Bis-octahydrophenanthrenecarboxamide and its protein conjugate

Abstract

To provide novel bis-octahydrophenanthrene carboxamides effective for treating diseases and disorders associated with the liver X receptor by forming protein (e.g., antibody) drug conjugates.SOLUTION: The invention provides a compound of Formula I or a pharmaceutically acceptable salt, solvate or stereoisomeric form thereof. (In the formula, Q1 and Q2 are each CH2, C(O), or the like; W is CH2, N(H), or the like; R1 and R2 are each H, OH, or the like; R7 is halogen, C1-6 alkyl, or the like; and n is an integer from 0 to 3.)SELECTED DRAWING: Figure 11

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application is fully incorporated herein by reference under Section 119 of the United States Patent Act. This is based on the benefits of U.S. Provisional Application No. 62 / 508,327, filed on May 18, 2017. be.

[0002] (Field) Provided herein are novel bis-octahydrophenanthrenecarboxamides and its protein conjugate, and the bis-octahydrophenanthrene carbo Various diseases and disorders, including the administration of xamide and its protein conjugates. And methods for treating diseases. [Background technology]

[0003] (background) Antibody-drug conjugates (ADCs) are attached to bioactive small molecule drugs, and therefore, antibodies This antibody combines the targeting specificity of ADCs with the mode of action and efficacy of small molecule drugs. Its therapeutic efficacy has been demonstrated in cancer treatment and it is a major ongoing research focus. ADCETRIS® (bentruximab vedotin) and KADCYLA® (registered trademark) Ad-trastuzumab emtansine is one of two ADCs approved for the treatment of certain cancer types. Therefore, at least 40 types of ADCs are currently in clinical development.

[0004] 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. It contains β. LXRα is highly expressed in the liver, intestines, adipose tissue, and differentiated macrophages. It is expressed; LXRβ is widely expressed. LXR is (i) a cholesterol transporter, for example If so, the expression of ABCA1 and ABCG1 (both of which mediate cellular cholesterol efflux) is stimulated. (ii) to intensify; and (ii) to reduce macrophage inflammatory gene expression through the suppression of NF-κB activation. It has various biological functions, including regulating. LXR is used in atherosclerosis It is also believed to be related to proliferative disorders, neurodegenerative disorders, and inflammation. Proliferative disorders include, This includes melanoma, lung cancer, oral squamous cell carcinoma, and prostate cancer (Pencheva et al., 2004). (Wu et al., 2015; Kaneko et al., 2015; Chuu et al., 2006). Neurodegenerative disorders include, This includes 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 and ulcerative colitis. This includes enteritis, Crohn's disease, and arthritis (Anderson et al., 2011; Huang et al., 2011) 15; Cui et al., 2012). Macrophage LXRs are known to possess anti-atherogenic activity. LXR agonists (i) inhibit the onset and progression of atherosclerosis. (ii) to delay; (ii) to alleviate atherosclerosis and established atherosclerotic lesions (iii) It is possible to stabilize the lesion macrophage content by apoptosis. It is thought that it is possible.

[0005] The therapeutic efficacy of small molecule LXR modulators is, for example, in the regulation of undesirable LXRs in non-target cells. It is limited by nodes and / or low bioavailability. Regulation of LXR in non-target cells is It may cause undesirable side effects, and its low bioavailability is limited. However, due to numerous reasons, including low solubility which further exacerbates the area of ​​treatment that is already inadequately treated, This is possible. If an ADC including an LXR modulator is developed, target-specific LXR modulation will become possible. This would thus avoid side effects caused by off-target adjustments of LXR. Furthermore, such ADCs offer improved modulation of biological targets and increased bioavailability. This will lead to improvements in the therapeutic range and the small molecule A of the LXR modulator. There is a continued need for effective treatment of metabolic diseases, for example, using DCs. [Overview of the Initiative]

[0006] (overview) Provided herein are, for example, metabolic diseases, including, but not limited to, dyslipidemia. This compound is useful for treating inflammation or nerve disease. Furthermore, this specification provides for, for example, the treatment of inflammation or nerve disease. This compound is useful for treating sexually transmitted diseases. The compound provided herein is of formula I. be.

[0007] In one embodiment, the foregoing provides a compound according to formula I or a pharmaceutical product thereof. It is an acceptable salt, solvate, or stereoisomer: [ka] (In the formula, Q 1 and Q 2 Each of these is independently -CH2-, -C(O)-, -C(H)(OH)-, -C(OH)2-, -SO2-, -SO-, -P O(OR 11 )-,-PO(NR11 NR 12 )-, -NR 11 -, or -N=; W contains -CH2-, -N(H)-, or -O-; R 1 is -H, -OR 6 , -OH, -NH2, alkyl, or -OP(O)(OR 6 )2; R 2 is -H, -OH, -OR 11 , halide, -SO2NR 11 R 12 , -CONR 11 R 12 , -CH2NH2, R 3 R 4 R 5 , ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ Contains a butylate, a biodegradable part, or an alkyl group; Each R 7 Independently, Halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O- amino acid residues, and O-PEG n This includes, where each n is an integer between 0 and 3; and Each R 11 and R 12 (These are independently selected from -H, alkyl, and aryl).

[0008] In one embodiment, the foregoing provides a compound according to formula I or a pharmaceutical product thereof. It is an acceptable salt, solvate, or stereoisomer: [ka] (In the formula, Q 1 and Q 2 Each of these independently contains -CH2-, -C(O)-, -C(H)(OH)-, or -C(OH)2-; W contains -CH2-, -N(H)-, or -O-; R 1 is -H, -OH, -NH2, alkyl, or -OP(O)(OR 6 ) including 2; R 2 -H, -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 Including, here, R 1 and R 2 At the same time For -H, not -H; R 3 is -N(R 6 ) including 2; R 4 -XYZ Includes; X contains groups consisting of -O- and -N(H)-; Y is an alkylene, a substituted alkylene (not limited to, but including oxo substitutions (i.e., =O)). ), heteroalkylenes, and substituted heteroalkylenes (not limited to oxo substitutions (i.e.) It includes a group consisting of (=O); Z includes groups consisting of -OH and -NH2; R 5 This includes alkyl, heterocycloalkyl, or substituted heterocycloalkyl, and here Each heterocycloalkyl or substituted heterocycloalkyl is selected from nitrogen and oxygen. It contains one, two, or three selected heteroatoms and at least one -OH or -CH2O group. A hydrogen substituent, or at least one primary or secondary nitrogen, such as O-glucose; Each R 6 In each case, independently, -H, amino acid residue, N-alkyl amino acid residue, and pe Containing a butyl or alkyl group; and Each R 7 Independently, Halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O- amino acid residues, and O-PEG n (including, where each n is an integer between 0 and 3).

[0009] Another embodiment, as shown herein, is a compound having the above formula I. It is a car payload.

[0010] In another embodiment, as shown herein, is an antibody or its antigen-binding fragment that binds to the antibody. Furthermore, the above formula I compound or antibody-drug conjugate having a linker-payload is ru.

[0011] Another embodiment, as shown herein, is a compound according to formula A or a pharmaceutical thereof. It is an acceptable salt, or stereoisomer: [ka] (In the formula, L is the linker; BA is a binder; k is an integer between 1 and 30; Q 1 and Q 2 Each of these is independently -CH2-, -C(O)-, -C(H)(OH)-, or -C(OH)2-; W is -CH2-, -N(H)-, or -O-; R is independently -H, -OH, or -OP(O)(OR 6 )2 and Each R 6 In each case, independently, -H, amino acid residue, N-alkyl amino acid residue, and pe It is a butylated or alkyl group; and Each R 7 Independently, Halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O- amino acid residues, and O-PEG n (where n is an integer between 0 and 3).

[0012] Another embodiment, as shown herein, is a compound described herein, phosphorus Car-payloads, or antibody-drug conjugates, and excipients and carriers that are acceptable as pharmaceuticals. or a pharmaceutical composition containing a diluent.

[0013] In another embodiment, as shown herein, the target dyslipidemia, metabolic disease, inflammation A method for the treatment of a disease or neurodegenerative disease, wherein the subject is subjected to the chemical described herein. Effectiveness of compound, linker-payload, antibody-drug conjugate, or pharmaceutical composition This method involves administering a therapeutic dose.

[0014] Another embodiment, as shown herein, is a compound described herein, phosphorus This invention relates to a method for preparing car payloads, or antibody-drug conjugates, and compositions. [Brief explanation of the drawing]

[0015] (Brief explanation of the drawing) [Figure 1] Figures 1a-1i show the synthetic chemical schemes for bis-octahydrophenanthrene carboxamide, a cyclodextrin-based linker-payload, and its protein conjugate. [Figure 2] Figure 2 shows the synthetic chemical scheme of bis-octahydrophenanthrene carboxamide, a cyclodextrin-based linker-payload, and its protein conjugate. [Figure 3] Figures 3a-3e show the synthetic chemical schemes for bis-octahydrophenanthrene carboxamide, a cyclodextrin-based linker-payload, and its protein conjugate. [Figure 4] Figure 4 shows the synthetic chemical scheme of bis-octahydrophenanthrene carboxamide, a cyclodextrin-based linker-payload, and its protein conjugate. [Figure 5] Figure 5 shows the synthetic chemical scheme of bis-octahydrophenanthrene carboxamide, a cyclodextrin-based linker-payload, and its protein conjugate. [Figure 6] Figure 6 shows the synthetic chemical scheme of bis-octahydrophenanthrene carboxamide, a cyclodextrin-based linker-payload, and its protein conjugate. [Figure 7] Figure 7 shows the synthetic chemical scheme of bis-octahydrophenanthrene carboxamide, a cyclodextrin-based linker-payload, and its protein conjugate. [Figure 8] Figure 8 shows the synthetic chemical scheme of bis-octahydrophenanthrene carboxamide, a cyclodextrin-based linker-payload, and its protein conjugate. [Figure 9] Figure 9 shows the synthetic chemical scheme of bis-octahydrophenanthrene carboxamide, a cyclodextrin-based linker-payload, and its protein conjugate. [Figure 10] Figure 10 shows the synthetic chemical scheme of bis-octahydrophenanthrene carboxamide, a cyclodextrin-based linker-payload, and its protein conjugate.

[0016] [Figure 11] Figure 11 shows Coomassie-stained SDS-PAGE gels for anti-Her2 antibody, anti-Her2-PEG3-N3, and anti-Her2-LP8.

[0017] [Figure 12] Figure 12 shows the SECs for anti-Her2 Ab, anti-Her2-PEG3-N3, and anti-Her2-LP8.

[0018] [Figure 13] Figure 13 shows the activation of the ABCA1 and ABCG1 genes by an LXR agonist.

[0019] [Figure 14] Figure 14 shows the EC50 value using a four-parameter logistic curve for a 10-point dose-response curve.

[0020] [Figure 15] Figure 15 is a graph showing the dose-dependent percentage of cholesterol efflux in THP-1 macrophages for exemplary MSR1 antibody-LXR conjugates, their unconjugated counterparts, isotype control-LXR conjugates, and corresponding free payloads.

[0021] [Figure 16] Figure 16 provides a series of bar graphs illustrating the effects of exemplary MSR1 antibody-LXR agonist conjugates and their unconjugated counterparts on serum lipid levels in a mouse model of atherosclerosis.

[0022] [Figure 17] Figure 17 provides a series of bar graphs illustrating the effects of exemplary MSR1 antibody-LXR agonist conjugates and their unconjugated counterparts on lesion lipid area and macrophage (CD68) content in a mouse model of atherosclerosis.

[0023] [Figure 18] Figure 18 provides a series of bar graphs illustrating the effects of exemplary MSR1 antibody-LXR agonist conjugates and their unconjugated counterparts on liver triglyceride and cholesterol levels in a mouse model of atherosclerosis.

[0024] [Figure 19] Figure 19 provides a series of bar graphs illustrating the effects of exemplary MSR1 antibody-LXR agonist conjugates and their unconjugated counterparts on de novo lipid production in a mouse model of atherosclerosis. [Modes for carrying out the invention]

[0025] (Description of exemplary embodiments) Provided herein are the subjects of, for example, dyslipidemia, metabolic disorders, inflammation, or neuropathy. Compounds, compositions, and methods useful for treating transdegenerative diseases.

[0026] (definition) When referring to the compounds provided herein, the following terms, unless otherwise indicated, are used: The following meanings apply. Unless otherwise defined, technical and scientific terms as used herein. All terms have the same meaning as generally understood by those skilled in the art. Provided herein If there are multiple definitions for a term, these definitions shall take precedence unless otherwise specified. ru.

[0027] As used herein, "alkyl" refers to monovalent and saturated hydrocarbon radical moieties. Alkyl is optionally substituted and can be linear, branched, or cyclic, i.e., cyclo It can be alkyl. Alkyl can be a radical having 1 to 20 carbon atoms. In other words, C 1-20 Alkyl; a radical having 1 to 12 carbon atoms, i.e., C 1-12 Al Kill; a radical having 1 to 8 carbon atoms, i.e., C 1-8 Alkyl; 1 to 6 carbon atoms A radical having C 1-6 Alkyl; and radicals having 1 to 3 carbon atoms, In other words, C 1-3 Examples of alkyl groups include, but are not limited to, alkyl groups. For example, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, i-butyl Tyl, pentyl portion, hexyl portion, cyclopropyl, cyclobutyl, cyclopentyl, Examples include, but are not limited to, cyclohexyl. As for the pentyl portion, n- Examples include, but are not limited to, pentyl and i-pentyl. The hexyl portion is Examples include n-hexyl, but are not limited to these.

[0028] As used herein, "alkylene" refers to a divalent alkyl group. Unless otherwise specified, alkylenes contain 1 to 20 carbon atoms, but are not limited to these. The len group is optionally substituted with alkyl as described herein. In some embodiments, the alkylene is not substituted.

[0029] As used herein, the terms "O-amino acid" or "HO-amino acid" refer to amino acids. The natural amino group at the N-terminus of an amino acid or amino acid sequence is, respectively, an oxygen or hydroxyl group. This indicates the substituted amino acid. For example, "O-AAAA" or "HO-AAAA" indicates the N-terminal amino acid. Amino acid sequences in which the natural amino groups are replaced by either oxygen or hydroxyl groups, respectively. (AAAA) (For example, [ka] Here, each R is intended to represent an amino acid side chain. Similarly, "O-Ami The terms "no-acid residue" or "HO-amino acid residue" refer to the chemical residues remaining in a compound after a chemical reaction. It refers to a part. For example, "O-amino acid residue" or "HO-amino acid residue" refers to an O-amino acid or H Amide coupling or peptide coupling between O-amino acids and a suitable coupling partner. This refers to the product of the ring; here, for example, a water molecule is the a of the O-amino acid or the HO-amino acid. It is ejected after mido or peptide coupling, resulting in the O-amino acid residue or the HO -A product is formed in which an amino acid residue is incorporated.

[0030] The notation for amino acids or amino acid residues whose stereochemistry is not specified is L-type amino acids, D-type amino acids. It is intended to contain amino acids, or racemic mixtures thereof.

[0031] As used herein, “haloalkyl” means alkyl as defined above. This refers to a halogen, where the alkyl is a halogen, such as fluorine (F), chlorine (Cl), bromine (Br), or comprising at least one substituent selected from iodine(I). Examples of haloalkyls include Examples include, but are not limited to, -CF3, -CH2CF3, -CCl2F, and -CCl3.

[0032] As used herein, “alkenyl” means at least two carbon atoms and one or more This refers to the monovalent hydrocarbon radical moiety containing a non-aromatic carbon-carbon double bond. They are optionally substituted and can be linear, branched, or annular. Therefore, a radical having 2 to 20 carbon atoms, i.e., C 2-20 Alkenil; 2-12 pieces of charcoal A radical containing an elementary atom, i.e., C 2-12 Alkenyl; a radian having 2 to 8 carbon atoms. Cal, that is, C 2-8 Alkenyl; a radical having 2 to 6 carbon atoms, i.e., C 2-6 Alkenyls; and radicals having 2 to 4 carbon atoms, i.e., C 2-4 Alkenil listed However, it is not limited to these. Examples of alkenyl moieties include vinyl, propenyl, Examples include, but are not limited to, buttenyl and cyclohexenyl.

[0033] As used herein, "alkynyl" means at least two carbon atoms and one or more This refers to the monovalent hydrocarbon radical moiety containing a carbon-carbon triple bond. The term "alkynyl" is optional. It is substituted and can be linear, branched, or cyclic. As for the alkynyl, 2 A radical having approximately 20 carbon atoms, i.e., C2-20 Alkynyl; 2 to 12 carbon atoms The radicals that possess, namely C 2-12 Alkynyl; a radical having 2 to 8 carbon atoms. Nawachi, C 2-8 Alkynyl; a radical having 2 to 6 carbon atoms, i.e., C 2-6 Alkini A radical having 2 to 4 carbon atoms, i.e., C 2-4 Alkinyl is one example, , but not limited to these. Examples of alkynyl moieties include ethinyl, propynyl, and b Tynyl is one example, but it is not limited to these.

[0034] As used herein, "alkoxy" refers to monovalent and saturated hydrocarbon radical portions. Here, the hydrocarbon contains a single bond with an oxygen atom, and the radical is on the oxygen atom. It is located, for example, in the case of ethoxy, it is CH3CH2-O·. The alkoxy substituent is such that it is The compound is substituted via this oxygen atom of the lucoxy substituent. The alkoxy is optional. It is substituted and is linear, branched, or cyclic, i.e., cycloalkoxy. Yes, it is possible. Alkoxy compounds include those having 1 to 20 carbon atoms, i.e., C 1-20 Arco Xy; having 1 to 12 carbon atoms, i.e., C 1-12 Alkoxy; 1 to 8 carbon atoms Those having, namely, 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 mentioned However, it is not limited to these. Examples of alkoxy moieties include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, i-butoxy, pen Toxy portion, hexoxy portion, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy (that is, respectively, [ka] ) are some examples, but are not limited to these.

[0035] As used herein, "haloalkoxy" means an alcohol as defined above. This refers to xy, where the alkoxy is selected from halogens, for example, F, Cl, Br, or I. It includes at least one substituent.

[0036] As used herein, “aryl” refers to an aromatic compound in which the ring atom is a carbon atom. This refers to the monovalent radical portion. The aryl group is optionally substituted and can be monocyclic or polycyclic. For example, it can be a biring or triring. An example of the aryl portion is 6-2 Those having 0 ring carbon atoms, i.e., C 6-20 Aryl; having 6 to 15 ring carbon atoms. Suddenly, that is, C 6-15 Aryls, and those having 6 to 10 ring carbon atoms, i.e., C 6-10 Examples of aryls include, but are not limited to, aryls. Phenyl, naphthyl, fluorenyl, azurenyl, anthrill, phenanthryl, and pyrethroid Examples include, but are not limited to, nil.

[0037] As used herein, “arylalkyl” is a radical of an alkyl compound. This refers to the monovalent portion, where the alkyl compound is substituted with an aromatic substituent, that is, The aromatic compound contains a single bond with an alkyl group, and the radical is located on the alkyl group. Arylalkyl groups are bonded to the illustrated chemical structure via alkyl groups. Arylalkyls have a structure, for example, [ka] (Here, B is an aromatic moiety, for example, phenyl.) This can be represented by... The aryl alkyl group is optionally substituted, i.e., the aryl group and / or alkyl group is They can be substituted as disclosed herein. Examples of arylalkyls include Examples include benzyl, but it is not limited to this.

[0038] As used herein, "alkylaryl" is a radical of an aryl compound. This refers to the monovalent portion, where the aryl compound is substituted with an alkyl substituent, that is, In other words, the aryl compound contains a single bond with an alkyl group, and the radical is on the aryl group. It is located at [location]. The alkylaryl group is linked to the illustrated chemical structure via the aryl group. They combine. Alkylaryls have a structure, for example, [ka] (Here, B is an aromatic moiety, for example, phenyl.) can be represented by A The aryl group is optionally substituted, i.e., the aryl group and / or alkyl group is They can be substituted as disclosed herein. Examples of alkylaryls include One example is Toluil, but it is not limited to this.

[0039] As used herein, "aryloxy" means that the ring atom is a carbon atom, and Refers to a monovalent moiety that is a radical of an aromatic compound in which the ring is substituted with an oxygen radical, i.e., the aromatic compound contains a single bond with an oxygen atom, and the radical is positioned on that oxygen atom. For example, in the case of phenoxy,

Chemical formula

[0040] and the ring is substituted with at least one R a R b N-substituent and at least one oxygen radical, i.e., the aromatic compound contains a single bond with an R R a R b N-substituent and a single bond with an oxygen atom, and the radical is positioned on that oxygen atom. For example, a R b it is as follows.

Chemical formula

Chemical formula

[0041] As used herein, "arylene" refers to the divalent moiety of an aromatic compound whose ring atoms are only carbon atoms. Arylene is optionally substituted and can be monocyclic or polycyclic, for example, bicyclic or tricyclic. Examples of the aryl moiety include those having 6 to 20 ring carbon atoms, that is, C arylene; those having 6 to 15 ring carbon atoms <000482..]] that is, C 6-20 arylene; those having 6 to 15 ring carbon atoms that is, C 6-15Arylene, and those having 6 to 10 ring carbon atoms, i.e., C6 -10 Arrines are one example, but are not limited to them.

[0042] As used herein, "heteroalkyl" means a heteroatom in which one or more carbon atoms are present. Refers to a substituted alkyl group. As used herein, "heteroalkenyl" means This refers to an alkenyl in which one or more carbon atoms are substituted with heteroatoms. In this case, "heteroalkynyl" is an albino compound in which one or more carbon atoms are replaced by heteroatoms. This refers to Kenyl. Suitable heteroatoms include nitrogen, oxygen, and sulfur atoms, These are not the only examples. Heteroalkyls are optionally substituted. Heteroalkyl portion Examples include aminoalkyl, sulfonylalkyl, and sulfinylalkyl. However, it is not limited to these. Examples of heteroalkyl moieties include methylamino, me Examples include, but are not limited to, cysulfonyl and methylsulfinyl.

[0043] As used herein, "heteroaryl" means a ring atom consisting of a carbon atom and at least A monovalent part is a radical of an aromatic compound containing one oxygen, sulfur, nitrogen, or phosphorus atom. This refers to a fraction. Examples of heteroaryl moieties include 5-20 ring atoms; 5-15 ring atoms; and 5 Examples include, but are not limited to, heteroaryl compounds having approximately 10 ring atoms. , has been arbitrarily replaced.

[0044] As used herein, "heterorialene" refers to a compound where one or more ring atoms of an aromatic ring are oxygenated. This refers to arylenes in which sulfur, nitrogen, or phosphorus atoms are substituted. Heteroarylenes are It has been arbitrarily replaced.

[0045] As used herein, "heterocycloalkyl" means a compound of one or more carbon atoms. This refers to cycloalkyl groups in which atoms are substituted. Suitable heteroatoms include nitrogen, oxygen, Examples include, but are not limited to, sulfur atoms. Heterocycloalkyls are optionally Substitutions are used. Examples of heterocycloalkyl moieties include morpholinyl and piperidinyl. Tetrahydropyranil, pyrrolidinil, imidazolidinil, oxazolidinil, thiazo Examples include lysinyl, dioxolanil, dithiolanil, oxanil, or thianil, This is not limited to these.

[0046] As used herein, "Lewis acid" refers to a molecule or ion that accepts a lone pair of electrons. The Lewis acids used in the methods described herein are non-proton-containing. Lewis acids include non-metallic acids, metallic acids, hard Lewis acids, and soft Lewis acids. However, it is not limited to these. Examples of Lewis acids include aluminum, boron, iron, tin, and thi. Tungsten, magnesium, copper, antimony, phosphorus, silver, ytterbium, scandium, nickel Examples include, but are not limited to, Lewis acids of Kell and zinc. Exemplary Lewis acids and For example, AlBr3, AlCl3, BCl3, methyl boron trichloride sulfide, BF3, methyl boron trifluoride methyl trifluoride, methyl boron trifluoride, tetrahydrofuran boron trifluoride, dicyclohexyl Silboron trifluoromethanesulfonate, iron(III) bromide, iron(III) chloride, tin(IV) Chloride, Titanium(IV) chloride, Titanium(IV) isopropoxide, Cu(OTf)2, CuCl2, CuBr2, Salt Zinc oxide, alkylaluminum halide (Rn AlX 3-n Here, R is hydrocarbil. ), Zn(OTf)2, ZnCl2, Yb(OTf)3, Sc(OTf)3, MgBr2, NiCl2, Sn(OTf)2, Ni(OTf)2, and Mg (OTf)2 is one example, but it is not limited to these.

[0047] As used herein, "N-containing heterocycloalkyl" means having one or more carbon atoms A cycloatomic atom that is substituted with a heteroatom, and at least one of the heteroatoms is a nitrogen atom. This refers to alkyl groups. Besides nitrogen, suitable heteroatoms include oxygen and sulfur atoms. However, it is not limited to these. N-containing heterocycloalkyls are optionally substituted. Examples of heterocycloalkyl moieties include morpholinyl, piperidinyl, and pyrrolidinyl. Examples include , imidazolidinyl, oxazolidinyl, or thiazolidinyl, but these Not limited to this.

[0048] When used herein, "optionally" is used to describe the radical portion. "Substituted," for example, an optionally substituted alkyl group, is defined as a moiety with one or more substituents. This means that it is arbitrarily bonded to it. Examples of such substituents include halo, cyano, Nitro, optionally substituted haloalkyl, azide, epoxy, optionally substituted heteroalkyl Reel, optionally substituted heterocycloalkyl, [ka] (Here, R A , R B , and R C Each time it appears, it independently produces a hydrogen atom, alkyl, alkenyl, Alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, hetero It is either aryl or heterocycloalkyl, or R A and R B They combine Together with the atoms present, they form saturated or unsaturated carbon rings, where the rings are optionally substituted. Examples include (where one or more ring atoms are arbitrarily substituted with heteroatoms), These are not the only embodiments. In one embodiment, the radical portion is an optionally substituted hetero Aryl, optionally substituted heterocycloalkyl, or optionally substituted saturated or When arbitrarily substituted with an unsaturated carbon ring, the arbitrarily substituted heteroaryl, arbitrarily A substituted heterocycloalkyl or optionally substituted saturated or unsaturated carbon ring Substituents, if they are substituted, are further optionally substituted with additional substituents. It is not substituted with substituents. In some embodiments, the groups described herein are left to the discretion of the user. When substituted, the substituent bonded to the group is, unless otherwise specified, substituted. It hasn't been done.

[0049] As used herein, “binding agent” refers to a given binding partner, for example, an antigen and a specific This refers to any molecule that can bind with a member of the opposite sex, such as a protein.

[0050] As used herein, “linker” means a binder comprising one or more of the binders described herein. Compounds such as divalent, trivalent, or polyvalent compounds that are covalently bonded to the payload compound and enhancer. It refers to a part.

[0051] As used herein, “amide synthesis conditions” refers to, for example, carboxylic acids, activated carboxylic acids. To achieve amide formation through the reaction of ammonium acid or acyl halide with amines This refers to suitable reaction conditions. In some examples, "amide synthesis conditions" refer to conditions for the reaction of a carboxylic acid and an amide. This refers to reaction conditions suitable for achieving the formation of amide bonds between mines. Several examples of these conditions are... In this process, the carboxylic acid is first converted to an activated carboxylic acid, and then the activated carboxylic acid Rubonic acid reacts with amines to form amides. Suitable for achieving amide formation. The conditions are not limited to dicyclohexylcarbodiimide (DCC) and diisopropyl Lucarbodiimide (DIC), (benzotriazole-1-yloxy)tris(dimethylamino) Suphonium hexafluorophosphate (BOP), (benzotriazole-1-yloxy)tri Pyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazole) (Lu-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), Romotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), O-(benzotri Azole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) ), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumtetrafluoro Borate (TBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyri Dinium 3-oxide hexafluorophosphate (HATU), N-ethoxycarbonyl-2-ethoxycarbonyl Xy-1,2-dihydroquinoline (EEDQ), N-ethyl-N'-(3-dimethylaminopropyl)carbody Imide (EDC), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (C IP), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), and carbonyl diimidazole Examples include those that utilize reagents containing carboxylic acid (CDI) to achieve the reaction between carboxylic acid and amine. However, it is not limited to these. In some cases, the carboxylic acid is first activated. Convert to a carboxylic acid ester, and then treat the activated carboxylic acid ester with an amine. , to form an amide bond. In one embodiment, the carboxylic acid is treated with a reagent. Reagent This involves deprotonating the carboxylic acid, and then protonating the deprotonated carboxylic acid. As a result of nucleophilic attack on the neutronated reagent, the product with the deprotonated carboxylic acid is compound By causing a bond to form, the carboxylic acid is activated. Subsequently, the activation of a specific carboxylic acid is performed. Activated carboxylic acid esters undergo nucleophilic attack by amines more readily than before the carboxylic acid is activated. It is highly sensitive to this. As a result, amide bond formation occurs. Therefore, the carbo The acid is described as being activated. Exemplary reagents include DCC and DIC. ru.

[0052] As used herein, "positional isomer (singular)", "positional isomer (plural)", or "position" The mixture of isomers is a suitable azide treated with a suitable alkyne (e.g., -N3, or PE). 1,3-cyclization or strain-promoting alkyne-azide cyclization (S) derived from G-N3 derivatized antibodies PAAC) refers to the product of a click reaction, For example, positional isomers and mixtures of positional isomers are reacted by the click reaction products shown below. Characterized by: [ka] In one embodiment, a plurality of suitable azides and a plurality of suitable alkynes are directed toward the product. It can be used in the intermediate synthesis scheme, and in this synthesis scheme, each azid - Alkyne pairs are involved in one or more independent click reactions, and positional isomerized click reaction products A mixture can be produced. For example, a person skilled in the art can produce a first preferred product on the way to the product. A suitable azide can react independently with a first suitable alkyne, and a second suitable azide It can react independently with a second suitable alkyne in a sample of ADC described herein. This results in four possible click-reaction positional isomers or a mixture of four possible click-reaction positional isomers. They will be aware that this will be produced as a result. As a further example, those skilled in the art will know During the process towards the final product, the first preferred azide reacts independently with the first preferred alkyne. This allows the second preferred azide to react independently with the second preferred alkyne, and the true In the LP sample described in the details, four possible click reaction positional isomers or four possible click reactions They will likely be aware that a mixture of regioisomers will be produced as a result of the reaction.

[0053] As used herein, the term “residue” refers to the chemical residue remaining in a compound after a chemical reaction. It refers to the specific part. For example, the term "amino acid residue" or "N-alkyl amino acid residue" , amide coupling of amino acids or N-alkyl amino acids with suitable coupling partners This refers to the product of a coupling or peptide coupling reaction; where, for example, a water molecule is the amino acid. Alternatively, the N-alkyl amino acid is expelled after amide or peptide coupling, resulting in This results in a product in which the amino acid residue or N-alkyl amino acid residue is incorporated. .

[0054] As used herein, “therapeutic dose” means the treatment or management of a disease or disorder. To provide therapeutic benefits to patients in or to treat one or more conditions associated with a disease or disorder This refers to the amount (of a compound, for example) sufficient to delay or minimize the state.

[0055] A specific group, part, substituent, and atom is an atom to which the group, part, substituent, and atom are bonded. To indicate this, the singular or plural combinations are shown with intersecting wavy lines. For example, The propyl group shown below: [ka] The substituted phenyl group has the following structure: [ka] It has a cyclic group (e.g., aromatic) via a bond between ring atoms. When used herein, it has a cyclic group (e.g., aromatic) via a bond between ring atoms. , heteroaromatic, condensed ring, and saturated or unsaturated cycloalkyl or heterocycloal Figures showing substituents bonded to the cyclic group (Kill) are, unless otherwise specified, described herein. Any ring position in the ring base, according to techniques described or known in the art relating to this disclosure The intention is to show that the substituent can be substituted in place or on any ring in the fused ring group. For example, if the subscript q is an integer between 0 and 4, and the substituent R 1 The location is generally described It is bonded, that is, directly bonded to any vertex of the bond line structure, i.e., to a specific ring carbon atom. The base that has not been [ka] is a substituent R 1 This includes the following non-limiting examples of groups in which a specific ring carbon atom is bonded: [ka] .

[0056] As used herein, the term "reactive linker" or the abbreviation "RL" means for example, [ka] (Here, RG is the reactive group and SP is the spacer group) Reactive group and spacer group This refers to a monovalent group containing a th-a- It contains a reactive group and multiple spacer groups. The spacer groups move the reactive group to another group. For example, any divalent portion that bridges the payload. A reactive linker (RL) is used to bridge it. Together with the combined payload, for the preparation of antibody conjugates as described herein. This provides a useful intermediate ("linker-payload") as a synthesis precursor for reactive linker. - is another group, for example, an antibody, a modified antibody, or an antigen-binding fragment thereof, or an enhancing group It contains a functional group or a reactive group that is a functional group ("RG") that can react with the reactive moiety. By reacting with an antibody, modified antibody, or antigen-binding fragment thereof, which possess both an adaptive group and a binding group. The resulting portion is the “binding linker” ("BL") portion of the conjugate as described herein. The minutes are included. In one embodiment, the “reactive group” is the cis of the antibody or its antigen-binding fragment. Functional groups or functional moieties that react with theine or lysine residues (e.g., maleimide or N-hydro It is xisuccinimide (NHS) ester. In one embodiment, the "reactive group" is cri. A functional group or functional moiety that can undergo a click chemical reaction (e.g., click chemical reaction, H uisgen's literature, Proc. Chem. Soc. 1961, Wang et al.'s literature, J. Am. Chem. Soc. 2003, and A See Gard et al., J. Am. Chem. Soc. 2004. Several implementations of the click reaction. In one embodiment, the reactive group is an alkyne capable of undergoing a 1,3-addition cycloaddition reaction with an azide. Yes, there are. Suitable reactants for this include strain alkynes, for example, strain-promoting alkynes. Suitable for zide addition cycloaddition (SPAAC), cycloalkynes, e.g., cyclooctyne, benz It can undergo 1,3-addition cycloaddition reactions with alkynes in the absence of cyclized alkynes and copper catalysts. Examples of alkynes include, but are not limited to, diben. Zoazacyclooctin or [ka] , dibenzocyclooctin or [ka] , biarylazacyclooctinone or [ka] , difluorinated cyclooctin or [ka] , substitutions, for example, fluorinated alkynes, aza-cycloalkynes, bicycl[6.1.0]nonine or [ka] (BCN, where R is alkyl, alkoxy, or acyl), and their derivatives While the body can also be mentioned, it is not limited to these. Particularly useful alkynes include: [ka] Examples include linker-payloads containing such reactive groups, which are functionalized with azide groups. It is useful for conjugating antibodies that are already functionalized. Such functionalized antibodies include azide- It contains an antibody functionalized with polyethylene glycol groups. In one embodiment, Such functionalized antibodies have at least one glutamine residue, for example, the heavy chain Gln295. The body is supported by amino groups and azide groups in the presence of the enzyme transglutaminase. It is obtained by treatment with a compound.

[0057] In some examples, the reactive group is an alkyne, for example, [ka] This is because, via a click chemical reaction, azide is produced, for example, [ka] It reacts with a click chemical reaction product, for example, [ka] It can form a modified antibody or its antigen binding cleavage. In some examples, the group can form a modified antibody or its antigen binding cleavage. It reacts with the azide on the surface. In some examples, the reactive group is an alkyne, for example, [ka] This is because, via a click chemical reaction, azide is produced, for example, [ka] It reacts with a click chemical reaction product, for example, [ka] It is possible to form an alkyne. In some examples, the reactive group is an alkyne, for example, [ka] This is because, via a click chemical reaction, azide is produced, for example, [ka] It reacts with a click chemical reaction product, for example, [ka] It can form a functional group, for example, [ka] This reacts with cysteine ​​residues on the antibody or its antigen-binding fragment, and binds to them. For example, [ka] (Here, Ab represents an antibody or its antigen-binding fragment, and S represents the functional group that is attached to Ab via it.) It forms a group (representing the S atom on the cysteine ​​residue to which it binds). In some examples, the reactive group is , functional groups, for example, [ka] This is because it reacts with lysine residues on the antibody or its antigen-binding fragment, and binds to them. for example, [ka] (Here, Ab represents an antibody or its antigen-binding fragment, and NH represents the functional group via the Ab) (This represents the NH atom on the lysine side chain residue that is bonded to it.)

[0058] As used herein, the term “biodegradable portion” refers to the normal biological process It breaks down in vivo into non-toxic, biocompatible components that can be removed from the body. This refers to minutes. In some embodiments, the biodegradable portion lasts for about 90 days or less, about 60 days or less, and It is completely or substantially broken down in vivo over a period of approximately 30 days or less, where the degree of breakdown is as follows: Based on the percentage mass loss of the biodegradable portion, where complete decomposition results in a 100% mass loss. Corresponding. An example of a biodegradable part is aliphatic polyester, for example, poly(ε-capsule). (PCL) poly(3-hydroxybutyrate) (PHB), poly(glycolic acid) (PGA), Li(lactic acid)(PLA) and its copolymer with glycolic acid (i.e., poly(D,L-lactide-co) Glycolide (PLGA) is one example, but it is not limited to these (each of which is fully cited by the citation). The references of Vert M, Schwach G, Engel R, and Coudane J (1998) are incorporated herein. J Control Release 53(1-3):85-92; Jain RA's Literature (2000) Biomaterials 21(23):2475-2 490; References by Uhrich KE, Cannizzaro SM, Langer RS, and Shakesheff KM (1999) Chem Medical Reviews 99(11):3181-3198; and Park TG's literature (1995) Biomaterials 16(15):112 3-1130).

[0059] As used herein, the terms "effective dose," "physiological effective dose," or "preventive effective dose" are used interchangeably. The phrase, when administered to a subject in need of such treatment, brings about the treatment. This refers to the amount of compound that is sufficient for [the patient's] needs. The "physiologically effective amount" of an active substance is determined by the external [perceived] amount of the active substance. This indicates the effective amount of the active substance that has a noticeable effect. Therefore, the physiological effective amount is the effective amount. It does not require special equipment to determine the result, and one of the patient's characteristics (e.g., phenotype) Or it affects multiple things. For example, the physiologically effective amount of the compounds disclosed herein is therapeutic By alleviating one or more of the symptoms of the disease being treated, the patient's behavior can be affected. It has a noticeable effect that can be observed from the outside. Therefore, by observing the patient, and active By observing whether the active substance caused any changes in the patient, the effective amount of the active substance can be determined. It is possible to determine whether or not the drug was administered.

[0060] As used herein, the terms “binding linker” or “BL” refer to a binding agent (e.g., For example, an antibody or its antigen-binding fragment) is used with a payload compound as shown herein (e.g., a vi (S-octahydrophenanthrenecarboxamide) and optionally one or more side chain compounds This refers to any divalent, trivalent, or polyvalent group or part that is linked, connected, or bonded. A suitable binding linker for antibody conjugates described herein is the antibody's circulating linker. It is sufficiently stable to utilize the ring half-life, and at the same time, the antigen-mediated endogenous properties of the conjugate The payload can be released after the transformation. The linker is cleavable or It can be non-cleaving. Cleaving linkers are involved in intracellular metabolism after internalization, for example, hydrolysis. Linkers that are cleaved by decomposition, reduction, or enzymatic reactions. Non-cleaving phosphorus Kerr releases the bound payload through lysosomal degradation of the antibody after internalization. It is a linker. Suitable linkers include acid-unstable linkers and hydrolysis-unstable linkers. , enzyme-cleaving linkers, reductively unstable linkers, self-destructing linkers, and non-cleaving linkers Examples include, but are not limited to, peptides and glucurolinkers. Nido, succinimide-thioether, polyethylene glycol (PEG) units, hydrazone, Mar-caproyl units, dipeptide units, valine-citrulline units, and para-aminobenes This includes, but is not limited to, units in the zirl (PAB) or units containing these units. In some embodiments, the binder linker (BL) is the reactive group (R) of the reactive linker (RL). G) and a binder, for example, an antibody, a modified antibody, or the reaction portion of their antigen-binding fragments react It includes the part that is formed.

[0061] In some examples, BL is the following part: [ka] or comprising a triazolyl positional isomer, where, [ka] This is the binding with the binder. In some examples, BL is the following part: [ka] Including, here, [ka] This is the binding with the binder. In some examples, BL is the following part: [ka] or comprising a triazolyl positional isomer, where, [ka] This is the binding with the binder. In some examples, BL is the following part: [ka] Including, here, [ka] This is the binding of an antibody or its antigen-binding fragment to cysteine. In some examples, BL This is the following part: [ka] Including, here, [ka] This refers to the binding of an antibody or its antigen-binding fragment to lysine.

[0062] (Compounds and payloads) In some examples, the compounds shown herein have the structure of formula (I) or are medical It is a medicinal salt, solvate, or stereoisomer: [ka] (In the formula, Q 1 and Q 2 Each of these is independently -CH2-, -C(O)-, -C(H)(OH)-, or -C(OH)2-; W is -CH2-, -N(H)-, or -O-; R 1 is -H, -OH, -NH2, alkyl, or -OP(O)(OR 6 )2; R 2 -H, -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 And here, R 1 and R 2 At the same time For -H, not -H; R 3 is -N(R 6 )2; R 4 is -XYZ; X is selected from the group consisting of -O- and -N(H)-; Y is an alkylene, a substituted alkylene (not limited to oxo substitutions, i.e., including =O). ), heteroalkylenes, and substituted heteroalkylenes (not limited to oxo substitutions (i.e.) Selected from the group consisting of (including = O); Z is selected from the group consisting of -OH and -NH2; R 5 is an alkyl, heterocycloalkyl, or substituted heterocycloalkyl, and here Each heterocycloalkyl or substituted heterocycloalkyl is selected from nitrogen and oxygen. It contains one, two, or three selected heteroatoms and at least one -OH and -CH2OH group. Containing a conversion group, or at least one primary or secondary nitrogen, such as O-glucose; Each R 6 In each case, -H, amino acid residue, N-alkyl amino acid residue, peptide, or alkyl; and Each R 7 Independently, Halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O- amino acid residues, and O-PEG n (where n is an integer between 0 and 3).

[0063] In formula I, in one embodiment, R 5 is heterocycloalkyl or substituted heterocycloalkyl It is lucyl. Useful heterocycloalkyl groups include tetrahydropyranyl, glyco Examples include sidyl and piperazinyl. These groups may be substituted or not substituted. They are not necessary. In some embodiments, they are not substituted. These are substituted. Exemplary substituents include at least one hydroxyl This includes at least one primary nitrogen or at least one secondary nitrogen.

[0064] In one embodiment of formula I, R 6 In each case, independently, amino acid residues and N-alkyl groups are involved. It is an amino acid residue or a peptide. Those skilled in the art will know whether the amino acid residue is achiral or chiral. They would recognize, for example, that it could be an L-amino acid or a D-amino acid. It typically includes an amino acid side chain. The side chain is the side chain of any amino acid known to those skilled in the art. This is possible. In one embodiment, the side chain may be histidine, alanine, or isoleucine. Arginine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine Ingredients, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, Phosphorus, ornithine, selenocysteine, serine, glycine, homoglycine (for example, β-H It is a side chain of moglycine or tyrosine. Those skilled in the art will know that the peptide is, for example, a racemic DL- Contains amino acids or non-racemic D- or L-amino acids and mixtures of their diastereomers. They will be aware that the peptide side chain may be achiral or chiral. As described in the context of the amino acids. Those skilled in the art will know that the N-alkyl amino acid residue is The terminal amino group of an amino acid residue or the terminal amino group of the peptide as defined herein It is likely that they are aware of the presence of alkyl substituents such as N-methylammonium compounds. Examples include ano acids and N-ethyl amino acids.

[0065] In formula I, in one embodiment, each R 7 Hello, C 1-6 Alkyl, C 1-6 Alkoxy, - CN, O-glucose, O-amino acid residue, or O-PEG n Here, each n is an integer between 0 and 3. It is a number. In one embodiment, the O-amino acid residue is the HO-amino acid defined above. Contains residues. In one embodiment, O-PEG n This is the case when n=0. In another embodiment... In O-PEG n This is the case for n=1. In another embodiment, O-PEG n This is for n=2 This is the case. In another embodiment, O-PEG n This is the case where n=3.

[0066] In some examples, the compounds shown herein have the structure of formula (Ia) or are medical It is a medicinal salt, solvate, or stereoisomer: [ka] (In the formula, Q 1 and Q 2 Each of these is independently -CH2-, -C(O)-, -C(H)(OH)-, or -C(OH)2-; W is -CH2-, -N(H)-, or -O-; R 1 is -H, -OH, -NH2, alkyl, or -OP(O)(OR 6 )(OH)-OP(O)(OR 6 )2; R 2 -H, -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 And here, R 1 and R2 At the same time For -H, not -H; R 3 is -N(R 6 )2; R 4 is -XYZ; X is selected from the group consisting of -O- and -N(H)-; Y is an alkylene, a substituted alkylene (not limited to oxo substitutions, i.e., including =O). ), heteroalkylenes, and substituted heteroalkylenes (not limited to oxo substitutions (i.e.) Selected from the group consisting of (including = O); Z is selected from the group consisting of -OH and -NH2; R 5 is an alkyl, heterocycloalkyl, or substituted heterocycloalkyl, and here Each heterocycloalkyl or substituted heterocycloalkyl is selected from nitrogen and oxygen. It contains one, two, or three selected heteroatoms and at least one -OH and -CH2OH group. Containing a conversion group, or at least one primary or secondary nitrogen, such as O-glucose; Each R 6 In each case, -H, amino acid residue, N-alkyl amino acid residue, peptide, or alkyl; and Each R 7 Independently, Halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O- amino acid residues, and O-PEG n (where n is an integer between 0 and 3).

[0067] In formula Ia, in one embodiment, R 5 is heterocycloalkyl or substituted heterocycloalkyl It is lucyl. Useful heterocycloalkyl groups include tetrahydropyranyl, glyco Examples include sidyl and piperazinyl. These groups may be substituted or not substituted. They are not necessary. In some embodiments, they are not substituted. These are substituted. Exemplary substituents include at least one hydroxyl This includes at least one primary nitrogen or at least one secondary nitrogen.

[0068] In one embodiment of formula Ia, R 6 In each case, independently, amino acid residues and N-alkyl groups are involved. It is an amino acid residue or a peptide. Those skilled in the art will know whether the amino acid residue is achiral or chiral. They would recognize, for example, that it could be an L-amino acid or a D-amino acid. It typically includes an amino acid side chain. The side chain is the side chain of any amino acid known to those skilled in the art. This is possible. In one embodiment, the side chain may be histidine, alanine, or isoleucine. Arginine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine Ingredients, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, Phosphorus, ornithine, selenocysteine, serine, glycine, homoglycine (for example, β-H It is a side chain of moglycine or tyrosine. Those skilled in the art will know that the peptide is, for example, a racemic DL- This includes amino acids or non-racemic D- or L-amino acids and mixtures of diastereomers thereof. They would recognize that the peptide may be achiral or chiral. The side chain of the peptide is above As described in relation to amino acids, those skilled in the art will know N-alkyl amino acids. The residue is the terminal amino group of the amino acid or the terminal amino group of the peptide as defined herein. They will likely be aware that it contains alkyl substituents.

[0069] In formula Ia, in one embodiment, R 7 Hello, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O - Glucose, O-amino acid residue, or O-PEG n Here, each n is an integer between 0 and 3. In one embodiment, the O-amino acid residue is the HO-amino acid residue defined above. Includes. One embodiment, O-PEG n This is the case where n=0. In another embodiment O-PEG n This is the case for n=1. In another embodiment, O-PEG n This is the case when n=2 In another embodiment, O-PEG n This is the case where n=3.

[0070] In one embodiment of formula I or Ia, Q 1 It is -CH2- and Q 2 It is -C(O)-. Another implementation In this regard, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-. In another embodiment, Q 1 is -C(O)- Yes, Q 2 is -CH2-. In yet another embodiment, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)-.

[0071] In one embodiment of formula I or Ia, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is -CH 2. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is -CH2 - and R 1 is -H, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 That is. Another reality In the implementation configuration, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 teeth,- H and R 2 is -OH. In another embodiment, Q 1 It is -CH2- and Q 2 is, -C(O)- And W is -CH2-, and R 1 is -H, and R 2 It is -CH2NH2. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -H, and R 2 R 3 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is , -CH2-, R 1 is -H, and R 2 R 4 In another embodiment, Q 1 -CH2- Q 2 is -C(O)-, W is -CH2-, and R 1 is -H, and R 2 R 5 That is. In this embodiment, Q 1 It is -CH2- and Q 2is -C(O)-, W is -CH2-, and R 1 is -H, and R 2 is -OR 5 In another embodiment, Q 1 It is -CH2- and Q 2 teeth, It is -C(O)-, W is -CH2-, and R 1 is -H, and R 2 It is amino, dimethylamino, hi Droxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 It is -CH2- and Q 2 is, -C(O)- And W is -CH2-, and R 1 is -OH, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or - Ure 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is -C It is H2- and R 1 is -OH, and R 2 is -OH. In another embodiment, Q 1 is -CH2- Yes, Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH, and R 2 It is -CH2NH2. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)- and W is -CH2- , R 1 is -OH, and R 2 R 3 In another embodiment, Q1 It is -CH2- and Q 2 teeth , is -C(O)-, W is -CH2-, R 1 is -OH, and R 2 R 4 This is another embodiment. In Q 1 It is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH R 2 R 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)- W is -CH2-, and R 1 is -OH, and R 2 is -OR 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH, and R 2 is, Mino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 It is -CH2- and Q 2 is, -C(O)- And W is -CH2-, and R 1 It is -NH2, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is - CH2- and R 1It is -NH2, and R 2 is -OH. In another embodiment, Q 1 -CH2- Q 2 is -C(O)-, W is -CH2-, and R 1 It is -NH2, and R 2 This is -CH2NH2 Yes. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)- and W is -CH2- Yes, R 1 It is -NH2, and R 2 R 3 In another embodiment, Q 1 It is -CH2- Q 2 is -C(O)-, W is -CH2-, and R 1 It is -NH2, and R 2 R 4 That is. Another reality In the implementation configuration, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 teeth,- It is NH2, R 2 R 5 In another embodiment, Q 1 It is -CH2- and Q 2 is, -C(O)- And W is -CH2-, and R 1 It is -NH2, and R 2 is -OR 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 It is -NH2. , R 2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 It is -CH2- and Q 2 is, -C(O)- And W is -CH2-, and R 1 is alkyl, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , OR 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)- and W It is -CH2- and R 1 is alkyl, and R 2 is -OH. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is alkyl, and R 2 is -CH2NH2. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is alkyl, and R 2 R 3 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is alkyl, and R 2 R 4 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is, -CH2- and R 1 is alkyl, and R 2 R 5 In another embodiment, Q 1teeth,- CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is alkyl, and R 2 is, -O -R 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is -CH 2- and R 1 is alkyl, and R 2 is amino, dimethylamino, hydroxyl, [ka] It is selected from the group consisting of the following.

[0072] In another embodiment of formula I or Ia, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is - CH2- and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 It is -OH, R 2 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is , -CH2-, R 1 is -OP(O)(OR 6 )(OH) and R 2 is -H. The aforementioned implementation in this paragraph In any one of the embodiments, R 6 This can be selected from the group consisting of hydroxyl and methyl. ru.

[0073] In one embodiment of formula I or Ia, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is -O- In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is -O-. Yes, R 1 is -H, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 That is. Another implementation In this regard, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is with -H Yes, R 2 is -OH. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)- W is -O-, and R 1 is -H, and R 2 is -CH2NH2. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is -H, and R 2 R 3 in Yes. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is -O-. R 1 is -H, and R 2 R 4 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is -H, and R 2 R 5In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is -H, and R 2 is -OR 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)- and W It is -CH2- and R 1 is -H, and R 2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 It is -CH2- and Q 2 is, -C(O)- And W is -O- and R 1 is -OH, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -O- R 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is -O- And R 1 is -OH, and R 2 is -OH. In another embodiment, Q 1 is -CH2- Q 2 is -C(O)-, W is -O-, and R 1 is -OH, and R 2 It is -CH2NH2. In this embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 teeth , -OH, R2 R 3 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O )- and W is -O- and R 1 is -OH, and R 2 R 4 In another example, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is -OH, and R 2 teeth, R 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is -O- And R 1 is -OH, and R 2 is -OR 5 In another embodiment, Q 1 is -CH2- Yes, Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH, and R 2 is amino, dimethyl Tylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 It is -CH2- and Q 2 is, -C(O)- And W is -O- and R 1 It is -NH2, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -O -R 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is -O- And R 1 It is -NH2, and R 2 is -OH. In another embodiment, Q 1 is -CH2- Q 2 is -C(O)-, W is -O-, and R 1 It is -NH2, and R 2 It is -CH2NH2. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 It is -NH2, and R 2 R 3 In another embodiment, Q 1 It is -CH2- and Q 2 teeth,- C(O)-, W is -O-, R 1 It is -NH2, and R 2 R 4 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 It is -NH2, and R 2 R 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is , -O-, R 1 It is -NH2, and R 2 is -OR 5 In another embodiment, Q 1 is -C H2- and Q 2 is -C(O)-, W is -CH2-, and R 1 It is -NH2, and R 2 is, amino dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 It is -CH2- and Q 2 is, -C(O)- And W is -O- and R 1 is alkyl, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 ,also は-OR 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is , -O-, R 1 is alkyl, and R 2 is -OH. In another embodiment, Q 1 teeth, -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is alkyl, and R 2 is, -CH It is 2NH2. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is -O - and R 1 is alkyl, and R 2 R 3 In another embodiment, Q 1 -CH2- Q 2 is -C(O)-, W is -O-, and R 1 is alkyl, and R 2 R 4 That is In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is alkyl, and R 2 R 5 In another embodiment, Q 1It is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is alkyl, and R 2 is -OR 5 That is. In this example, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 teeth , alkyl, R 2 is amino, dimethylamino, hydroxyl, [ka] It is selected from the group consisting of the following.

[0074] In another embodiment of formula I or Ia, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is - O- and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is -OH, and R 2 teeth , -H. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is -O - and R 1 is -OP(O)(OR 6 )(OH) and R 2 is -H. The embodiment described above in this paragraph In any one of them, R 6 This can be selected from the group consisting of hydroxyl and methyl.

[0075] In one embodiment of formula I or Ia, Q1 It is -CH2- and Q 2 is -C(O)-, and W is -NH -. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is -NH- And R 1 is -H, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 That is. Another reality In the implementation configuration, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -NH-, and R 1 is, -H And R 2 is -OH. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)- Yes, W is -NH-, and R 1 is -H, and R 2 This is -CH2NH2. In another embodiment Q 1 It is -CH2- and Q 2 is -C(O)-, W is -NH-, and R 1 is -H, and R 2 teeth, R 3 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is -NH- And R 1 is -H, and R 2 R 4 In another embodiment, Q 1 It is -CH2- Q 2 is -C(O)-, W is -NH-, and R 1 is -H, and R 2 R 5 That is. Another implementation In this regard, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -NH-, and R 1 is with -H Yes, R 2 is -OR 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)- Yes, W is -CH2-, and R 1 is -H, and R 2 These are amino, dimethylamino, and hydroxy Ru, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 It is -CH2- and Q 2 is, -C(O)- And W is -NH- and R 1 is -OH, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -O -R 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is -NH - and R 1 is -OH, and R 2 is -OH. In another embodiment, Q 1 is -CH2- Q 2 is -C(O)-, W is -NH-, and R 1 is -OH, and R 2 It is -CH2NH2. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -NH-, and R 1 is -OH, and R2 R 3 In another embodiment, Q 1 It is -CH2- and Q 2 is -C (O)-, W is -NH-, R 1 is -OH, and R 2 R 4 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -NH-, and R 1 is -OH, and R 2 R 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is, -NH- and R 1 is -OH, and R 2 is -OR 5 In another embodiment, Q 1 -CH2 - and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH, and R 2 It is amino, di Methylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 It is -CH2- and Q 2 is, -C(O)- And W is -NH- and R 1 It is -NH2, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or - Ure 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is -N H- and R 1 It is -NH2, and R 2 is -OH. In another embodiment, Q 1 is -CH2- Yes, Q 2 is -C(O)-, W is -NH-, and R 1 It is -NH2, and R 2 It is -CH2NH2. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is -NH-, R 1 It is -NH2, and R 2 R 3 In another embodiment, Q 1 It is -CH2- and Q 2 teeth , is -C(O)-, W is -NH-, R 1 It is -NH2, and R 2 R 4 This is another embodiment. In Q 1 It is -CH2- and Q 2 is -C(O)-, W is -NH-, and R 1 is -NH2 R 2 R 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)- W is -NH-, and R 1 It is -NH2, and R 2 is -OR 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 It is -NH2, and R 2 teeth, Amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 It is -CH2- and Q 2 is, -C(O)- And W is -NH- and R 1 is alkyl, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , OR 5 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)- and W It is -NH- and R 1 is alkyl, and R 2 is -OH. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -NH-, and R 1 is alkyl, and R 2 teeth , -CH2NH2. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)- and W It is -NH- and R 1 is alkyl, and R 2 R 3 In another embodiment, Q 1 teeth , -CH2-, Q 2 is -C(O)-, W is -NH-, and R 1 is alkyl, and R 2 teeth, R 4 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is -NH- And R 1 is alkyl, and R 2 R 5In another embodiment, Q 1 -CH2- Q 2 is -C(O)-, W is -NH-, and R 1 is alkyl, and R 2 is -OR 5 in Yes. In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)- and W is -CH2- Yes, R 1 is alkyl, and R 2 is amino, dimethylamino, hydroxyl, [ka] It is selected from the group consisting of the following.

[0076] In another embodiment of formula I or Ia, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is - NH- and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, W is -NH-, and R 1 is -OH, and R 2 In another embodiment, Q 1 It is -CH2- and Q 2 is -C(O)-, and W is , -NH-, R 1 is -OP(O)(OR 6 )(OH) and R 2 is -H. The aforementioned implementation in this paragraph In any one of the embodiments, R 6 This can be selected from the group consisting of hydroxyl and methyl. ru.

[0077] In one embodiment of formula I or Ia, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, and W is , -CH2-. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- W is -CH2-, and R 1 is -H, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 in Yes. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, and W is -CH 2- and R 1 is -H, and R 2 is -OH. In another embodiment, Q 1 is -C(H)(OH) - and Q 2 is -C(O)-, W is -CH2-, and R 1 is -H, and R 2 is -CH2NH2 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, and W is -CH2- And R 1 is -H, and R 2 R 3 In another embodiment, Q 1 It is -C(H)(OH)- Yes, Q 2 is -C(O)-, W is -CH2-, and R 1 is -H, and R 2 R 4 That is. In this example, Q 1 It is -C(H)(OH)- and Q 2is -C(O)-, and W is -CH2-, R 1 is -H, and R 2 R 5 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -H, and R 2 is -OR 5 That is. Another implementation In this regard, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 teeth , -H and R 2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C (O)-, W is -CH2-, R 1 is -OH, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , OR 5 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- W is -CH2-, and R 1 is -OH, and R 2 is -OH. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH, and R 2 is -CH2NH2. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- Yes, W is -CH2-, and R 1 is -OH, and R 2 R 3 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH, and R 2 R 4 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH, and R 2 R 5 In another embodiment, Q 1 teeth,- It is C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH, and R 2 is, -O -R 5 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, and W is , -CH2-, R 1 is -OH, and R 2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C (O)-, W is -CH2-, R 1 It is -NH2, and R 2-OH, -CH2NH2, R 3 , R 4 , R 5 , OR 5 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- W is -CH2-, and R 1 It is -NH2, and R 2 is -OH. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 It is -NH2, and R 2 is -CH2NH2. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- Yes, W is -CH2-, and R 1 It is -NH2, and R 2 R 3 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 It is -NH2, R 2 R 4 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- W is -CH2-, and R 1 It is -NH2, and R 2 R 5 In another embodiment, Q 1 teeth , -C(H)(OH)-, Q 2 is -C(O)-, W is -CH2-, and R 1 It is -NH2, and R 2 teeth , -OR 5 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- W is -CH2-, and R 1 It is -NH2, and R 2 is amino, dimethylamino, hydroxyl , [ka] Selected from the group consisting of Q. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C (O)-, W is -CH2-, R 1 is alkyl, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is, -C(O)- And W is -CH2-, and R 1 is alkyl, and R 2 It is -OH. In another embodiment Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is, Al It's a kill, R 2 is -CH2NH2. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is alkyl, and R 2 R 3 That is. In this example, Q 1 It is -C(H)(OH)- and Q2 is -C(O)-, and W is -CH2-, R 1 is alkyl, and R 2 R 4 In another embodiment, Q 1 is -C(H)(OH)- Q 2 is -C(O)-, W is -CH2-, and R 1 is alkyl, and R 2 R 5 That is the case. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- and W is -CH2- R 1 is alkyl, and R 2 is -OR 5 In another embodiment, Q 1 is -C(H)(O H)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is alkyl, and R 2 is, Mino, dimethylamino, hydroxyl, [ka] It is selected from the group consisting of the following.

[0078] In another embodiment of formula I or Ia, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- and W It is -CH2- and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 It is -H. Another implementation In Mr. / Ms. Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 teeth, -OH, and R 2 is -H. In another embodiment, Q 1 is -C(H)(OH)-, and Q 2 is - C(O)-, W is -CH2-, and R 1 is -OP(O)(OR 6 )(OH), and R 2 is -H. In any one of the foregoing embodiments of this paragraph, R 6 can be selected from the group consisting of hydroxyl and methyl .

[0079] In one embodiment of Formula I or Ia, Q 1 is -C(H)(OH)-, and Q 2 is -C(O)-, and W is -O-. In another embodiment, Q 1 is -C(H)(OH)-, and Q 2 is -C(O)-, and W is -O-, and R 1 is -H, and R 2 is -OH, -CH2NH2, R 3 、R 4 、R 5 、or -O-R 5 . In another embodiment, Q 1 is -C(H,OH)-, and Q 2 is -C(O)-, and W is -O- 、R 1 is -H, and R 2 is -OH. In another embodiment, Q 1 is -C(H,OH)-, Q 2 is -C(O)-, and W is -O-, and R 1 is -H, and R 2 is -CH2NH2. In another embodiment, Q 1 is -C(H,OH)-, and Q 2 is -C(O)-, and W is -O-, and R1 teeth , -H and R 2 R 3 In another embodiment, Q 1 It is -C(H,OH)- and Q 2 teeth,- C(O)-, W is -O-, R 1 is -H, and R 2 R 4 In another embodiment, Q 1 It is -C(H,OH)- and Q 2 is -C(O)-, W is -O-, and R 1 is -H, and R 2 R 5 In another embodiment, Q 1 It is -C(H,OH)- and Q 2 is -C(O)-, W is -O- and R 1 is -H, and R 2 is -OR 5 In another embodiment, Q 1 teeth,- CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -H, and R 2 is amino, Dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C (O)-, W is -O-, R 1 is -OH, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 ,also は-OR 5 In another embodiment, Q 1is -C(H)(OH)-, and Q 2 is -C(O)- , W is -O-, and R 1 is -OH, and R 2 is -OH. In another embodiment, Q 1 is -C(H)(OH)-, and Q 2 is -C(O)-, W is -O-, and R 1 is -OH, and R 2 is -CH 2NH2. In another embodiment, Q 1 is -C(H)(OH)-, and Q 2 is -C(O)-, W is -O-, and R 1 is -OH, and R 2 is R 3 is. In another embodiment, Q 1 is -C(H )(OH)-, and Q 2 is -C(O)-, W is -O-, and R 1 is -OH, and R 2 is R 4 is In another embodiment, Q 1 is -C(H)(OH)-, and Q 2 is -C(O)-, W is -O- is, and R 1 is -OH, and R 2 is R 5 is. In another embodiment, Q 1 is -C(H)(OH)- is, and Q 2 is -C(O)-, W is -O-, and R 1 is -OH, and R 2 is -O-R 5 is. Another embodiment, Q 1 is -C(H)(OH)-, and Q 2 is -C(O)-, W is -O-, R 1 is -OH, and R2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C (O)-, W is -O-, R 1 It is -NH2, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 ,also は-OR 5 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- W is -O-, and R 1 It is -NH2, and R 2 is -OH. In another embodiment, Q 1 teeth , -C(H)(OH)-, Q 2 is -C(O)-, W is -O-, and R 1 It is -NH2, and R 2 teeth, -CH2NH2 is another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- W is -O-, and R 1 It is -NH2, and R 2 R 3 In another embodiment, Q 1 teeth, It is -C(H)(OH)- and Q 2 is -C(O)-, W is -O-, and R 1 It is -NH2, and R 2 R 4 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2is -C(O)-, and W is - O- and R 1 It is -NH2, and R 2 R 5 In another embodiment, Q 1 is -C(H)(OH )- and Q 2 is -C(O)-, W is -O-, and R 1 It is -NH2, and R 2 is -OR 5 dea In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, and W is -O-. Yes, R 1 It is -NH2, and R 2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C (O)-, W is -O-, R 1 is alkyl, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- Yes, W is -O-, and R 1 is alkyl, and R 2 It is -OH. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -O-, and R 1 is alkyl Yes, R 2is -CH2NH2. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 teeth,- C(O)-, W is -O-, R 1 is alkyl, and R 2 R 3 This is another embodiment. In Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -O-, and R 1 is, Al It's a kill, R 2 R 4 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 teeth, It is -C(O)-, and W is -O-, R 1 is alkyl, and R 2 R 5 This is another embodiment. In Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -O-, and R 1 is, Al It's a kill, R 2 is -OR 5 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -O-, and R 1 is alkyl, and R 2 It is amino, dimethyl Mino, hydroxyl, [ka] It is selected from the group consisting of the following.

[0080] In another embodiment of formula I or Ia, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- and W is -O- and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. Another embodiment In Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -O-, and R 1 is, -OH And R 2 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O )- and W is -O- and R 1 is -OP(O)(OR 6 )(OH) and R 2 This paragraph is -H. In any one of the above embodiments, R 6 is a group consisting of hydroxyl and methyl They can be selected.

[0081] In one embodiment of formula I or Ia, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, and W is , -NH-. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -H, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 That is In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- and W is -NH- Yes, R 1 is -H, and R 2 is -OH. In another embodiment, Q1 It is -C(H)(OH)- Yes, Q 2 is -C(O)-, W is -NH-, and R 1 is -H, and R 2 It is -CH2NH2. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- and W is -NH- R 1 is -H, and R 2 R 3 In another embodiment, Q 1 It is -C(H)(OH)- Q 2 is -C(O)-, W is -NH-, and R 1 is -H, and R 2 R 4 That is. Another implementation In this regard, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 teeth , -H and R 2 R 5 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 teeth, It is -C(O)-, W is -NH-, and R 1 is -H, and R 2 is -OR 5 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 is with -H Yes, R 2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q1 It is -C(H)(OH)- and Q 2 is -C (O)-, W is -NH-, R 1 is -OH, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 ,also は-OR 5 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- W is -NH-, and R 1 is -OH, and R 2 is -OH. In another embodiment, Q 1 teeth , -C(H)(OH)-, Q 2 is -C(O)-, W is -NH-, and R 1 is -OH, and R 2 teeth, -CH2NH2 is another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- W is -NH-, and R 1 is -OH, and R 2 R 3 In another embodiment, Q 1 teeth, It is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -OH, and R 2 R 4 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, and W is - NH- and R 1 is -OH, and R 2 R 5 In another embodiment, Q 1 is -C(H)(OH )- and Q 2 is -C(O)-, W is -NH-, and R 1 is -OH, and R 2 is -OR 5 dea In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, and W is -NH- And R 1 is -OH, and R 2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C (O)-, W is -NH-, R 1 It is -NH2, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , OR 5 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- W is -NH-, and R 1 It is -NH2, and R 2 is -OH. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 It is -NH2, and R 2 is -CH2NH2. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- Yes, W is -NH-, and R 1 It is -NH2, and R 2R 3 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 It is -NH2, and R 2 R 4 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 It is -NH2, and R 2 R 5 In another embodiment, Q 1 teeth,- It is C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 It is -NH2, and R 2 is, -O -R 5 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, and W is , -NH-, R 1 It is -NH2, and R 2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C (O)-, W is -NH-, R 1 is alkyl, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 In another embodiment, Q 1 It is -C(H)(OH)- and Q2 is -C(O)- Yes, W is -NH-, and R 1 is alkyl, and R 2 It is -OH. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 is alkyl And R 2 is -CH2NH2. In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 teeth , is -C(O)-, W is -NH-, R 1 is alkyl, and R 2 R 3 That is. Another implementation In this regard, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 teeth , alkyl, R 2 R 4 In another embodiment, Q 1 It is -C(H)(OH)-, Q 2 is -C(O)-, W is -NH-, and R 1 is alkyl, and R 2 R 5 That is. In this example, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 is alkyl, and R 2 is -OR 5 In another embodiment, Q 1 It is -C(H)(OH)- Yes, Q 2 is -C(O)-, W is -NH-, and R 1 is alkyl, and R 2is amino, Dimethylamino, hydroxyl, [ka] It is selected from the group consisting of the following.

[0082] In another embodiment of formula I or Ia, Q 1 It is -C(H)(OH)- and Q 2 is -C(O)- and W It is -NH- and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. Another embodiment In Q 1 It is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 is, -OH And R 2 In another embodiment, Q 1 It is -C(H)(OH)- and Q 2 is -C(O )- and W is -NH- and R 1 is -OP(O)(OR 6 )(OH) and R 2 This paragraph is -H. In any one of the above embodiments, R 6 is a group consisting of hydroxyl and methyl They can be selected.

[0083] In one embodiment of formula I or Ia, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is -C In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is -C It is H2- and R 1 is -H, and R 2 -OH, -CH2NH2, R3 , R 4 , R 5 , or -OR 5 That is. In this example, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 teeth , -H and R 2 is -OH. In another embodiment, Q 1 is -C(O)- and Q 2 is -C( O)-, W is -CH2-, R 1 is -H, and R 2 It is -CH2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -H , R 2 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -H, and R 2 R 4 In another embodiment, Q 1 is -C (O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -H, and R 2 R 5 That is In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- and W is -CH2- , R 1 is -H, and R 2 is -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -H, and R 2 is amino, dimethylamine No, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 is, -C(O)- And W is -CH2-, and R 1 is -OH, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or - Ure 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is - CH2- and R 1 is -OH, and R 2 is -OH. In another embodiment, Q 1 is, -C(O)- Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH, and R 2 is -CH2NH2 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- and W is -CH2- R 1 is -OH, and R 2 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH, and R 2 R 4 This is a different implementation. In Mr. / Ms. Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is, -OH And R 2 R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- Yes, W is -CH2-, and R 1 is -OH, and R 2 is -OR 5 In another example, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH, and R 2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 is, -C(O)- And W is -CH2-, and R 1 It is -NH2, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is, -CH2- and R 1 It is -NH2, and R 2 is -OH. In another embodiment, Q 1 is -C(O )- and Q 2 is -C(O)-, W is -CH2-, and R 1It is -NH2, and R 2 -CH2NH2 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is -CH2- And R 1 It is -NH2, and R 2 R 3 In another embodiment, Q 1 is -C(O)- Q 2 is -C(O)-, W is -CH2-, and R 1 It is -NH2, and R 2 R 4 That is. In this example, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 teeth , -NH2, R 2 R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C (O)-, W is -CH2-, R 1 It is -NH2, and R 2 is -OR 5 This is another embodiment. In Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -NH2 Yes, R 2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 is, -C(O)- And W is -CH2-, and R 1is alkyl, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- and W It is -CH2- and R 1 is alkyl, and R 2 is -OH. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is alkyl, and R 2 is -CH2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- W is -CH2-, and R 1 is alkyl, and R 2 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 It is an alkyl, R 2 R 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- and W It is -CH2- and R 1 is alkyl, and R 2 R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is alkyl, and R 2 is -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- and W It is -CH2- and R 1 is alkyl, and R 2 These are amino, dimethylamino, and hydroxy Ru, [ka] It is selected from the group consisting of the following.

[0084] In another embodiment of formula I or Ia, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is, -CH2- and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH R 2 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- W is -CH2-, and R 1 is -OP(O)(OR 6 )(OH) and R 2 It is -H. As mentioned earlier in this paragraph In any one of the embodiments, R 6 The selected element is chosen from the group consisting of hydroxyl and methyl. It is possible.

[0085] In one embodiment of formula I or Ia, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is -O -. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is -O- And R 1 is -H, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 That is. Another reality In the implementation configuration, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -O-, and R 1 is, -H And R 2 is -OH. In another embodiment, Q 1 is -C(O)- and Q 2 is, -C(O)- And W is -O- and R 1 is -H, and R 2 It is -CH2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -O-, and R 1 is -H, and R 2 teeth , R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is - O- and R 1 is -H, and R 2 R 4 In another embodiment, Q 1 is -C(O)- Q 2 is -C(O)-, W is -O-, and R 1 is -H, and R 2 R 5 That is. Another implementation In this regard, Q 1 is -C(O)- and Q 2is -C(O)-, W is -O-, and R 1 is with -H Yes, R 2 is -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is, -C(O)- And W is -O- and R 1 is -H, and R 2 These are amino, dimethylamino, and hydroxy Ru, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 is, -C(O)- And W is -O- and R 1 is -OH, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -O- R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is -O- And R 1 is -OH, and R 2 is -OH. In another embodiment, Q 1 is -C(O)- Q 2 is -C(O)-, W is -O-, and R 1 is -OH, and R 2 It is -CH2NH2. In this embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -O-, and R 1 teeth , -OH, R 2 R 3 In another embodiment, Q 1is -C(O)- and Q 2 is -C( O)-, W is -O-, R 1 is -OH, and R 2 R 4 In another example, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -O-, and R 1 is -OH, and R 2 teeth , R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is - O- and R 1 is -OH, and R 2 is -OR 5 In another embodiment, Q 1 is, -C(O)- Q 2 is -C(O)-, W is -O-, and R 1 is -OH, and R 2 is amino, dimethyl Tylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 is, -C(O)- And W is -O- and R 1 It is -NH2, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -O -R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is -O - and R 1 It is -NH2, and R 2is -OH. In another embodiment, Q 1 is -C(O)- Yes, Q 2 is -C(O)-, W is -O-, and R 1 It is -NH2, and R 2 It is -CH2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is -O-, R 1 It is -NH2, and R 2 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 teeth , is -C(O)-, and W is -O-, R 1 It is -NH2, and R 2 R 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -O-, and R 1 It is -NH2. , R 2 R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -O- and R 1 It is -NH2, and R 2 is -OR 5 In another embodiment, Q 1 teeth , -C(O)-, Q 2 is -C(O)-, W is -O-, and R 1 It is -NH2, and R 2 , Ami No, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 is, -C(O)- And W is -O- and R 1 is alkyl, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 ,also は-OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is , -O-, R 1 is alkyl, and R 2 is -OH. In another embodiment, Q 1 teeth, -C(O)- and Q 2 is -C(O)-, W is -O-, and R 1 is alkyl, and R 2 is -C In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is, -O- and R 1 is alkyl, and R 2 R 3 In another embodiment, Q 1 is -C( O)- and Q 2 is -C(O)-, W is -O-, and R 1 is alkyl, and R 2 R 4 in Yes. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is -O-. R 1 is alkyl, and R 2 R 5 In another embodiment, Q 1 is -C(O)- Q 2 is -C(O)-, W is -O-, and R 1 is alkyl, and R 2 is -OR 5 That is In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is -O-, R 1 is alkyl, and R 2 is amino, dimethylamino, hydroxyl, [ka] It is selected from the group consisting of the following.

[0086] In another embodiment of formula I or Ia, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is, -O- and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -O-, and R 1 is -OH, and R 2 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is , -O-, R 1 is -OP(O)(OR 6 )(OH) and R 2 is -H. The aforementioned implementation in this paragraph In any one of the following, R 6 This can be selected from the group consisting of hydroxyl and methyl. .

[0087] In one embodiment of formula I or Ia, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is -N In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is -NH - and R 1 is -H, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 That is. Another reality In the implementation configuration, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -NH-, and R 1 teeth,- H and R 2 is -OH. In another embodiment, Q 1 is -C(O)- and Q 2 is, -C(O)- And W is -NH- and R 1 is -H, and R 2 It is -CH2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -H, and R 2 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is , -NH-, R 1 is -H, and R 2 R 4 In another embodiment, Q 1 is, -C(O)- Q 2 is -C(O)-, W is -NH-, and R 1 is -H, and R 2R 5 That is. In this embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -H, and R 2 is -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 teeth , is -C(O)-, W is -NH-, R 1 is -H, and R 2 is amino, dimethylamino, Hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 is, -C(O)- And W is -NH- and R 1 is -OH, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -O -R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is -N H- and R 1 is -OH, and R 2 is -OH. In another embodiment, Q 1 is -C(O)- Yes, Q 2 is -C(O)-, W is -NH-, and R 1 is -OH, and R 2 It is -CH2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- and W is -NH- , R 1 is -OH, and R 2 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -OH, and R 2 R 4 This is another embodiment. In Q 1 is -C(O)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -OH R 2 R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- W is -NH-, and R 1 is -OH, and R 2 is -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -OH, and R 2 is, Mino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 is, -C(O)- And W is -NH- and R 1 It is -NH2, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or - Ure 5 In another embodiment, Q 1is -C(O)- and Q 2 is -C(O)-, and W is - NH- and R 1 It is -NH2, and R 2 is -OH. In another embodiment, Q 1 is, -C(O)- Q 2 is -C(O)-, W is -NH-, and R 1 It is -NH2, and R 2 is -CH2NH2 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- and W is -NH- R 1 It is -NH2, and R 2 R 3 In another embodiment, Q 1 is -C(O)-, Q 2 is -C(O)-, W is -NH-, and R 1 It is -NH2, and R 2 R 4 That is. Another implementation In this regard, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -NH-, and R 1 is, -NH 2, R 2 R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is, -C(O)- And W is -NH- and R 1 It is -NH2, and R 2 is -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -NH-, and R 1 It is -NH2, and R 2is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 is, -C(O)- And W is -NH- and R 1 is alkyl, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- and W It is -NH- and R 1 is alkyl, and R 2 is -OH. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -NH-, and R 1 is alkyl, and R 2 is -CH2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- W is -NH-, and R 1 is alkyl, and R 2 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -NH-, and R 1 is alkyl, and R 2 R 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is , -NH-, R1 is alkyl, and R 2 R 5 In another embodiment, Q 1 teeth, -C(O)- and Q 2 is -C(O)-, W is -NH-, and R 1 is alkyl, and R 2 teeth,- Ure 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is - NH- and R 1 is alkyl, and R 2 is amino, dimethylamino, hydroxyl, [ka] It is selected from the group consisting of the following.

[0088] In another embodiment of formula I or Ia, Q 1 is -C(O)- and Q 2 is -C(O)-, and W is, -NH- and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -NH-, and R 1 It is -OH, R 2 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- and W It is -NH- and R 1 is -OP(O)(OR 6 )(OH) and R 2 It is -H. The aforementioned fact in this paragraph In any one of the application methods, R 6is selected from the group consisting of hydroxyl and methyl. obtain.

[0089] In one embodiment of formula I or Ia, Q 1 is -C(O)- and Q 2 is -CH2-, and W is -CH 2. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is -CH2 - and R 1 is -H, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 That is. Another reality In the implementation configuration, Q 1 is -C(O)- and Q 2 is -CH2-, W is -CH2-, and R 1 teeth,- H and R 2 is -OH. In another embodiment, Q 1 is -C(O)- and Q 2 -CH2- And W is -CH2-, and R 1 is -H, and R 2 It is -CH2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -CH2-, and R 1 is -H, and R 2 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is , -CH2-, R 1 is -H, and R 2 R 4 In another embodiment, Q 1 is -C(O) - and Q 2 is -CH2-, W is -CH2-, and R 1 is -H, and R 2 R 5 That is. In this embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -CH2-, and R 1 is -H, and R 2 is -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 teeth , is -CH2-, W is -CH2-, R 1 is -H, and R 2 is amino, dimethylamino, Hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 -CH2- And W is -CH2-, and R 1 is -OH, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or - Ure 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is -C It is H2- and R 1 is -OH, and R 2 is -OH. In another embodiment, Q 1 is, -C(O)- Q 2 is -CH2-, W is -CH2-, and R 1 is -OH, and R 2 is -CH2NH2 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is -CH2-. R 1 is -OH, and R 2 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -CH2-, and R 1 is -OH, and R 2 R 4 This is a different implementation. In Mr. / Ms. Q 1 is -C(O)- and Q 2 is -CH2-, W is -CH2-, and R 1 is -OH Yes, R 2 R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2- W is -CH2-, and R 1 is -OH, and R 2 is -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -CH2-, and R 1 is -OH, and R 2 teeth, Amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 -CH2- And W is -CH2-, and R 1 It is -NH2, and R 2 -OH, -CH2NH2, R 3 , R 4, R 5 , or -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is - CH2- and R 1 It is -NH2, and R 2 is -OH. In another embodiment, Q 1 is -C(O) - and Q 2 is -CH2-, W is -CH2-, and R 1 It is -NH2, and R 2 This is -CH2NH2 Yes. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is -CH2-. Yes, R 1 It is -NH2, and R 2 R 3 In another embodiment, Q 1 is -C(O)- Q 2 is -CH2-, W is -CH2-, and R 1 It is -NH2, and R 2 R 4 That is. Another reality In the implementation configuration, Q 1 is -C(O)- and Q 2 is -CH2-, W is -CH2-, and R 1 teeth,- It is NH2, R 2 R 5 In another embodiment, Q 1 is -C(O)- and Q 2 -CH2- And W is -CH2-, and R 1 It is -NH2, and R 2 is -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2is -CH2-, W is -CH2-, and R 1 It is -NH2. , R 2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 -CH2- And W is -CH2-, and R 1 is alkyl, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 It is -CH2- and W It is -CH2- and R 1 is alkyl, and R 2 is -OH. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -CH2-, and R 1 is alkyl, and R 2 is -CH2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 It is -CH2-, W is -CH2-, and R 1 is alkyl, and R 2 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -CH2-, and R 1 is alkyl, and R 2 R 4 In another embodiment, Q1 is -C(O)- and Q 2 is -CH2-, and W is, -CH2- and R 1 is alkyl, and R 2 R 5 In another embodiment, Q 1 teeth,- C(O)- and Q 2 is -CH2-, W is -CH2-, and R 1 is alkyl, and R 2 is, -O -R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is -CH 2- and R 1 is alkyl, and R 2 is amino, dimethylamino, hydroxyl, [ka] It is selected from the group consisting of the following.

[0090] In another embodiment of formula I or Ia, Q 1 is -C(O)- and Q 2 is -CH2-, and W is - CH2- and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -CH2-, and R 1 It is -OH, R 2 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is , -CH2-, R 1 is -OP(O)(OR 6)(OH) and R 2 is -H. The aforementioned implementation in this paragraph In any one of the embodiments, R 6 This can be selected from the group consisting of hydroxyl and methyl. ru.

[0091] In one embodiment of formula I or Ia, Q 1 is -C(O)- and Q 2 is -CH2-, and W is -O- In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2- and W is -O- Yes, R 1 is -H, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 That is. Another implementation In this regard, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 is with -H Yes, R 2 is -OH. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2- W is -O-, and R 1 is -H, and R 2 is -CH2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 is -H, and R 2 R 3 in Yes. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2- and W is -O- R 1 is -H, and R2 R 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 is -H, and R 2 R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 is -H, and R 2 is -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 It is -CH2- and W is -O- and R 1 is -H, and R 2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 -CH2- And W is -O- and R 1 is -OH, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -O- R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is -O- And R 1 is -OH, and R 2 is -OH. In another embodiment, Q 1 is -C(O)- Q 2 is -CH2-, W is -O-, and R 1is -OH, and R 2 It is -CH2NH2. In this embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 teeth , -OH, R 2 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is, -CH 2-, W is -O-, R 1 is -OH, and R 2 R 4 In another example, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 is -OH, and R 2 teeth, R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is -O- And R 1 is -OH, and R 2 is -OR 5 In another embodiment, Q 1 is -C(O)- Yes, Q 2 is -CH2-, W is -O-, and R 1 is -OH, and R 2 It is amino, dimethyl Amino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 -CH2- And W is -O- and R 1 It is -NH2, and R 2-OH, -CH2NH2, R 3 , R 4 , R 5 , or -O -R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is -O- And R 1 It is -NH2, and R 2 is -OH. In another embodiment, Q 1 is -C(O)- Yes, Q 2 is -CH2-, W is -O-, and R 1 It is -NH2, and R 2 It is -CH2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 It is -NH2, and R 2 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 teeth, It is -CH2-, W is -O-, and R 1 It is -NH2, and R 2 R 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 It is -NH2, and R 2 R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is , -O-, R 1 It is -NH2, and R 2 is -OR 5 In another embodiment, Q 1 is -C (O)- and Q 2 is -CH2-, W is -O-, and R 1 It is -NH2, and R 2 is amino, Dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 -CH2- And W is -O- and R 1 is alkyl, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 ,also は-OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is , -O-, R 1 is alkyl, and R 2 is -OH. In another embodiment, Q 1 teeth, -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 is alkyl, and R 2 is, -CH It is 2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is -O - and R 1 is alkyl, and R 2 R 3 In another embodiment, Q 1 is -C(O) - and Q 2 is -CH2-, W is -O-, and R 1 is alkyl, and R 2 R 4 That is In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 is alkyl, and R 2 R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 is alkyl, and R 2 is -OR 5 That is. In this example, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 teeth, It is alkyl, R 2 is amino, dimethylamino, hydroxyl, [ka] It is selected from the group consisting of the following.

[0092] In another embodiment of formula I or Ia, Q 1 is -C(O)- and Q 2 is -CH2-, and W is - O- and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 is -OH, and R 2 teeth , -H. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is -O - and R 1 is -OP(O)(OR6 )(OH) and R 2 is -H. The embodiment described above in this paragraph In any one of them, R 6 This can be selected from the group consisting of hydroxyl and methyl.

[0093] In one embodiment of formula I or Ia, Q 1 is -C(O)- and Q 2 is -CH2-, and W is -NH -. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is -NH- And R 1 is -H, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 That is. Another reality In the implementation configuration, Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is, -H And R 2 is -OH. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2- Yes, W is -NH-, and R 1 is -H, and R 2 This is -CH2NH2. In another embodiment Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is -H, and R 2 teeth, R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is -NH- And R 1 is -H, and R2 R 4 In another embodiment, Q 1 is -C(O)- Q 2 is -CH2-, W is -NH-, and R 1 is -H, and R 2 R 5 This is a different implementation. In Mr. / Ms. Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is -H R 2 is -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2- W is -NH-, and R 1 is -H, and R 2 is amino, dimethylamino, hydroxyl , [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 -CH2- And W is -NH- and R 1 is -OH, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -O -R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is -NH - and R 1 is -OH, and R 2 is -OH. In another embodiment, Q 1 is -C(O)- Yes, Q 2is -CH2-, W is -NH-, and R 1 is -OH, and R 2 It is -CH2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is -OH, and R 2 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 teeth,- CH2-, W is -NH-, R 1 is -OH, and R 2 R 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is -OH, and R 2 R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is, -NH- and R 1 is -OH, and R 2 is -OR 5 In another embodiment, Q 1 is -C(O )- and Q 2 is -CH2-, W is -NH-, and R 1 is -OH, and R 2 It is amino, di Methylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 -CH2- And W is -NH- and R1 It is -NH2, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or - Ure 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is -N H- and R 1 It is -NH2, and R 2 is -OH. In another embodiment, Q 1 is, -C(O)- Q 2 is -CH2-, W is -NH-, and R 1 It is -NH2, and R 2 is -CH2NH2 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2- and W is -NH- , R 1 It is -NH2, and R 2 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 It is -NH2, and R 2 R 4 This is another embodiment. In Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is -NH2 R 2 R 5 In another embodiment, Q 1 is -C(O)- and Q 2 It is -CH2- W is -NH-, and R 1 It is -NH2, and R 2 is -OR 5In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is -OH, and R 2 is, Mino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 -CH2- And W is -NH- and R 1 is alkyl, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 It is -CH2- and W It is -NH- and R 1 is alkyl, and R 2 is -OH. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is alkyl, and R 2 teeth , -CH2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 It is -CH2- and W It is -NH- and R 1 is alkyl, and R 2 R 3 In another embodiment, Q 1 teeth , -C(O)-, Q 2 is -CH2-, W is -NH-, and R 1 is alkyl, and R2 teeth, R 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is -NH- And R 1 is alkyl, and R 2 R 5 In another embodiment, Q 1 is, -C(O)- Q 2 is -CH2-, W is -NH-, and R 1 is alkyl, and R 2 is -OR 5 in Yes. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2- and W is -NH- R 1 is alkyl, and R 2 is amino, dimethylamino, hydroxyl, [ka] It is selected from the group consisting of the following.

[0094] In another embodiment of formula I or Ia, Q 1 is -C(O)- and Q 2 is -CH2-, and W is - NH- and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is -OH, and R 2 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, and W is , -NH-, R 1 is -OP(O)(OR 6 )(OH) and R 2 is -H. The aforementioned implementation in this paragraph In any one of the embodiments, R 6 This can be selected from the group consisting of hydroxyl and methyl. ru.

[0095] In one embodiment of formula I or Ia, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, and W is , -CH2-. In another embodiment, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)- W is -CH2-, and R 1 is -H, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 in Yes. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, and W is -CH 2- and R 1 is -H, and R 2 is -OH. In another embodiment, Q 1 is -C(O)- Yes, Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 is -H, and R 2 This is -CH2NH2 Yes. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, and W is -CH 2- and R 1 is -H, and R 2 R 3 In another embodiment, Q 1is -C(O)- Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 is -H, and R 2 R 4 That is. In this embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- and W is -CH2- , R 1 is -H, and R 2 R 5 In another embodiment, Q 1 is -C(O)- and Q 2 teeth , is -C(H)(OH)-, W is -CH2-, R 1 is -H, and R 2 is -OR 5 That is. Another reality In the implementation configuration, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 is -H, and R 2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)( OH)-, W is -CH2-, R 1 is -OH, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- W is -CH2-, and R1 is -OH, and R 2 is -OH. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 is -OH, and R 2 is -CH2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)- Yes, W is -CH2-, and R 1 is -OH, and R 2 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 is -OH, and R 2 R 4 In another embodiment, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)-, W is -CH2-, and R 1 is -OH, and R 2 R 5 In another embodiment, Q 1 teeth,- C(O)- and Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 is -OH, and R 2 is, -O -R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, and W is , -CH2-, R 1 is -OH, and R 2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)( OH)-, W is -CH2-, R 1 It is -NH2, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- W is -CH2-, and R 1 It is -NH2, and R 2 is -OH. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 It is -NH2, and R 2 is -CH2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)- Yes, W is -CH2-, and R 1 It is -NH2, and R 2 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 It is -NH2, R 2 R 4 In another embodiment, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)- W is -CH2-, and R 1It is -NH2, and R 2 R 5 In another embodiment, Q 1 teeth , -C(O)-, Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 It is -NH2, and R 2 teeth , -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)- W is -CH2-, and R 1 It is -NH2, and R 2 is amino, dimethylamino, hydroxyl , [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)( OH)-, W is -CH2-, R 1 is alkyl, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- And W is -CH2-, and R 1 is alkyl, and R 2 It is -OH. In another embodiment Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 is, Al It's a kill, R 2 is -CH2NH2. In another embodiment, Q 1is -C(O)- and Q 2 teeth , is -C(H)(OH)-, W is -CH2-, R 1 is alkyl, and R 2 R 3 That is. In this example, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, and W is -CH2-, R 1 is alkyl, and R 2 R 4 In another embodiment, Q 1 is -C(O)-, Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 is alkyl, and R 2 R 5 That is the case. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- and W is -CH2- R 1 is alkyl, and R 2 is -OR 5 In another embodiment, Q 1 is, -C(O)- Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 is alkyl, and R 2 is, Mino, dimethylamino, hydroxyl, [ka] It is selected from the group consisting of the following.

[0096] In another embodiment of formula I or Ia, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)- and W It is -CH2- and R 1is -OH or -OP(O)(OR 6 )(OH) and R 2 It is -H. Another implementation In Mr. / Ms. Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 teeth, -OH and R 2 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H) (OH)-, W is -CH2-, R 1 is -OP(O)(OR 6 )(OH) and R 2 This is -H. In any one of the embodiments described in the paragraph above, R 6 It consists of hydroxyl and methyl. They can be selected from the group.

[0097] In one embodiment of formula I or Ia, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, and W is , -O-. In another embodiment, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)- and W is -O- and R 1 is -H, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 That is the case. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- and W is -O- , R 1 is -H, and R 2 is -OH. In another embodiment, Q 1 is -C(O)- and Q2 is -C(H)(OH)-, W is -O-, and R 1 is -H, and R 2 It is -CH2NH2. In this example, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 is -H, and R 2 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -C (H)(OH)-, W is -O-, R 1 is -H, and R 2 R 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 is -H , R 2 R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- W is -O-, and R 1 is -H, and R 2 is -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 is -H, and R 2 teeth, Amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q2 is -C(H)( OH)-, W is -O-, R 1 is -OH, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 ,also は-OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)- W is -O-, and R 1 is -OH, and R 2 is -OH. In another embodiment, Q 1 teeth, -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 is -OH, and R 2 is, -CH It is 2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)- and W is -O- and R 1 is -OH, and R 2 R 3 In another embodiment, Q 1 is -C(O )- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 is -OH, and R 2 R 4 dea In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- and W is -O- Yes, R 1 is -OH, and R 2 R 5 In another embodiment, Q 1 is -C(O)- Q 2is -C(H)(OH)-, W is -O-, and R 1 is -OH, and R 2 is -OR 5 That is. In this embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, and W is -O-, R 1 is -OH, and R 2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)( OH)-, W is -O-, R 1 It is -NH2, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 ,also は-OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)- W is -O-, and R 1 It is -NH2, and R 2 is -OH. In another embodiment, Q 1 teeth , -C(O)-, Q 2 is -C(H)(OH)-, W is -O-, and R 1 It is -NH2, and R 2 teeth, -CH2NH2 is another embodiment, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)- W is -O-, and R 1 It is -NH2, and R 2 R 3In another embodiment, Q 1 teeth, -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 It is -NH2, and R 2 R 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, and W is - O- and R 1 It is -NH2, and R 2 R 5 In another embodiment, Q 1 is -C(O)- Yes, Q 2 is -C(H)(OH)-, W is -O-, and R 1 It is -NH2, and R 2 is -OR 5 dea In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- and W is -O- Yes, R 1 It is -NH2, and R 2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)( OH)-, W is -O-, R 1 is alkyl, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)- Yes, W is -O-, and R 1 is alkyl, and R 2 It is -OH. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 is alkyl Yes, R 2 is -CH2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H) (OH)-, W is -O-, R 1 is alkyl, and R 2 R 3 This is another embodiment. In Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 is, Al It's a kill, R 2 R 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H )(OH)-, W is -O-, R 1 is alkyl, and R 2 R 5 This is another embodiment. In Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 is, Al It's a kill, R 2 is -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 teeth,- C(H)(OH)-, W is -O-, R 1 is alkyl, and R 2 It is amino, dimethyl Mino, hydroxyl, [ka] It is selected from the group consisting of the following.

[0098] In another embodiment of formula I or Ia, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)- and W is -O- and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. Another embodiment In Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 is, -OH And R 2 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH )- and W is -O- and R 1 is -OP(O)(OR 6 )(OH) and R 2 This paragraph is -H. In any one of the above embodiments, R 6 is a group consisting of hydroxyl and methyl They can be selected.

[0099] In one embodiment of formula I or Ia, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, and W is , -NH-. In another embodiment, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)-, W is -NH-, and R 1 is -H, and R 2 -OH, -CH2NH2, R 3 , R4 , R 5 , or -OR 5 That is In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- and W is -NH- Yes, R 1 is -H, and R 2 is -OH. In another embodiment, Q 1 is -C(O)- Q 2 is -C(H)(OH)-, W is -NH-, and R 1 is -H, and R 2 It is -CH2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- and W is -NH- R 1 is -H, and R 2 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -NH-, and R 1 is -H, and R 2 R 4 That is. Another implementation In this regard, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -NH-, and R 1 teeth , -H and R 2 R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H )(OH)-, W is -NH-, R 1 is -H, and R 2 is -OR 5 In another embodiment, Q 1is -C(O)- and Q 2 is -C(H)(OH)-, W is -NH-, and R 1 is with -H Yes, R 2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)( OH)-, W is -NH-, R 1 is -OH, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 ,also は-OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)- W is -NH-, and R 1 is -OH, and R 2 is -OH. In another embodiment, Q 1 teeth , -C(O)-, Q 2 is -C(H)(OH)-, W is -NH-, and R 1 is -OH, and R 2 teeth, -CH2NH2 is another embodiment, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)- W is -NH-, and R 1 is -OH, and R 2 R 3 In another embodiment, Q 1 teeth, -C(O)- and Q 2 is -C(H)(OH)-, W is -NH-, and R 1 is -OH, and R 2 R4 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, and W is - NH- and R 1 is -OH, and R 2 R 5 In another embodiment, Q 1 is -C(O)- Yes, Q 2 is -C(H)(OH)-, W is -NH-, and R 1 is -OH, and R 2 is -OR 5 dea In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, and W is -NH- And R 1 is -OH, and R 2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)( OH)-, W is -NH-, R 1 It is -NH2, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- W is -NH-, and R 1 It is -NH2, and R 2 is -OH. In another embodiment, Q 1 is -C(O)- and Q 2is -C(H)(OH)-, W is -NH-, and R 1 It is -NH2, and R 2 is -CH2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)- Yes, W is -NH-, and R 1 It is -NH2, and R 2 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -NH-, and R 1 It is -NH2, and R 2 R 4 In another embodiment, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)-, W is -NH-, and R 1 It is -NH2, and R 2 R 5 In another embodiment, Q 1 teeth,- C(O)- and Q 2 is -C(H)(OH)-, W is -NH-, and R 1 It is -NH2, and R 2 is, -O -R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, and W is , -NH-, R 1 It is -NH2, and R 2 is amino, dimethylamino, hydroxyl, [ka] Selected from the group consisting of Q. In another embodiment, Q 1 is -C(O)- and Q 2is -C(H)( OH)-, W is -NH-, R 1 is alkyl, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)- Yes, W is -NH-, and R 1 is alkyl, and R 2 It is -OH. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -NH-, and R 1 is alkyl And R 2 is -CH2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 is -C( H)(OH)-, W is -NH-, R 1 is alkyl, and R 2 R 3 This is a different implementation. In Mr. / Ms. Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -NH-, and R 1 teeth, It is alkyl, R 2 R 4 In another embodiment, Q 1 is -C(O)- and Q 2 teeth, It is -C(H)(OH)-, W is -NH-, and R 1 is alkyl, and R 2 R 5 That is. Another reality In the implementation configuration, Q 1 is -C(O)- and Q 2is -C(H)(OH)-, W is -NH-, and R 1 is alkyl, and R 2 is -OR 5 In another embodiment, Q 1 is -C(O)- Q 2 is -C(H)(OH)-, W is -NH-, and R 1 is alkyl, and R 2 is amino, Dimethylamino, hydroxyl, [ka] It is selected from the group consisting of the following.

[0100] In another embodiment of formula I or Ia, Q 1 is -C(O)- and Q 2 It is -C(H)(OH)- and W It is -NH- and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. Another embodiment In Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -NH-, and R 1 is, -OH And R 2 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH )- and W is -NH- and R 1 is -OP(O)(OR 6 )(OH) and R 2 This paragraph is -H. In any one of the above embodiments, R 6 is a group consisting of hydroxyl and methyl They can be selected.

[0101] In some examples, the compounds shown herein have the structure of formula (Ib) or are medical It is a medicinal salt, solvate, or stereoisomer: [ka] (In the formula, W is -CH2-, -N(H)-, or -O-; R 1 is -H, -OH, -NH2, alkyl, or -OP(O)(OR 6 )2; R 2 -H, -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 And here, R 1 and R 2 At the same time For -H, not -H; R 3 is -N(R 6 )2; R 4 is -XYZ; X is selected from the group consisting of -O- and -N(H)-; Y is an alkylene, a substituted alkylene (not limited to, but including oxo substitutions (i.e., =O)). ), heteroalkylenes, and substituted heteroalkylenes (not limited to oxo substitutions (i.e.) Selected from the group consisting of (including = O); Z is selected from the group consisting of -OH and -NH2; R 5 is an alkyl, heterocycloalkyl, or substituted heterocycloalkyl, and here Each heterocycloalkyl or substituted heterocycloalkyl is selected from nitrogen and oxygen. It contains one, two, or three selected heteroatoms and at least one -OH and -CH2OH group. Containing a conversion group, or at least one primary or secondary nitrogen, such as O-glucose; Each R6 In each case, -H, amino acid residue, N-alkyl amino acid residue, peptide, or alkyl; and Each R 7 Independently, Halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O- amino acid residues, and O-PEG n (where n is an integer between 0 and 3).

[0102] In formula Ib, in one embodiment, R 5 is heterocycloalkyl or substituted heterocycloalkyl It is lucyl. Useful heterocycloalkyl groups include tetrahydropyranyl, glyco Examples include sidyl and piperazinyl. These groups may be substituted or not substituted. They are not necessary. In some embodiments, they are not substituted. These are substituted. Exemplary substituents include at least one hydroxyl This includes at least one primary nitrogen or at least one secondary nitrogen.

[0103] In one embodiment of formula Ib, R 6 In each case, independently, amino acid residues and N-alkyl groups are involved. It is an amino acid residue or a peptide. Those skilled in the art will know whether the amino acid residue is achiral or chiral. They would recognize, for example, that it could be an L-amino acid or a D-amino acid. It typically includes an amino acid side chain. The side chain is the side chain of any amino acid known to those skilled in the art. This is possible. In one embodiment, the side chain may be histidine, alanine, or isoleucine. Arginine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine Ingredients, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, Phosphorus, ornithine, selenocysteine, serine, glycine, homoglycine (for example, β-H It is a side chain of moglycine or tyrosine. Those skilled in the art will know that the peptide is, for example, a racemic DL- This includes amino acids or non-racemic D- or L-amino acids and mixtures of diastereomers thereof. They would recognize that the peptide may be achiral or chiral. The side chain of the peptide is above As described in relation to amino acids, those skilled in the art will know N-alkyl amino acids. The residue is the terminal amino group of the amino acid or the terminal amino group of the peptide as defined herein. They will likely be aware that it contains alkyl substituents.

[0104] In formula Ib, in one embodiment, R 7 Hello, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O - Glucose, O-amino acid residue, or O-PEG n Here, each n is an integer between 0 and 3. In one embodiment, the O-amino acid residue is the HO-amino acid residue defined above. Includes. One embodiment, O-PEG n This is the case where n=0. In another embodiment O-PEG n This is the case for n=1. In another embodiment, O-PEG n This is the case when n=2 In another embodiment, O-PEG n This is the case where n=3.

[0105] In one embodiment of formula Ib, R 1 is -OH. In another embodiment, R 1 is -OH R 2 is -O-(CH2) n-Z, where n is an integer between 1 and 4. In one embodiment, , R 1 is -OH, and R 2 is -O-(CH2) n -Z and n is 1. In one embodiment, R 1 is -OH, and R 2 is -O-(CH2) n -Z and n is 2. In one embodiment, R 1 teeth, -OH and R 2 is -O-(CH2) n -Z and n is 3. In one embodiment, R 1 is, -OH And R 2 is -O-(CH2) n -Z, and n is 4.

[0106] In one embodiment of formula Ib, R 1 is -OH, and R 2 is -N(H)C(O)-(CH2) n -NH2, Here, n is an integer from 1 to 4. In one embodiment, R 1 is -OH, and R 2 is, -N(H )C(O)-(CH2) n -NH2, and n is 1. In one embodiment, R 1 is -OH, and R 2 teeth ,-N(H)C(O)-(CH2) n -NH2, where n is 2. In one example, R 1 It is -OH , R 2 is -N(H)C(O)-(CH2) n -NH2, and n is 3. In one embodiment, R 1 is, -OH And R 2 is -N(H)C(O)-(CH2) n The compound is -NH2, and n is 4.

[0107] In one embodiment of formula Ib, R 1 is -OH, and R 2 is -N(H)C(O)-(CRR) n -NH2, Here, each R is -H, -OH, or -CH2OH, and n is an integer from 1 to 4. In this embodiment, R 1 is -OH, and R 2 is -N(H)C(O)-(CRR) n -NH2, and each R is, -H is an integer between 1 and 4. In one embodiment, R 1 is -OH, and R 2 is, -N (H)C(O)-(CRR) n It is -NH2, where each R is -OH, and n is an integer from 1 to 4. In the following manner, R 1 is -OH, and R 2 is -N(H)C(O)-(CRR) n It is -NH2, and each R is -CH2 OH is an integer between 1 and 4. In any one of the embodiments described in this paragraph, n is 1. In any of the embodiments described in this paragraph, n is 2. In any of the embodiments described above, n is 3. In one of the cases, n is 4.

[0108] In one embodiment of formula Ib, R 1 is -OH, and R 2 It is N-piperazinyl. Another fruit In the manner of implementation, R 1 is -OH, and R 2 is -N(R 6 )2. In another embodiment, R 1 teeth , -OH, R2 is N-serinyl. In another embodiment, R 1 It is -OH, R 2 It is O-glycosyl.

[0109] In one embodiment of formula Ib, R 1 is -OP(O)(OR 6 )(OH) and R 2 It is -NH2.

[0110] One embodiment provided herein is: [ka] A compound according to any of formulas I, Ia, and Ib, which can be selected from the group consisting of the above, or a pharmaceutical thereof. These are acceptable salts, solvates, or stereoisomers.

[0111] (Conjugate / Antibody-drug conjugate (ADC)) Provided herein are the conjugate of formula A or a pharmaceutically acceptable salt thereof. It is a solvate or stereoisomer: [ka] (In the formula, L is the linker or XYZ, where X is -NH- or -O-; Y is the enzyme cleavage. moiety, self-destructive group, acid-labile moiety, PEG n , sugar moiety, or reinforcing group; and Z is a binder This is a nucleus (BL), where Z is covalently bonded to BA; BA is a binder; k is an integer between 1 and 30; Q 1 and Q 2 Each of these is independently -CH2-, -C(O)-, -C(H)(OH)-, or -C(OH)2-; W is -CH2-, -N(H)-, or -O-; R is -H, -OR 6 -OH, -NH2, alkyl, or -OP(O)(OR 6 )2; Each R 6 In each case, independently, -H, an amino acid residue, a peptide, or an alkyl group ri; katsu Here, R 1 , R 2 , R 3 , R 4 , and R 5 (This is as described in relation to Equation I.) . Examples of enzymatically cleavable moieties include any dipeptide or tripeptide (for example, the present specification) Examples include, but are not limited to, VC-PAB and VA, which are mentioned elsewhere in the book. Exemplary self-destructing groups are described elsewhere in this specification. Exemplary acid-unstable parts Examples of such compounds include alkoxyamines, ketoxyamines, carbonates, or phosphonates. Exemplary enhancing groups are described elsewhere in this specification. Exemplary reactive parts are described elsewhere in this specification. In this case, Y is PEG n It does not contain. In one embodiment, using amino acids, this specification As is described elsewhere in the book and is evident, the payload, enhancer, and antibody (each Those described elsewhere in this specification can be connected to one another. As can be understood, the connection of the payload, enhancer, and antibody via amino acids is... This is carried out by a coupling reaction, thio-Michael addition, or phenol-O-alkylation. For example, the amino acids connecting the payload, the enhancer, and the antibody are lig As a further example, in one embodiment, the payload, enhancer, and antibody are The amino acid to be linked is D-lysine. As a further example, in one embodiment, the pay The amino acid that connects the load, enhancer, and antibody is aspartic acid. Further examples and In one embodiment, the amino acids connecting the payload, the enhancing group, and the antibody are, It is glutamic acid. As a further example, in one embodiment, the payload, the enhancing group, and The amino acid that binds the antibody is serine. As a further example, in one embodiment, The amino acid connecting the payload, the enhancer, and the antibody is cysteine. Further examples In one embodiment, the amino acids connecting the payload, the enhancer, and the antibody are, It is tyrosine.

[0112] Provided herein are conjugates of formula (A) or pharmaceutically acceptable salts thereof. , solvates, or stereoisomers: [ka] (In the formula, L is the linker; BA is a binder; k is an integer between 1 and 30; R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, and Z are described in relation to Equation I. As stated above. In one example, R is R 1 That is the case.

[0113] Provided herein are compounds of formula (Aa) or pharmaceutically acceptable salts thereof: [ka] (In the formula, L is the linker; BA is a binder; k is an integer between 1 and 30; R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, and Z are described in relation to As stated above. Equation Ia. In one embodiment, R is R 1 That is the case.

[0114] Provided herein are compounds of formula (Ab) or pharmaceutically acceptable salts thereof: [ka] (In the formula, L is the linker; BA is a binder; k is an integer between 1 and 30; R is -H, R 1 , or R 2 and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, and Z are described in relation to formula Ib. That is correct. In one example, R is R 1 That is the case.

[0115] (Binder) A suitable binder for any of the conjugates provided in this disclosure Antibodies, lymphokines, hormones, growth factors, viral receptors, interleukins, Or any other cell-binding or peptide-binding molecule or substance, This is not limited to these.

[0116] In some embodiments, the binder is an antibody or an antigen-binding fragment thereof. The "antibody" used herein may be in any form known to those skilled in the art. The term "specific antigen" refers to a small number of antigens that specifically bind to or interact with a particular antigen. This refers to any antigen-binding molecule or molecular complex that contains at least one complementarity-determining region (CDR). The term "body" refers to a structure consisting of two heavy (H) chains and two other chains connected to each other by disulfide bonds. Immunoglobulin molecules containing four light (L) chain polypeptide chains, and their polymers (e.g., IgM) Each heavy chain includes a heavy chain variable region (HCVR or V in this specification). H (abbreviated as) and heavy chain steady region It includes the region. The heavy chain constant region consists of three domains, C H 1, C H 2, and C H Includes 3. Each light chain is Light chain variable region (LCVR or V in this specification) L It includes the (abbreviated as) and the light chain steady region. The light chain steady region is , one domain (C L Includes 1). V H and V L The domain is more than what is called the framework domain (FR). The conserved regions are scattered throughout a highly variable region called the complementarity-determining region (CDR), and these regions are further subdivided into these highly variable regions. It can be divided. Each V H and V LIt consists of three CDRs and four FRs, and amino powder From the end to the carboxyl terminus, in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 It is arranged. Various embodiments of the present invention, suitable antibodies for the compounds herein The FR of the body (or its antigen-binding region) may be identical to that of the human germline sequence, or may be naturally Alternatively, it may be artificially modified. The amino acid consensus sequence is a pair of 2 or more CDRs. It can be defined based on ratio analysis. The term "antibody" as used herein is This also includes antigen-binding fragments of complete antibody molecules. The "antigen-binding portion" of an antibody as used herein. Terms such as "antigen-binding fragment" of an antibody refer to a fragment that specifically binds to an antigen and forms a complex. Naturally occurring, enzymatically obtained, synthesized, or genetically modified polypeptides It contains an antibody or glycoprotein. The antigen-binding fragment of the antibody is processed using any suitable standard technique, for example, Proteolytic digestion or manipulation of DNA encoding an antibody variable domain and optionally a constant domain It can be obtained from complete antibody molecules using recombinant gene engineering techniques involving synthesis and expression. Such DNA is publicly known and / or from, for example, a commercial source, DNA library (e.g.) If available, they can be readily obtained from (including phage-antibody libraries) or synthesized. This can be done by sequencing DNA and using chemical or molecular biological techniques. By performing this operation, for example, one or more variable and / or constant domains can be arranged in a suitable configuration. Or, by introducing codons, generating cysteine ​​residues, modifying and adding amino acids, if It is possible to delete or otherwise remove the antigen. Non-limited examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragment; (iii) Fd fragment; (iv) Fv fragment; (v) single-chain Fv(scFv) molecule; (vi) dAb fragment; and (vii) The smallest recognition unit consisting of amino acid residues that mimic the hypervariable region of an antibody (e.g., CDR3 peptide) Examples include isolated CDRs (such as CDRs) or restrictive FR3-CDR3-FR4 peptides. Other modified molecules, For example, domain-specific antibodies, single-domain antibodies, domain deletion antibodies, chimeric antibodies, CDRs Transplanted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (for example) For example, monovalent nanobodies, divalent nanobodies, etc., small modular immunotherapy drugs (SMIPs), and Variable IgNAR domains are also included in the term "antigen-binding fragment" as used herein. The antigen-binding fragment of an antibody typically contains at least one variable domain. This can be of any size or amino acid composition, and is usually one or more framework sequences. Includes at least one CDR that is adjacent to or in frame with it. H Domain is V L In the antigen-binding fragment associated with the domain, V H Domain and V L The domain is They may be in any preferred configuration relative to each other. For example, the variable region is a dimer, V H -V H , V H -V L , or V L -V L It may contain a dimer, or an antigen-binding fragment of an antibody. V is a monomer. H or V L It may contain domains. In one embodiment, the antibody The original binding fragment is covalently bound to at least one constant domain and at least one variable domain It may contain a variable and constant domain that can be found within the antigen-binding fragment of the antibody of the present invention. A non-restrictive and exemplary arrangement of 'in' is: (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 These include Any arrangement of variable domains and stationary domains, including any of the exemplary arrangements described above. In this configuration, the variable domain and the stationary domain may be directly linked to each other, or they may be completely connected. Alternatively, they may be connected by a partial hinge or linker region. The region is flexible between adjacent variable domains and / or constant domains within a single polypeptide molecule. At least two (for example, 5, 10, 15, 20, 40) that create a semi-flexible connection. It may consist of 1, 60, or more amino acids, similar to a complete antibody molecule. The antigen-binding fragment may be monospecific or multispecific (e.g., bispecific). The body's multispecific antigen-binding fragments typically contain at least two different variable domains, Thus, each variable domain is specific to different antigens or to different epitopes on the same antigen. It can bind to. Exemplary bispecific antibody formats disclosed herein Any multispecific antibody format, including any other, can be handled using routine techniques available in the art. This can be used to adapt the antigen-binding fragment of the antibody of the present invention to its associated use. In one embodiment described in this document, the antibody described herein is a human antibody. As used herein, the term "human antibody" refers to a human germline immunoglobulin sequence. The present invention is intended to include antibodies having variable and constant regions. For example, the human antibodies of the present invention include For example, CDRs, particularly CDR3, are not encoded by human germline immunoglobulin sequences. Amino acid residues (for example, in random or site-specific mutagenesis in vitro) This may include mutations introduced by somatic mutations in vivo. However, as used herein, the term "human antibody" refers to another mammal such as a mouse. This includes antibodies in which a CDR sequence derived from the germline of a species is transplanted onto a human framework sequence. It is not intended to be modified or manipulated by human intervention / manipulation. The term "human antibody" usually refers to modified or manipulated human antibodies. Therefore, it does not contain naturally occurring molecules found in naturally occurring, unmodified organisms. In some embodiments, the antibody may be a recombinant human antibody. The term "recombinant human antibody" as used refers to an antibody prepared, expressed, and processed by recombinant means. All human antibodies that are released or isolated, for example, sets transfected into host cells. Antibodies expressed using alternative expression vectors (described further below), recombinant combinatorial Antibodies isolated from the human antibody library (described further below), human immunoglobulin Antibodies isolated from animals (e.g., mice) that are transgenic regarding the phosphorus gene. (For example, see Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or human immunology. By any other means involving splicing of the globulin gene sequence to other DNA sequences It is intended to include antibodies that are prepared, expressed, produced, or isolated. Recombinant human antibodies such as human germline immunoglobulin sequences have variable and constant regions derived from human germline immunoglobulin sequences. It has. However, in one embodiment, such recombinant human antibodies are inv Mutagenesis in Toro (or in the case of using transgenic animals for human Ig sequences) In combination, the recombinant antibody undergoes somatic mutagenesis in vivo, and therefore, the V H and V L territory The amino acid sequence in this region is human germline V H and V L It originates from and is related to the array, but This sequence does not necessarily need to be naturally present in the human antibody germline repertoire in vivo. The body can exist in two forms related to the non-uniformity of the hinge. In one form, Immunoglobulin molecules consist of dimers linked by interchain heavy chain disulfide bonds, approximately 15 It contains stable 4-chain constructs with a range of 0-160 kDa. In the second form, the dimer is linked by interchain disulfide bonds. Therefore, it is composed of covalently bonded light and heavy chains (half of the antibody) that are not linked together, with an antibody of approximately 75-80 kD Molecules of a are formed. These forms are extremely difficult to separate, even after affinity purification. The frequency of occurrence of the second form in various intact IgG isotypes is limited. However, this is due to structural differences related to the hinge region isotype of the antibody. (Human) Single amino acid substitutions in the hinge region of the IgG4 hinge are typically observed using human IgG1 hinges. The appearance of the second form can be significantly reduced to the level of (Angal et al. (1 993) Molecular Immunology 30:105). This disclosure relates to hinges, C H 2, or C H One or more in the three regions This includes antibodies that have mutations, and these mutations, for example, in production, result in a desired antibody form. This may be desirable to improve the yield. The antibodies described herein are isolated. It may also be an antibody. As used herein, “isolated antibody” means an identified and its This refers to antibodies isolated and / or recovered from at least one component of the natural environment. For example, From at least one component of an organism, or from antibodies that are naturally present or naturally produced Antibodies isolated or removed from tissue or cells are "isolated" for the purposes of the present invention. It is an "antibody". Isolated antibodies also include antibodies in situ within recombinant cells. The antibody is an antibody that has undergone at least one purification or isolation step. In one embodiment, Therefore, isolated antibodies are substantially free of other cellular material and / or chemical substances. It may be present. The antibodies used herein are compared with the corresponding germline sequence from which the antibody originated. In contrast, one or more amixes in the framework of heavy and light chain variable domains and / or CDR region This may include no-acid substitutions, insertions, and / or deletions. Such mutations are described herein. The amino acid sequences disclosed herein are, for example, available from public antibody sequence databases. This can be easily verified by comparing it with the sequence sequence. The present invention provides one or more frames One or more amino acids within the bloat and / or CDR region are paired with the germline sequence from which the antibody originated. In the corresponding residue, or in the corresponding residue of another human germline sequence, or in the corresponding germline residue It has been mutated with a conserved amino acid substitution (such sequence changes are described herein). In this specification, any of the amino acid sequences disclosed are collectively referred to as "germline mutations." It comprises antibodies derived from any of the above and their antigen-binding fragments. Those skilled in the art will recognize the heavy chains disclosed herein. And starting from the light chain variable region sequence, one or more individual germline mutations or combinations thereof It can produce many antibodies and antigen-binding fragments. In one embodiment, V H Reach bi / or V L Mutating all frameworks and / or CDR residues within the domain, the antibody It returns to the residue found in the original germline sequence from which it originated. In other embodiments, specific Only the residues of the first eight amino acids of FR1 or the last eight amino acids of FR4 are found. Only the mutant residues that are produced, or CDR1, By mutating only the mutant residues found in CDR2 or CDR3, the original germline Return to column. In other embodiments, one or more of the framework and / or CDR residues are different A germline sequence (i.e., a germline sequence different from the germline sequence from which the antibody originally originated) The corresponding residue is mutated. Furthermore, the antibody of this disclosure mutates, for example, specific individual residues While the original germline sequence has been mutated to the corresponding residue in a specific germline sequence, Certain other residues that differ from the sequence are maintained, or the corresponding residues in a different germline sequence are maintained. The framework and / or CDR region has been mutated to contain two or more germline mutations. It may contain any combination of different germline mutations. Once obtained, it contains one or more germline mutations. Antibodies and antigen-binding fragments are modified, for example, to have improved binding specificity, increased binding affinity, and improved properties. Beneficial or enhanced antagonistic or operative biological properties (depending on the case), reduced immunogenicity, etc. The desired properties described above can be easily tested. Antibodies obtained by this general method can be easily tested. And antigen-binding fragments are included within the scope of this disclosure. The compounds herein are useful for antibodies. This refers to HCVR, LCVR, and / or CDR amino acids disclosed herein having one or more conservative substitutions. This also includes antibodies containing any variant of the acid sequence. The term "epitope" is a parato Antigenicity is a process that interacts with specific antigen-binding sites in the variable region of an antibody molecule, known as a link. This refers to the baseline. A single antigen can have multiple epitopes. Therefore, different antibodies can be anti- Epitopes can bind to different parts of the original molecule and have different biological effects. It can be either structural or linear. The three-dimensional structural epitope is a different linear polypeptide chain. It is caused by spatially juxtaposed amino acids derived from a segment. Linear epitopes are, This is caused by adjacent amino acid residues in the lipeptide chain. The pitope may contain a saccharide, phosphoryl group, or sulfonyl group portion of the antigen.

[0117] In one embodiment, the antibody includes a light chain. In one embodiment, the light chain is κ It is a light chain. In one embodiment, the light chain is a λ light chain. In one embodiment, The antibody contains 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. 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.

[0118] In some embodiments, the antibody is an antibody fragment. In some embodiments, The antibody fragment is an Fv fragment. In some embodiments, the antibody fragment is a Fab fragment. In some embodiments, the antibody fragment is the F(ab')2 fragment. The antibody fragment is a Fab' fragment. In some embodiments, the antibody fragment is scFv(sFv ) is a fragment. In some embodiments, the antibody fragment is an scFv-Fc fragment.

[0119] In some embodiments, the antibody is a monoclonal antibody. In this embodiment, the antibody is a polyclonal antibody.

[0120] In some embodiments, the antibody is a chimeric antibody. Furthermore, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody. That is the case.

[0121] The antibody has binding specificity to any antigen that is considered suitable by those skilled in the art. This is possible. In one embodiment, the antigen is a transmembrane molecule (e.g., a receptor) or a growth factor. It is a child. Exemplary antigens include scavenger receptor A (SR-A or MSR1) and collagen. Macrophage receptors with a similar structure (MARCO), scavengers with C-type lectins - Receptor (SRCL), and class A scavenger receptor A-5 (SCARA5), COLEC12 and other class A scavenger receptors. Class B macrophage scavengers including Ranger receptors, CD36, LIMPII, SRBI, and SRBII - Receptors, class D scavenger receptor CD68, and lysosomal membrane glycoprotein (LAMP), Lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) and class E scavenging cells containing Dectin-1 Scavenger receptors, scavenger receptor-I (SREC-I) and SREC expressed by endothelial cells -II and Class F scavenger receptors including multiple epidermal growth factor (EGF)-like domain (MEGF) 10 Body, class G scavenger receptor CXC chemokine ligand 16 (CXCL16), faciclinicrin, EG F-like, lamin-type EGF-like, and link domain-containing scavenger receptor-1 (FEEL-1) and -2 (F Class H scavenger receptors including EEL-2, class I scavenger receptor CD163, and Class J scavenger receptors against advanced glycation end products (RAGE), DEC205, CD206, and Dectin -2, Minkle, DC-SIGN, and other C-type lectin superfamily members including DNGR-1 Members, as well as B7 family related members including V-set and Ig domain-containing 4 (VSIG4), Colony-stimulating factor 1 receptor (CSF1R), asialoglycoprotein receptor (ASGPR), and amylol Other membrane proteins such as Id-β precursor-like protein 2 (APLP-2) are examples of molecules. , but not limited to these. In some embodiments, the antigen is PRLR or HER2. In some embodiments, the antibody is an anti-PRLR or anti-HER2 antibody.

[0122] The binding agent linker binds via binding to specific amino acids within the antibody or antigen-binding molecule. It can be conjugated to an agent, for example, an antibody or antigen-binding molecule. Examples of amino acid bonds that can be used in a chain include, for example, lysine (for example) See also US No. 5,208,020; US No. 2010 / 0129314; Hollander et al., Bioconjugate Chem., 20 08, 19:358-361; WO 2005 / 089808; US 5,714,586; US 2013 / 0101546; and US 2012 / See issue 0585592), cysteine ​​(e.g., US 2007 / 0258987; WO 2013 / 055993; WO 201 3 / 055990; WO 2013 / 053873; WO 2013 / 053872; WO 2011 / 130598; US 2013 / 010154 See No. 6; and US No. 7,750,116), selenocysteine ​​(e.g., WO 2008 / 122039; and Hof (See er et al., Proc. Natl. Acad. Sci., USA, 2008, 105: 12451-12456), formil Glycin (for example, Carrico et al., Nat. Chem. Biol., 2007, 3:321-322; Agarwal et al.) References, Proc. Natl. Acad. Sci., USA, 2013, 110:46-51, and the literature by Rabuka et al., Nat. Pro See Tocols, 2012, 10:1052-1067, non-natural amino acids (e.g., WO 2013 / 068874 and WO Examples include (see WO 2012 / 166559), and acidic amino acids (see, for example, WO 2012 / 05982). The linker conjugates to antigen-binding proteins via binding to carbohydrates. It is also possible (for example, US 2008 / 0305497, WO 2014 / 065661, and the literature by Ryan et al., Food See & Agriculture Immunol., 2001, 13: 127-130.

[0123] In some cases, the binder is an antibody or an antigen-binding molecule, and the antibody is lysine. It is bound to the linker via residues. In some embodiments, the antibody or antigen binds. The molecule is bound to the linker via a cysteine ​​residue.

[0124] The linker is transmitted via transglutaminase-based chemical enzymatic conjugation. It can also be conjugated to one or more glutamine residues (for example, Dennler et al.'s literature). (See Bioconjugate Chem. 2014, 25, 569-578 and WO 2017 / 147542). For example, In the presence of lanceglutaminase, one or more glutamine residues of the antibody are converted into a primary amine compound. It can be coupled to an object. To put it simply, in some embodiments, An antibody containing a glutamine residue (e.g., Gln295 residue) is used in the presence of the enzyme transglutaminase. Under these conditions, the material is treated with a primary amine compound, which is described in more detail below. Primary amine formation The compound includes, for example, antibody-drug conjugates via transglutaminase-mediated coupling. Includes a payload or linker-payload that directly provides the gate. The compound is subsequently treated with further compounds for the synthesis of antibody-drug conjugates. This also includes linkers and spacers functionalized with reactive groups that can perform the following actions. Glutamine residue Antibodies containing the group are either isolated from natural sources or modified to contain one or more glutamine residues. This is possible. Glutamine residues in the antibody polypeptide chain (glutaminyl-modified antibody or antibody) Techniques for artificially producing the original bond molecule are within the capabilities of those skilled in the art. In one embodiment, The antibody is then aglycosylated.

[0125] In one embodiment, the antibody or glutaminyl-modified antibody or antigen-binding molecule is small At least one polypeptide chain sequence contains at least one glutamine residue. In this embodiment, the antibody, glutaminyl-modified antibody, or antigen-binding molecule each contains one G It comprises two heavy chain polypeptides having ln295 residues. In further embodiments, the antibody or Glutaminyl-modified antibodies or antigen-binding molecules have one or more glutaminyl molecules at a site other than heavy chain 295. Contains n residues. Included herein are the Asn297Gln(N297Q) mutations described herein. This section contains antibodies that carry the Gln55(Q55) residue. This is the antibody in this section.

[0126] (Primary amine compounds) Transglutaminase-mediated coupling of glutamine-containing antibodies (or antigen-binding compounds) A primary amine compound useful for this purpose is any primary amine that is considered useful by those skilled in the art. It can be an amine compound. Typically, primary amine compounds have the formula H2N-R, where R is It can be any group that is compatible with the antibody and reaction conditions. In one embodiment, R is It is alkyl, substituted alkyl, heteroalkyl, or substituted heteroalkyl.

[0127] In some embodiments, the primary amine compound has a reactant group or a protected reactant group. Includes. Useful reactive groups include azides, alkynes, cycloalkynes, thiols, and alcohols. Examples include ions, ketones, aldehydes, acids, esters, hydrazides, anilines, and amines. In one embodiment, the reactive group is an azide, an alkyne, a sulfhydryl, or a cycloa. Selected from the group consisting of lukynes, aldehydes, and carboxyls.

[0128] In one embodiment, the primary amine compound is represented by the formula H2N-LL-X, where, LL is a divalent spacer, and X is a reactive group or a protected reactive group. Specific implementation In this example, LL is a divalent polyethylene glycol (PEG) group. X is selected from the group consisting of -SH, -N3, alkynes, aldehydes, and tetrazoles. In a particular embodiment, X is -N3.

[0129] In one embodiment, the primary amine compound is represented by one of the following formulas: ru: H2N-(CH2) n -X; H2N-(CH2CH2O) n -(CH2) p -X; H2N-(CH2) n -N(H)C(O)-(CH2) m -X; H2N-(CH2CH2O) n -N(H)C(O)-(CH2CH2O) m -(CH2) p -X; H2N-(CH2) n -C(O)N(H)-(CH2) m -X; H2N-(CH2CH2O) n -C(O)N(H)-(CH2CH2O) m -(CH2) p -X; H2N-(CH2) n -N(H)C(O)-(CH2CH2O) m -(CH2) p -X; H2N-(CH2CH2O) n -N(H)C(O)-(CH2) m -X; H2N-(CH2) n -C(O)N(H)-(CH2CH2O) m -(CH2) p -X; and H2N-(CH2CH2O) n -C(O)N(H)-(CH2) m -X; (wherein n is an integer selected from 1 to 12; m is an integer selected from 0 to 12; p is an integer selected from 0 to 2; And X is -SH, -N3, -C≡CH, -C(O)H, tetrazole, and [ka] (Selected from the group consisting of any of the following).

[0130] In the above, any of the alkyl (i.e., -CH2-) groups is, for example, C 1-8 Alkyl It may be optionally substituted with methylformyl or -SO3H. In one embodiment, Alkyl groups are not substituted.

[0131] In one embodiment, the primary amine compound is: [ka] It is selected from the group consisting of the following.

[0132] In a particular embodiment, the primary amine compound is [ka] Exemplary conditions for the above reaction are provided in the following examples.

[0133] (Linker) The linker L portion of the conjugate described herein contains a binder as described herein. This is the portion that is covalently bonded to the payload compound, for example, the divalent portion. The linker L covalently bonds the binder to the payload compound described herein. It is a valence or polyvalent part. A suitable linker is, for example, one in which each content is fully revealed by citation. Antibody-drug conjugates and immunotoxins incorporated into the document Antibodies and Immunotoxins); Phillips, GL (ed.); Springer Verlag: New York, 2013; Antibody-drugs Antibody-Drug Conjugates; edited by Ducry, L.; Humana Press, 2013; Antibody - Antibody-Drug Conjugates; Wang, J., Shen, W.-C., and Zaro, This can be found in JL (ed.); Springer International Publishing, 2015. Payload The compounds include the compounds of formulas I, Ia, and Ib above, and the compounds bonded with linker L or linked with linker L. The residue after integration is included. Those skilled in the art will recognize that a specific functional group of the payload portion is linked to the linker. They will recognize that these groups are favorable for binding with and / or binders. It contains amines, hydroxyls, phosphates, and sugars.

[0134] In one embodiment, the linker is stable under physiological conditions. The linker is cleavable, for example, in the presence of an enzyme or within a specific pH range or value. , at least the payload portion can be released. In some embodiments, The linker contains an enzymatically cleavable moiety. Examples of enzymatically cleavable moieties include peptide bonds and enzymes. Examples include, but are not limited to, steric linkages, hydrazones, and disulfide linkages. In some embodiments, the linker includes a cathepsin-cleaving linker.

[0135] In some embodiments, the linker includes a non-cutting portion. In this case, the non-cutting linker is [ka] or derived from the residue thereof. In some embodiments, the non-cleavable linker-paylow Do is, [ka] or a positional isomer thereof. In some embodiments, the non-cleaving linker is [ka] or derived from the residue thereof. In some embodiments, the non-cleavable linker-paylow Do is, [ka] or a positional isomer thereof. In one embodiment, the linker is maleimidecyclohexyl Suncarboxylate or 4-(N-maleimidomethyl)cyclohexanecarboxylic acid (MCC) In the structure, [ka] This indicates a binder. In some examples of the structure, [ka] This indicates, for example, the click chemical residue obtained by the reaction of the binder and the linker payload. vinegar.

[0136] In some embodiments, a preferred linker is a single binder, such as an antibody. Examples include those chemically bound to the two cysteine ​​residues, but are not limited to these. No. Such linkers are destroyed by antibodies as a result of the conjugation process. It can mimic the function of a disulfide bond.

[0137] In some embodiments, the linker contains one or more amino acids. Acids include natural, unnatural, standard, non-standard, protein-constitutive, and non-protein-constitutive. Examples include 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 Gin, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or includes citrulline, derivatives thereof, or combinations thereof. In one embodiment, In some embodiments, one or more side chains of the amino acid are linked to the following side chain groups. The linker contains valine and citrulline. In some embodiments, the The injector contains lysine, valine, and citrulline. In some embodiments, the The phosphate contains lysine, valine, and alanine. In some embodiments, the phosphate Car contains valine and alanine.

[0138] In some embodiments, the linker includes a self-destructing group. The self-destructing group is known to those skilled in the art. It can be any such base of knowledge. In a particular embodiment, the self-destructing base is p- It is aminobenzyl (PAB) or its derivatives. A useful derivative is p-aminobenzyl Oxycarbonyl (PABC) is one example. Those skilled in the art will know that the self-destructing group is removed from the payload and the linker remains They are likely aware that they can perform chemical reactions that release atoms.

[0139] In some embodiments, the linker is: [ka] And here: SP 1 It is a spacer; SP 2 It is a spacer; [ka] is one or more bonds with the binder; [ka] is one or more connections with the payload; Each AA is an amino acid; and n is an integer between 1 and 10.

[0140] SP 1 The spacer is (AA) n The portion is attached to the binder (BA) or to the reactive group residues bound to the BA. This is the part. Suitable SP 1 As spacers, alkylene or polyether, Examples include, but are not limited to, those that include both. The end of the spacer, for example If the binder or the spacer portion bound to AA is used during the chemical synthesis of the conjugate, the antibody or derived from a reactive part used for the purpose of coupling AA to the spacer. It can be a part. In one embodiment, n is 1, 2, 3, or 4. In one embodiment, n is 2. In a specific embodiment, n is 3. In this case, n is 4.

[0141] In some embodiments, SP 1 The spacer contains alkylene. Several implementations In this manner, SP 1 The spacer is C 5-7 Contains alkylene. In some embodiments, SP 1 The spacer contains polyether. In some embodiments, SP 1 Spacer This includes polymers of ethylene oxide, such as polyethylene glycol.

[0142] In some embodiments, SP 1 Spacers are: [ka] And here: RG' is the reactive group residue after the reaction between the reactive group RG and the binder; [ka] This is bonding with the binder; [ka] (AA) n It is a union with; and b is an integer between 2 and 8.

[0143] Those skilled in the art know that the reactive group RG can form one or more bonds with the binder. It can be any reactive group. The reactive group RG reacts with a binder (for example, an antibody and , at the cysteine ​​or lysine residue, or at the azide moiety, for example, PEG-N3 functionalized antibody (By reacting with one or more glutamine residues), compounds of formula A, Aa, or Ab can be formed. It is the part that contains the part within its structure. After conjugation with the binder, the reactive group It becomes a reactive group (RG'). An example of a reactive group is a haloacetate that can react with a binder. Chill, isothiocyanate, succinimide, N-hydroxysuccinimide, or Murray Examples include, but are not limited to, those containing the mid-green portion.

[0144] In one embodiment, the reactive group may be an alkyne, but is not limited thereto. In one embodiment, the alkyne undergoes 1,3-addition cycloaddition with an azide in the absence of a copper catalyst. Alkynes that can receive a reaction, for example, strained alkynes. Strained alkynes are strained Promoting alkyne-azide cycloaddition (SPAAC), cycloalkynes, for example, cyclooctin, and It is suitable for benz cycloalkynes. Suitable alkynes include dibenzoazacyclooc. Chin or [ka] , dibenzocyclooctin or [ka] , biarylazacyclooctinone or [ka] , difluorinated cyclooctin or [ka] , substitutions, for example, fluorinated alkynes, aza-cycloalkynes, bicycl[6.1.0]nonine or [ka] Examples include, but are not limited to, alkynes, and their derivatives. Particularly useful alkynes are So, [ka] These are some examples.

[0145] In one embodiment, the binder is directly bonded to RG'. The binder is placed on the spacer below, for example, SP 4 It is connected to RG' via a specific implementation. In this configuration, the binder is bonded to RG' via a PEG spacer. This will be discussed in detail below. In one embodiment, the binder is functionalized by having one or more azide groups Each azide group can react with RG to form RG'. In this embodiment, the binder is derivatized with -PEG-N3 linked to a glutamine residue. Exemplary -N3 derivatizing binders, methods for preparing the same, and methods for using the same in reactions with RG are described below. Provided herein, in one embodiment, RG is suitable for involvement in 1,3-addition cyclization. It is an alkyne, and RG' is formed from the reaction of RG with an azide functionalizing binder, resulting in 1,2,3-tri This is the azolyl moiety. As a further example, in one embodiment, RG' is [ka] Alternatively, they are linked to a binder shown in a mixture of their respective positional isomers. Each R and R' is a part of this It is as stated in the specifications.

[0146] SP 2 The spacer is (AA) n This is the part that connects to the payload. Suitable spacers and SP 1 The spacers listed above are examples, but are not limited to these. Not possible. Further suitable SP 2 As spacers, alkylene or polyether, This includes, but is not limited to, those that include both. 2 The end of the spacer, For example, the spacer portion directly coupled to the payload or AA is conjugated. During synthesis, the payload or AA is SP 2 Used for coupling to spacers. It can be a part derived from the reactive part that is being treated. In some examples, SP 2 Spec SP directly coupled to the end of the ser, for example, the payload or AA. 2 The spacer part is During the chemical synthesis of the conjugate, the payload or AA is coupled to the spacer. It can be a residue of the reactive portion used for the purpose.

[0147] In some embodiments, SP 2 Spacers are -O-, -N(R 6 )-,-R 4' -, -R 5' -, -OR 5' -, and -OP(O)(OR 6 Selected from the group consisting of )O-, where: R 4' is -Z'-YX-; X is selected from the group consisting of -O- and -N(H)-; Y is an alkylene, a substituted alkylene (not limited to oxo substitutions, i.e., including =O). ), selected from the group consisting of heteroalkylenes and substituted heteroalkylenes; Z' is selected from the group consisting of -O- and -N(H)-; R 5' is a heterocycloalkylene or a substituted heterocycloalkylene, where each Each heterocycloalkylene or substituted heterocycloalkylene interacts with the rest of the molecule. -O-, -N(H)-, and are useful for bonding. [ka] One selected from nitrogen and oxygen, comprising at least two parts selected from the group consisting of , containing two or three heteroatoms; and Each R 6 (wherein this is -H, an amino acid residue, a peptide, or an alkyl group).

[0148] In one statement, SP 2 Spacers are -O-, -N(H)-, [ka] Selected from the group consisting of. In one embodiment, each [ka] This is the coupling with the payload, and each [ka] (AA) n It is a combination of the two.

[0149] In the above formula, each AA is an amino acid or, optionally, p-aminobenzyloxycarbone. This is a nyl residue (PABC). If a PABC is present, preferably there is only one PABC. Preferably, if present, the PABC residues are located proximal to the payload (AA). n At the terminal AA of the base Yes. Suitable amino acids for each AA include natural, unnatural, standard, non-standard, and protein. Examples include protein-structural, non-protein-structural, and L- or D-α-amino acids. In one embodiment, the linker is alanine, valine, leucine, isoleucine, methionine n, tryptophan, phenylalanine, proline, serine, threonine, cysteine, Tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, argy This includes nin, histidine, or citrulline, their derivatives, or combinations thereof. In one embodiment, one or more side chains of the amino acid are linked to the following side chain groups. In some embodiments, n is 2. In some embodiments, (AA) n is, valine- It is citrulline. In some embodiments, (AA) n It is citrulline-valine. In some embodiments, (AA) n It is valine-alanine. In some embodiments (AA) n This is alanine-valine. In some embodiments, (AA) n is, It is phosphorus-glycine. In some embodiments, (AA) n It is glycine-valine. In some embodiments, n is 3. In some embodiments, the (AA) n teeth , valine-citrulline-PABC. In some embodiments, (AA) n Citrulline- It is valine-PABC. In some embodiments, (AA) n , glutamate-valine-cyto It is Lurin. In some embodiments, (AA) n This is glutamine-valine-citrulline In some embodiments, (AA) n It is lysine-valine-alanine. A few embodiments, (AA) n It is lysine-valine-citrulline. Several implementations In some embodiments, n is 4. In some embodiments, (AA) n is glutamic acid-bari It is n-citrulline-PAB. In some embodiments, (AA) n is glutamine-valine- It is citrulline-PABC. Those skilled in the art will know that PABC has the following structure: [ka] It is likely recognized as a p-aminobenzyloxycarbonyl residue containing the PABC residue. The base has been shown to promote the cleavage of specific linkers in vitro and in vivo.

[0150] In some embodiments, the linker is: [ka] And here: Each [ka] This is a bond with a binder; Each [ka] This is the coupling with the payload; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, bonding with the binder can be direct or mediated through a spacer. It is possible to have something. In one embodiment, the binding with the binder is the glutamate of the binder. This involves interaction with the residue via a PEG spacer.

[0151] In some embodiments, the linker is: [ka] And here: Each [ka] This is a bond with a binder; Each [ka] This is the coupling with the payload; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, bonding with the binder can be direct or mediated through a spacer. It is possible to have something. In one embodiment, the binding with the binder is the glutamate of the binder. This involves interaction with the residue via a PEG spacer.

[0152] In any of the above embodiments, (AA) n The group can be modified with one or more enhancing groups. . Advantageously, the enhancing group is (AA) n It can be linked to the side chain of any amino acid within it. Useful amino acids for linking the enhancing group include lysine, asparagine, and asparagus. Examples include arginate, glutamine, glutamic acid, and citrulline. Linking with the enhancing group. This can be a direct bond with the amino acid side chain, or the bond may be a spacer and / or The reaction can be indirect, involving a reactive group. A useful spacer and reactive group can be used. For example, any of the above. The enhancing group is considered useful by those skilled in the art. It can be any group that enhances biological effects. For example, the enhancing group may have any biological effect, though not limited to those mentioned above. , biochemical effects, synthesis effects, solubilization effects, imaging effects, detection effects, and reactivity effects, etc. Including beneficial effects of compounds, payloads, linker payloads, or antibody conjugates. It can be any group to be attached to. In one embodiment, the enhancing group is a hydrophilic group. Yes. In one embodiment, the enhancing group is a cyclodextrin. In this context, the enhancing group is alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl It is sulfonic acid. Cyclodextrin is any cyclodextrin known to those skilled in the art. It can be. In one embodiment, cyclodextrin is α-cyclodextrin Phosphorus, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof In one embodiment, the cyclodextrin is α-cyclodextrin. In one embodiment, the cyclodextrin is β-cyclodextrin. In one embodiment, the cyclodextrin is γ-cyclodextrin. The enhancing group can improve the solubility of the rest of the conjugate. Application methods, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl The sulfonic acid may be substituted or unsubstituted. In one embodiment, alkyl Heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) 1-5 SO3 H, -(CH2) n -NH-(CH2) 1-5 SO3H, -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m -C(O)NH-(CH2 ) 1-5 SO3H, -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(C H2) 1-5 SO3H)2, or -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2)1-5 SO3H)2, and here, n is 1, 2, 3, 4, or 5, and m is 1, 2, 3, 4, or 5. In one embodiment, Alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH 2) 1-5 In another embodiment, alkyl, heteroalkyl, alkylenyl, Alternatively, heteroalkylenyl sulfonic acid is -(CH2) n -NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroalkyl, alkyl Renyl or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H is Here, n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroal Kill, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, Kill, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n - N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In this embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl Sulfonic acid is -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroalkyl, alkylene Or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where m is 1, 2, 3, 4, or 5. In some embodiments, The linker is: [ka] And here: SP 1 It is a spacer; SP 2 It is a spacer; SP 3 (AA) n It is a spacer connected to one of the AAs; [ka] is one or more bonds with the binder; [ka] is one or more connections with the payload; [ka] This is one or more bonds with the reinforcing group EG; Each AA is an amino acid; and n is an integer between 1 and 10. As discussed above, bonding with the binder can be direct or mediated through a spacer. It is possible to have something. In one embodiment, the binding with the binder is the glutamate of the binder. This involves interaction with the residue via a PEG spacer.

[0153] SP 1 The spacer base is as described above. SP 2The spacer base is as described above. (AA) n The basis is as stated above.

[0154] SP 3 The spacer is (AA) n This is the part that connects to the reinforcing group (EG). Suitable SP 3 Spacer Examples include those containing alkylenes, polyethers, or both. , and not limited to these. SP 3 The end of the spacer, i.e., directly bonded to the reinforcing group or AA. Combined SP 3 The spacer portion is used to enhance the conjugate during chemical synthesis by adding an SP (splitting) group or AA. 3 Spec This is a part derived from the reactive part used for coupling with the ser. This is possible. In some examples, SP 3 The end of the spacer, i.e., the reinforcing group or AA The directly bonded spacer portion, during the chemical synthesis of the conjugate, contains reinforcing groups or AA. It is a reactive residue used for the purpose of coupling to the spacer. This is possible. In one embodiment, SP 3 (AA) n With a single AA connected spacer Yes. In one example, SP 3 The spacer is (AA) n It is linked to the side chain of the lysine residue. .

[0155] to In some embodiments, SP 3 Spacers are: [ka] And here: RG' is the reactive group residue after the reaction between the reactive group RG and the enhancer EG; [ka] This is the binding with the enhancer; [ka] (AA) n It is a union with; and a is an integer between 2 and 8.

[0156] Those skilled in the art know that the reactive group RG can form one or more bonds with the enhancer. It can be any reactive group. The reactive group RG reacts with a binder (for example, an antibody and (reacting at the cysteine ​​or lysine residue, or at the azide moiety), formula A, Aa, or Ab This is a portion of the structure that contains a part that can form a compound. After reaction, the reactive group becomes the reactive group residue (RG'). The reactive group RG is involved in any of the above reactions. It can be a group. An example of a reactive group is a halo that can react with a binder. Cetyl, isothiocyanate, succinimide, N-hydroxysuccinimide, or male Examples include, but are not limited to, substances containing an imide portion.

[0157] In one embodiment, the reactive group may be an alkyne, but is not limited thereto. In one embodiment, the alkyne undergoes 1,3-addition cycloaddition with an azide in the absence of a copper catalyst. Alkynes that can receive a reaction, for example, strained alkynes. Strained alkynes are strained Promoting alkyne-azide cycloaddition (SPAAC), cycloalkynes, for example, cyclooctin, and It is suitable for benz cycloalkynes. Suitable alkynes include dibenzoazacyclooc. Chin or [ka] , dibenzocyclooctin or [ka] , biarylazacyclooctinone or [ka] , difluorinated cyclooctin or [ka] , substitutions, for example, fluorinated alkynes, aza-cycloalkynes, bicycl[6.1.0]nonine or [ka] Examples include, but are not limited to, alkynes, and their derivatives. Particularly useful alkynes are So, [ka] These are some examples.

[0158] In some embodiments, the linker is: [ka] And here: RG' is the reactive group residue after the reaction between the reactive group RG and the binder; PEG is PEG3; SP 2 It is a spacer; SP 3 (AA) n It is a spacer connected to one of the AAs; [ka] is one or more bonds with the binder; [ka] is one or more connections with the payload; [ka] This is one or more bonds with the reinforcing group EG; Each AA is an amino acid; and n is an integer between 1 and 10. As discussed above, bonding with the binder can be direct or mediated through a spacer. It is possible to have something. In one embodiment, the binding with the binder is the glutamate of the binder. This involves interaction with the residue via a PEG spacer.

[0159] In one embodiment, the linker is: [ka] Or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a position thereof. A positional isomer, or a mixture of these positional isomers, where: Each [ka] This is a bond with a binder; Each [ka] This is the coupling with the payload; Each [ka] This is a binding with an enhancer; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is a heteroalkyl. In one embodiment, 1,3- Cycloaddition or SPAAC positional isomers, or mixtures of positional isomers, are treated with suitable alkynes. It is derived from a PEG-N3 derivatized antibody. For example, in one embodiment, the linker is: [ka] Or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a position thereof. It is a positional isomer, or a mixture of these positional isomers. As a further example, the linker is : [ka] Or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a position thereof. These are positional isomers, or mixtures thereof. As a further example, in one embodiment... In this case, the linker is: [ka] Or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a position thereof. It is a positional isomer, or a mixture of these positional isomers. As discussed above, bonding with the binder can be direct or mediated through a spacer. It is possible to have something. In one embodiment, the binding with the binder is the glutamate of the binder. This is via a PEG spacer with the residue. In one embodiment, the enhancer is parent It is a water group. In one embodiment, the enhancer is a cyclodextrin. In this context, the reinforcing group is alkyl, heteroalkyl, alkylenyl, or heteroalkyl It is nylsulfonic acid. Cyclodextrin is any cyclodextrin known to those skilled in the art. It can be . In one embodiment, cyclodextrin is α-cyclodextrin Thrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof Yes. In one embodiment, the cyclodextrin is α-cyclodextrin. In one embodiment, the cyclodextrin is β-cyclodextrin. In this embodiment, cyclodextrin is γ-cyclodextrin. Alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) 1-5 SO3H, -(CH2) n -NH-(CH2) 1-5 SO3H, -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2) n -C(O)N((CH2 ) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 Here, n is 1, 2, 3, 4, or 5, and m is 1, 2, 3, 4, or 5. In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Acid is -(CH2) 1-5 In another embodiment, alkyl, heteroalkyl, and Lukirenyl, or heteroalkylenyl sulfonic acid, is -(CH2) n -NH-(CH2) 1-5 SO3H is Here, n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroal Kill, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 S O3H, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl Heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m - C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment... In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is, -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5 In another embodiment, alkyl, heteroalkyl, alkylenyl, or hetero Alkyrenyl sulfonic acid is -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 is here Then n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroalkyl , alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)N((CH2) 1-5C( O)NH(CH2) 1-5 SO3H)2, where m is 1, 2, 3, 4, or 5.

[0160] In some embodiments, the linker is: [ka] Or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a position thereof. A positional isomer, or a mixture of these positional isomers, where: Each [ka] This is a bond with a binder; Each [ka] This is a binding with an enhancer; Each [ka] This is the coupling with the payload; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, bonding with the binder can be direct or mediated through a spacer. It is possible to have something. In one embodiment, the binding with the binder is the glutamate of the binder. This is via a PEG spacer with the residue. In one embodiment, the enhancer is parent It is a water group. In one embodiment, the enhancer is a cyclodextrin. In this context, the reinforcing group is alkyl, heteroalkyl, alkylenyl, or heteroalkyl It is nylsulfonic acid. Cyclodextrin is any cyclodextrin known to those skilled in the art. It can be . In one embodiment, cyclodextrin is α-cyclodextrin Thrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof Yes. In one embodiment, the cyclodextrin is α-cyclodextrin. In one embodiment, the cyclodextrin is β-cyclodextrin. In this embodiment, cyclodextrin is γ-cyclodextrin. Alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) 1-5 SO3H, -(CH2) n -NH-(CH2) 1-5 SO3H, -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2) n -C(O)N((CH2 ) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 Here, n is 1, 2, 3, 4, or 5, and m is 1, 2, 3, 4, or 5. In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Acid is -(CH2) 1-5 In another embodiment, alkyl, heteroalkyl, and Lukirenyl, or heteroalkylenyl sulfonic acid, is -(CH2) n -NH-(CH2) 1-5 SO3H is Here, n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroal Kill, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 S O3H, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl Heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m - C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment... In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is, -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5 In another embodiment, alkyl, heteroalkyl, alkylenyl, or hetero Alkyrenyl sulfonic acid is -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 is here Then n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroalkyl , alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C( O)NH(CH2) 1-5 SO3H)2, where m is 1, 2, 3, 4, or 5.

[0161] In some embodiments, the linker is: [ka] TIFF0007843731000181.tif134170 or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, or these A positional isomer of, or a mixture of these positional isomers, where: Each [ka] This is a bond with a binder; Each [ka] This is the coupling with the payload; R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, bonding with the binder can be direct or mediated through a spacer. It is possible to have something. In one embodiment, the binding with the binder is the glutamate of the binder. This involves interaction with the residue via a PEG spacer. In some embodiments, the linker is: [ka] TIFF0007843731000186.tif216170 or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, or these A positional isomer of, or a mixture of these positional isomers, where: Each [ka] This is a bond with a binder; Each [ka] This is the coupling with the payload; R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, bonding with the binder can be direct or mediated through a spacer. It is possible to have something. In one embodiment, the binding with the binder is the glutamate of the binder. This involves interaction with the residue via a PEG spacer.

[0162] In some embodiments, the linker is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or positional isomers thereof, or mixtures of these positional isomers, wherein: each of

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Chem.

Chem.

[0163] In some embodiments, the linker is: [ka] Or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a position thereof. A positional isomer, or a mixture of these positional isomers, where: Each [ka] This is a bond with a binder; Each [ka] This is the coupling with the payload; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, bonding with the binder can be direct or mediated through a spacer. It is possible to have something. In one embodiment, the binding with the binder is the glutamate of the binder. This is via a PEG spacer with the residue. In one embodiment, the enhancer is parent It is a water group. In one embodiment, the enhancer is a cyclodextrin. In this context, the reinforcing group is alkyl, heteroalkyl, alkylenyl, or heteroalkyl It is nylsulfonic acid. Cyclodextrin is any cyclodextrin known to those skilled in the art. It can be . In one embodiment, cyclodextrin is α-cyclodextrin Thrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof Yes. In one embodiment, the cyclodextrin is α-cyclodextrin. In one embodiment, the cyclodextrin is β-cyclodextrin. In this embodiment, cyclodextrin is γ-cyclodextrin. Alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) 1-5 SO3H, -(CH2) n -NH-(CH2) 1-5 SO3H, -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2) n -C(O)N((CH2 ) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 Here, n is 1, 2, 3, 4, or 5, and m is 1, 2, 3, 4, or 5. In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Acid is -(CH2) 1-5 In another embodiment, alkyl, heteroalkyl, and Lukirenyl, or heteroalkylenyl sulfonic acid, is -(CH2) n -NH-(CH2) 1-5 SO3H is Here, n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroal Kill, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 S O3H, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl Heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m - C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment... In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is, -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5 In another embodiment, alkyl, heteroalkyl, alkylenyl, or hetero Alkyrenyl sulfonic acid is -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 is here Then n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroalkyl , alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C( O)NH(CH2) 1-5 SO3H)2, where m is 1, 2, 3, 4, or 5.

[0164] In some embodiments, the linker is: [ka] TIFF0007843731000200.tif69170 or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, or these A positional isomer of, or a mixture of these positional isomers, where: Each [ka] This is a bond with a binder; Each [ka] This is the coupling with the payload; R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, bonding with the binder can be direct or mediated through a spacer. It is possible to have something. In one embodiment, the binding with the binder is the glutamate of the binder. This involves interaction with the residue via a PEG spacer.

[0165] In some embodiments, the linker is: [ka] TIFF0007843731000205.tif98170 or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, or these A positional isomer of, or a mixture of these positional isomers, where: Each [ka] This is a bond with a binder; Each [ka] This is the coupling with the payload; R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, bonding with the binder can be direct or mediated through a spacer. It is possible to have something. In one embodiment, the binding with the binder is the glutamate of the binder. This involves interaction with the residue via a PEG spacer.

[0166] The linker described above is useful for providing the following conjugates:

[0167] In some embodiments, the conjugate is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the position thereof They are isomers, and here: BA is a binder; Each SP 1 SP 2 , and SP 3 This is the spacer base described above, where SP 3 (AA) n brain It is linked to one AA; EG is an enhancer; k is an integer between 1 and 30; R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A, in each case, independently, -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, bonding with the binder can be direct or mediated through a spacer. It is possible to have something. In one embodiment, the binding with the binder is the glutamate of the binder. This is via a PEG spacer with the residue. In one embodiment, the enhancer is parent It is a water group. In one embodiment, the enhancer is a cyclodextrin. In this context, the reinforcing group is alkyl, heteroalkyl, alkylenyl, or heteroalkyl It is nylsulfonic acid. Cyclodextrin is any cyclodextrin known to those skilled in the art. It can be . In one embodiment, cyclodextrin is α-cyclodextrin Thrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof Yes. In one embodiment, the cyclodextrin is α-cyclodextrin. In one embodiment, the cyclodextrin is β-cyclodextrin. In this embodiment, cyclodextrin is γ-cyclodextrin. Alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) 1-5 SO3H, -(CH2) n -NH-(CH2) 1-5 SO3H, -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2) n -C(O)N((CH2 ) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 Here, n is 1, 2, 3, 4, or 5, and m is 1, 2, 3, 4, or 5. In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Acid is -(CH2) 1-5 In another embodiment, alkyl, heteroalkyl, and Lukirenyl, or heteroalkylenyl sulfonic acid, is -(CH2) n -NH-(CH2) 1-5 SO3H is Here, n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroal Kill, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 S O3H, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl Heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m - C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment... In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is, -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5 In another embodiment, alkyl, heteroalkyl, alkylenyl, or hetero Alkyrenyl sulfonic acid is -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 is here Then n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroalkyl , alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C( O)NH(CH2) 1-5 SO3H)2, where m is 1, 2, 3, 4, or 5. In one embodiment... And R is R 1 That is the case.

[0168] In some embodiments, the conjuate is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the position thereof They are isomers, and here: BA is a binder; Each RG' is a residue of the reactive group described herein; EG is an enhancer; k is an integer between 1 and 30; R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, bonding with the binder can be direct or mediated through a spacer. It is possible to have something. In one embodiment, the binding with the binder is the glutamate of the binder. This is via a PEG spacer with the residue. In one embodiment, the enhancer is parent It is a water group. In one embodiment, the enhancer is a cyclodextrin. In this context, the reinforcing group is alkyl, heteroalkyl, alkylenyl, or heteroalkyl It is nylsulfonic acid. Cyclodextrin is any cyclodextrin known to those skilled in the art. It can be . In one embodiment, cyclodextrin is α-cyclodextrin Thrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof Yes. In one embodiment, the cyclodextrin is α-cyclodextrin. In one embodiment, the cyclodextrin is β-cyclodextrin. In this embodiment, cyclodextrin is γ-cyclodextrin. Alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) 1-5 SO3H, -(CH2) n -NH-(CH2) 1-5 SO3H, -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2)n -C(O)N((CH2 ) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 Here, n is 1, 2, 3, 4, or 5, and m is 1, 2, 3, 4, or 5. In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Acid is -(CH2) 1-5 In another embodiment, alkyl, heteroalkyl, and Lukirenyl, or heteroalkylenyl sulfonic acid, is -(CH2) n -NH-(CH2) 1-5 SO3H is Here, n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroal Kill, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 S O3H, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl Heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m - C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment... In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is, -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5 In another embodiment, alkyl, heteroalkyl, alkylenyl, or hetero Alkyrenyl sulfonic acid is -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 is here Then n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroalkyl , alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C( O)NH(CH2) 1-5 SO3H)2, where m is 1, 2, 3, 4, or 5. In one embodiment... And R is R 1 That is the case.

[0169] In some embodiments, the conjuate is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the position thereof They are isomers, and here: BA is a binder; Each RG' is a residue of the reactive group described herein; EG is an enhancer; k is an integer between 1 and 30; R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, bonding with the binder can be direct or mediated through a spacer. It is possible to have something. In one embodiment, the binding with the binder is the glutamate of the binder. This is via a PEG spacer with the residue. In one embodiment, the enhancer is parent It is a water group. In one embodiment, the enhancer is a cyclodextrin. In this context, the reinforcing group is alkyl, heteroalkyl, alkylenyl, or heteroalkyl It is nylsulfonic acid. Cyclodextrin is any cyclodextrin known to those skilled in the art. It can be . In one embodiment, cyclodextrin is α-cyclodextrin Thrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof Yes. In one embodiment, the cyclodextrin is α-cyclodextrin. In one embodiment, the cyclodextrin is β-cyclodextrin. In this embodiment, cyclodextrin is γ-cyclodextrin. Alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) 1-5 SO3H, -(CH2) n -NH-(CH2) 1-5 SO3H, -(CH2) n -C(O)NH-(CH2)1-5 SO3H, -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2) n -C(O)N((CH2 ) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 Here, n is 1, 2, 3, 4, or 5, and m is 1, 2, 3, 4, or 5. In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Acid is -(CH2) 1-5 In another embodiment, alkyl, heteroalkyl, and Lukirenyl, or heteroalkylenyl sulfonic acid, is -(CH2) n -NH-(CH2) 1-5 SO3H is Here, n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroal Kill, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 S O3H, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl Heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m - C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment... In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is, -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5 In another embodiment, alkyl, heteroalkyl, alkylenyl, or hetero Alkyrenyl sulfonic acid is -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 is here Then n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroalkyl , alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C( O)NH(CH2) 1-5 SO3H)2, where m is 1, 2, 3, 4, or 5. In one embodiment... And R is R 1 That is the case.

[0170] In some embodiments, the conjuate is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the position thereof They are isomers, and here: BA is a binder; k is an integer between 1 and 30; R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each [ka] This is a bond with a strengthening group; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. In one embodiment, the enhancer is a hydrophilic group. In another embodiment, the enhancer is a cy It is a clodextrin. In one embodiment, the reinforcing group is alkyl, heteroalkyl These are alkylenyl or heteroalkylenyl sulfonic acid. Cyclodextrin is, It can be any cyclodextrin known to the manufacturer. In one embodiment, Clodextrins include α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin. Dextrin, or a mixture thereof. In one embodiment, cyclodextrin This is α-cyclodextrin. In one embodiment, cyclodextrin is β-cyclodextrin It is a clodextrin. In one embodiment, the cyclodextrin is γ-cyclodextrin It is a string. In one embodiment, alkyl, heteroalkyl, alkylenyl, and Heteroalkylenylsulfonic acid is -(CH2) 1-5 SO3H, -(CH2) n -NH-(CH2)1-5 SO3H, -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n -N((CH2) 1-5 C(O)NH (CH2) 1-5 SO3H)2, -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m -C(O) N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5, and m is , 1, 2, 3, 4, or 5. In one embodiment, alkyl, heteroalkyl, alkyl Renyl or heteroalkylenyl sulfonic acid is -(CH2) 1-5 In another embodiment, In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is, -(CH2) n -NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. Another real Application methods, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl Auronic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. Yes. In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkyl Lukirenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2 , 3, 4, or 5. In another embodiment, alkyl, heteroalkyl, alkylene L, or heteroalkylenyl sulfonic acid, is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 Yes, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, hetero Roalkyl, alkylenyl, or heteroalkylenyl sulfonic acids are -(CH2) n -C(O)N((CH2 ) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. Another implementation In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where m is 1, 2 , 3, 4, or 5. In one embodiment, R is R 1 That is the case.

[0171] In some embodiments, the conjugate is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the position thereof They are isomers, and here: BA is a binder; k is an integer between 1 and 30; R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5, R 6 , R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each [ka] This is a bond with a strengthening group; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. In one embodiment, the enhancer is a hydrophilic group. In another embodiment, the enhancer is a cy It is a clodextrin. In one embodiment, the reinforcing group is alkyl, heteroalkyl These are alkylenyl or heteroalkylenyl sulfonic acid. Cyclodextrin is, It can be any cyclodextrin known to the manufacturer. In one embodiment, Clodextrins include α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin. Dextrin, or a mixture thereof. In one embodiment, cyclodextrin This is α-cyclodextrin. In one embodiment, cyclodextrin is β-cyclodextrin It is a clodextrin. In one embodiment, the cyclodextrin is γ-cyclodextrin It is a string. In one embodiment, alkyl, heteroalkyl, alkylenyl, and Heteroalkylenylsulfonic acid is -(CH2) 1-5 SO3H, -(CH2) n -NH-(CH2) 1-5 SO3H, -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n -N((CH2) 1-5 C(O)NH (CH2) 1-5 SO3H)2, -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m -C(O) N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5, and m is , 1, 2, 3, 4, or 5. In one embodiment, alkyl, heteroalkyl, alkyl Renyl or heteroalkylenyl sulfonic acid is -(CH2) 1-5 In another embodiment, In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is, -(CH2) n -NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. Another real Application methods, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl Auronic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. Yes. In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkyl Lukirenyl sulfonic acid is -(CH2CH2O) m-C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2 , 3, 4, or 5. In another embodiment, alkyl, heteroalkyl, alkylene L, or heteroalkylenyl sulfonic acid, is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 Yes, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, hetero Roalkyl, alkylenyl, or heteroalkylenyl sulfonic acids are -(CH2) n -C(O)N((CH2 ) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. Another implementation In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where m is 1, 2 , 3, 4, or 5. In one embodiment, R is R 1 That is the case.

[0172] In some embodiments, the conjugate is: [ka] TIFF0007843731000222.tif196170 or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, or these They are positional isomers, and here: BA is a binder; k is an integer between 1 and 30; R is -H, R 1 , or R 2 and Q 1Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. For some reason, R is R 1 That is the case.

[0173] In some embodiments, the conjugate is: [ka] TIFF0007843731000225.tif199170 or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, or these They are positional isomers, and here: BA is a binder; k is an integer between 1 and 30; R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6, R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. For some reason, R is R 1 That is the case.

[0174] In some embodiments, the conjugate is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the position thereof They are isomers, and here: BA is a binder; k is an integer between 1 and 30; R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each [ka] This is a bond with a strengthening group; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. In one embodiment, the enhancer is a hydrophilic group. In another embodiment, the enhancer is a cy It is a clodextrin. In one embodiment, the reinforcing group is alkyl, heteroalkyl These are alkylenyl or heteroalkylenyl sulfonic acid. Cyclodextrin is, It can be any cyclodextrin known to the manufacturer. In one embodiment, Clodextrins include α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin. Dextrin, or a mixture thereof. In one embodiment, cyclodextrin This is α-cyclodextrin. In one embodiment, cyclodextrin is β-cyclodextrin It is a clodextrin. In one embodiment, the cyclodextrin is γ-cyclodextrin It is a string. In one embodiment, alkyl, heteroalkyl, alkylenyl, and Heteroalkylenylsulfonic acid is -(CH2) 1-5 SO3H, -(CH2) n -NH-(CH2) 1-5 SO3H, -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O)m -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n -N((CH2) 1-5 C(O)NH (CH2) 1-5 SO3H)2, -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m -C(O) N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5, and m is , 1, 2, 3, 4, or 5. In one embodiment, alkyl, heteroalkyl, alkyl Renyl or heteroalkylenyl sulfonic acid is -(CH2) 1-5 In another embodiment, In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is, -(CH2) n -NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. Another real Application methods, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl Auronic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. Yes. In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkyl Lukirenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2 , 3, 4, or 5. In another embodiment, alkyl, heteroalkyl, alkylene L, or heteroalkylenyl sulfonic acid, is -(CH2) n -N((CH2)1-5 C(O)NH(CH2) 1-5 SO3H)2 Yes, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, hetero Roalkyl, alkylenyl, or heteroalkylenyl sulfonic acids are -(CH2) n -C(O)N((CH2 ) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. Another implementation In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where m is 1, 2 , 3, 4, or 5. In one embodiment, R is R 1 That is the case.

[0175] In some embodiments, the conjugate is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the position thereof They are isomers, and here: BA is a binder; k is an integer between 1 and 30; R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each [ka] This is a bond with a strengthening group; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. In one embodiment, the enhancer is a hydrophilic group. In another embodiment, the enhancer is a cy It is a clodextrin. In one embodiment, the reinforcing group is alkyl, heteroalkyl These are alkylenyl or heteroalkylenyl sulfonic acid. Cyclodextrin is, It can be any cyclodextrin known to the manufacturer. In one embodiment, Clodextrins include α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin. Dextrin, or a mixture thereof. In one embodiment, cyclodextrin This is α-cyclodextrin. In one embodiment, cyclodextrin is β-cyclodextrin It is a clodextrin. In one embodiment, the cyclodextrin is γ-cyclodextrin It is a string. In one embodiment, alkyl, heteroalkyl, alkylenyl, and Heteroalkylenylsulfonic acid is -(CH2) 1-5 SO3H, -(CH2) n -NH-(CH2) 1-5 SO3H, -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, -(CH2) n -N((CH2) 1-5 C(O)NH (CH2) 1-5 SO3H)2, -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m -C(O) N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5, and m is , 1, 2, 3, 4, or 5. In one embodiment, alkyl, heteroalkyl, alkyl Renyl or heteroalkylenyl sulfonic acid is -(CH2) 1-5 In another embodiment, In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is, -(CH2) n -NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. Another real Application methods, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl Auronic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. Yes. In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroalkyl Lukirenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2 , 3, 4, or 5. In another embodiment, alkyl, heteroalkyl, alkylene L, or heteroalkylenyl sulfonic acid, is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 Yes, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, hetero Roalkyl, alkylenyl, or heteroalkylenyl sulfonic acids are -(CH2) n -C(O)N((CH2 ) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. Another implementation In this context, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where m is 1, 2 , 3, 4, or 5. In one embodiment, R is R 1 That is the case.

[0176] In some embodiments, the conjugate is: [ka] TIFF0007843731000234.tif83170 or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, or these They are positional isomers, and here: BA is a binder; k is an integer between 1 and 30; R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R7 X, Y, Z, and n are described in relation to Equation I. As stated; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. For some reason, R is R 1 That is the case.

[0177] In some embodiments, the conjugate is: [ka] TIFF0007843731000237.tif90170 or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, or these They are positional isomers, and here: BA is a binder; k is an integer between 1 and 30; R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each R 9is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. For some reason, R is R 1 That is the case.

[0178] In each of the embodiments described above, the conjugate is as described in the section below. It can be prepared from a binder functionalized with an azide group, and its residues. The triazole residues in some of the above structures are shown in parentheses. Those skilled in the art will know The trazole is formed from the azide group of the azide derivatization binder and the linker payload LP. They are likely aware that it can be formed from alkynes.

[0179] In some embodiments, the conjugate is: [ka] TIFF0007843731000240.tif243170TIFF0007843731000241.tif246170TIFF0007843731000242.tif219170TIFF0007843731000243.tif200170TIFF0007843731000244.tif249170 or their positional isomers, stereoisomers, pharmaceutically acceptable salts, solvates, etc. Selected. In the above embodiment, k is an integer from 1 to 30. In one embodiment, k is an integer between 1 and 8. In one embodiment, k is an integer between 1 and 4. In one embodiment In this embodiment, k is 8, 7, 6, 5, 4, 3, 2, or 1. In one embodiment, k is 4. In one embodiment, k is 3. In another embodiment, k is 2. In one embodiment In this embodiment, k is 1.

[0180] (Reactive linker-payload) The conjugate provided herein is a reactive linker-pe having the above-mentioned reactive group RG. It can be prepared from iRod. The reactive linker payload is prepared according to the following method. It can then be linked to reinforcing groups and / or binders.

[0181] In some embodiments, the reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the position thereof They are isomers, and here: Each of the RGs is the reactant described above; R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. For some reason, R is R 1 That is the case.

[0182] In some embodiments, the reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the position thereof They are isomers, and here: Each of the RGs is the reactant described above; R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. For some reason, R is R 1 That is the case.

[0183] In some embodiments, the reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the position thereof They are isomers, and here: R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. For some reason, R is R 1 That is the case.

[0184] In some embodiments, the reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the position thereof They are isomers, and here: R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. For some reason, R is R 1 That is the case.

[0185] In some embodiments, the reactive linker-payload is: [ka] TIFF0007843731000254.tif153170 or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, or these They are positional isomers, and here: R is -H, R 1, or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. For some reason, R is R 1 That is the case.

[0186] In some embodiments, the reactive linker-payload is: [ka] TIFF0007843731000257.tif155170 or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, or these They are positional isomers, and here: R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R6 , R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. For some reason, R is R 1 That is the case.

[0187] In some embodiments, the reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the position thereof They are isomers, and here: R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. For some reason, R is R 1 That is the case.

[0188] In some embodiments, the reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the position thereof They are isomers, and here: R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. For some reason, R is R 1 That is the case.

[0189] In some embodiments, the reactive linker-payload is: [ka] Or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, or these They are positional isomers, and here: R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. For some reason, R is R 1 That is the case.

[0190] In some embodiments, the reactive linker-payload is: [ka] Or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, or these They are positional isomers, and here: R is -H, R 1 , or R 2 and Q 1 Q 2 , W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 X, Y, Z, and n are described in relation to Equation I. As stated; Each R 9 is -CH3 or -(CH2)3N(H)C(O)NH2; and Each A is -O-, -N(H)-, [ka] Here, ZZ is hydrogen, or the side of an amino acid discussed elsewhere in this specification. It is a chain. For example, in one embodiment, ZZ is C 1-6 It is alkyl. As further examples... In one embodiment, ZZ is C 1-6 It is heteroalkyl. For some reason, R is R 1 That is the case.

[0191] In some embodiments, the reactive linker-payload is: [ka] TIFF0007843731000268.tif242170TIFF0007843731000269.tif247170TIFF0007843731000270.tif242170TIFF0007843731000271.tif246170 or their positional isomers, stereoisomers, pharmaceutically acceptable salts, solvates, etc. It will be selected.

[0192] (Method for preparing compounds) The compounds provided herein are prepared and isolated by any method obvious to those skilled in the art, Alternatively, it can be obtained. An exemplary preparation method is described in detail in the following examples. In one embodiment, the compounds provided herein are prepared according to scheme A. It is possible.

[0193] (Scheme A. Exemplary preparation scheme) [ka] In an exemplary preparation scheme, Q 1 Q 2 , R 1 , R 2 , R 7 W and n are related to equation (I). It is defined as described in [the document]. After the initial esterification, R 1 Protection and / or R 1 If any of the aminations follow, 2 P occurs. 1 After protection, for example, the carboxylic acid moiety Through saponification and activation, Q 1 A first coupling partner having is provided. After the nomination, for example, by saponification and amidation of the carboxylic acid moiety, Q 2 The second cup Ring partners will be provided. Each, Q 1 and Q 2Coupling partners that have Combine them into one, and then, for each, R 1 and R 2 By deprotecting, the compound of formula I is provided. Exemplary preparation methods are described in detail in the following examples.

[0194] In one embodiment, one or more protection or deprotection steps are described in scheme A above. This may be included in the preparation method.

[0195] The linker-payload described herein is synthesized by a series of coupling steps. It is possible. [ka] For example, the payload on the right undergoes SP through one or more standard coupling reactions. 2 Connected to In an advantageous embodiment, the payload compound described herein may be Free amino groups available for coupling by amide synthesis conditions as described herein Includes. (AA) n The amino acids are added under amide synthesis conditions, for example, peptide synthesis conditions. It is possible. Spacer SP 2 (AA) n It can be connected to the SP described herein. In an advantageous embodiment, the SP described herein 2 and (AA ) n The group is a free amide that can be used for coupling under the amide synthesis conditions described herein. Contains mino or carboxyl groups. If present, spacer SP 3 This is one or more standard cuts via the Pulling reaction (AA) n It can be connected to a favorable embodiment, SP as described in the details 3 and (AA) n The base is a cut by amide synthesis conditions as described herein. It contains free amino or carboxyl groups that can be used for pulling.

[0196] Spacer SP 3 If present, it terminates with the reactive group RG. This reactive group is suitable for those skilled in the art. It can be coupled to the enhancer EG via a coupling condition that is considered to exist. In this embodiment, Spacer SP 3 It is linked to the enhancer EG via amide synthesis conditions. In one embodiment, Spacer SP 3 It is linked to the enhancer EG via click chemistry. In these embodiments, the spacer SP 3 This refers to a reactive group suitable for click reactions, for example The reaction ends with an azide or alkyne, and the enhancer EG is a complementary reactive group suitable for click reactions, for example For example, it includes alkynes or azides. In a preferred embodiment, SP 3 It ends with a distorted alkyne. For example, does EG contain azide; or SP 3 It ends in a carboxylic acid, and EG contains an amine. If the cyclodextrin portion is a cyclodextrin, the cyclodextrin may contain an azide. Azidocyclodextrin can be prepared by synthesis or commercially available. It can be obtained from the source. If EG is a sulfonic acid portion, one end of the EG is It ends with a sulfonic acid group, and the other end ends with a primary or secondary amine.

[0197] The conjugates described herein are linked to the linker-payloads described herein. This is coupled with a binder, such as an antibody, under standard conjugation conditions. It can be synthesized by (for example, fully incorporated herein by reference) (See Doronina et al., Nature Biotechnology 2003, 21, 7, 778). The binder is an antibody In that case, the antibody is linked via one or more cysteine ​​or lysine residues of the antibody. It can be coupled to the payload. The linker-payload is, for example, the anti The body is subjected to a reducing agent, for example, dithiotheritol, and the disulfide of the antibody is obtained. The antibody is cleaved and reduced, and then purified, for example, by gel filtration, and then the antibody The body is treated with a suitable reaction site, for example, a linker-payload containing a maleimide group. This allows coupling to cysteine ​​residues. Suitable solvents include Examples include, but are not limited to, water, DMA, DMF, and DMSO. Reactive groups, for example, active The linker-payload containing a fermented ester or acid halide group is the lysine residue of the antibody. It can be coupled to water, DMA, DMF, and DMSO. However, it is not limited to these. Conjugates are, for example, size exclusion chromatography. Purification is performed using known protein techniques, including dialysis and ultrafiltration / diafiltration. It is possible.

[0198] Binding agents, such as antibodies, can also be conjugated via click chemical reactions. In some embodiments of the click chemical reaction, the linker-payload is Aji The reaction group includes, for example, alkynes, which can undergo 1,3-addition cycloaddition with a dol. Suitable reactive groups are described above. The antibody contains one or more azide groups. It is included. Such antibodies are functionalized with, for example, an azide-polyethylene glycol group. It contains antibodies that have been functionalized. In one embodiment, such functionalized antibodies include at least one An antibody having glutamine residues, for example, heavy chain Gln295 or Gln55, is transglutamated by an enzyme. It is induced by treatment with a primary amine compound in the presence of a minase. In one embodiment, such a functionalized antibody contains at least one glutamine residue, for example, An antibody containing the heavy chain Gln297 is subjected to primary amine in the presence of the enzyme transglutaminase. It is induced by treatment with a compound. Such antibodies have the Asn297Gln(N297Q) mutation. It contains heteromorphs. In one embodiment, such a functionalized antibody contains at least two g Antibodies having glutamine residues, for example, heavy chain Gln295 and heavy chain Gln297, are transglutaminated by enzyme transglutamination. It is induced by treatment with a primary amine compound in the presence of a minase. The eel antibody contains the Asn297Gln(N297Q) mutant. In one embodiment, the antibody For a total of two or a total of four glutamine residues, the two weights described in this paragraph Chains.

[0199] In one embodiment, the antibody has one or more heavy chain positions numbered 295 in the EU numbering system. Contains a glutamine residue. In this disclosure, this position is glutamine 295, Gln295, or Q295. This is called [a specific term]. Those skilled in the art will know that this is a conserved glutamine residue in the wild-type sequences of many antibodies. You will be aware of this. In other useful embodiments, the antibody is glutamine The sequence can be modified to include a residue. The antibody sequence can be modified to include a glutamine residue. The techniques described are within the scope of the skills of those skilled in the art (for example, the literature of Ausubel et al., Current Protoc. Mo (See l. Biol.)

[0200] In one embodiment, the antibody contains two glutamine residues, one in each heavy chain. In one embodiment, the antibody contains a Q295 residue in each heavy chain. In further embodiments... And the antibody contains one, two, three, four, five, six, seven, eight, or more gluta It contains glutamine residues. These glutamine residues are located in the heavy chain, light chain, or both the heavy and light chains. This is possible. An example of a glutamine residue is Q55. These glutamine residues This can be a wild-type residue or a modified residue. The antibody is prepared according to standard techniques. It is possible.

[0201] Those skilled in the art would know that the antibody is glycosylated at residue N297, near residue Q295 in the heavy chain sequence. They are likely aware that there are many of them. Glycosylation at residue N297 is at residue Q295. This can inhibit transglutaminase (Dennler et al., see above). Therefore In a favorable embodiment, the antibody is not glycosylated. The antibody is deglycosylated or aglycosylated. The antibody heavy chain has an N297 mutation. In other words, the antibody has an N297 mutation at position 297. The paragine residue has been mutated to no longer have it. In a specific embodiment. The antibody heavy chain has the N297Q mutation. Such antibodies also have the glycosylated sequence removed. Alternatively, this can be achieved through site-directed mutagenesis or by inactivating the function or binding of the antibody. Prepared by site-directed mutagenesis, which involves inserting glutamine residues into sites where no mutation occurs. It is possible. In some embodiments, the Q295 residue and / or N297Q mutation is present. The antibody allows transglutaminase to approach, and therefore the linker or One or more additional natural glutamines that can be conjugated into the carb-payload. The residue is contained within its variable region. An example of a natural glutamine residue is, for example, Q5 of the light chain. It can be found in 5. In such cases, the conjugate is mediated by transglutaminase. The tested antibody may have a higher DAR value than expected (e.g., a DAR greater than 4). Yes, it is possible. Any such antibody can be isolated from natural or artificial sources.

[0202] Next, an antibody that does not have interfering glycosylation is reacted with a primary amine compound. In this embodiment, an aglycosylated antibody is reacted with a primary amine compound to modify glutaminyl To produce an adjuvant antibody. In one embodiment, a deglycosylated antibody is produced using a primary amine compound. The sample is processed to produce glutaminyl-modified antibodies.

[0203] Primary amines form covalent bonds with glutamine residues in the presence of transglutaminase. It can be any primary amine that can do this. Useful primary amines are listed below. It is listed. Transglutaminase is any which is considered suitable by those skilled in the art. It can be a transglutaminase. In one embodiment, transgluta Minase is a compound that combines the free amine group on a primary amine compound with the acyl group on the side chain of a glutamine residue. It is an enzyme that catalyzes the formation of isopeptide bonds between substances. Transglutaminase is an enzyme that catalyzes the formation of isopeptide bonds between substances. Also known as protein-glutamine-γ-glutamyltransferase. In certain embodiments the transglutaminase is classified as EC 2.3.2.13. The transglutaminase can be derived from any source that is considered suitable. In some embodiments, the transglutaminase is of microbial origin. Useful transglutaminases have been isolated from Streptomyces mobaraense, Streptomyces cinnamoneum, Streptomyces griseo-carneum, Streptomyces lavendulae, and Bacillus subtilis. Non-microbial transglutaminases, including mammalian transglutaminases, can also be used. In some embodiments, the transglutaminase can be produced by any technique or obtained from any source that is considered suitable by one of ordinary skill in the art. In certain embodiments, the transglutaminase is obtained from a commercial source.

[0204] In certain embodiments, the primary amine compound contains a reactive group that allows for further reactions after transglutamination. In these embodiments, the glutaminyl-modified antibody can be reacted with or treated with a reactive payload compound or a reactive linker-payload compound to form an

[0205] In one embodiment, a glutaminyl-modified antibody is reacted with a reactive linker-payload. To form an antibody-payload conjugate, either by rinsing or processing with this. The process can proceed under conditions deemed suitable by those skilled in the art. In this process, the glutaminyl-modified antibody is linked to the linker payload. Under conditions suitable for forming bonds between the compound, a reactive linker-payload compound and Bring them into contact. Suitable reaction conditions are well known to those skilled in the art.

[0206] Exemplary reactions are provided in the following examples.

[0207] (Pharmaceutical compositions and therapeutic methods) Provided herein are methods for treating and preventing diseases, illnesses, or disorders, One or more compounds disclosed herein, for example, one or more compounds of the formula provided herein. A method comprising administering a therapeutic or prophylactic effective dose of the disease, disorder, and / or illness. Diseases include, but are not limited to, those associated with the antigens listed in this specification.

[0208] The compounds described herein are administered alone or in combination with one or more additional therapeutic agents. One or more additional therapeutic agents may be administered immediately before administration of the compounds described herein. It can be administered simultaneously with or immediately after the administration of the drug. This disclosure is provided herein. A pharmaceutical composition comprising any of the compounds described in the list in combination with one or more further therapeutic agents, and also include therapeutic methods that involve administering such combinations to subjects who need them. .

[0209] Suitable further therapeutic agents include: secondary glucocorticoids, autoimmune agents, hormones Examples include, but are not limited to, steroids, biologics, or monoclonal antibodies. No. Any of the compounds described herein may be accepted as pharmaceutically acceptable therapeutic agents. Salts, acids, or derivatives are also examples, but are not limited to these.

[0210] In some embodiments of the methods described herein, multiple doses are described herein. Compounds (or compounds described herein and further therapeutic agents referred to herein) Administering a pharmaceutical composition containing any combination of the above to the subject over a specified period of time. This method according to this aspect of the disclosure can be applied to a subject to multiple doses of the chemicals described herein. This includes administering the mixture sequentially. As used herein, “administer sequentially” means each Each dose of the compound is taken at different times, for example, at predetermined intervals (e.g., hours, days, weeks, or This means administering the drug to the subject on different days separated by the month. This disclosure means that the patient will be given a single dose. A first dose of the compound described herein, thereafter one or more secondary doses of the compound, and The method includes optionally subsequently administering one or more tertiary doses of the compound sequentially.

[0211] The terms “initial dose,” “secondary dose,” and “tertiary dose” are defined herein. This refers to the timeline of compound administration. Therefore, the "initial dose" is the dose administered at the start of the treatment regimen. The dose administered (also known as the "baseline dose"); the "secondary dose" is administered after the initial dose. The dose administered; the "tertiary dose" is the dose administered after the secondary dose. Initial dose The secondary and tertiary doses may all contain the same amount of the compound described herein. The frequency of administration can usually differ from one another. In one embodiment, the initial dose, the second dose, etc. The amount of the compound contained in the secondary dose, and / or the tertiary dose, varies relative to each other during the course of treatment (e.g., , as necessary, adjusted upward or downward). In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered as a "loading dose" at the start of the treatment regimen, and then administered as subsequent doses (e.g., "maintenance doses") at lower frequencies.

[0212] In certain exemplary embodiments of the present disclosure, each secondary and / or tertiary dose is administered 1 to 26 weeks (e.g., 1, 1 1 / 2, 2, 2 1 1 / 2, 3, 3 1 1 / 2, 4, 4 1 1 / 2, 5, 5 1 1 / 2, 6, 6 1 1 / 2, 7 1 7 7 1 1 / 2, 8, 8 1 1 / 2, 9, 9 1 1 / 2, 10, 10 1 1 / 2, 11, 11 1 1 / 2, 12, 12 1 1 / 2, 13, 13 1 1 / 2, 14, 14 1 1 / 2 15, 15 1 1 / 2, 16, 16 1 1 / 2, 17, 17 1 1 / 2, 18, 18 1 1 / 2, 19, 19 1 1 / 2, 20, 2 1 21, 21 1 1 / 2, 2 22 1 1 / 2, 23, 23 1 1 / 2, 24, 24 1 1 / 2, 25, 25 1 1 / 2, 26, 26 1 weeks, or longer) after the immediately preceding dose. As used herein, the phrase "immediately preceding dose" refers to a series of multiple administrations ​​In administration, the intervention dose is administered to the patient immediately before the next dose, in an order that does not involve an intervention dose. It refers to the dosage of the mixture.

[0213] A method according to this aspect of the disclosure involves administering to a patient any number of secondary and / or tertiary doses of compounds. This may include administering a single secondary dose to the patient. For example, in one embodiment, only a single secondary dose may be administered to the patient. It is administered to. In other embodiments, two or more (for example, 2, 3, 4, 5, 6, 7, 8, or so) A secondary dose (more than) is administered to the patient. Similarly, in one embodiment, a single tertiary dose Only the dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7) A tertiary dose of 8, or more, is administered to the patient. The administration regimen is tailored to the specific target. For life, indefinitely, or until such treatment is no longer therapeutically necessary. It can be carried out until it is no longer beneficial.

[0214] In embodiments including multiple secondary doses, each secondary dose is administered at the same frequency as the other secondary doses. It may be administered as follows: For example, each secondary dose may be given to the patient 1-2 weeks after the previous dose. It may be administered 1 to 2 months later. Similarly, in embodiments including multiple tertiary doses, each Each tertiary dose may be administered at the same frequency as other tertiary doses. For example, each tertiary dose It may be administered to the patient 2 to 12 weeks after the most recent dose. In one embodiment of the present disclosure In this regard, the frequency with which secondary and / or tertiary doses are administered to patients is determined over the course of the treatment regimen. The frequency of administration may also change depending on the individual patient's needs after clinical examinations, as advised by the physician. It may be adjusted during the course of treatment.

[0215] This disclosure states that loading doses 2-6 are administered at a first frequency (e.g., once a week, once every two weeks). The medication is administered to the patient at intervals of 3 weeks, 1 month, 1 month every 2 months, etc., followed by 2 or more maintenance doses. Includes a dosing regimen in which the amount is administered to the patient at a lower frequency. For example, in this aspect of the present disclosure According to this, if the loading dose is administered once a month, the maintenance dose is 1 every 6 weeks. It may be administered to the patient once every two months, once every three months, or so on.

[0216] This disclosure relates to the compounds and / or conjugates described herein, for example, formulas I, Ia, Pharmaceutical compositions of compounds Ib, A, Aa, or Ab, for example, the compounds described herein, Salts, stereoisomers, polymorphs, and pharmaceutically acceptable carriers, diluents, and / or excipients Includes compositions containing: Suitable carriers, diluents, and excipients include: Suitable composition pH maintenance Buffers for retention (e.g., citrate buffer, succinate buffer, acetate) Buffers, phosphate buffers, lactate buffers, oxalate buffers, etc. Body proteins (e.g., human serum albumin), saline solution, polyols (e.g., trehalose) (e.g., sucrose, xylitol, sorbitol), surfactants (e.g., polysorbate) Examples include T20, polysorbate 80, polyoxolates, etc., antibacterial agents, and antioxidants. However, it is not limited to these.

[0217] In some cases, as shown herein, this specification refers to a person who treats a disease, disorder, or illness. A law that provides to a patient having the said disorder a compound of formula I, Ia, Ib, A, Aa, or Ab, or The method comprises administering a therapeutically effective amount of the pharmaceutical composition.

[0218] In some cases, the methods described herein are for preventing diseases, disorders, or illnesses. A law that provides to a patient having the said disorder a compound of formula I, Ia, Ib, A, Aa, or Ab, or The method comprises administering a prophylactically effective amount of the pharmaceutical composition.

[0219] In some examples, as shown herein, the responsiveness to the modulation of LXR signaling A method for treating or preventing any disease, disorder, or illness. In some examples, the Disease or disorder is related to LXR function, LXR polymorphism, LXR agonist activity, or LXR antagonist activity. Related. In some examples shown herein are proliferative disorders, neurodegenerative disorders. immunological disorders, autoimmune diseases, inflammatory disorders, skin diseases, metabolic diseases, cardiovascular diseases, and A method for treating or preventing a disease, disorder, or illness selected from the group consisting of gastrointestinal disorders. .

[0220] The proliferative disorder can be any proliferative disorder known to those skilled in the art. In one embodiment, In this context, proliferative disorders are not limited to oncological disorders, but include oncological disorders. Here, the oncological disorder can be any cancerous disorder known to those skilled in the art. In embodiments, the foregoing provides a method for treating or preventing melanoma. In one embodiment, the foregoing provides a method for treating or preventing metastatic melanoma. This is a method for treating or preventing lung cancer. In one embodiment, the method provided herein is for treating or preventing lung cancer. This is a method of prevention. In one embodiment, provided herein is EGFR-tyrosine A method for treating or preventing kinase inhibitor-resistant lung cancer. In one embodiment Provided herein are methods for treating or preventing oral cancer. In one embodiment... Provided herein are methods for treating or preventing oral squamous cell carcinoma. In one embodiment, a method for treating or preventing prostate cancer is provided herein. Yes. In one embodiment, the following is provided herein: to treat Hodgkin lymphoma or This is a method of prevention. In one embodiment, what is provided herein is a method of treating or This is a method of prevention.

[0221] The neurodegenerative disorder may be any neurodegenerative disorder known to those skilled in the art. In this specification, the present invention provides a method for treating or preventing Alzheimer's disease. In one embodiment, the foregoing provides a method for treating or preventing Parkinson's disease. This is a method. In one embodiment, provided herein is a method for treating Huntington's disease. A method for treating or preventing muscle atrophy. In one embodiment, the following is provided herein: A method for treating or preventing lateral sclerosis (ALS). One embodiment is provided herein. The invention relates to a method for treating or preventing myelin gene expression. In one embodiment, Provided herein are methods for treating diseases, disorders, or impairments of myelin formation and myelin regeneration. This is a method of prevention.

[0222] An immunological disorder can be any immunological disorder known to those skilled in the art. In this specification, the present invention provides a method for treating or preventing inflammatory bowel disease. In one embodiment, the foregoing provides a method for treating or preventing ulcerative colitis. This is a law. In one embodiment, provided herein is a method for treating or preventing Crohn's disease. This is a method of prevention.

[0223] The inflammatory disorder can be any inflammatory disorder known to those skilled in the art. In one embodiment, Provided herein is a method for treating or preventing arthritis. In this specification, a method for treating or preventing rheumatoid arthritis is provided.

[0224] Metabolic diseases can be any metabolic diseases known to those skilled in the art. In one embodiment, In this context, metabolic diseases include dyslipidemia. Dyslipidemia is any lipid disorder known to those skilled in the art. It can be a common condition. In one embodiment, dyslipidemia is hyperlipidemia, hypercholesterolemia Lilo-leukemia, hypertriglyceridemia, hyperlipoproteinemia, HDL deficiency, ApoA-I deficiency, Furthermore, cardiovascular diseases, such as coronary artery disease (e.g., angina pectoris, myocardial infarction, and sudden cardiac death) Including treatment and prevention; atherosclerosis (for example, treatment of atherosclerosis) and prevention; as well as restenosis (for example, as a result of medical procedures such as balloon angioplasty). A group consisting of (including treatment or prevention of atherosclerotic plaques that occur as a result of) In one embodiment, the foregoing provides a method for treating or preventing diabetes. It is the law.

[0225] The cardiovascular disease can be any cardiovascular disease known to those skilled in the art. In one embodiment, Provided herein are methods for treating or preventing atherosclerosis. Yes. In one embodiment, the abnormal macrophage process is provided herein. A method for treating or preventing atherosclerosis resulting from shing. In one embodiment In this specification, the process by which macrophages process oxLDL is provided. Atherosclerosis resulting from the formation of oxidized low-density lipoprotein (oxLDL) that cannot be properly processed. A method for treating or preventing a void. In one embodiment, what is provided herein is a method for treating a void. A method for treating or preventing hematopoietic heart disease. In one embodiment, provided herein This is a method for treating or preventing stroke. In one embodiment, provided herein The present invention relates to a method for treating or preventing hypertensive heart disease. In one embodiment, the present invention Provided in this document are methods for treating or preventing aortic aneurysms. In one embodiment, Provided herein are methods for treating or preventing endocarditis. In one embodiment... Provided herein are methods for treating or preventing peripheral artery disease. In some embodiments, the Specified Information is provided for any of the diseases described in this paragraph. This is a method of treating or preventing that combination.

[0226] In some examples, the methods described herein involve modulating the function of nuclear receptors. Yes. As a non-limiting example, this function involves inflammatory mediators (e.g., cytokines). Chemokine expression / secretion, cholesterol regulation, cholesterol intake, cholesterol flow Cholesterol release, cholesterol oxidation, migration, chemotaxis, apoptosis and necrosis, inflammatory activity, lipid regulation, Apoptosis, migration, chemotaxis, gene transcription, and protein expression may be selected from these. [Examples]

[0227] (Examples) Provided herein are novel bis-octahydrophenanthrenecarboxamides , the protein conjugate thereof, and methods for treating diseases, disorders, and illnesses. , administer the bis-octahydrophenanthrene carboxamide and conjugate This method includes the following:

[0228] In some cases, the compound of formula (I) is one of the compounds identified in Table 1. Table 1. Payload List [Table 1] TIFF0007843731000275.tif249170TIFF0007843731000276.tif183170

[0229] reference: Structure of compound 31 [ka] Structure of GW3965 [ka] Structure of T0901317 [ka]

[0230] Examples of linker payloads in this disclosure are listed in Table 2 below. However, it is not limited to these. Table 2. List of linker-payloads [Table 2] TIFF0007843731000281.tif209170TIFF0007843731000282.tif207170TIFF0007843731000283.tif230170TIFF0007843731000284.tif207170

[0231] Specific embodiments of the present invention will be described by the following non-limiting examples.

[0232] Unless otherwise explicitly stated, reagents and solvents shall be from commercially available sources, e.g., Sinopharm Obtained from Chemical Reagent Co. (SCRC), Sigma-Aldrich, Alfa, or other suppliers.

[0233] 1 1H NMR and other NMR spectra were recorded using a Bruker AVIII 400 or Bruker AVIII 500. The data is processed with Nuts software or MestReNova software, and the proton shift is internal. Measurements were taken in parts per million (ppm) by shifting from standard tetramethylsilane (TMS) towards the lower magnetic field direction.

[0234] HPLC-MS measurements were performed on an Agilent 1200 HPLC / 6100 SQ system under the following conditions. .

[0235] Method A for HPLC-MS measurement uses the following mobile phase: A: Water (0.01% trifluoroacetic acid (TFA)) B: Acetonitrile (0.01% TFA); Gradient phase: Increase 5% B to 95% B within 15 minutes (min) Flow rate: 1.0 mL / min; Column: SunFire C18, 4.6 × 50 mm, 3.5 μm; Column temperature: 50°C; Detection Instruments: Analog-to-digital converter (ADC), evaporative light scattering detector (ELSD), diode array detector (D AD (214nm and 254nm), electrospray ionization-air ionization (ES-API) was included.

[0236] Method B for HPLC-MS measurement uses the following mobile phases: A: Water (10 mM NH4HCO3), B: Acetonenitrile Gradient phase: 5% to 95% within 15 minutes; Flow rate: 1.0 mL / min; Column: XBridge C18, 4.6 × 50 m m, 3.5 μm; Column temperature: 50°C; Detector: ADC ELSD, DAD (214 nm and 254 nm); Mass-selective detection The output device (MSD) (ES-API) was included.

[0237] LC-MS measurements were performed on an Agilent 1200 HPLC / 6100 SQ system under the following conditions:

[0238] Method A for LC-MS measurement uses the following equipment: WATERS 2767; two columns connected in series. Shimadzu Shim-Pack, PRC-ODS, 20×250mm, 15μm; Mobile phase: A: Water (0.01% TFA), B: Acetonitrile (0.01% TFA); gradient phase: 5% B increased to 95% B within 3 minutes; flow rate: 1 0.8~2.3 mL / min; Column: SunFire C18, 4.6 × 50 mm, 3.5 μm; Column temperature: 50°C; Detector: AD This included C ELSD, DAD (214nm and 254nm), and ES-API.

[0239] Method B for LC-MS measurement uses the following instruments: Gilson GX-281; ​​column: Xbridge Prep C18. 10µm OBD, 19×250mm; Mobile phase: A: Water (10mM NH4HCO3), B: Acetonitrile; Gradient phase: 3 mins Internally, 5% to 95% B; Flow rate: 1.8~2.3 mL / min; Column: XBridge C18, 4.6 × 50 mm, 3.5 μm; Ram temperature: 50°C. Detectors included ADC ELSD, DAD (214nm and 254nm), and MSD (ES-API).

[0240] Preparative high-pressure liquid chromatography (preparative HPLC) in acidic or basic solvent systems using a Gilson GX-28 One instrument was used. In acidic solvent systems, a Waters SunFire 10 μm C18 column (100 Å, 250 × 19 mm) was used. ) is used, and solvent A for preparative HPLC is water / 0.05% TFA, and solvent B is acetonitrile Yes, it was. The elution conditions were a linear gradient of solvent B from 5% to 100% over 20 minutes at a flow rate of 30 mL / min. The ratio increased. In the basic solvent system, a Waters Xbridge 10 μm C18 column (100 Å, 250 × 19 m) was used. (m) is included, and solvent A for preparative HPLC is water / 10 mM ammonium bicarbonate (NH4HCO3), and solvent B The elution agent was acetonitrile. The elution conditions were 5% to 10% over 20 minutes at a flow rate of 30 mL / min. The increase in solvent B towards 0% was linear.

[0241] Flash chromatography uses Agela flash column silica-CS cartridges. The procedure is performed using a Biotage instrument; reverse-phase flash chromatography is performed using Boston ODS or Agel. The procedure was performed using a C18 cartridge with a Biotage device.

[0242] When used herein, the descriptions used in these processes, schemes, and examples are... Numbers and conventions, whether specific abbreviations are specifically defined or not, are part of modern science. References, for example, the Journal of the American Chemical Society or the Journal of Bio It matches what is used in logical chemistry. Specifically, but not limited to The following abbreviations may be used throughout the examples and this specification: [Table 3] TIFF0007843731000286.tif245170TIFF0007843731000287.tif247170TIFF0007843731000288.tif110170

[0243] (Preparation method) (Example 1) This example demonstrates a general synthesis method for the podcarpic acid derivatives 9a-9r, 9t, and 9u shown in Table 1 above. This example refers to the compounds numbered 1 to 9a-p in Figure 1.

[0244] In Figure 1, the starting material, podcarpic acid 1, was originally discovered in plant resin in 1873. This was later reported in several species of the genus Podocarpus (e.g., J. Chem. Soc. 1). See 938, 1006-1013). The synthesis of compound 4 from podocarpic acid 1 has been previously reported (e.g. For example, Bioorg. Med. Chem. Lett. 2005, 15, 2824; Bioorg. Med. Chem. Lett. 2005, 15 (See 4574). Acyl chloride 6a was prepared from treatment with thionyl chloride; active ester R6b was prepared from treatment 4 by 5. Symmetric imide 8a was prepared from acid chloride 6a or activated ester It is synthesized from the treatment of amide 7a with 6b, and then subjected to debenzylation by hydrogenation. Imide 9a was obtained. Similarly, asymmetric imides 8b-e and 8g were activated with amides 7b-g. Synthesized from a coupling reaction with tel 6b or acid chloride 6a. Asymmetric imide 8b from 6a... The yields of e and 8g were lower compared to the yield of symmetric imide 8a, but when activated ester 6b was used... The yields of 8b-e and 8g increased from ~40% to 50-85%.

[0245] Imids 9a~e correspond to the protecting groups - Bn in 8a, TBS in 8b, or 8c, 8d, and Deprotection of Boc in 8e yielded from 8a to e. The N,N-dimethylated analog 9f has a benzyl group Hydrogenation of 8d in methanol while simultaneously removing aniline nitrogen and N,N-dimethylating it. Obtained from; N-Boc analog 9g was obtained from debenzylation of 8d. Compound 9h~o was obtained from HATU and Amide coupling reaction of 9d with amino acid derivatives in the presence of DIPEA, and subsequent reaction in DCM Deprotection of the Boc group by 10-25% TFA, or by 20% piperidine in an organic solvent. It was obtained by deprotection of the oc group. The amide coupling reaction between 9d and Fmoc-Gly-OH was performed separately. Then, by deprotection of Fmoc, 9h was obtained; and the amide coupler between 9d and Boc-β-Ala-OH The reaction and subsequent deprotection of Boc yielded 9i; and the amide cut of 9d with Boc-Ser-OH was performed. The pulling reaction and subsequent deprotection of Boc yielded 9j; and the amide of 9d with Boc-Sar-OH. The coupling reaction and subsequent deprotection of Boc yielded 9k; and 9d and Boc-Lys(Boc)-OH The amide coupling reaction of 9L was followed by the deprotection of Boc, yielding 9D and Boc-His-O The amide coupling reaction with H and subsequent deprotection of Boc yielded 9m; 9d and Boc-As The amide coupling reaction with p-OtBu, followed by the deprotection of Boc and -OtBu, results in 9n being one Obtained in a pot; amide coupling reaction of 9d with Boc-Glu-OtBu, and subsequent Boc and -Ot Deprotection of Bu yielded 9o in a one-pot reaction. Compound 9p was formed by the presence of LiHMDS, which formed 8g. The amide coupling reaction between 7g and 6b under the presence of a nitrile, and the subsequent conversion of the nitrile to an amine. Compound 9q was synthesized by nickel-catalyzed reduction and debenzylation with boron tribromide (BBr3). Compound 9r was obtained from the amide coupling reaction of 9d and glutaric acid anhydride. Compound 9r was obtained from the amide coupling reaction of 9d and It was obtained by amide coupling reaction with Boc-iminodiacetic acid and subsequent Boc deprotection. Compound 9t is an amide of 7d and the activated ester of dehydroabietic acid (Cas number 1740-19-8). It was obtained from a plucking reaction followed by Boc deprotection.

[0246] (Example 1a) Synthesis of payload 9d (Figure 1a) Methyl(1S,4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydro Phenanthrene-1-carboxylate (P1-2) [ka] Dissolution of podcarpic acid (P1-1, 90g, 0.33mol) in methanol (200mL) and toluene (600mL) (Trimethylsilyl) diazomethane (2M in hexane, 200 mL) was added to the solution. Reaction mixture The mixture was stirred at room temperature for 2 hours. Subsequently, LC-MS confirmed that the podcarpic acid was completely consumed. When the catalytic substance is removed in a vacuum and the residue is triturated from petroleum ether (2L), the compound P1-2 (91g, 96% yield) was obtained as a white solid. ESI m / z: 289 (M+H) + . [ka]

[0247] Methyl(1S,4aS,10aR)-1,4a-dimethyl-6-(trifluoromethanesulfonyloxy)-1,2,3,4 ,4a,9,10,10a-Octahydrophenanthrene-1-carboxylate (P1-3) [ka] To a solution of compound P1-2 (10 g, 35 mmol) in methylene chloride (200 mL), pyridine (3.3 g, 42 mmol) and DMAP (0.84 g, 6.9 mmol) was added under a nitrogen atmosphere. The mixture was cooled to -78°C and trifluorinated. Add to romethanesulfonic acid anhydride (12g, 42 mmol), and warm the resulting mixture to 25°C. The mixture was then stirred at 25°C for a further 4 hours. The reaction mixture was diluted with DCM (500 mL), water (100 mL), and aqueous salt. Wash with acid (1N, 150 mL) and brine (100 mL), dry on sodium sulfate, and in a vacuum. Upon concentration, crude compound P1-3 (14g, 97% crude yield) is obtained as a viscous oily substance. , it was pure enough for the next step. Crude compound P1-3 was flash-chromatographed ( When purified with 0-10% ethyl acetate in petroleum ether, the pure product becomes a viscous oil. I was able to obtain it as a physical object. ESI m / z: 421.2 (M+1) + . [ka]

[0248] Methyl(1S,4aS,10aR)-6-((tert-butoxycarbonyl)amino)-1,4a-dimethyl-1,2,3,4,4a ,9,10,10a-Octahydrophenanthrene-1-carboxylate (P1-4) [ka] Compound P1-3 (14g, 34mmol) and tert-butylcarbamate (BocNH2, 7.9g, 68mmol) -Butanol (100 mL) solution, cesium carbonate (22 g, 68 mmol), Tris (dibenzylidene acetone) Dipalladium (0)(Pd2(dba)3, 1.8g, 2.0 mmol) and X-Phos (1.8g, 4.0 mmol) were heated at room temperature. The substances were added sequentially. The mixture was degassed, purged three times with argon, and then monitored by TLC. Then, stir overnight under argon (balloon) at 80°C until compound P1-3 is completely consumed. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through Celite. The solid was washed three times with ethyl acetate. The combined filtrate was concentrated under vacuum, and the residue was collected in silica gel. When purified by Lamb chromatography (0-6.25% ethyl acetate in petroleum ether), Compound P1-4 (11g, 82% yield) was obtained as a white solid. ESI m / z: 410 (M+23) + . [ka]

[0249] (1S,4aS,10aR)-6-{[(tert-butoxy)carbonyl]amino}-1,4a-dimethyl-1,2,3,4,4a,9,1 0,10a-Octahydrophenanthrene-1-carboxylic acid (P1-5) [ka] Potassium tert-butoxide (15g, 0.13mol) is added to a DMSO solution of compound P1-4 (4.9g, 13 mmol). The mixture was added all at once at room temperature. The reaction mixture was kept under argon for 60°C until the reaction was complete by LC-MS. The mixture was stirred at °C for 3 hours. After cooling to room temperature, the reaction mixture was poured onto ice and mixed with aqueous hydrochloric acid (0.5M). The solution was slowly acidified to pH 5, during which time the temperature did not exceed 25°C. The precipitate was then filtered. The product was collected and washed several times with water. The crude product was subjected to silica gel column chromatography (Petroleum A Further purification with 0-20% ethyl acetate in telamine yields compound P1-5 (4.5g, 93% yield) white. It was obtained as a solid of color. ESI m / z: 318 (M-55) + . [ka]

[0250] tert-butyl N-[(4bS,8S,8aR)-8-carbamoyl-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-oc [Tahydrophenanthren-3-yl]carbamate (P1-6) [ka] Diisopropyl ethyl acetate is added to a 50 mL solution of P1-5 (4.5 g, 12 mmol) and HATU (4.9 g, 13 mmol) in DMF (50 mL). Luamine (20 mL, 0.12 mol) was added, and the mixture was stirred at 25°C for 1 hour. Then, the mixture was... Then, ammonium chloride (16 g, 0.30 mol) was added, and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with water and brine, dried on sodium sulfate, and then... The residue was concentrated in the air. Flash chromatography was performed on the residue (0-20% acetate in petroleum ether). Upon purification by chilling, compound P1-6 (4.2 g, 94% yield) was obtained as a white solid. ESI m / z: 373.3 (M+1) + . [ka]

[0251] Methyl(1S,4aS,10aR)-6-(benzyloxy)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octa Hydrophenanthrene-1-carboxylate (P1-8) [ka] A mixture of compound P1-2 (12g, 40 mmol) and cesium carbonate (14g, 44 mmol) in DMF (100 mL) is used for 20 minutes. The mixture was stirred at ~25°C for 15 minutes. Benzyl bromide (7.1 mL, 60 mmol) was added to the mixture 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 on sodium sulfate, and concentrated in a vacuum. Shrinkage occurred. The crude product was flash-chromatographed (0-10% ethyl acetate in petroleum ether). Upon purification using ), the title compound P1-8 (13g, 89% yield) was obtained as a white solid. ESI m / z: 379 (M+H) + . [ka]

[0252] (1S,4aS,10aR)-6-(benzyloxy)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydro Phenanthrene-1-carboxylic acid (P1-9) [ka] Monitor by LCMS and TLC, and add DMSO (0.19L) until the methyl group is completely removed. A mixture of compound P1-8 (11g, 29mmol) and potassium tert-butoxide (33g, 0.29mol) is used. The mixture was stirred at 0°C for 1 hour. After cooling to 25°C, the mixture was quenched with aqueous hydrochloric acid (1N) and acetic acid. Extracted with ethyl acetate. The combined organic solution was washed with brine and dried on sodium sulfate. The residue was concentrated in a vacuum. The residue was subjected to silica gel column chromatography (in petroleum ether). Upon purification with 24% ethyl acetate, compound P1-9 (7.5 g, 71% yield) was obtained as a white solid. It was done. ESI m / z: 365 (M+H) + . [ka]

[0253] Pentafluorophenyl (1S,4aS,10aR)-6-(benzyloxy)-1,4a-dimethyl-1,2,3,4,4a, 9,10,10a-Octahydrophenanthrene-1-carboxylate (P1-10) [ka] A solution of P1-9 (9.6 g, 26 mmol) in DMF (100 mL) is mixed with DIPEA (14 mL, 79 mmol) and perfluoroelastomer. Nyl 2,2,2-trifluoroacetate (15 g, 53 mmol) was added. This mixture was left at room temperature overnight. The mixture was stirred and monitored by LC-MS. The reaction mixture was then diluted with ether (200 mL). The samples were washed with water (300 mL) and brine (200 mL). The organic solution was dried on sodium sulfate. Concentrated in a vacuum. Residue flash chromatography (0-10% acetic acid in petroleum ether). Upon purification with ethyl(E), compound P1-10 (12g, 88% yield) was obtained as a white solid. SI m / z: 531(M+H) + . [ka]

[0254] tert-butyl N-[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-(benzyloxy)-1,4a-dimethyl- 1,2,3,4,4a,9,10,10a-Octahydrophenanthren-1-yl]formamide}carbonyl)-4 b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]carbamate (P 1-11) [ka] To a solution of compound P1-6 (2.3 g, 6.2 mmol) in THF (20 mL), add n-BuLi (2.5 M in hexane, 5.5 mL, 14 mm) Add 0.5g of P1-10 to the mixture at -78°C. Stir the reaction mixture at this temperature for 1 hour. A solution of mmol of THF (20 mL) was added, and then the compound P1-10 was monitored by LC-MS. The resulting mixture was stirred overnight at 10-20°C until consumed. The reaction mixture was then saturated with aqueous ammonium chloride. The solution was quenched with monoum and extracted with ethyl acetate. The combined organic solution was washed with water and brine. The residue was purified, dried on sodium sulfate, and concentrated in a vacuum. The residue was then flash-chromatographed. When purified with Phi (0-30% ethyl acetate in petroleum ether), compound P1-11 (1.59g, 51 The product (in % yield) was obtained as a white solid. ESI m / z: 719 (M+1) + .

[0255] tert-butyl N-[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2,3, 4,4a,9,10,10a-Octahydrophenanthren-1-yl]formamide}carbonyl)-4b,8-di Methyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]carbamate (P1-12) [ka] In a 40 mL solution of P1-11 (2.0 g, 2.78 mmol) in ethyl acetate, add wet palladium carbon (10% Pd, 0.9 g). It was added under nitrogen protection. The mixture was degassed and purged with hydrogen until P1-11 was completely consumed. The mixture was stirred overnight at room temperature under hydrogen balloon conditions and monitored by LCMS. The solution was filtered through Celite, and the filtrate was concentrated under vacuum. The residue was then subjected to silica gel column chromatography. When purified by Graphy (0-55% ethyl acetate in petroleum ether), P1-12 (1.06g, 61%) The yield was obtained as a white solid. ESI m / z: 629(M+H) + . [ka]

[0256] 1S,4aS,10aR)-N-[(1S,4aS,10aR)-6-amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octa Hydrophenanthrene-1-carbonyl]-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10 α-Octahydrophenanthrene-1-carboxamide (9d) [ka] To a 10 mL solution of compound P1-12 (0.17 g, 0.27 mmol) in DCM, TFA (3 mL) was added dropwise at room temperature. LC-MS The reaction mixture was stirred at room temperature for 1 hour until Boc was removed. The volatile substances were then removed under vacuum. After removal, the residue was purified by preparative HPLC (Method B), and 9d (0.10g, 70% yield) was obtained as a white solid. This was obtained.

[0257] ESI m / z: 529.3 (M+1) + .

[0258] [ka]

[0259] [ka]

[0260] [ka]

[0261] HPLC (Method B): Retention time: 8.92 mins, purity: 99.4%. Chiral HPLC: >99.9% (column AD, AS, OD) , and during OJ).

[0262] Optical rotation (α): +2.53° (1.7g / 100mL THF, 25℃).

[0263] (Example 1b) LP8 (Figure 1b) 1S,4aS,10aR)-6-((S)-2-((S)-2-amino-3-methylbutanamide)propanamide)-N-((1S, 4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenant Len-1-carbonyl)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene- Synthesis of 1-carboxamide (LP1-2) [ka] In a 1 mL solution of 9d (53 mg, 0.10 mmol) in DMF, add Fmoc-Val-Ala-OH (41 mg, 0.10 mmol) and HATU (38 mg) (0.1 mmol), and diisopropylethylamine (26 mg, 0.20 mmol) were added sequentially to LCMS. After stirring at 25°C for 24 hours until 9d is consumed, add piperidine (0.1 mL) to the mixture. The solution was added and stirred at 25°C for a further 3 hours. After filtration, the filtrate was separated and subjected to preparative HPLC (Method B). Further purification yielded compound LP1-2 (45 mg, 64% yield) as a white solid. SI m / z: 699 (M+1) + . [ka]

[0264] 1S,4aS,10aR)-6-((2S)-2-((2S)-2-((2R)-2-amino-6-(2-(cycloocta-2-inyloxy) Acetamide)Hexaneamide)-3-Methylbutanamide)Propanamide)-N-((1S,4aS,10a R)-6-hydroxy-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-cal Boxamide (LP1-4) [ka] A solution of compound LP1-3 (35 mg, 0.064 mmol) in DMF (1 mL) is mixed with HATU (24 mg, 0.064 mmol) and compound L P1-2 (45 mg, 0.064 mmol) was added sequentially at room temperature. The mixture was heated in a room until homogeneous. Stirred at warm temperature for several minutes. Diisopropylethylamine (41 mg, 0.32 mmol) was added to this mixture in a room. It was added using a syringe at warm temperature. LC-MS was used until LP1-2 was almost completely consumed. The mixture was stirred at room temperature overnight (16 hours). Then, piperidine (0.1 mL) was added to this reaction mixture. Add the excess (Fmoc) dropwise at room temperature and monitor by LC-MS until the mixture is removed. The reaction mixture was stirred for another 3 hours. The reaction mixture was then subjected to reverse-phase flash chromatography or preparative HPLC. When purified directly under Method B (basic conditions), compound LP1-4 (30 mg, 47% yield) is obtained as a white solid. Obtained as a whole. ESI m / z: 991 (M+1) + . [ka]

[0265] 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(hydro Xymethyl)-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]triazole-4-yl)oxy]acetamide}hexanamide]-3 -methylbutanamide]propanamide]-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahide [Rophenanthrene-1-yl]carbonyl}-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,1 0a-Octahydrophenanthrene-1-carboxamide (LP1-5) [ka] To a solution of compound LP1-4 (30 mg, 30 μmol) in DMF (0.5 mL), add CD-N3 (60 mg, 60 μmol) in DMF (0.5 mL). The solution was added using a syringe at room temperature. The mixture was stirred at 20-25°C for 3 days. By LC-MS... Compounds LP1-4 were almost completely consumed. The reaction mixture was purified directly by preparative HPLC (Method B). Compound LP1-5 (14 mg, 23% yield) was obtained as a white solid. ESI m / z: 995 (M / 2+ 1) + . [ka]

[0266] 1-(4-{2-Azatricyclo[10.4.0.0 4,9 ]Hexadeca-1(12),4(9),5,7,13,15-Hexaene-10 -in-2-yl}-4-oxobutanamide)-N-[(1R)-1-{[(1S)-1-{[(1S)-1-{[(4bS,8S,8aR)-8 -({[(1S,4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrof [Xenanthrene-1-yl]formamide}carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-o [Cutahydrophenanthrene-3-yl]carbamoyl}ethyl]carbamoyl}2-methylpropyl [Lu]carbamoyl}-5-{2-[(1-{[31,32,33,34,35,36,37,38,39,40,41,42-dodecahydroxy -10,15,20,25,30-Pentakis(hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29-dodecaoxaheptacyclo[26.2.2.2 .2 3,6 .2 8,11 .2 13,16 .2 18,21 .2 23,26 dotetracosane-5 -yl]methyl}-1H,4H,5H,6H,7H,8H,9H-cycloocta[d][1,2,3]triazol-4-yl)oxy xy]acetamide}pentyl]-3,6,9,12-tetraoxapentadecan-15-amide (LP8) [Chemical formula] To a DMF (1 mL) solution of compound LP1-5 (14 mg, 7.4 μmol) and DIBAC-Suc-PEG4-OSu (6.5 mg, 10 μmol), triethylamine (2.0 mg, 20 μmol) was added, and the mixture was stirred at 20 - 25 °C for 16 hours. Most of the volatile substances were removed in vacuo, and the residue was purified by preparative HPLC (method B) to obtain compound LP8 (5.0 mg, 27% yield) as a white solid. ESI m / z: 1261 (M / 2 + 1) . + . [Chemical formula]

[0267] (Example 1c) Synthesis of LP32 (Figure 1c) (1S,4aS,10aR)-N-{[(1S,4aS,10aR)-6-[(2S)-2-[(2S)-2-[(2R)-2-amino-6-{2-[(1-{[41,42 ,43,44,45,46,47,48,49,50,51,52,53,54,55,56-hexadecahydroxy-10,15,20,25,30,3 5,40-Heptakis(hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39 Xadecaoxanonacyclo[36.2.2.2 3,6 .2 8,11 .2 13,16 .2 18,21 .2 23,26 .2 28,31 .2 33,36 ] Xapentacontan-5-ylmethyl}-1H,4H,5H,6H,7H,8H,9H-cycloocta[d][1,2,3] [Riazole-4-yl)oxy]acetamide}hexanamide]-3-methylbutanamide]pro [Panamide]-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-yl] Carbonyl-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenane Tren-1-carboxamide (LP2-5) [ka] γCD-N3 (0.12 mg, 0.091 mmol) was added to a solution of compound LP1-4 (30 mg, 0.030 mmol) in DMF (2 mL). The mixture was stirred in RT for 16 hours and monitored by LCMS. After filtering, the filtrate was separated and purified by HPLC (Method A), and compound LP2-5 (40 mg, 5 A 7% yield was obtained as a white solid. ESI m / z: 1157.6 (M / 2+1) + . [ka]

[0268] 1-(4-{2-Azatricyclo[10.4.0.0 4,9]Hexadeca-1(12),4(9),5,7,13,15-Hexaene-10 -in-2-yl}-4-oxobutanamide)-N-[(1R)-1-{[(1S)-1-{[(1S)-1-{[(4bS,8S,8aR)-8 -({[(1S,4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrof [Xenanthrene-1-yl]formamide}carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-o [Cutahydrophenanthrene-3-yl]carbamoyl}ethyl]carbamoyl}2-methylpropyl [Lu]carbamoyl}-5-{2-[(1-{[41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56-hex Sadecahydroxy-10,15,20,25,30,35,40-heptakis(hydroxymethyl)-2,4,7,9,12,14 ,17,19,22,24,27,29,32,34,37,39-Hexadecaoxanonacyclo[36.2.2.2 3,6 .2 8,11 .2 13, 16 .2 18,21 .2 23,26 .2 28,31 .2 33,36 ]Hexapentacontan-5-yl]methyl}-1H,4H,5H,6H,7 H,8H,9H-Cycloocta[d][1,2,3]triazole-4-yl)oxy]acetamide}pentyl]- 3,6,9,12-tetraoxapentadecane-15-amide (LP32) [ka] Add HATU (3.0 mg, 7.8 μmol) to a solution of compound LP2-6 (4.3 mg, 7.8 μmol) in anhydrous DMF (1 mL). The mixture was stirred at 10°C for 10 minutes, then compound LP2-5 (15 mg, 6.5 μmol) and DIPEA (1.7 mg) were added. (13 μmol) was added. Monitoring by LC-MS was performed until LP2-5 was completely consumed. The mixture was stirred at RT for 2 hours. The mixture was filtered through a membrane, and the filtrate was separated and analyzed by HPLC (Method B). Upon purification, compound LP32 (6.0 mg, 32% yield) was obtained as a white solid. ESI m / z: 14 24.2 (M / 2 + 1) + . [ka] Solubility: 0.075 mg per 1 mL of H2O.

[0269] (Example 1d) Synthesis of LP13 (Figure 1d) {4-[(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(hydroxymethyl)-2,4,7,9,12,14,17,1 9,22,24,27,29-Dodecaoxaheptacyclo[26.2.2.2 3,6 .2 8,11 .2 13,16 .2 18,21 .2 23,26 ] Tetracontan-5-ylmethyl}-1H,4H,5H,6H,7H,8H,9H-cycloocta[d][1,2,3]tri [Zol-4-yl)oxy]acetamide}hexanamide]-3-methylbutanamide]-5-(cal Bamoylamino)pentanamide]phenyl}methyl N-[(1S)-1-{[(4bS,8S,8aR)-8-({[(1S, 4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenant Len-1-yl]formamide}carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahide [Rophenanthren-3-yl]carbamoyl}-2-hydroxyethyl]carbamate (LP5-1) [ka] A solution of compound LP15 (20 mg, 15 μmol) in DMF (1 mL) is mixed with acetonitrile (2 mL) and water (2 mL) C A solution of D-N3 (46 mg, 45 μmol) was added by RT. The mixture was stirred at 30°C for 16 hours. LC-MS was used to analyze the mixture. Compound LP15 was almost completely consumed. The reaction mixture was then purified by preparative HPLC (Method B). Upon preparation, compound LP5-1 (20 mg, 57% yield) was obtained as a white solid. ESI m / z: 1156.0 (M / 2+1) + .

[0270] {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-in-2-yl}-4-oxobutanamide)-3,6,9,12-tetra Oxapentadecane-15-amide]-6-{2-[(1-{[31,32,33,34,35,36,37,38,39,40,41,42- 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 [Tracontan-5-yl]methyl}-1H,4H,5H,6H,7H,8H,9H-cycloocta[d][1,2,3]triazo [I-4-yl)oxy]acetamide}hexamide]-3-methylbutanamide]-5-(carbamide) [moylamino)pentanamide]phenyl}methyl N-[(1S)-1-{[(4bS,8S,8aR)-8-({[(1S,4a S,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-octahydro Phenanthren-3-yl]carbamoyl}-2-hydroxyethyl]carbamate (LP13) [ka] A solution of DIBAC-PEG4-acid LP5-2 (4.3 mg, 7.8 μmol) in DMF (1 mL) contains HATU (3.0 mg, 3.6 μmol) and DIPEA (1.7 mg, 13 μmol) was added via RT. The resulting mixture was stirred via RT for 10 minutes. LP5-1 (15 mg, 6.5 μmol) was added to the mixture. The reaction was monitored by LC-MS. The reaction mixture was stirred at 30°C for 2 hours until completion. The reaction mixture was filtered and preparatively HPLC ( Purification by method B) yielded LP13 (10 mg, 42% yield) as a white solid. ESI m / z: 1424.3 (M / 2+1) + . [ka]

[0271] (Example 1e) Synthesis of LP36 (Figure 1e) 1-Azide-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecane-18-sulfonic acid (L6-2) [ka] A solution of azid-PEG4-NHS (L6-1, 0.10 g, 0.26 mmol) in anhydrous DMF (4 mL) is mixed with taurine (39...

Claims

1. Compounds of formula A or pharmaceutically acceptable salts or stereoisomers thereof: 【Chemistry 1】 (In the formula, L is a linker or XYZ, where X is -NH- or -O-; Y is an enzymatically cleavable moiety selected from dipeptides, tripeptides or peptides, a self-destructing group selected from p-aminobenzyl (PAB), p-aminobenzyloxycarbonyl (PABC) or derivatives thereof, an acid-unstable moiety selected from alkoxyamines, ketoxyamines, carbonates or phosphonates, (CH 2 CH 2 O) n , a sugar moiety, or an enhancing group selected from alkyl, heteroalkyl, alkylenyl or heteroalkylenylsulfonic acid and / or cyclodextrin; and Z is a binder linker (BL), where Z is covalently bonded to BA; BA is a conjugate selected from antibodies, antigen-binding fragments of antibodies, lymphokines, hormones, growth factors, viral receptors, or interleukins; k is an integer between 1 and 30; Q 1 and Q 2 Each of them independently, -CH 2 - or -C(O)-; W is either -N(H)- or -O-; R is independently -OH or -OP(O)(OR 6 )(OH) is; Each R 6 is, in each case independently, hydrogen or C 1-20 alkyl; Each R 7 Independently, Halo, C 1-6 Alkyl, C 1-6 It is an alkoxy, -CN, O-glycosyl, O-amino acid residue, or O-PEG; and Each n is an independent integer between 0 and 3.

2. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

3. A compound according to claim 1 having formula B, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a positional isomer thereof: 【Chemistry 2】 (In the formula, Each SP 1 SP 2 , and SP 3 This is a spacer base, where SP 3 (AA) n It is linked to one AA; Each AA is an amino acid; n is an integer from 1 to 10; and EG is a strengthening group.

4. The aforementioned SP 1 The spacer, 【Transformation 3】 Here, RG' is the reactive group residue after the reaction between the reactive group RG and the binder. 【Chemistry 4】 b is a direct or indirect bond with the binder via a PEG spacer, and b is an integer from 1 to 4; (AA) n but 【Transformation 5】 And; SP 2 However, it is a combination or PABC; The aforementioned SP 3 The spacer, 【Transformation 6】 Here, RG' is the reactive group residue after the reaction between the reactive group RG and the reinforcing group EG; 【Transformation 7】 is a bond with EG; and 【Transformation 8】 (AA) n A compound according to claim 3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is a combination of the above.

5. The compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to any one of claims 1, 3, or 4 is selected from the group consisting of the following: 【Chemistry 9】 (In the formula, each 【Chemistry 10】 This refers to direct or indirect bonding with the binder via a PEG spacer.

6. The compound according to claim 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is the following compound or a positional isomer thereof: 【Chemistry 11】 (In the formula, 【Chemistry 12】 This refers to direct or indirect bonding with the binder via a PEG spacer.

7. The compound according to claim 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is the following compound or a positional isomer thereof: 【Chemistry 13】 (In the formula, 【Chemistry 14】 This refers to direct or indirect bonding with the binder via a PEG spacer.

8. The compound according to claim 3 or 4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is the following compound: 【Chemistry 15】 。

9. The compound according to claim 3 or 4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is the following compound: 【Chemistry 16】 。

10. The compound according to claim 3 or 4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is the following compound: 【Chemistry 17】 。

11. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the antigen-binding fragment of the antibody is selected from a Fab fragment, an F(ab')2 fragment, an Fd fragment, an Fv fragment, a single-chain Fv(scFv), a dAb fragment, a minimal recognition unit consisting of amino acid residues that mimic the hypervariable region of the antibody, or a restrictive FR3-CDR3-FR4 peptide.

12. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the antibody or antigen-binding fragment of the antibody is selected from domain-specific antibodies, single-domain antibodies, domain deletion antibodies, chimeric antibodies, CDR-transplant antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies, small modular immunotherapy drugs (SMIPs), and shark variable IgNAR domains.

13. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the antibody or antigen-binding fragment of the antibody is selected from monoclonal antibodies and polyclonal antibodies.

14. The compound according to claim 1, or a positional isomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, comprising BA linked via a linker L to a compound selected from the group consisting of the following: [Chemistry 18] 【change】 (In the formula, k is an integer between 1 and 4).

15. The compound according to claim 1, or its positional isomer, stereoisomer, pharmaceutically acceptable salt, or solvate, comprising BA linked to a compound selected from the group consisting of the following: 【Chemistry 19】 【change】 【change】 【change】 【change】 (In the formula, k is an integer between 1 and 4).

16. A compound according to claim 1, or a positional isomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of the following: 【Chemistry 20】 【change】 【change】 【change】 【change】 【change】 【change】 (In the formula, k is an integer between 1 and 4).

17. A compound according to any one of claims 14 to 16, wherein k is 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

18. A compound according to any one of claims 14 to 16, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein k is 4.

19. A compound according to claim 1 having the following structure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemistry 21】 (wherein BA is a binder selected from an antibody, an antigen-binding fragment of an antibody, a lymphokine, a hormone, a growth factor, a viral receptor, or an interleukin, and k is an integer from 1 to 30).

20. A compound according to claim 1 having the following structure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemistry 22】 (wherein BA is a binder selected from an antibody, an antigen-binding fragment of an antibody, a lymphokine, a hormone, a growth factor, a viral receptor, or an interleukin, and k is an integer from 1 to 30.)

21. A compound according to claim 1 having the following structure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemistry 23】 (wherein BA is a binder selected from an antibody, an antigen-binding fragment of an antibody, a lymphokine, a hormone, a growth factor, a viral receptor, or an interleukin, and k is an integer from 1 to 30.)

22. A compound according to claim 1 having the following structure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemistry 24】 (wherein BA is a binder selected from an antibody, an antigen-binding fragment of an antibody, a lymphokine, a hormone, a growth factor, a viral receptor, or an interleukin, and k is an integer from 1 to 30.)

23. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, comprising BA linked via a linker L to the compound of the following formula or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemistry 25】 。

24. A compound according to claim 1 having the following formula, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemistry 26】 。

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