . [ka]

[0268] ((1S,4aS,10aR)-6-amino-N-((1S,4aS,10aR)-6-((S)-2-amino-3-hydroxypropanediol (mido)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonyl) -1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide (P 5)) [ka] Following the general procedure for payloads P4-8, compound P5 (41 mg, 67% yield) was obtained as a white solid ESI m / z: 615 (M + 1) + . [ka]

[0269] ((1S,4aS,10aR)-6-amino-N-((1S,4aS,10aR)-6-((S)-2,6-diaminohexanamide)-1,4a -dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonyl)-1,4a-dimethyl thyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide (P6) [ka] Following the general procedure for payloads P4–8, compound P6 (5 mg, 17% yield) was obtained as a white solid. ESI m / z: 656 (M + 1) + . [ka]

[0270] ((S)-3-amino-4-((4bS,8S,8aR)-8-((1S,4aS,10aR)-6-amino-1,4a-dimethyl-1,2,3,4,4a ,9,10,10a-Octahydrophenanthrene-1-carbonylcarbamoyl)-4b,8-dimethyl-4b, 5,6,7,8,8a,9,10-Octahydrophenanthrene-3-ylamino)-4-oxobutanoic acid (P7) [ka] Following the general procedure for payloads P4-8, compound P7 (39 mg, 51% yield) was obtained as a white solid ESI m / z: 643 (M + 1) + . [ka]

[0271] ((S)-4-amino-5-((4bS,8S,8aR)-8-((1S,4aS,10aR)-6-amino-1,4a-dimethyl-1,2,3,4,4a ,9,10,10a-Octahydrophenanthrene-1-carbonylcarbamoyl)-4b,8-dimethyl-4b, 5,6,7,8,8a,9,10-Octahydrophenanthrene-3-ylamino)-5-oxopentanoic acid (P8) [ka] Following the general procedure for payloads P4-8, compound P8 (44 mg, 58% yield) was obtained as a white solid ESI m / z: 657 (M + 1) + . [ka]

[0272] ((1S,4aS,10aR)-6-amino-N-((1S,4aS,10aR)-6-((S)-2-amino-3-(1H-imidazol-4-yl) Propanamido)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene- 1-carbonyl)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonyl Ruboxamide (P9) [ka] A solution of Fmoc-His-OH (0.38 g, 1.0 mmol) in DCM (5 mL) was treated with Fmoc-OSu (0.37 g, 1.1 mmol) and DIPEA. (0.26 g, 2.0 mmol) was added. The reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo. and the residue was purified by flash chromatography (5-10% methanol in DCM). Purified and obtained Fmoc-His(Fmoc)-OH (0.50 g, 84% yield, ESI m / z: 600 (M + 1) + ) into a white solid was obtained as.

[0273] To a solution of compound 12b (0.31 g, 0.50 mmol) in DCM (20 mL), the above-obtained Fmoc-His(Fmoc)-OH (0.3 HATU (0.3 g, 0.55 mmol), HATU (0.23 g, 0.60 mmol), and DIPEA (0.19 g, 1.5 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 4 hours and monitored by LCMS. To the reaction mixture, piperidine (0.5 mL) was added and monitored by LCMS to confirm complete Fmoc conversion. The mixture was stirred at room temperature for 1 hour until complete removal of the solvent. The mixture was concentrated in vacuo and the residue was Purification by reverse-phase flash chromatography (50-80% acetonitrile in water) Boc-P9 (0.15 g) was obtained as a white solid, half of which was dissolved in DCM (20 mL). To the solution was added TFA (3 mL). The mixture was stirred at room temperature for 1 hour until the Boc was removed by LCMS. The volatiles were removed in vacuo and the residue was purified by preparative HPLC (Method B). Compound P9 (17 mg, 12% yield) was obtained as a white solid. ESI m / z: 665 (M + 1) + . [ka]

[0274] ((1S,4aS,10aR)-N-[(1S,4aS,10aR)-6-amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octyl [(2S)-2-aminopropanamido]-1,4a-dimethyl- 1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide (P13) [ka] A similar procedure to P9 was followed, except that Fmoc-Ala-OH was used instead of Fmoc-His(Fmoc)-OH. The payload P13 (12 mg, 59% yield) was obtained as a white solid. [ka]

[0275] ((1S,4aS,10aR)-N-[(1S,4aS,10aR)-6-(2-hydroxyacetamido)-1,4a-dimethyl-1,2,3 ,4,4a,9,10,10a-Octahydrophenanthrene-1-carbonyl]-6-amino-1,4a-dimethyl-1 ,2,3,4,4a,9,10,10a-Octahydrophenanthrene-1-carboxamide (P14) [ka] To a mixture of glycolic acid (2.2 mg, 29 μmol) and HATU (18.2 mg, 48 μmol) in DMF (2.0 mL) DIPEA (12 μL, 72 μmol) and compound 12b (15 mg, 24 μmol) were added. The reaction mixture was stirred at room temperature. The mixture was stirred at rt for 2 h, which was monitored by LCMS. Wash chromatography (0-100% acetonitrile in 10 mM aqueous ammonium bicarbonate) Direct purification gave Boc-P14, which was dissolved in DCM (2 mL). To this, TFA (0.5 mL) was added and the mixture was stirred until the Boc was completely removed as monitored by LCMS. The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (method B) to give payload P14 (4.3 mg, 31% yield) as a white solid. ESI m / z: 686.5 (M + 1) + . [ka]

[0276] ((1S,4aS,10aR)-N-[(1S,4aS,10aR)-6-(2-hydroxyacetamido)-1,4a-dimethyl-1,2,3 ,4,4a,9,10,10a-Octahydrophenanthrene-1-carbonyl]-6-hydroxy-1,4a-dimethyl 1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide (P17) [ka] A solution of payload P1 (10 mg, 0.019 mmol) in DMF (2 mL) was added with HATU (14 mg, 0.038 mmol) and DIPEA ( The mixture was stirred at room temperature for 15 minutes, and then the glycosylated 1,4-diol (9.8 mg, 0.076 mmol) was added. To the reaction mixture was added carboxylic acid (1.73 mg, 0.0228 mmol). The reaction mixture was stirred at room temperature and was found to be The resulting mixture was directly purified by preparative HPLC (Method B) to give P17 (5.7 mg, 51% yield) was obtained as a white solid. ESI m / z: 587.4 (M + 1) + . [ka]

[0277] Example 4 This example describes a general procedure for the synthesis of podocarpic acid derivatives P10 and P11 in Table 1 above. This example shows the method of manufacturing the ion implantation devices numbered 14a, 15a-b, and P10 and P11 in FIG. This refers to compounds that have been

[0278] ((S)-tert-butyl 4-amino-5-((4bS,8S,8aR)-8-((1S,4aS,10aR)-6-(2-aminoacetamido) 1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonylcarbonyl (rubamoyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl a (amino)-5-oxopentanoate, di-trifluoroacetate (15a) [ka] A solution of Fmoc-Glu(OtBu)-OH (74 mg, 0.17 mmol) and DIPEA (55 μL, 0.32 mmol) in DMF (5.0 mL) HATU (91 mg, 0.24 mmol) was added. The mixture was stirred at room temperature for 15 minutes, and then compound 14a ( 0.14 g, 0.16 mmol) was added. The reaction mixture was stirred at room temperature overnight and this was found by LCMS to be After that, piperidine (1 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour until the Fmoc was completely removed. By reversed-phase flash chromatography (0–100% acetonitrile in TFA water (0.01%)), Direct isolation by ESI gave compound 15a (0.13 g, 80% yield) as a yellow solid. 770.5 (M + 1) + .

[0279] ((4S,4'S)-tert-butyl 5,5'-(4bS,4b'S,8S,8aR,8'S,8a'R)-8,8'-(azanediylbis(o hexomethylene)bis(4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-8 ,3-diyl)bis(azanediyl)bis(4-amino-5-oxopentanoate)di-trifluoro Acetate (15b) [ka] A solution of Fmoc-Glu(OtBu)-OH (0.15 g, 0.35 mmol) and DIPEA (83 μL, 0.48 mmol) in DMF (5.0 mL) HATU (0.15 g, 0.40 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then compound P2 ( The reaction mixture was stirred at room temperature overnight and was found to be soluble in water by LCMS. After that, piperidine (1 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours until the Fmoc was completely removed. , by reversed-phase flash chromatography (0-100% acetonitrile in TFA water (0.01%)). Direct isolation by ESI m / gave compound 15b (0.14 g, 78% yield) as a yellow solid. z: 899 (M + 1) + .

[0280] ((S)-4-amino-5-((4bS,8S,8aR)-8-((1S,4aS,10aR)-6-(2-aminoacetamido)-1,4a-di Methyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonylcarbamoyl)- 4b,8-Dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-ylamino)-5-ox isopentanoic acid (P10) [ka] A mixture of compound 15a (0.13 g, 0.13 mmol) in neat TFA (2.0 mL) was stirred at room temperature for 1 h. This was monitored by LCMS. The resulting mixture was diluted with DCM (20 mL) and The residue was purified by reversed-phase flash chromatography (aqueous sodium bicarbonate (10 mM) Purification by elution with 0-100% acetonitrile gave P10 (20 mg, 22% yield) as a white solid. ESI m / z: 358 (M / 2 + 1) + ; 714.5 (M + 1) + . [ka]

[0281] ((4S,4'S)-5,5'-(4bS,4b'S,8S,8aR,8'S,8a'R)-8,8'-(azanediylbis(oxomethylene) )bis(4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-8,3-diyl)bis (azanediyl)bis(4-amino-5-oxopentanoic acid) (P11) [ka] A mixture of compound 15b (0.14 g, 0.14 mmol) in neat TFA (3.0 mL) was stirred at room temperature for 1 h. This was monitored by LCMS. The resulting mixture was diluted with DCM (30 mL) and The residue was purified by reversed-phase flash chromatography (aqueous sodium bicarbonate (10 mM) Purification by elution with 0-100% acetonitrile gave P11 (20 mg, 18% yield) as a white solid. ESI m / z: 394 (M / 2 + 1) + . [ka]

[0282] Example 4a This example describes a general method for the synthesis of podocarpic acid derivative P19 in Table 1 above. This example refers to the compound of Figure 2C.

[0283] ((4bS,8S,8aR)-8-{[(1S,4aS,10aR)-6-{[(tert-butoxy)carbonyl]amino}-1,4a-dimethyl methyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonyl]carbamoyl}-4 b,8-Dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl tert-butyl ester Carbonate (16) [ka] To a mixture of payload P1 (0.10 g, 0.19 mmol) in tert-butanol (2 mL) was added potassium carbonate ( HCl (0.78 mg, 0.57 mmol) and Boc anhydride (0.12 g, 0.57 mmol) were added at room temperature, and the reaction mixture was heated to 60° C. for 3 h. The resulting mixture was then cooled and stirred for 1 hour, which was monitored by LCMS. The residue was dissolved in DCM (100 mL) and the solution was washed with water and brine. , dried over anhydrous sodium sulfate, and concentrated in vacuo to give crude product 16 (0.14 g, crude) as a white solid. of HCl was obtained as a solid, which was used in the next step without further purification. ESI m / z: 7 29.4 (M + 1) + .

[0284] ((4bS,8S,8aR)-8-{[(1S,4aS,10aR)-7-bromo-6-{[(tert-butoxy)carbonyl]amino}-1 ,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonyl]carba tert-moyl}-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl Butyl carbonate (17) [ka] To a solution of crude compound 16 (0.14 g, obtained above) in DMF (4 mL) was added NBS (50 mg, 0.28 mmol). The reaction mixture was added and stirred at room temperature overnight, which was monitored by LCMS. The resulting mixture was subjected to reversed-phase flash chromatography (0-100% acetonitrile in TFA water (0.01%)). Direct purification by HCl afforded compound 17 (40 mg, 26% yield over two steps) as a yellow solid. Obtained. ESI m / z: 807.3 (M + 1) + .

[0285] ((4bS,8S,8aR)-8-{[(1S,4aS,10aR)-6-{[(tert-butoxy)carbonyl]amino}-7-hydroxy bis-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonyl rubamoyl}-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl t ert-butyl carbonate (19) [ka] Compound 17 (40 mg, 50 μmol), potassium acetate (12 mg, 0.12 mmol) in dry dioxane (5 mL), A mixture of 18 (50 mg, 0.20 mmol) and bis(pinacolato)diboron 18 was degassed and refilled with nitrogen three times. To the mixture was added Pd(dppf)Cl2 (1.8 mg, 2.5 μmol) under nitrogen. The resulting suspension The mixture was stirred under nitrogen at 90° C. for 30 minutes, which was monitored by LCMS. The mixture was cooled to RT and filtered through Celite. The filtrate was diluted with hydrogen peroxide (30% aqueous solution) , 2.0 mL) was added dropwise over 10 minutes at 0° C. The reaction mixture was stirred for an additional 30 minutes at 0° C. The resulting mixture was then analyzed by reversed-phase flash chromatography. Direct purification by chromatography (0-100% acetonitrile in TFA water (0.01%)) afforded the crude Compound 19 (35 mg, 50% purity, 95% crude yield) was obtained as a yellow solid, which was further purified Used in the next step without further purification. ESI m / z: 745.5 (M + 1) + .

[0286] ((1S,4aS,10aR)-N-[(1S,4aS,10aR)-6-amino-7-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9 ,10,10a-Octahydrophenanthrene-1-carbonyl]-6-hydroxy-1,4a-dimethyl-1,2, 3,4,4a,9,10,10a-Octahydrophenanthrene-1-carboxamide (P19) [ka] To a solution of crude compound 19 (35 mg, obtained above) in DCM (5 mL) was added TFA (2 mL) dropwise over 5 min at 0°C. The reaction mixture was stirred at room temperature for 30 minutes until the Boc was completely removed (this was confirmed by LCMS The volatiles were removed in vacuo and the residue purified by preparative HPLC (Method A). Purification by HPLC afforded payload P19 (6.5 mg, 24% yield from compound 17) as an off-white Obtained as a solid. ESI m / z: 545.3 (M + 1) + . [ka]

[0287] Example 5 This example describes the synthesis of linker-payloads LP1 to LP5 and LP20 in Table 2 above. This example shows the method for preparing the compounds numbered 12b and 102a-b to 106a-e in FIG. The linker-payload LP1 to LP5 are mentioned below.

[0288] Example 5a (Intermediates 102a-b) [ka] To a DMF solution of the acid (Fmoc-Val-Ala-OH (101a, 1.2 equiv.) or Fmoc-Val-Cit-OH (101b, 1.2 equiv.) HATU (1.2 equivalents) and DIPEA (2.0-3.0 equivalents) were added at room temperature. The mixture was stirred at room temperature for 5 minutes. After this, compound 12b (1.0 equiv.) was added. The resulting mixture was stirred until the amine was consumed according to LCMS. The resulting mixture was stirred at room temperature for 4 to 20 hours. Then, piperidine (excess) was added to the mixture. The mixture was stirred at room temperature for 1-6 hours until the Fmoc was completely removed, as monitored by LCMS. The reaction mixture was filtered through a membrane and the filtrate was purified by preparative HPLC (Method B) or reverse phase chromatography. Direct purification by flash chromatography gave compound 102 (38–72% yield) as a white solid. Obtained as a solid. [Table 7]

[0289] (tert-butyl N-[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-[(2S)-2-[(2S)-2-amino-3-methyl [Butanamide]propanamide]-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrofuran (phenanthrene-1-yl)carbonyl}carbamoyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-o [Cutahydrophenanthrene-3-yl]carbamate (102a) [ka] Compound 102a (0.29 g, 72% yield) was obtained as a white solid by following the general procedure for intermediates 102a,b. ESI m / z: 799 (M + 1) + .

[0290] (tert-butyl N-[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-[(2S)-2-[(2S)-2-amino-3-methyl [Carbamoylamino]-5-(carbamoylamino)pentanamido]-1,4a-dimethyl-1,2,3,4,4a,9 ,10,10a-octahydrophenanthrene-1-yl]carbonyl}carbamoyl)-4b,8-dimethyl -4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]carbamate (102b) [ka] Compound 102b (0.27 g, 38% yield) was obtained as a white solid by following the general procedure for intermediates 102a,b. ESI m / z: 885 (M + 1) + .

[0291] Example 5b (Intermediate 104a-b) (tert-butyl N-[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-[(2S)-2-[(2S)-2-{2-amino-6-[2 -(cyclooct-2-yn-1-yloxy)acetamido]hexanamido}-3-methylbutanal [mido]propanamido]-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene 4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydro- ... phenanthrene-3-yl]carbamate (104a) [ka] A solution of compound 103 (70 mg, 0.13 mmol) in DMF (2 mL) was added with HATU (68 mg, 0.18 mmol) and DIPEA (44 μL The mixture was stirred at room temperature for 5 minutes, and then compound 102a (95 mg, 0 0.12 mmol) was added, and then, as monitored by LCMS, compound 102a was completely consumed. The reaction mixture was stirred at room temperature for 3 hours until the reaction mixture was cooled to room temperature. Then, piperidine (0.5 mL) was added to the reaction mixture. (excess) was added. The mixture was stirred at room temperature for 2 hours. After that, the mixture was filtered and the filtrate was The residue was purified by reversed-phase flash chromatography (0.05% ammonium bicarbonate in 10 mM aqueous ammonium bicarbonate). Purification by acetonitrile (~100%) afforded compound 104a (0.13 g, 96% yield) as a white solid. Obtained as a solid. ESI m / z: 518.0 ((M-55) / 2) + .

[0292] (tert-butyl N-[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-[(2S)-2-[(2S)-2-{2-amino-6-[2 -(cyclooct-2-yn-1-yloxy)acetamido]hexanamido}-3-methylbutanal [Iodo]-5-(carbamoylamino)pentanamido]-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-o (4b,8-dimethyl-4b,5,6,7,6-octahydrophenanthrene-1-yl)carbonyl}carbamoyl)-4b,8-dimethyl-4b,5,6,7,6-octahydrophenanthrene-1-yl 8,8a,9,10-octahydrophenanthrene-3-yl]carbamate (104b) [ka] To a solution of compound 103 (0.27 g, 0.31 mmol) and DIPEA (0.11 mL, 0.61 mmol) in DMF (6 mL) was added compound 1 02b (0.18 g, 0.34 mmol) was added, followed by HATU (0.14 g, 0.37 mmol). The mixture was stirred at room temperature for 3 hours, which was monitored by LCMS. , which was directly purified by reverse-phase flash chromatography to give compound Fmoc-104b (0.30 g , ESI m / z: 711 ((M + Na) / 2 +1) + ) was obtained as a pale yellow solid, which was dissolved in DCM (6.0 mL) and To this solution, piperidine (0.5 mL) was added, and Fmoc was completely removed according to LCMS. The reaction mixture was stirred at room temperature for 2 hours until the volatiles were removed in vacuo. Trituration with petroleum ether gave compound 104b (0.26 g, 65% yield) as a pale yellow solid. ESI m / z: 1177.6 ((M + H) + .

[0293] Example 5c (Intermediates 105a-c) The azide intermediate α-CD-N3 (105a) was synthesized as follows: J. Am. Chem. Soc., 2012, 134(46), 19108-19117 Therefore, it was synthesized (Figure 10).

[0294] (Azido-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecane-18-sulfonic acid (105b) Figure 11) 2,5-Dioxopyrrolidin-1-yl 1-azido-3,6,9,12-tetraoxapentadecan-15-o N-PEG-OSu (0.10 g, 0.26 mmol) and taurine 105b-A (39 mg, 0.31 mmol) in anhydrous DMF ( To the solution (4 mL) was added DIPEA (15 mg, 0.52 mmol). The mixture was stirred at room temperature overnight. The mixture was filtered and the solution was purified by preparative HPLC (Method A) to give intermediate 105b (0.80 g, 7% yield). 8%) was obtained as a colorless oil. ESI m / z: 399.1 (M + H) + . [ka]

[0295] ([2-(1-azido-3,6,9,12-tetraoxapentadecan-15-amido)ethyl]trimethylaza Niobium chloride (105d) Follow a procedure similar to that for 105b above, except use 105d-A instead of 105b-A. , trimethylammonium chloride 105d (0.13 g, 64% yield) was obtained as a colorless oil. ESI m / z: 376 (M + H) + . [ka]

[0296] The azide intermediate maltose-N3 (105c) was synthesized as described in Tetrahedron Letters, 2001, 42 (7), 1325-132. 8 was synthesized (Figure 12).

[0297] Example 5d (Intermediate 106a~f) [ka] To a solution of compound 104 in DMF was added the azide intermediate 105 at room temperature. Complete reaction was confirmed by LCMS. The reaction was stirred at room temperature for 3-48 hours until indicated. The reaction mixture was analyzed directly by preparative HPLC. After purification, compound Boc-106 was obtained as a white solid, which was then purified by distillation in TFA (or neat). The solution was stirred at room temperature for 0.5-20 hours until the Boc group was removed by LCMS. The solution was concentrated to give 106 (as the TFA salt). [Table 8] *Not all of the Boc-106a was used for Boc removal.

[0298] ((1S,4aS,10aR)-N-[(1S,4aS,10aR)-6-amino-1,4a-dimethyl-2,3,4,9,10,10a-hexahydride 31,32 ,33,34,35,36,37,38,39,40,41,42-dodecahydroxy-10,15,20,25,30-pentakis(hydrogen Oxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29-dodecaoxaheptacyclo[26.2.2.2 3 , 6 .2 8 , 11 .2 13 , 16 .2 18 , 21 .2 23 , 26]dotetracontan-5-yl]methyl}-4H,5H,6H,7H,8H,9H- Chloocta[d][1,2,3]triazol-4-yl)oxy]acetamido}hexanamido]-3-methyl Thiobutanamido]propanamido]-1,4a-dimethyl-2,3,4,9,10,10a-hexahydrophenanthracene Nthren-1-carboxamide trifluoroacetate (106a) [ka] Following the general procedure for intermediates 106a-e, compound Boc-106a (72 mg, 76% yield, triazole) was obtained. The compound (as a mixture of regioisomers) was obtained as a white solid (ESI m / z: 1045 (M / 2 + 1) + ).reverse Further analysis by phase flash chromatography (0-60% acetonitrile in TFA water (0.01%)) After further purification, a small amount of pure major isomer (7 mg) was obtained, which was 1 H NMR (500 MHz, DMSO d6 ) was determined. [ka] To a mixture of Boc-106a (as a mixture of regioisomers) (20 mg, 9.6 μmol) in DCM (3 mL) was added TFA ( 1 mL) was added. The resulting mixture was monitored by LCMS until Boc was removed. The mixture was stirred at room temperature for 1 hour. The volatiles were removed in vacuo to give compound 106a (19 mg, 104a-106b). The compound was obtained in a 69% yield as a pale yellow solid, which was carried to the next step without further purification. ESI m / z: 995 (M / 2 + 1) + .

[0299] ((1S,4aS,10aR)-N-{[(1S,4aS,10aR)-6-[(2S)-2-[(2S)-2-[(2R)-2-amino-6-{2-[(1-{[31, 32,33,34,35,36,37,38,39,40,41,42-dodecahydroxy-10,15,20,25,30-pentakis(hydrogen) (hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29-dodecaoxaheptacyclo[26.2.2.2 3 , 6 .2 8 , 11 .2 13 , 16 .2 18 , 21 .2 23 , 26 ]dotetracontan-5-yl]methyl}-1H,4H,5H,6H,7H,8H, 9H-Cycloocta[d][1,2,3]triazol-4-yl)oxy]acetamide}hexanamide] -3-methylbutanamido]-5-(carbamoylamino)pentanamido]-1,4a-dimethyl-1,2,3 ,4,4a,9,10,10a-octahydrophenanthrene-1-yl]carbonyl}-6-amino-1,4a-dimethyl Trifluoromethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide Acetate (106b) [ka] Compound 106b (76 mg, 87% yield from 104b) was prepared by the general procedure for intermediates 106a-e using Obtained as a yellow solid. ESI m / z: 692 (M / 3 + 1) + .

[0300] ((1-(4-(2-(((R)-5-amino-6-(((S)-1-(((S)-1-(((4bS,8S,8aR)-8-(((1S,4aS,10aR)-6-amino amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonyl (carbamoyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl )amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)- 6-Oxohexyl)amino)-2-oxoethoxy)-4,5,6,7,8,9-hexahydro-1H-cyclohexyl octa[d][1,2,3]triazol-1-yl)-15-oxo-3,6,9,12-tetraoxa-16-azaocta Decane-18-sulfonic acid (106c) [ka] Compound 106c (90 mg, 39% yield from 104c) was obtained by elution with the general procedure for intermediates 106a-e. Obtained as a yellow solid. ESI m / z: 463.8 (M / 3 + 1) + .

[0301] (1-(4-(((6S,9S,12R)-1,12-diamino-6-(((4bS,8S,8aR)-8-(((1S,4aS,10aR)-6-amino-1, 4a-Dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonylcarbamo (yl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl)carba 1,8,11,18-tetraoxo-2,7,10,17-tetraazanonadecane-19- (yl)oxy)-4,5,6,7,8,9-hexahydro-1H-cycloocta[d][1,2,3]triazole-1-yl (I)-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecane-18-sulfonic acid (106d) [ka] Following the general procedure for intermediates 106a-e, the intermediates were purified by reversed-phase flash chromatography (0-8 in water). After purification with 0% acetonitrile for 25 min), compound 106d (22 mg, Yield 36%) was obtained as a white solid. ESI m / z: 788 (M / 2 + H) + .

[0302] ((1S,4aS,10aR)-6-amino-N-((1S,4aS,10aR)-6-((2S)-2-((2S)-2-((2R)-2-amino-6-(2-( (1-((2S,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2R,3R,4S,5S,6R)- 3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)te tetrahydro-2H-pyran-2-yl)-3a,4,5,6,7,8,9,9a-octahydro-1H-cycloocta[d][1 ,2,3]triazol-4-yl)oxy)acetamido)hexanamido)-3-methylbutanamido 1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene- 1-carbonyl)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonyl Ruboxamide (106e) [ka] Compound 106e (34 mg, 77% yield) as its TFA salt was obtained by following the general procedure for intermediates 106a-e. %) as a colorless oil. ESI m / z: 1358 (M + H) + .

[0303] ((2-{1-[4-({[(5R)-5-amino-5-{[(1S)-1-{[(1S)-1-{[(4bS,8S,8aR)-8-({[(1S,4aS,10aR) -6-amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-yl]phosphatase (4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrenyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrenyl phenyl-3-yl]carbamoyl}ethyl]carbamoyl}-2-methylpropyl]carbamoyl} (1H,4H,5H,6H,7H,8H,9H-cycloocta[d][1,2,3]triazole) (1-yl)-3,6,9,12-tetraoxapentadecan-15-amido}ethyl)trimethylazan Trifluoroacetate (106f) [ka] Following the general procedure, compound 106f (20 mg, 42% yield from 104a) was obtained as a white solid. ESI m / z: 455.8 (M / 3) + .

[0304] Example 5e (Linker-Payload LP1 to LP5 and LP20) [ka] To a solution of compound 106 in DMF, compound DIBAC-PEG4-NHS 107 and DIPEA were added at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by preparative HPLC (Method B) or reverse phase flash chromatography. Direct purification by chromatography (Method B) gave compounds LP1-5 and LP20. [Table 9] *7 mg of compound 106a as the free base was recycled.

[0305] (1-(4-{2-azatricyclo[10.4.0.0 4 , 9 ]Hexadeca-1(12),4(9),5,7,13,15-hexaene-1 0-yn-2-yl}-4-oxobutanamide)-N-[(1R)-1-{[(1S)-1-{[(1S)-1-{[(4bS,8S,8aR)- 8-{[(1S,4aS,10aR)-6-amino-1,4a-dimethyl-2,3,4,9,10,10a-hexahydrophenanthrene {4b,8-dimethyl-5,6,7,8a,9,10-hexahydrophenanthrene-1-carbonyl]carbamoyl}-4b,8-dimethyl-5,6,7,8a,9,10-hexahydrophenanthrene phenyl-3-yl]carbamoyl}ethyl]carbamoyl}-2-methylpropyl]carbamoyl}-5-{ 2-[(1-{[31,32,33,34,35,36,37,38,39,40,41,42-dodecahydroxy-10,15,20,25,30-pentane Takis(hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29-dodecaoxaheptacycl 26.2.2.2 3 , 6 .2 8 , 11 .2 13 , 16 .2 18 , 21 .2 23 , 26 ]dotetracontan-5-yl]methyl}-4H,5H, 6H,7H,8H,9H-Cycloocta[d][1,2,3]triazol-4-yl)oxy]acetamide} [Isopropyl]-3,6,9,12-tetraoxapentadecan-15-amide (LP1) [ka] Following the general procedure for Linker-Payload LP1-5, Linker-Payload LP1 (8 mg, Yield 36%) was obtained as a white solid. ESI m / z: 842 (M / 3 + 1) + ; 1262 (M / 2 + 1) + . [ka]

[0306] Analytical HPLC: 95%, retention time: 7.93 minutes (Method B).

[0307] (1-(4-{2-azatricyclo[10.4.0.0 4 , 9 ]Hexadeca-1(12),4(9),5,7,13,15-hexaene-1 0-yn-2-yl}-4-oxobutanamide)-N-[(1R)-1-{[(1S)-1-{[(1S)-1-{[(4bS,8S,8aR)- 8-({[(1S,4aS,10aR)-6-amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthracene 4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octabenzoxanthren-1-yl]formamide}carbonyl Hydrophenanthrene-3-yl]carbamoyl}-4-(carbamoylamino)butyl]carbamo yl}-2-methylpropyl]carbamoyl}-5-{2-[(1-{[31,32,33,34,35,36,37,38,39,40,41 ,42-dodecahydroxy-10,15,20,25,30-pentakis(hydroxymethyl)-2,4,7,9,12,14,1 7,19,22,24,27,29-dodecaoxaheptacyclo[26.2.2.2 3 , 6 .2 8 , 11 .2 13 , 16 .2 18 ,21 .2 23 , 26 ]dotetracontan-5-yl]methyl}-1H,4H,5H,6H,7H,8H,9H-cycloocta[d][1,2,3]trimethyl Azol-4-yl)oxy]acetamido}pentyl]-3,6,9,12-tetraoxapentadecane- 15-amide (LP2) [ka] Following the general procedure for linker-payload LP1-5, linker-payload LP2 (20 mg , 21% yield) was obtained as a white solid. ESI m / z: 870 (M / 3 + H) + . [ka] Analytical HPLC: 100%, retention time: 7.35 minutes (Method B). Solubility: <0.1mg / mL water.

[0308] (2-{1-[4-({[(5R)-5-[1-(4-{2-azatricyclo[10.4.0.0 4,9 ]Hexadeca-1(12),4(9),5,7 ,13,15-Hexaen-10-yn-2-yl}-4-oxobutanamide)-3,6,9,12-tetraoxapeptide pentadecan-15-amido]-5-{[(1S)-1-{[(1S)-1-{[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-a Amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-yl]carbo (nyl}carbamoyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3 -yl]carbamoyl}ethyl]carbamoyl}-2-methylpropyl]carbamoyl}pentyl] (carbamoyl}methoxy)-1H,4H,5H,6H,7H,8H,9H-cycloocta[d][1,2,3]triazole-1 -yl]-3,6,9,12-tetraoxapentadecane-15-amido}ethane-1-sulfonic acid (LP3) [ka] Following the general procedure for Linker-Payload LP1-5, Linker-Payload LP3 (60 mg, Yield 52%) was obtained as a white solid. ESI m / z: 642 (M / 3 + H) + . [ka]

[0309] (2-{1-[4-({[(5R)-5-[1-(4-{2-azatricyclo[10.4.0.0 4,9 ]Hexadeca-1(12),4(9),5,7 ,13,15-Hexaen-10-yn-2-yl}-4-oxobutanamide)-3,6,9,12-tetraoxapeptide pentadecan-15-amido]-5-{[(1S)-1-{[(1S)-1-{[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-a Amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-yl]carbo (nyl}carbamoyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3 -yl]carbamoyl}-4-(carbamoylamino)butyl]carbamoyl}-2-methylpropyl] carbamoyl}pentyl]carbamoyl}methoxy)-1H,4H,5H,6H,7H,8H,9H-cycloocta[d ][1,2,3]triazol-1-yl]-3,6,9,12-tetraoxapentadecan-15-amido}ethane- 1-sulfonic acid (LP4) [ka] Compound LP4 (6.0 mg, 20% yield) was prepared by following the general procedure for linker-payload LP1-5. , obtained as a white solid. ESI m / z: 671 (M / 3 + H) + . [ka]

[0310] (1-(4-{2-azatricyclo[10.4.0.0 4,9 ]Hexadeca-1(12),4(9),5,7,13,15-hexaene-1 0-yn-2-yl}-4-oxobutanamide)-N-[(1R)-1-{[(1S)-1-{[(1S)-1-{[(4bS,8S,8aR)- 8-{[(1S,4aS,10aR)-6-amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthracene {4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrobenzoate}-1-carbonylcarbamoyl -3-phenanthrene-3-yl]carbamoyl}ethyl]carbamoyl}-2-methylpropyl]carbamoyl bamoyl}-5-[2-({1-[(2S,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-{[( 2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy} oxan-2-yl]-1H,4H,5H,6H,7H,8H,9H-cycloocta[d][1,2,3]triazol-4-yl} Oxy)acetamido]pentyl]-3,6,9,12-tetraoxapentadecan-15-amide (LP5) [ka] Compound LP5 (15 mg, 27% yield) was prepared by following the general procedure for linker-payload LP1-5. Obtained as a white solid. ESI m / z: 947 (M / 2 + H) + . [ka]

[0311] ((2-{1-[4-({[(5R)-5-[1-(4-{2-azatricyclo[10.4.0.0 4 , 9 ]Hexadeca-1(12),4(9),5, 7,13,15-Hexaen-10-yn-2-yl}-4-oxobutanamido)-3,6,9,12-tetraoxapeptide pentadecan-15-amido]-5-{[(1S)-1-{[(1S)-1-{[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-a [amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-yl]formamide Amido}carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3 -yl]carbamoyl}ethyl]carbamoyl}-2-methylpropyl]carbamoyl}pentyl] (carbamoyl}methoxy)-1H,4H,5H,6H,7H,8H,9H-cycloocta[d][1,2,3]triazole-1 -yl]-3,6,9,12-tetraoxapentadecan-15-amido}ethyl)trimethylazanium Trifluoroacetate (LP20) [ka] Compound LP20 (7 mg, 24% yield) was prepared by following the general procedure for linker-payload LP1-5. Obtained as a white solid. ESI m / z: 950.8 (M / 2) + .

[0312] Example 6 (Linker-Payload LP6) This example demonstrates a method for the synthesis of linker-payload LP6 in Table 2 above. Examples include compounds numbered 109-113 and linker-payload LP6 in FIG. mentions.

[0313] (1-(4-{2-azatricyclo[10.4.0.0 4,9 ]Hexadeca-1(12),4(9),5,7,13,15-hexaene-1 0-yn-2-yl}-4-oxobutanamido)-N-[(1S)-1-{[(1S)-4-(carbamoylamino)-1-{ [4-(hydroxymethyl)phenyl]carbamoyl}butyl]carbamoyl}-2-methylpropyl ]-3,6,9,12-tetraoxapentadecan-15-amide (110) [ka] A solution of compound 108 (0.30 g, 0.54 mmol) in DMF (10 mL) was added with HATU (0.31 g, 0.81 mmol) and DIPEA (0. 14 g, 1.1 mmol) were added successively at room temperature. The mixture was stirred at room temperature for 15 minutes. Then, the reaction To the solution, VC-PAB-OH 109 (CAS: 159857-79-1, 0.21 g, 0.54 mmol) was added at room temperature, and the The resulting mixture was stirred at room temperature for 3 hours until 108 or 109 was consumed, as monitored by HPLC. The reaction mixture was then filtered through a membrane filter, and the filtrate was concentrated and purified by reversed-phase flash chromatography. Chromatography (0-100% acetonitrile in water (containing 10 mmol / L ammonium bicarbonate) Direct purification by HCl afforded compound 110 (0.30 g, 60% yield) as a white solid. ESI m / z: 617 (M + H) + .

[0314] ({4-[(2S)-2-[(2S)-2-[1-(4-{2-azatricyclo[10.4.0.0 4,9 ]Hexadeca-1(12),4(9),5, 7,13,15-Hexaen-10-yn-2-yl}-4-oxobutanamido)-3,6,9,12-tetraoxapeptide Pentadecane-15-amido]-3-methylbutanamido]-5-(carbamoylamino)pentanamide ]phenyl}methyl 4-nitrophenyl carbonate (112) [ka] To a solution of compound 110 (0.15 g, 0.16 mmol) in DMF (10 mL) was added bis(4-nitrophenyl) carbonate. 111 (0.15 g, 0.49 mmol) and DIPEA (63 mg, 0.49 mmol) were added sequentially at 0 °C. Then, LCMS The mixture was stirred at room temperature for 3 hours until 110 was consumed, as monitored by HPLC. The mixture was filtered through a membrane filter, and the filtrate was concentrated and purified by reversed-phase flash chromatography (water ( Direct purification by acetonitrile (0-100% in 10 mmol / L ammonium bicarbonate) This gave compound 112 (50 mg, 28% yield) as a white solid. ESI m / z: 1079 (M + H). + .

[0315] (9H-fluoren-9-ylmethyl N-({[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-{[({4-[(2S)-2 -[(2S)-2-[1-(4-{2-azatricyclo[10.4.0.0 4,9 ]Hexadeca-1(12),4(9),5,7,13,15-H {4-oxaen-10-yn-2-yl}-4-oxobutanamido)-3,6,9,12-tetraoxapentadecane -15-amido]-3-methylbutanamido]-5-(carbamoylamino)pentanamido]phenyl} (Methoxy)carbonyl]amino}-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthracene 4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octabenzoxanthren-1-yl]formamide}carbonyl Hydrophenanthrene-3-yl]carbamoyl}methyl)carbamate (113) [ka] To a mixture of compound 14a (0.10 g, 0.12 mmol) and compound 112 (0.15 g, 0.14 mmol) in DMF (5 mL) HOBt (20 mg, 0.15 mmol) and DIPEA (48 mg, 0.37 mmol) were added, and the mixture was stirred at room temperature for 4 hours. This was monitored by LCMS. The reaction mixture was purified by preparative HPLC (Method B). Purification gave compound 113 (0.16 g, 72% yield) as a pale yellow solid. ESI m / z: 874 ( M / 2 + 1) + .

[0316] ({4-[(2S)-2-[(2S)-2-[1-(4-{2-azatricyclo[10.4.0.0 4,9 ]Hexadeca-1(12),4(9),5, 7,13,15-Hexaen-10-yn-2-yl}-4-oxobutanamido)-3,6,9,12-tetraoxapeptide Pentadecane-15-amido]-3-methylbutanamido]-5-(carbamoylamino)pentanamide ]phenyl}methyl N-[(4bS,8S,8aR)-8-{[(1S,4aS,10aR)-6-(2-aminoacetamido)-1,4a -Dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonyl]carbamoyl {4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl}carbame (LP6) [ka] To a solution of compound 113 (0.10 g, 0.057 mmol) in DMF (5 mL), piperidine (1 mL) was added and the resulting mixture was analyzed by LCMS. The mixture was stirred at room temperature for 30 minutes until the Fmoc was completely removed. Direct purification by preparative HPLC (Method B) gave compound LP6 (35 mg, 23% yield) as a white solid. ESI m / z: 763 (M / 2 + 1) + . [ka]

[0317] Example 7 (Linker-Payload LP7) This example demonstrates a method for the synthesis of linker-payload LP7 in Table 2 above. Examples are numbers 14a, 107, 114, and 115 in FIG. 5, and linker-payload LP7. This refers to compounds marked with .

[0318] (9H-fluoren-9-ylmethyl N-({[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-[(2S)-2-[(2S) -2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanamido]propanamido]-1,4a -dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-yl]formamide} (carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]ca (rubamoyl)methyl)carbamate (114) [ka] A solution of compound 14a (66 mg, 0.082 mmol) in DMF (10 mL) was treated with Boc-Val-Ala-OH 101c (28 mg, 0.098 mmol). mol), DIPEA (32 mg, 0.25 mmol), and HATU (47 mg, 0.12 mmol) were added. The mixture was stirred at room temperature for 4 hours and monitored by LCMS. Direct purification by chromatography (50-90% acetonitrile in 10 mM aqueous ammonium bicarbonate) Compound 114 (74 mg, 84% yield) was obtained as a white solid. ESI m / z: 978 (M - Boc + 1) + .

[0319] (9H-fluoren-9-ylmethyl N-({[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-[(2S)-2-[(2S) -2-amino-3-methylbutanamido]propanamido]-1,4a-dimethyl-1,2,3,4,4a,9,10,10a -octahydrophenanthrene-1-yl]formamide}carbonyl)-4b,8-dimethyl-4b,5,6 ,7,8,8a,9,10-Octahydrophenanthrene-3-yl]carbamoyl}methyl)carbamate Trifluoroacetate (115) [ka] To a solution of compound 114 (74 mg, 0.069 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 1 hour until the Boc was completely removed. The volatiles were removed in vacuo. Removal gave crude product 115 (66 mg, 97% yield as the TFA salt) as a colorless oil. ESI m / z: 978 (M + 1) + .

[0320] (1-(4-{2-azatricyclo[10.4.0.0 4,9 ]Hexadeca-1(12),4(9),5,7,13,15-hexaene-1 0-yn-2-yl}-4-oxobutanamide)-N-[(1S)-1-{[(1S)-1-{[(4bS,8S,8aR)-8-{[(1S,4 aS,10aR)-6-(2-aminoacetamido)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydro {phenanthrene-1-carbonyl]carbamoyl}-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octyl [(trihydrophenanthrene-3-yl)carbamoyl}ethyl]carbamoyl}-2-methylpropyl ]-3,6,9,12-tetraoxapentadecan-15-amide (LP7) [ka] A solution of compound 115 (60 mg, 61 μmol) in DMF (5 mL) was diluted with DIBAC-suc-PEG-OSu 107 (48 mg, 74 μmol) ) and DIPEA (24 mg, 0.18 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours and The reaction was then monitored by LCMS. Piperidine (0.2 mL, excess) was then added to the reaction. The reaction mixture was stirred at room temperature for 30 minutes until the Fmoc was completely removed according to the reaction mixture. The product was directly purified by preparative HPLC (Method B) to give LP7 (22 mg, 28% yield) as a white solid. Obtained by ESI m / z: 1292 (M + H) + . [ka]

[0321] Example 8 (Linker-Payload LP8) This example demonstrates a method for the synthesis of linker-payload LP8 in Table 2 above. Examples are shown in Figure 6, where compounds are numbered P4, 117-120 and linker-payload LP8. Refers to the compound.

[0322] ({4-[(2S)-2-[(2S)-2-amino-3-methylbutanamido]-5-(carbamoylamino)pentane Amido]phenyl}methyl N-({[(4bS,8S,8aR)-8-{[(1S,4aS,10aR)-6-amino-1,4a-dimethyl {1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonyl]carbamoyl}-4b, 8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]carbamoyl}methyl ethyl) carbamate (117) [ka] Fmoc-vc-PAB-PNP 116 (0.14 g, 0.18 mmol) and payload P4 (0.11 g, 0.18 mmol) in DMF (2 mL To the solution, HOBt (24 mg, 0.18 mmol) and DIPEA (70 mg, 0.54 mmol) were added via syringe at room temperature. The mixture was stirred at room temperature for 2 hours, and compound P4 was consumed by LCMS. To the mixture was added piperidine (42 mg, 0.50 mmol), and monitored by LCMS to confirm that the Fmoc The reaction was stirred at room temperature for 2 hours until complete removal. After filtration through a membrane, the filtrate was concentrated. Condensation and direct purification by preparative HPLC (Method B) gave compound 117 (45 mg, 27% yield) as a white solid. ESI m / z: 991 (M + 1) + . [ka]

[0323] (2,5-dioxopyrrolidin-1-yl (2R)-6-[2-(cyclooct-2-yn-1-yloxy)acetate [(9H-fluoren-9-ylmethoxy)carbonyl]amino}hexanoate (118 )) [ka] Compound 103 (0.10 g, 0.19 mmol), EDCI (72 mg, 0.38 mmol), and HOSu (43 mg, 0 The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was added to a silica gel column. Purification by column chromatography (70% ethyl acetate in petroleum ether) gave the intermediate 118 (55 mg, 47% yield) was obtained as a white solid, which was carried on to the next step without purification. ESI m / z: 630 (M + 1) + .

[0324] ({4-[(2S)-2-[(2S)-2-[(2R)-2-amino-6-[2-(cyclooct-2-yn-1-yloxy)acetate Amido]hexanamido]-3-methylbutanamido]-5-(carbamoylamino)pentanamido do]phenyl}methyl N-({[(4bS,8S,8aR)-8-{[(1S,4aS,10aR)-6-amino-1,4a-dimethyl-1, 2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonyl]carbamoyl}-4b,8-di Methyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]carbamoyl}methyl Carbamate (119) [ka] To a solution of compound 117 (55 mg, 56 μmol) and DIPEA (24 mg, 0.19 mmol) in DMF (1.5 mL) was added crude intermediate 1 18 (40 mg, 63 μmol) was added. The reaction mixture was stirred at room temperature until 118 was consumed according to LCMS. The reaction mixture was stirred at rt for 2 h. The reaction mixture was purified by reversed-phase flash chromatography (0-100% acetone in water). Direct purification by acetonitrile gave Fmoc-119 (60 mg, ESI m / z: 753 (M / 2 + 1) + ) is white This was obtained as a colored solid, which was dissolved in DMF (1.5 mL). (24 mg, 0.33 mmol) was added and the solution was stirred at room temperature until complete removal of Fmoc by LCMS. The reaction mixture was stirred for 2 hours. The reaction mixture was purified by reversed-phase flash chromatography (ammonium bicarbonate). Direct purification by acetonitrile (0-100% in water) gave compound 119 (35 mg, from compound 117). The product was obtained in 50% yield as a white solid. ESI m / z: 1282 (M + H) + .

[0325] ({4-[(2S)-2-[(2S)-2-[(2R)-2-amino-6-{2-[(1-{[31,32,33,34,35,36,37,38,39,40,41,4 2-dodecahydroxy-10,15,20,25,30-pentakis(hydroxymethyl)-2,4,7,9,12,14,17, 19,22,24,27,29-dodecaoxaheptacyclo[26.2.2.2 3 , 6 .2 8 , 11 .2 13 , 16 .2 18 , 21 .2 23 , 26 ] dotetracontan-5-yl]methyl}-1H,4H,5H,6H,7H,8H,9H-cycloocta[d][1,2,3]trimethyl azole-4-yl)oxy]acetamido}hexanamido]-3-methylbutanamido]-5-(caprolactone) N-({[(4bS,8S,8aR)-8-{[(1S,4aS,10 aR)-6-amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbohydrate 4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene -3-yl]carbamoyl}methyl)carbamate (120) [ka] To a solution of compound 119 (70 mg, 54 μmol) in DMF (3 mL), α-CD-N3105a (0.16 g, 0.16 mmol) was added. The reaction mixture was stirred at 50°C for 3 days and monitored by LCMS. The resulting mixture was then purified by reversed-phase flash chromatography (aqueous ammonium bicarbonate (10 mM) Direct purification by acetonitrile (0-100% acetonitrile) gave compound 120 (20 mg, 16% yield). Obtained as a colored solid. ESI m / z: 1141 (M / 2 + 1) + .

[0326] ({4-[(2S)-2-[(2S)-2-[(2R)-2-[1-(4-{2-azatricyclo[10.4.0.0 4 , 9 ]Hexadeca-1(12) ,4(9),5,7,13,15-Hexaen-10-yn-2-yl}-4-oxobutanamide)-3,6,9,12-tetramethyl Oxapentadecan-15-amido]-6-{2-[(1-{[31,32,33,34,35,36,37,38,39,40,41,42-de Decahydroxy-10,15,20,25,30-pentakis(hydroxymethyl)-2,4,7,9,12,14,17,19,2 2,24,27,29-dodecaoxaheptacyclo[26.2.2.2 3 , 6 .2 8 , 11 .2 13 , 16 .2 18 , 21 .2 23 , 26 ]Dote cycloocta[d][1,2,3]triazo[1H,4H,5H,6H,7H,8H,9H- ... hexanamido]-3-methylbutanamido]-5-(carbamoyl-4-yl)oxy]acetamido} ... methyl N-({[(4bS,8S,8aR)-8-{[(1S,4aS,10aR)- 6-Amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonyl 1,2-Dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3- (Il)carbamoyl}methyl)carbamate (LP8) [ka] A solution of compound 120 (10 mg, 4.4 μmol) and intermediate 107 (5 mg, 7.7 μmol) in DMF (2 mL) was treated with DIPEA (1 6 mg, 0.12 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was analyzed by preparative HPLC ( Two direct purifications by method B) gave LP8 (1.5 mg, 12% yield) as a white solid. ESI m / z: 939 (M / 3 + H) + . [ka] Analytical HPLC (as a mixture of triazole regioisomers): 63%, retention time: 6.03 min; Duration: 6.13 minutes (Method B).

[0327] Example 9 (Linker-Payload LP9) This example demonstrates a method for the synthesis of linker-payload LP9 in Table 2 above. Examples are 12b, 15, 112, 121, and 122 in Figure 7, and linker-payload LP9. Reference is made to numbered compounds.

[0328] (9H-fluoren-9-ylmethyl N-[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-amino-1,4a-di Methyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-yl]formamide}carbo (nyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]carba Mate, trifluoroacetate (15) [ka] A solution of compound 12b (0.63 g, 1.0 mmol) in DCM (50 mL) was treated with Fmoc-OSu (0.40 g, 1.2 mmol) and DIPEA ( The mixture was stirred at room temperature for 16 hours and was monitored by LCMS. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography ( Purification by 50-80% ethyl acetate in petroleum ether gave Boc-15 (0.71 g) as a white solid. This was dissolved in DCM (10 mL). To this solution was added TFA (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours until the Boc was completely removed according to LCMS. The volatile material was removed in vacuo to give compound 15 as the TFA salt (0.62 g, 74% yield) and a colorless oil. ESI m / z: 751 (M + H) + .

[0329] (9H-fluoren-9-ylmethyl N-[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-[(2S)-6-amino- 2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}hexanamide]-1,4a-dimethyl {1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-yl}formamide}carbonyl )-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]carbamate Trifluoroacetate (122) [ka] To a solution of compound 15 (0.30 g, 0.40 mmol) in DMF (20 mL), Fmoc-Lys(Boc)-OH 121 (0.23 g, 0.48 mmol) was added. mol), HATU (228 mg, 0.60 mmol), and DIPEA (0.16 g, 1.2 mmol) were added sequentially at room temperature. The mixture was stirred at room temperature for 4 hours and monitored by LCMS. Flash chromatography (50–90% acetonitrile in 10 mM aqueous ammonium bicarbonate) Direct purification by HCl afforded Boc-122 (0.41 g) as a white solid, of which 0.2 4g was dissolved in DCM (20 mL). To this solution was added TFA (3 mL) and complete Boc conversion was observed according to LCMS. The reaction mixture was stirred at room temperature for 1 hour until complete removal of volatiles. This gave compound 122 (0.22 g, 79% yield) as the TFA salt and a colorless oil. : 1101 (M + H) + .

[0330] ({4-[(2S)-2-[(2S)-2-[1-(4-{2-azatricyclo[10.4.0.0 4,9 ]Hexadeca-1(12),4(9),5, 7,13,15-Hexaen-10-yn-2-yl}-4-oxobutanamido)-3,6,9,12-tetraoxapeptide Pentadecane-15-amido]-3-methylbutanamido]-5-(carbamoylamino)pentanamide ]phenyl}methyl N-[(5S)-5-amino-5-{[(4bS,8S,8aR)-8-{[(1S,4aS,10aR)-6-amino-1, 4a-Dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonyl]carbamo yl}-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]carba

[0042] 1,2-dichloro-1,2-diphenyl ... [ka] A mixture of compound 122 (14 mg, 12 μmol) and compound 112 (15 mg, 14 μmol) in DMF (5 mL) was treated with HO. Bt (2 mg, 15 μmol) and DIPEA (5 mg, 37 μmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was monitored by LCMS. Then, piperidine (0.5 mL) was added. The mixture was stirred at room temperature for 0.5 hours until the Fmoc was completely removed according to LCMS. After this time, the reaction mixture was filtered through a membrane and the filtrate was concentrated and purified directly by preparative HPLC (Method B). The purification afforded LP9 (6 mg, 31% yield) as a white solid. ESI m / z: 798 (M / 2 + H). + . [ka]

[0331] Example 10 (Linker-Payload LP10 and LP11) This example illustrates methods for the synthesis of linker-payloads LP10-LP11 in Table 2 above. In this example, P7, P8, 116, 123a-b, linker-payload LP10 and LP11 are shown in FIG. The compounds referred to are numbered as follows:

[0332] ((S)-4-((4bS,8S,8aR)-8-((1S,4aS,10aR)-6-amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a -octahydrophenanthrene-1-carbonylcarbamoyl)-4b,8-dimethyl-4b,5,6,7,8,8 a,9,10-octahydrophenanthrene-3-ylamino)-3-((4-((S)-2-((S)-2-amino-3-methyl)-4 ... Benzyloxy)carbonylamino)-4-(4-methylbutanamido)-5-ureidopentanamido)benzyloxy)carbonylamino)-4-(4-methylbutanamido) Isobutanoic acid (123a) [ka] A solution of payload P7 (64 mg, 0.10 mmol) in DMF (5 mL) was added with intermediate 116 (92 mg, 0.12 mmol) and DIP EA (26 mg, 0.20 mmol) was added sequentially at room temperature. The reaction mixture was stirred at room temperature for 4 hours and Then piperidine (0.5 mL) was added to the mixture, and the reaction mixture was monitored by LCMS. The reaction mixture was stirred at room temperature for 10 min until complete removal of Fmoc by reversed-phase chromatography. chromatograph (40-70% acetonitrile in 10 mM aqueous ammonium bicarbonate) Direct purification gave compound 123a (41 mg, 39% yield) as a white solid. m / z: 1049 (M + H) + .

[0333] ((S)-5-((4bS,8S,8aR)-8-((1S,4aS,10aR)-6-amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a -octahydrophenanthrene-1-carbonylcarbamoyl)-4b,8-dimethyl-4b,5,6,7,8,8 a,9,10-octahydrophenanthrene-3-ylamino)-4-((4-((S)-2-((S)-2-amino-3-methylamino)-4-( ... Benzyloxy)carbonylamino)-5-ureidopentanamido Dibenzofuran-123b) [ka] A procedure similar to that for 123a was used except that P8 (0.53 g, 0.81 mmol) was used instead of P7. Thus, compound 123b (0.61 g, 71% yield) was obtained as a white solid. ESI m / z: 1063 (M + H) + .

[0334] ((3S)-3-{[({4-[(2S)-2-[(2S)-2-[1-(4-{2-azatricyclo[10.4.0.0 4,9 ]Hexadeca-1(1 2),4(9),5,7,13,15-Hexaen-10-yn-2-yl}-4-oxobutanamido)-3,6,9,12-tet Laoxapentadecan-15-amido]-3-methylbutanamido]-5-(carbamoylamino)pentane Tanami...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof 【Chemical 1】 (In the formula, Q 1 and Q 2 is -C(O)-; W is -CH 2 -, -N(H)-, or -O-; R 1 is -N(H)R 4 or -N(R 5 ) 2 and; R 2 is -N(H)R 4 and; Each R 4 is in each case independently hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, group, biodegradable moiety, alkyl, substituted alkyl, acyl, or substituted acyl, wherein: The biodegradable portion is selected from poly(ε-caprolactone) (PCL), poly(3-hydroxybutyrate) (PHB), Poly(glycolic acid) (PGA), poly(lactic acid) (PLA), and poly(D,L-lactide-coglycolide) (PL GA); R 5 is alkyl, aryl, arylalkyl, heterocycloalkyl, or substituted heterocyclic alkyl. wherein each heterocycloalkyl or substituted heterocycloalkyl The alkyl group contains 1, 2, or 3 heteroatoms selected from nitrogen and oxygen and is substituted. If present, at least one of -OH and -CH 2 Contains OH or at least one primary or containing secondary nitrogen; and Each R 6 are independently halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O-amino O-PEG or O-acid residue n1 where each n is an integer from 0 to 14, and each n1 is an integer from 1 to 12. is an integer).

2. 10. A compound according to claim 1 according to formula I, or a pharmaceutically acceptable salt, solvate, or is a stereoisomer 【Chemistry 2】 (In the formula, Q 1 and Q 2 is -C(O)-; W is -CH 2 -, -N(H)-, or -O-; R 1 is -N(H)R 4 or -N(R 5 ) 2 and; R 2 is -N(H)R 4 and; Each R 4 is in each case independently hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, a group, a biodegradable moiety, or an alkyl, wherein the biodegradable moiety is poly(ε-caprolactone). Poly(3-hydroxybutyrate) (PCL), Poly(3-hydroxybutyrate) (PHB), Poly(glycolic acid) (PGA), Poly(lactic acid) (PLA), and poly(D,L-lactide-co-glycolide) (PLGA); R 5 is alkyl, aryl, arylalkyl, heterocycloalkyl, or substituted heterocyclic alkyl. wherein each heterocycloalkyl or substituted heterocycloalkyl The alkyl group contains 1, 2, or 3 heteroatoms selected from nitrogen and oxygen and is substituted. If present, at least one of -OH and -CH 2 Contains OH or at least one primary or containing secondary nitrogen; and Each R 6 are independently halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O-amino O-PEG or O-acid residue n1 where each n is an integer from 0 to 14, and each n1 is an integer from 1 to 12. is an integer).

3. 10. A compound according to claim 1 according to formula I, or a pharmaceutically acceptable salt, solvate, or is a stereoisomer 【Chemistry 3】 (In the formula, Q 1 and Q 2 is -C(O)-; W is -CH 2 -, -N(H)-, or -O-; R 1 is -N(H)R 4 or -N(R 5 ) 2 and; R 2 is -N(H)R 4 and; Each R 4 is in each case independently hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, a group, a biodegradable moiety, or an alkyl, wherein the biodegradable moiety is poly(ε-caprolactone). Poly(3-hydroxybutyrate) (PCL), Poly(3-hydroxybutyrate) (PHB), Poly(glycolic acid) (PGA), Poly(lactic acid) (PLA), and poly(D,L-lactide-co-glycolide) (PLGA); R 5 is alkyl, aryl, arylalkyl, heterocycloalkyl, or substituted heterocyclic alkyl. wherein each heterocycloalkyl or substituted heterocycloalkyl The alkyl group contains 1, 2, or 3 heteroatoms selected from nitrogen and oxygen and is substituted. If present, at least one of -OH and -CH 2 Contains OH or at least one primary or containing secondary nitrogen; and Each R 6 are independently halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O-amino O-PEG or O-acid residue n1 where each n is an integer from 0 to 14, and each n1 is an integer from 1 to 12. is an integer).

4. 10. The compound of claim 3 according to formula II, or a pharmaceutically acceptable salt, solvate, or Stereoisomers 【Chemistry 4】 。

5. W is -CH 2 The compound according to any one of claims 1 to 4, wherein

6. 5. The compound of claim 1, wherein W is -O-.

7. 5. The compound of claim 1, wherein W is -NH-.

8. A compound according to any one of claims 1 to 4 or 7, according to formula III, or a pharmaceutically acceptable salt thereof salts, solvates, or stereoisomers thereof 【Chemistry 5】 。

9. R 1 But -N(H)R 4 9. The compound according to any one of claims 1 to 8, wherein

10. R 1 But -N(R 5 ) 2 9. The compound according to any one of claims 1 to 8, wherein

11. R 1 But -NH 2 and Each R 4 In each case independently, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, a biosynthetic degradable moiety, or alkyl, wherein the biodegradable moiety is poly(ε-caprolactone ) (PCL), poly(3-hydroxybutyrate) (PHB), poly(glycolic acid) (PGA), poly(lactic acid) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA), 10. The compound of claim 9.

12. Each R 4 is, independently in each occurrence, an amino acid residue; and The amino acid residue is alanine, isoleucine, leucine, methionine, phenylalanine, tryptophan, tyrosine, valine, serine, threonine, asparagine, glutamine cysteine, selenocysteine, glycine, proline, arginine, histidine, sucralose, aspartic acid, and glutamic acid; 12. The compound of claim 11.

13. below 【Chemistry 6】 【change】 【change】 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: or solvates.

14. Each R 4 is, independently in each occurrence, a peptide residue, wherein the peptide residue is alanine, Isoleucine, leucine, methionine, phenylalanine, tryptophan, tyrosine, Valine, serine, threonine, asparagine, glutamine, cysteine, selenocysteine glycine, proline, arginine, histidine, lysine, aspartic acid, and glutamic acid and amino acids selected from the group consisting of thiamin, ...

12. The compound of claim 11.

15. The following 【Chemistry 7】 15. The compound of claim 14, wherein:

16. The following 【Chemistry 8】 10. The compound of claim 9, wherein:

17. R 1 and R 2 But -N(H)R 4 9. The compound according to any one of claims 1 to 8, wherein

18. Each R 4 is, independently in each occurrence, an amino acid residue; The amino acid is alanine, isoleucine, leucine, methionine, phenylalanine, Tryptophan, tyrosine, valine, serine, threonine, asparagine, glutamine, Cysteine, selenocysteine, glycine, proline, arginine, histidine, lysine , aspartic acid, and glutamic acid, and residues thereof; 18. The compound of claim 17.

19. below 【Chemistry 9】 or a pharmaceutically acceptable salt thereof. or solvates.

20. The following 【Chemistry 10】 11. The compound of claim 10, wherein:

21. The following 【Chemistry 11】 18. The compound of claim 17, wherein:

22. A linker-payload comprising the compound of any one of claims 1 to 21 attached to a linker. Do.

23. 23. The linker-payload of claim 22, having the formula LPa, the formula LPb, the formula LPc, or the formula LPd; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof 【Chemistry 12】 (In the ceremony L is a linker; Q 1 and Q 2 is -C(O)-; W is -CH 2 -, -N(H)-, or -O-; R 1 is -N(H)R 4 , -N(H)-R 4 -, -N(H)-, -N(R 5 ) 2 , or -N(R 5 )-R 5 - and; R 2 is -N(H)R 4 , -N(H)-R 4 - or -N(H)-; Each R 4 is in each case independently hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, group, biodegradable moiety, alkyl, substituted alkyl, acyl, substituted acyl, or -alkylene- wherein the biodegradable portion is selected from the group consisting of poly(ε-caprolactone) (PCL), poly(3-hydroxybenzoyl)propanol (PCL), and poly(3-hydroxybenzoyl)propanol (PCL). butyrate) (PHB), poly(glycolic acid) (PGA), poly(lactic acid) (PLA), and poly(D,L-lactide-co) glycolide) (PLGA); R 5 is alkyl, aryl, arylalkyl, heterocycloalkyl, or substituted heterocyclic alkyl. wherein each heterocycloalkyl or substituted heterocycloalkyl The alkyl group contains 1, 2, or 3 heteroatoms selected from nitrogen and oxygen and is substituted. If present, at least one of -OH and -CH 2 Contains OH or at least one primary or containing secondary nitrogen; and Each R 6 are independently halo, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Alkoxy, -CN, O-g glucose, O-amino acid residue, or O-PEG n1 where each n is an integer from 0 to 14, Each n1 is an integer from 1 to 12.

24. Each R 4 independently in each case hydrogen, amino acid residue, N-alkyl amino acid residue, peptide residue a group, a biodegradable moiety, an alkyl, or an -alkylene-, wherein the biodegradable moiety is a poly Poly(ε-caprolactone) (PCL), poly(3-hydroxybutyrate) (PHB), poly(glycolic acid) (PG A), poly(lactic acid) (PLA), and poly(D,L-lactide-co-glycolide) (PLGA), according to claim 23. The linker-payload is as described above.

25. 24. The linker-paylo of claim 23 having the formula LPa′, the formula LPb′, the formula LPc′, or the formula LPd′. Card 【Chemistry 13】 (In the formula, SP 1 and SP 2 is a spacer group, if present; each AA is an amino acid residue; and p1 is an integer from 1 to 10).

26. The linker L or spacer SP 2 is at an aryl nitrogen, or alone or within a peptide 26. The linker-payload of any one of claims 22 to 25, which is attached to an amino acid residue.

27. below 【Chemistry 14】 【change】 【change】 【change】 【change】 27. The linker-payload of any one of claims 22 to 26, selected from the group consisting of: is a pharmaceutically acceptable salt or solvate thereof.

28. A compound of Formula A, Formula B, Formula C, or Formula D, or a pharmaceutically acceptable salt or stereoisomer thereof body 【Chemistry 15】 (In the formula, L is a linker; BA is an antibody or an antigen-binding fragment thereof; k is an integer from 1 to 30; Q 1 and Q 2 is -C(O)-; W is -CH 2 -, -N(H)-, or -O-; R 1 is -N(H)R 4 , -N(H)-R 4 -, -N(H)-, -N(R 5 ) 2 , or -N(R 5 )-R 5 - and; R 2 is -N(H)R 4 , -N(H)-R 4 - or -N(H)-; Each R 4 is in each case independently hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, group, biodegradable moiety, alkyl, substituted alkyl, acyl, substituted acyl, or -alkylene- wherein the biodegradable portion is selected from the group consisting of poly(ε-caprolactone) (PCL), poly(3-hydroxybenzoyl)propanol (PCL), and poly(3-hydroxybenzoyl)propanol (PCL). butyrate) (PHB), poly(glycolic acid) (PGA), poly(lactic acid) (PLA), and poly(D,L-lactide-co) glycolide) (PLGA); R 5 is alkyl, aryl, arylalkyl, heterocycloalkyl, or substituted heterocyclic alkyl. wherein each heterocycloalkyl or substituted heterocycloalkyl The alkyl group contains 1, 2, or 3 heteroatoms selected from nitrogen and oxygen and is substituted. If present, at least one of -OH and -CH 2 Contains OH or at least one primary or containing secondary nitrogen; and Each R 6 are independently halo, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Alkoxy, -CN, O-g glucose, O-amino acid residue, or O-PEG n1 where each n is an integer from 0 to 14, Each n1 is an integer from 1 to 12.

29. Each R 4 independently in each case hydrogen, amino acid residue, N-alkyl amino acid residue, peptide residue a group, a biodegradable moiety, an alkyl, or an -alkylene-, wherein the biodegradable moiety is a poly Poly(ε-caprolactone) (PCL), poly(3-hydroxybutyrate) (PHB), poly(glycolic acid) (PG A), poly(lactic acid) (PLA), and poly(D,L-lactide-co-glycolide) (PLGA), according to claim 28. The compounds listed above.

30. 29. The compound of claim 28 having formula A', formula B', formula C', or formula D'. 【Chemistry 16】 (In the formula, SP 1 and SP 2 is a spacer group, if present; each AA is an amino acid residue; and p1 is an integer from 1 to 10).

31. below 【Chemistry 17】 【change】 【change】 【change】 【change】 31. The compound of claim 30, selected from the group consisting of:

32. 29. The compound of claim 28 having the formula (A″), or a pharmaceutically acceptable salt thereof, is a stereoisomer or its positional isomer 【Chemistry 18】 (In the formula, SP 1 , SP 2 , and SP 3 are each a spacer group, where SP 3 is (AA) p1 Of linked into one AA; each AA is an amino acid residue; p1 is an integer from 1 to 10; and EG is a cyclodextrin or an alkyl, heteroalkyl, alkylenyl or hetero alkylenyl sulfonic acid).

33. The SP 1 The spacer 【Chemistry 19】 and (In the formula, RG′ is a reactive group resulting from the reaction of the reactive group RG with an antibody or antigen-binding fragment thereof. residue; 【Chemistry 20】 is directly or indirectly bound to the antibody or antigen-binding fragment thereof; and b is an integer from 1 to 4); (AA) p1 but, 【Chemical 21】 and SP 2 is a bond or PABC; The SP 3 Spacer: 【Chemical 22】 is (In the formula, RG′ is the reactive group residue resulting from the reaction of the reactive group RG with EG; 【Chemical 23】 is a bond to EG; and 【Chemistry 24】 is (AA) p1 33. The compound of claim 32, wherein

34. below 【Chemistry 25】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 34. The compound of claim 32 or 33, selected from the group consisting of:

35. 35. The compound of any one of claims 28-34, wherein k is an integer from 1 to 4.

36. Any one of claims 28 to 35, wherein the BA is an antibody or antigen-binding fragment thereof that binds to HER2. The compound described.

37. Any one of claims 28 to 35, wherein the BA is an antibody or antigen-binding fragment thereof that binds to PRLR. The compound described.

38. Any one of claims 28 to 35, wherein the BA is an antibody or an antigen-binding fragment thereof that binds to MSR1. The compound described.

39. BA is an antibody or an antigen-binding fragment thereof, and the conjugation is at least one The compound according to any one of claims 28 to 38, wherein the Q295 residue of

40. BA is an antibody or antigen-binding fragment thereof, and the conjugation is between two Q295 residues The compound of any one of claims 28 to 38, wherein the compound is mediated by

41. The compound of any one of claims 28 to 40, wherein the BA is an N297Q antibody or an antigen-binding fragment thereof. thing.

42. BA is the N297Q antibody or an antigen-binding fragment thereof, and the conjugation is at least any of claims 28 to 41, wherein the amino acid sequence is via at least one Q295 and at least one Q297 residue.

1. The compound according to claim 1.

43. BA is an N297Q antibody or an antigen-binding fragment thereof, and the conjugation is 43. The compound of any one of claims 28 to 42, wherein the compound is mediated by the Q297 residue and two Q298 residues.

44. A compound selected from the group consisting of: ​ 【change】 【change】 【change】 。

45. 29. The compound of claim 28, selected from the group consisting of: 【Chemical 27】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 wherein BA is an antibody or an antigen-binding fragment thereof; and and k is an integer from 1 to 4.

46. A compound selected from the group consisting of the following, or a salt thereof: ​ 【change】 【change】 【change】 。

47. BA is H 2 an antibody or antigen-binding fragment thereof modified with N-LL-X, wherein LL is a bivalent polypeptide; and X is -N 3 Claims 28 to 30, 32, 33 and 35 to 42 The compound according to any one of claims 1 to 4.

48. 48. The compound of claim 47, wherein k is an integer from 1 to 4.

49. 48. The method of claim 47, wherein the BA is an antibody or antigen-binding fragment thereof that binds to HER2, PRLR, or MSR1. The compounds listed above.

50. BA is an antibody or an antigen-binding fragment thereof, and the conjugation is at least one or the conjugation is via two Q295 residues 48. The compound of claim 47,

51. The BA is the N297Q antibody or an antigen-binding fragment thereof, or the BA is the N297Q antibody or an antigen-binding fragment thereof. and the conjugation is at least one Q295 and at least one Q2 48. The compound of claim 47, wherein said compound is via residue 97.

52. A compound according to any one of claims 1 to 21, 44 or 46 conjugated to an antibody or antigen-binding fragment thereof. or a linker-payload according to any one of claims 22 to 27. Jugate.

53. A compound according to any one of claims 1 to 4, 5, 8, 9, 11 to 21 or 28 to 45, a compound according to claims 22 to 27 The linker-payload of any one of claims 52 or the antibody-drug-conjugate of claim 52. A pharmaceutical composition comprising:

54. For use in treating dyslipidemia, metabolic disorders, inflammation, or neurodegenerative disorders in a subject.

54. The pharmaceutical composition of claim 53 for use in administering to a patient in need thereof.

55. 54. The pharmaceutical composition of claim 53, for use in treating dyslipidemia in a subject.

56. 54. The pharmaceutical composition of claim 53, for use in treating a metabolic disease in a subject.

57. 54. The pharmaceutical composition of claim 53, for use in treating inflammation in a subject.

58. 54. The pharmaceutical composition of claim 53 for use in treating a neurodegenerative disease in a subject. 。

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