Bis-octahydrophenanthrene carboxamides and protein conjugates thereof

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 TO RELATED APPLICATIONS) This application is hereby incorporated by reference in its entirety under 35 U.S.C. § 119. This application claims the benefit of U.S. Provisional Application No. 62 / 508,327, filed May 18, 2017, which includes the following: be.

[0002] (Field) Provided herein are novel bis-octahydrophenanthrenecarboxamides and protein conjugates thereof, and the bis-octahydrophenanthrene carbo and the administration of oxamides and their protein conjugates to treat various diseases, disorders, and methods of treating diseases. [Background technology]

[0003] (background) Antibody-drug conjugates (ADCs) are conjugated to bioactive small molecule drugs, thus ADCs are antibodies that combine the targeting specificity of antibodies with the mode of action and efficacy of small molecule drugs. Therapeutic utility has been demonstrated in cancer treatment, which is a major ongoing research focus. ADCETRIS® (bentruximab vedotin) and KADCYLA® ( Ato-trastuzumab emtansine) are two ADCs approved for the treatment of certain cancer types. At least 40 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. LXRα is highly expressed in the liver, intestine, adipose tissue, and differentiated macrophages. LXRs are expressed as (i) cholesterol transporters, e.g. For example, it stimulates the expression of ABCA1 and ABCG1, both of which mediate cellular cholesterol efflux. and (ii) negatively affect macrophage inflammatory gene expression through the suppression of NF-kB activation. LXRs have various biological functions, including regulating atherosclerosis. It has also been implicated in proliferative disorders, neurodegenerative disorders, and inflammation. These include 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: Alzheimer's disease and myelin gene expression (Terwel et al., 2011; Sandoval- Hernandez et al., 2016; Meffre et al., 2014). Inflammation includes inflammatory bowel disease, ulcerative colitis, and These include enteritis, Crohn's disease, and arthritis (Anderson et al., 2011; Huang et al., 20 15; Cui et al., 2012). Macrophage LXRs are known to contain anti-atherogenic activity. LXR agonists have been shown to (i) inhibit the initiation of atherosclerosis and slow its progression; (ii) delay atherosclerosis and improve established atherosclerotic lesions; and (iii) reduce lesion macrophage content by apoptosis. It is believed that this will be possible.

[0005] The therapeutic efficacy of small molecule LXR modulators may be improved by, for example, controlling unwanted LXRs in non-target cells. Regulation of LXRs in non-target cells is limited by their limited activity and / or low bioavailability. However, poor bioavailability can lead to undesirable side effects, including but not limited to: However, this is occurring for a number of reasons, including low solubility, which exacerbates the inadequate therapeutic window for treatment. If ADCs containing LXR modulators are developed, target-specific LXR regulation will become possible. This would avoid side effects due to off-target regulation of LXRs. Furthermore, such ADCs may offer benefits such as improved modulation of biological targets, increased bioavailability, and Therefore, small molecule LXR modulators A There is a continuing need for effective treatment of, for example, metabolic diseases using DCs. Summary of the Invention

[0006] (overview) Provided herein are methods for treating metabolic disorders, including, but not limited to, dyslipidemia. Also provided herein are compounds useful in the treatment of, for example, inflammation or neurodegeneration. The compounds provided herein are compounds according to Formula I, which are useful for treating sexual disorders. be.

[0007] In one embodiment, provided herein are compounds according to Formula I or as medicaments thereof. and its acceptable salts, solvates, or stereoisomeric forms: [ka] (In the formula, Q 1 and Q 2 each independently represents -CH2-, -C(O)-, -C(H)(OH)-, -C(OH)2-, -SO2-, -SO-, -P O(OR 11 )-, -PO(NR11 NR 12 )-, -NR 11 - or -N=; W comprises -CH2-, -N(H)-, or -O-; R 1 -H, -OR 6 , -OH, -NH2, alkyl, or -OP(O)(OR 6 )2 included; R 2 -H, -OH, -OR 11 , halide, -SO2NR 11 R 12 , -CONR 11 R 12 , -CH2NH2, R 3 , R 4 , R 5 , -OR 5 where R 1 and R 2 At the same time, -H is not; R 3 is -N(R 6 )2 included; R 4 contains -XYZ; X comprises a group consisting of -O- and -N(H)-; Y is alkylene, substituted alkylene (including oxo, i.e., =O), heteroalkylene and substituted heteroalkylene (including oxo, i.e., =O); Z comprises a group consisting of -OH and -NH; R 5 includes alkyl, heterocycloalkyl, or substituted heterocycloalkyl, wherein each heterocycloalkyl or substituted heterocycloalkyl is selected from nitrogen and oxygen. and at least one -OH or -CHO H, or at least one primary or secondary nitrogen; Each R 6 is, in each occurrence, independently -H, an amino acid residue, an N-alkyl amino acid residue, a peptide, a biodegradable moiety, or an alkyl; Each R 7 are independently halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O- Amino acid residues and O-PEG n wherein each n is an integer from 0 to 3; and Each R 11 and R 12 are independently selected from —H, alkyl, and aryl.

[0008] In one embodiment, provided herein are compounds according to Formula I or as medicaments thereof. and its acceptable salts, solvates, or stereoisomeric forms: [ka] (In the formula, Q 1 and Q 2 each independently comprises —CH—, —C(O)—, —C(H)(OH)—, or —C(OH)—; W comprises -CH2-, -N(H)-, or -O-; R 1 is -H, -OH, -NH2, alkyl, or -OP(O)(OR 6 )2 included; R 2 -H, -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 where R 1 and R 2 is simultaneously has -H instead; R 3 is -N(R 6 )2 included; R 4 contains -XYZ; X comprises a group consisting of -O- and -N(H)-; Y is alkylene, substituted alkylene (including but not limited to, oxo-substituted (i.e., ═O) ), heteroalkylene, and substituted heteroalkylene (including but not limited to, oxo-substituted (i.e., including ═O); Z comprises a group consisting of -OH and -NH; R 5 includes alkyl, heterocycloalkyl, or substituted heterocycloalkyl, wherein each heterocycloalkyl or substituted heterocycloalkyl is selected from nitrogen and oxygen. and at least one -OH or -CHO H substituent, or at least one primary or secondary nitrogen, e.g., O-glucose; Each R 6 is, in each occurrence, independently -H, an amino acid residue, an N-alkyl amino acid residue, containing a peptide or alkyl; and Each R 7 are independently halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O- Amino acid residues and O-PEG n where each n is an integer from 0 to 3.

[0009] In another embodiment, provided herein are ligands having compounds according to Formula I above. anchor-payload.

[0010] In another embodiment, provided herein are antibodies that bind to an antibody or antigen-binding fragment thereof. Also, the compound of formula I above or an antibody-drug conjugate having a linker-payload do.

[0011] In another embodiment, provided herein are compounds according to Formula A or medicaments thereof. and its corresponding acceptable salts, or stereoisomeric forms: [ka] (In the formula, L is a linker; BA is a binder; k is an integer from 1 to 30; Q 1 and Q 2 each is independently —CH—, —C(O)—, —C(H)(OH)—, or —C(OH)—; W is -CH2-, -N(H)-, or -O-; R is independently -H, -OH, or -OP(O)(OR 6 )2; and Each R 6 is, in each occurrence, independently -H, an amino acid residue, an N-alkyl amino acid residue, peptide, or alkyl; and Each R 7 are independently halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O- Amino acid residues and O-PEG n where each n is an integer from 0 to 3.

[0012] In another embodiment, provided herein are compounds described herein, including phosphorus Car-payload or antibody-drug conjugate and a pharmaceutically acceptable excipient, carrier or a pharmaceutical composition comprising a diluent.

[0013] In another embodiment, provided herein is a method for treating dyslipidemia, metabolic disorders, inflammation, or the like in a subject. a method for the treatment of a neurodegenerative disease, or a neurodegenerative disorder, comprising administering to said subject a compound described herein. Efficacy of the compound, linker-payload, or antibody-drug conjugate, or pharmaceutical composition The method comprises administering a therapeutic amount.

[0014] In another embodiment, provided herein are compounds described herein, including phosphorus Car-payload or antibody-drug conjugates and methods of making the compositions. [Brief explanation of the drawings]

[0015] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] Figure 1 1a-1i shows the synthetic chemistry schemes for bis-octahydrophenanthrenecarboxamide, cyclodextrin-based linker-payload, and its protein conjugates. [Figure 2] FIG. 2 shows the synthetic chemistry scheme of bis-octahydrophenanthrenecarboxamide, cyclodextrin-based linker-payload, and its protein conjugate. [Figure 3] Figures 3a-3e show the synthetic chemistry schemes for bis-octahydrophenanthrenecarboxamide, cyclodextrin-based linker-payload, and its protein conjugates. [Figure 4] FIG. 4 shows the synthetic chemistry scheme of bis-octahydrophenanthrenecarboxamide, cyclodextrin-based linker-payload, and its protein conjugate. [Figure 5] FIG. 5 shows the synthetic chemistry scheme of bis-octahydrophenanthrenecarboxamide, cyclodextrin-based linker-payload, and its protein conjugate. [Figure 6] FIG. 6 shows the synthetic chemistry scheme of bis-octahydrophenanthrenecarboxamide, cyclodextrin-based linker-payload, and its protein conjugate. [Figure 7] FIG. 7 shows the synthetic chemistry scheme of bis-octahydrophenanthrenecarboxamide, cyclodextrin-based linker-payload, and its protein conjugate. [Figure 8] FIG. 8 shows the synthetic chemistry scheme of bis-octahydrophenanthrenecarboxamide, cyclodextrin-based linker-payload, and its protein conjugate. [Figure 9] FIG. 9 shows the synthetic chemistry scheme of bis-octahydrophenanthrenecarboxamide, cyclodextrin-based linker-payload, and its protein conjugate. [Figure 10] FIG. 10 shows the synthetic chemistry scheme of bis-octahydrophenanthrenecarboxamide, cyclodextrin-based linker-payload, and its protein conjugate.

[0016] [Figure 11] FIG. 11 shows a Coomassie stained SDS-PAGE gel of anti-Her2 antibodies, anti-Her2-PEG3-N3, and anti-Her2-LP8.

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

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

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

[0020] [Figure 15] FIG. 15 is a graph showing the percentage of dose-dependent cholesterol efflux in THP-1 macrophages for an exemplary MSR1 antibody-LXR conjugate, its unconjugated counterpart, an isotype control-LXR conjugate, and the corresponding free payload.

[0021] [Figure 16] FIG. 16 provides a series of bar graphs showing the effect of an exemplary MSR1 antibody-LXR agonist conjugate and its unconjugated counterpart on serum lipid levels in a mouse model of atherosclerosis.

[0022] [Figure 17] Figure 17 provides a series of bar graphs showing the effect of an exemplary MSR1 antibody-LXR agonist conjugate and its unconjugated counterpart on lesion lipid area and macrophage (CD68) content in a mouse model of atherosclerosis.

[0023] [Figure 18] FIG. 18 provides a series of bar graphs showing the effects of an exemplary MSR1 antibody-LXR agonist conjugate and its unconjugated counterpart on hepatic triglyceride and cholesterol levels in a mouse model of atherosclerosis.

[0024] [Figure 19] FIG. 19 provides a series of bar graphs showing the effect of an exemplary MSR1 antibody-LXR agonist conjugate and its unconjugated counterpart on de novo lipogenesis in a mouse model of atherosclerosis. DETAILED DESCRIPTION OF THE INVENTION

[0025] DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS Provided herein are methods for treating a subject's condition, e.g., dyslipidemia, metabolic disease, inflammation, or diabetes. Compounds, compositions, and methods useful for treating degenerative diseases.

[0026] (definition) When referring to the compounds provided herein, the following terms are used interchangeably unless otherwise indicated: Unless otherwise defined, technical and scientific terms used herein have the following meanings: All terms have the same meaning as commonly understood by one of ordinary skill in the art. In the event that there are multiple definitions for terms used herein, those definitions shall prevail unless expressly stated otherwise. do.

[0027] As used herein, "alkyl" refers to a monovalent and saturated hydrocarbon radical moiety. Alkyl is optionally substituted and may be linear, branched, or cyclic, i.e., cycloalkenyl. Alkyl can be a radical having 1 to 20 carbon atoms, That is, C 1-20 Alkyl; a radical having 1 to 12 carbon atoms, i.e., C 1-12 Al radicals having 1 to 8 carbon atoms, i.e., C 1-8 Alkyl; 1 to 6 carbon atoms radicals having the formula C 1-6 alkyl; and radicals having 1 to 3 carbon atoms, That is, C 1-3 Examples of alkyl moieties include, but are not limited to, alkyl. The following are examples of methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, i-butyl ethyl, pentyl moiety, hexyl moiety, cyclopropyl, cyclobutyl, cyclopentyl, Pentyl moieties include, but are not limited to, n- and cyclohexyl. Examples of hexyl moieties include, but are not limited to, pentyl and i-pentyl. and n-hexyl.

[0028] As used herein, "alkylene" refers to a divalent alkyl group. Unless otherwise specified, alkylene includes, but is not limited to, 1 to 20 carbon atoms. The olefin group is optionally substituted as described herein for alkyl. In some embodiments, the alkylene is unsubstituted.

[0029] As used herein, the term "O-amino acid" or "HO-amino acid" refers to an amino acid. The amino acid or the natural amino group at the N-terminus of the amino acid sequence is converted to an oxygen or a hydroxyl group, respectively. For example, "O-AAAA" or "HO-AAAA" represents the N-terminal amino acid that has been replaced. an amino acid sequence in which the natural amino group is replaced by an oxygen or a hydroxyl group, respectively (AAAA) (e.g., [ka] where each R is an amino acid side chain. The term "HO-amino acid residue" or "HO-amino acid residue" refers to the chemical residue in a compound that remains after a chemical reaction. For example, "O-amino acid residue" or "HO-amino acid residue" refers to an O-amino acid or H-amino acid residue. Amide coupling or peptide coupling of O-amino acids with suitable coupling partners where, for example, a water molecule is present in the O-amino acid or the HO-amino acid. After peptide or amino acid coupling, the O-amino acid residue or the HO -A product is produced in which the amino acid residue is incorporated.

[0030] The designation of an amino acid or amino acid residue without specifying its stereochemistry refers to an L-amino acid, a D-amino acid, It is intended to include amino acids, or racemic mixtures thereof.

[0031] As used herein, "haloalkyl" refers to an alkyl group as defined above. wherein the alkyl is a halogen, such as fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Examples of haloalkyl include: , -CF3, -CH2CF3, -CCl2F, and -CCl3.

[0032] As used herein, "alkenyl" refers to an alkyl group having at least two carbon atoms and one or more alkyl groups. Alkenyl refers to a monovalent hydrocarbon radical moiety containing a non-aromatic carbon-carbon double bond. Alkenyl is optionally substituted and can be linear, branched, or cyclic. For example, radicals with 2 to 20 carbon atoms, i.e., C 2-20 Alkenyl; 2-12 carbons Radicals with elementary atoms, i.e., C 2-12 Alkenyl; Radicals containing 2 to 8 carbon atoms Cal, i.e., C 2-8 Alkenyl; a radical having 2 to 6 carbon atoms, i.e., C 2-6 alkenyl; and radicals having 2 to 4 carbon atoms, i.e., C 2-4 Alkenyl is mentioned. Examples of alkenyl moieties include, but are not limited to, vinyl, propenyl, Examples include, but are not limited to, butenyl and cyclohexenyl.

[0033] As used herein, "alkynyl" refers to an alkyl group having at least two carbon atoms and one or more alkyl groups. Alkynyl refers to a monovalent hydrocarbon radical moiety containing a carbon-carbon triple bond. It can be substituted and linear, branched, or cyclic. Alkynyl includes 2 Radicals with ∼20 carbon atoms, i.e., C2-20 Alkynyl; 2 to 12 carbon atoms radicals, i.e., C 2-12 Alkynyl; a radical having 2 to 8 carbon atoms, That is, C 2-8 Alkynyl; a radical having 2 to 6 carbon atoms, i.e., C 2-6 Alkini and radicals having 2 to 4 carbon atoms, i.e., C 2-4 Alkynyl is an example Examples of alkynyl moieties include, but are not limited to, ethynyl, propynyl, and bromine. These include, but are not limited to, thionyl.

[0034] As used herein, "alkoxy" refers to a monovalent and saturated hydrocarbon radical moiety. wherein the hydrocarbon contains a single bond to an oxygen atom and the radical is For example, in the case of ethoxy, it is CH3CH2-O·. An alkoxy substituent is one that is The alkoxy substituent is attached to the compound it substitutes through this oxygen atom. and may be linear, branched, or cyclic, i.e., cycloalkoxy. The alkoxy includes those having 1 to 20 carbon atoms, i.e., C 1-20 Arco oxy; having 1 to 12 carbon atoms, i.e., C 1-12 Alkoxy; 1 to 8 carbon atoms That is, C 1-8 Alkoxy; having 1 to 6 carbon atoms, i.e., C 1-6 Alkoxy; and those having 1 to 3 carbon atoms, i.e., C 1-3 Alkoxy is mentioned Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, i-butoxy, pentoxoxy cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy (i.e., respectively, [ka] ), but are not limited to these.

[0035] As used herein, "haloalkoxy" refers to an alkoxy group as defined above. alkoxy refers to alkoxy, where the alkoxy is selected from halogen, e.g., F, Cl, Br, or I. It contains at least one substituent that is

[0036] As used herein, "aryl" refers to an aromatic compound in which the ring atoms are carbon atoms. Aryl refers to a monovalent moiety that is an optionally substituted, monocyclic or polycyclic Examples of aryl moieties include 6-2 those with 0 ring carbon atoms, i.e., C 6-20 Aryl; having 6 to 15 ring carbon atoms That is, C 6-15 Aryl and those having 6 to 10 ring carbon atoms, i.e., C 6-10 Examples of aryl moieties include, but are not limited to, fluoro ... phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, and pyrene Examples of suitable amines include, but are not limited to, methylaminobenzoates ...

[0037] As used herein, "arylalkyl" refers to the radical of an alkyl compound. where the alkyl compound is substituted with an aromatic substituent, i.e., That is, the aromatic compound contains a single bond to an alkyl group, and the radical is positioned on the alkyl group. The arylalkyl group is attached to the depicted chemical structure via the alkyl group. Arylalkyl has the structure, for example: [ka] where B is an aromatic moiety, e.g., phenyl. The aryl alkyl is optionally substituted, i.e., the aryl and / or alkyl group is It can be substituted as disclosed herein. Examples of arylalkyl include: Examples include, but are not limited to, benzyl.

[0038] As used herein, "alkylaryl" is a radical of an aryl compound. refers to a monovalent moiety in which the aryl compound is substituted with alkyl substituents, i.e., That is, the aryl compound contains a single bond to an alkyl group, and the radical is attached to the aryl group. The alkylaryl group is linked to the chemical structure shown through the aryl group. Alkylaryl has the structure, for example: [ka] where B is an aromatic moiety, e.g., phenyl. The alkylaryl is optionally substituted, i.e., the aryl and / or alkyl group is It can be substituted as disclosed herein. Examples of alkylaryl include: Examples of suitable amines include, but are not limited to, toluyl.

[0039] As used herein, "aryloxy" refers to an aryl group in which the ring atoms are carbon atoms and the It 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. That is, the aromatic compound contains a single bond to an oxygen atom, and the radical is positioned on the oxygen atom. For example, in the case of phenoxy, [ka] The aryloxy substituent is attached to the compound it substitutes through this oxygen atom. The aryloxy is optionally substituted. The aryloxy is a group having 6 to 20 rings. Radicals with carbon atoms, i.e., C 6-20 Aryloxy; having 6 to 15 ring carbon atoms That is, C 6-15 Aryloxy and those having 6 to 10 ring carbon atoms, That is, C 6-10 Aryloxy includes, but is not limited to, aryloxy. Examples of moieties include phenoxy, naphthoxy, and anthroxy. Not limited to.

[0040] As used herein, "R a R b "N-aryloxy" means that the ring atoms are carbon atoms, and the ring is at least one R a R b substituted with an N-substituent and at least one oxygen radical refers to a monovalent moiety that is a radical of an aromatic compound that is a R b It contains a single bond to the N-substituent and a single bond to the oxygen atom, and the radical is positioned on the oxygen atom. For example, [ka] R a R bThe N-aryloxy substituent is a substituent that is substituted through this oxygen atom in the compound it substitutes. Combine. R a R b N-aryloxy is optionally substituted. a R b N-aryloxy For example, those having 6 to 20 ring carbon atoms, such as C 6-20 (R a R b N) n -aryloxy, 6 those with 15 ring carbon atoms, e.g., C 6-15 (R a R b N) n -aryloxy, and 6 to 10 those having ring carbon atoms of, for example, C 6-10 (R a R b N) n -aryloxy (where n is R a R b N- represents the number of substituents), but is not limited to these. a R b N-aryloxy moiety Examples of moieties include 4-(dimethylamino)-phenoxy, [ka] These include, but are not limited to:

[0041] As used herein, "arylene" refers to an aromatic ring in which the ring atoms are only carbon atoms. Arylene refers to a divalent moiety of a compound that is optionally substituted and is monocyclic or polycyclic, e.g., For example, the aryl moiety may be bicyclic or tricyclic. Examples of the aryl moiety include aryl moieties having 6 to 20 rings. Those with ring carbon atoms, i.e., C 6-20 Arylene; 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 Examples include, but are not limited to, arylene.

[0042] As used herein, "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced by a heteroatom. As used herein, "heteroalkenyl" refers to an alkyl that is substituted. As used herein, an alkenyl group refers to an alkenyl group in which one or more carbon atoms are replaced by a heteroatom. When the term "heteroalkynyl" is used, one or more carbon atoms are replaced by a heteroatom. Suitable heteroatoms include nitrogen, oxygen, and sulfur atoms, Heteroalkyl is optionally substituted. Heteroalkyl moiety Examples of alkyl include aminoalkyl, sulfonylalkyl, and sulfinylalkyl. Examples of heteroalkyl moieties include, but are not limited to, methylamino, methylamino, Also included are, but are not limited to, methylsulfonyl and methylsulfinyl.

[0043] As used herein, "heteroaryl" refers to a group of ring atoms in which the ring atoms are carbon atoms and at least one heteroaryl. A univalent moiety that is a radical of an aromatic compound containing one oxygen, sulfur, nitrogen, or phosphorus atom Examples of heteroaryl moieties include those with 5 to 20 ring atoms; those with 5 to 15 ring atoms; and those with 5 Heteroaryl includes, but is not limited to, those having up to 10 ring atoms. , optionally substituted.

[0044] As used herein, "heteroarylene" refers to an aromatic group in which one or more ring atoms of the aromatic ring is oxygen. Heteroarylene refers to an arylene substituted with a sulfur, nitrogen, or phosphorus atom. are arbitrarily substituted.

[0045] As used herein, "heterocycloalkyl" refers to a group in which one or more carbon atoms are heterocyclic. Suitable heteroatoms include nitrogen, oxygen, and sulfur atoms. Heterocycloalkyls are optionally Examples of heterocycloalkyl moieties include morpholinyl, piperidinyl, and the like. , tetrahydropyranyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl Examples include lysinyl, dioxolanyl, dithiolanyl, oxanyl, or thianyl, Not limited to these.

[0046] As used herein, a "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 other than protons. Lewis acids include non-metallic acids, metallic acids, hard Lewis acids, and soft Lewis acids. Lewis acids include, but are not limited to, aluminum, boron, iron, tin, and thiamin. Tungsten, magnesium, copper, antimony, phosphorus, silver, ytterbium, scandium, nickel Exemplary Lewis acids include, but are not limited to, Lewis acids of zinc, zinc ions, and zinc chloride. Examples include AlBr3, AlCl3, BCl3, boron trichloride methyl sulfide, BF3, boron trifluoride methyl ethene ether, boron trifluoride methyl sulfide, boron trifluoride tetrahydrofuran, dicyclohexane Silboron trifluoromethanesulfonate, iron(III) bromide, iron(III) chloride, tin(IV) Chloride, Titanium(IV) Chloride, Titanium(IV) Isopropoxide, Cu(OTf)2, CuCl2, CuBr2, Salt zinc halide, alkylaluminum halide (Rn AlX 3-n , where R is hydrocarbyl ), Zn(OTf)2, ZnCl2, Yb(OTf)3, Sc(OTf)3, MgBr2, NiCl2, Sn(OTf)2, Ni(OTf)2, and Mg (OTf)2, but are not limited to these.

[0047] As used herein, an "N-containing heterocycloalkyl" refers to an N-containing heterocycloalkyl group having one or more carbon atoms. Cycloalkyl groups substituted with heteroatoms, at least one of which is a nitrogen atom In addition to nitrogen, suitable heteroatoms include oxygen and sulfur atoms. N-containing heterocycloalkyls include, but are not limited to, optionally substituted N- Examples of heterocycloalkyl-containing moieties include morpholinyl, piperidinyl, pyrrolidinyl, and the like. Examples of the alkyl groups include aryl, imidazolidinyl, oxazolidinyl, and thiazolidinyl. Not limited to.

[0048] As used herein, "optionally" when used to describe a radical moiety "Substituted," e.g., optionally substituted alkyl, means that such moiety has one or more substituents. Examples of such substituents include halo, cyano, Nitro, optionally substituted haloalkyl, azido, epoxy, optionally substituted heteroaromatic groups aryl, optionally substituted heterocycloalkyl; [ka] (where R A , R B , and R C independently at each occurrence, represent a hydrogen atom, an alkyl, an alkenyl, Alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, hetero aryl, or heterocycloalkyl, or R A and R B are combined together with the atoms forming a saturated or unsaturated carbocyclic ring, wherein the ring is optionally substituted and one or more ring atoms are optionally substituted with a heteroatom), In some embodiments, the radical moiety is an optionally substituted heterocyclic group. aryl, optionally substituted heterocycloalkyl, or optionally substituted saturated or When an unsaturated carbocyclic ring is optionally substituted, the optionally substituted heteroaryl, optionally substituted heterocycloalkyl or optionally substituted saturated or unsaturated carbocyclic rings; The substituents, when substituted, are optionally further substituted with further substituents. In some embodiments, any of the groups described herein is not substituted with a substituent. When optionally substituted, the substituents attached to the group are substituted unless otherwise specified. It has not been done.

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

[0050] As used herein, a "linker" refers to a linker that connects a binding agent to one or more of the compounds described herein. compounds, e.g., bivalent, trivalent, or multivalent compounds covalently linked to payload compounds and enhancers. refers to a part.

[0051] As used herein, "amide synthesis conditions" refers to, for example, carboxylic acids, activated carboxylic acids, to achieve amide formation by reaction of carboxylic acids or acyl halides with amines In some instances, "amide synthesis conditions" refer to suitable reaction conditions for the synthesis of a carboxylic acid and an amide. Some of these examples refer to reaction conditions suitable for achieving the formation of an amide bond between the amines. In some cases, the carboxylic acid is first converted to an activated carboxylic acid, and then the activated carboxylic acid is reacted with the activated carboxylic acid. The carboxylic acid reacts with the amine to form an amide. The conditions include, but are not limited to, dicyclohexylcarbodiimide (DCC), diisopropyl Dicarboxylic acid (DIC), (benzotriazol-1-yloxy)tris(dimethylamino)phosphatase Sulfonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)trifluoromethyl Pyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazo (1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), Bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), O-(benzotri Azol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU ), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoro Borate (TBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine Dinium 3-oxide hexafluorophosphate (HATU), N-ethoxycarbonyl-2-ethoxy hydroxy-1,2-dihydroquinoline (EEDQ), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide Imide (EDC), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (C IP), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), and carbonyldiimidazoline These include the use of reagents to effect the reaction of carboxylic acids with amines, including CDI. In some examples, the carboxylic acid is first activated. carboxylic acid ester, and then treating the activated carboxylic acid ester with an amine to give , to form an amide bond. In some embodiments, the carboxylic acid is treated with a reagent. deprotonates the carboxylic acid, followed by protonation by the deprotonated carboxylic acid. Nucleophilic attack on the protonated reagent results in a product complex with the deprotonated carboxylic acid. The carboxylic acid is activated by forming a bond. The activated carboxylic acid ester is more susceptible to nucleophilic attack by amines than before the carboxylic acid is activated. This results in amide bond formation. The phosphoric acid is described as activated. Exemplary reagents include DCC and DIC. do.

[0052] As used herein, "positional isomer," "positional isomers," or "positional isomers" refers to a group of isomers that are heterocyclic or heterocyclic. A "mixture of isomers" refers to the reaction of a suitable azide (e.g., -N3, or PE) with a suitable alkyne. 1,3-cycloaddition or strain-promoted alkyne-azide cycloaddition (S-G-N3 derivatized antibody) derived from In one embodiment, the term "PAAC" refers to the product of a click reaction. For example, positional isomers and mixtures of positional isomers can be synthesized by the click reaction products shown below. It is characterized by: [ka] In some embodiments, multiple suitable azides and multiple suitable alkynes are catalyzed toward the product. In this synthesis scheme, each azide -Alkyne pairs may participate in one or more independent click reactions to form regioisomeric click products For example, one skilled in the art can generate a mixture of the first preferred A suitable azide can be reacted independently with a first suitable alkyne, and a second suitable azide can be reacted with In a sample of the ADC described herein, which can be reacted independently with a second suitable alkyne, four possible click reaction regioisomers or a mixture of four possible click reaction regioisomers As a further example, those skilled in the art will recognize that a first suitable azide independently reacting with a first suitable alkyne en route to the product; and a second suitable azide can be reacted independently with a second suitable alkyne, In the samples of LP described in the specification, the four possible click reaction regioisomers or the four possible click It will be appreciated that a mixture of regioisomers may result from the back reaction.

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

[0054] As used herein, a "therapeutically effective amount" refers to a dose that is effective in treating or managing a disease or disorder. to provide a therapeutic benefit to a patient in or to treat one or more symptoms associated with a disease or disorder It refers to an amount (e.g., of a compound) that is sufficient to delay or minimize the effects of an allergic reaction.

[0055] Particular groups, moieties, substituents, and atoms are defined as the atoms to which they are attached. The bond or bonds are shown with a wavy line crossing them to indicate A propyl group, shown as follows: [ka] The phenyl group substituted with has the following structure: [ka] As used herein, a cyclic group (e.g., an aromatic group) is defined as having a bond between the ring atoms. , heteroaromatic, fused ring, and saturated or unsaturated cycloalkyl or heterocycloalkanes Diagrams depicting substituents attached to a cyclic group indicate that the cyclic group is a ring-type group as described herein, unless otherwise specified. Any ring position in the cyclic group may be bonded according to techniques described or known in the art to which this disclosure pertains. It is intended to indicate that the substituent may be substituted at any position or on any ring in a fused ring group. For example, when the subscript q is an integer from 0 to 4 and the substituent R 1 The location of that is, any vertex of the bond line structure, i.e., a direct bond to a specific ring carbon atom Not yet [ka] is the substituent R 1 includes the following non-limiting example groups attached to specific ring carbon atoms: [ka] .

[0056] As used herein, the phrase "reactive linker" or the abbreviation "RL" means: for example, [ka] (where RG is a reactive group and SP is a spacer group). As described herein, a reactive linker refers to a monovalent group that contains multiple reactive groups. The spacer group may connect the reactive group to another group, For example, a reactive linker (RL) is any bivalent moiety that crosslinks to a payload. For the preparation of antibody conjugates as described herein together with an associated payload. The present invention provides intermediates ("linker-payloads") useful as synthetic precursors for reactive linkers. The group may be a group selected from the group consisting of an antibody, a modified antibody, or an antigen-binding fragment thereof, or an enhancing group. It contains a reactive group ("RG"), which is a functional group or moiety that can react with a reactive moiety. by reacting the reactive group with an antibody, modified antibody, or antigen-binding fragment thereof, which also has a linking group. The resulting moiety includes the "binder linker" ("BL") portion of the conjugate described herein. In certain embodiments, the "reactive group" is a cis- or trans-linked group of an antibody or antigen-binding fragment thereof. A functional group or moiety (e.g., maleimide or N-hydroxybenzoate) that reacts with lecithin or lysine residues. In some embodiments, the "reactive group" is a chlorine-containing ester of A functional group or moiety that can undergo click chemistry (e.g., click chemistry, H Uisgen, Proc. Chem. Soc. 1961; Wang et al., J. Am. Chem. Soc. 2003; and A (See Gard et al., J. Am. Chem. Soc. 2004). In embodiments, the reactive group is an alkyne capable of undergoing a 1,3 cycloaddition reaction with an azide. Suitable such reactive groups include strained alkynes, e.g., strain-promoting alkyne-alkynes. Suitable for cycloaddition of cyclopentyl groups (SPAAC), cycloalkynes such as cyclooctynes, benzyl groups, cyclized alkynes, and can undergo 1,3 cycloaddition with alkynes in the absence of a copper catalyst. Suitable alkynes include, but are not limited to, dibenzoyl alkynes. Zoazacyclooctyne or [ka] , dibenzocyclooctyne or [ka] , biarylazacyclooctynone or [ka] , difluorinated cyclooctyne or [ka] , substituted, for example, fluorinated alkynes, aza-cycloalkynes, bicycle[6.1.0]nonynes or [ka] (BCN, where R is alkyl, alkoxy, or acyl), and derivatives thereof Particularly useful alkynes include, but are not limited to, [ka] The linker-payload containing such a reactive group is functionalized with an azide group. Such functionalized antibodies are useful for conjugating antibodies containing azido- Antibodies functionalized with polyethylene glycol groups are included. Such functionalized antibodies include antibodies having at least one glutamine residue, e.g., heavy chain Gln295. The resulting product is treated with an enzyme, transglutaminase, to give a product bearing amino and azide groups. It can be obtained by treating with a compound.

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

[0058] As used herein, the phrase "biodegradable moiety" refers to a moiety that is biodegradable by normal biological processes. Decompose in vivo into non-toxic, biocompatible components that can be removed from the body by In some embodiments, the biodegradable portion is biodegradable for about 90 days or less, about 60 days or less, or is completely or substantially degraded in vivo over a period of about 30 days or less, wherein the extent of degradation is Based on percent mass loss of the biodegradable portion, where complete degradation corresponds to 100% mass loss. Exemplary biodegradable moieties include aliphatic polyesters, such as poly(ε-caproate). Poly(3-hydroxybutyrate) (PCL), Poly(glycolic acid) (PGA), Poly(3-hydroxybutyrate) (PHB), Poly(glycolic acid) (PGA), Poly(lactic acid) (PLA) and its copolymers with glycolic acid (i.e., poly(D,L-lactide-co) glycolide) (PLGA), each of which is incorporated herein by reference in its entirety. Vert M, Schwach G, Engel R, and Coudane J (1998), incorporated herein by reference. J Control Release 53(1-3):85-92; Jain RA (2000) Biomaterials 21(23):2475-2 490; Uhrich KE, Cannizzaro SM, Langer RS, and Shakesheff KM (1999) Chem ical Reviews 99(11):3181-3198; and Park TG (1995) Biomaterials 16(15):112 3-1130).

[0059] As used herein, the terms "effective amount," "physiologically effective amount," or "prophylactically effective amount" are used interchangeably. The phrase "therapeutic agent" refers to a compound that, when administered to a subject in need of such treatment, effects treatment. A "physiologically effective amount" of an active substance refers to an amount of a compound that is sufficient to produce an externally observable effect on a patient. A physiologically effective amount refers to the amount of an active substance that has a noticeable and significant effect. It does not require special equipment to determine the outcome, and is based on one of the patient's characteristics (e.g., phenotype). For example, a physiologically effective amount of a compound disclosed herein may affect a therapeutic Therapeutic effects of the drug on the patient's behavior by alleviating one or more of the symptoms of the disease It has a significant effect that can be observed externally. Therefore, by observing the patient and By observing whether any changes occur in the patient due to the active substance, an effective amount of the active substance can be determined. It can be determined whether or not a dose has been administered.

[0060] As used herein, the phrase "binder linker" or "BL" refers to a binder (e.g., For example, an antibody or antigen-binding fragment thereof may be coupled to a payload compound (e.g., a biotin-binding fragment thereof) as described herein. octahydrophenanthrenecarboxamide), and optionally one or more side chain compounds. refers to any divalent, trivalent, or polyvalent group or moiety that bonds, connects, or joins. Suitable binder linkers for the antibody conjugates described herein are those that allow the antibody to circulate Stable enough to take advantage of the ring half-life and at the same time, to prevent antigen-mediated internalization of the conjugate. The linker may be cleavable or Cleavable linkers can be non-cleavable. Cleavable linkers can be cleaved by intracellular metabolism after internalization, e.g., hydrolysis. A linker that is cleaved by decomposition, reduction, or enzymatic cleavage. Carriers are phospholipids that release their bound payloads via lysosomal degradation of the antibody after internalization. Suitable linkers include acid labile linkers, hydrolytically labile linkers, , enzyme-cleavable linkers, reduction-labile linkers, self-immolative linkers, and non-cleavable linkers Suitable linkers include, but are not limited to, peptides, glycosaminoglycans, and the like. Nido, succinimide-thioether, polyethylene glycol (PEG) unit, hydrazone, A mal-caproyl unit, a dipeptide unit, a valine-citrulline unit, and a para-aminobenzyl Also included are, but are not limited to, those that are or contain alkyl (PAB) units. In some embodiments, the binder linker (BL) is a reactive group (R G) with a binding agent, e.g., a reactive portion of an antibody, modified antibody, or antigen-binding fragment thereof. It includes a portion formed by

[0061] In some examples, the BL comprises the following moiety: [ka] or triazolyl positional isomers, wherein: [ka] is a bond to a binding agent. In some examples, BL is a bond to a binding agent. [ka] where: [ka] is a bond to a binding agent. In some examples, BL is a bond to a binding agent. [ka] or triazolyl positional isomers, wherein: [ka] is a bond to a binding agent. In some examples, BL is a bond to a binding agent. [ka] where: [ka] is a bond to a cysteine ​​of the antibody or antigen-binding fragment thereof. The following part: [ka] where: [ka] is a bond to a lysine of an antibody or antigen-binding fragment thereof.

[0062] (Compounds and Payloads) In some instances, provided herein are compounds or pharmaceuticals having the structure of Formula (I): A pharmaceutically acceptable salt, solvate, or stereoisomeric form of: [ka] (In the formula, Q 1 and Q 2 each is independently —CH—, —C(O)—, —C(H)(OH)—, or —C(OH)—; W is -CH2-, -N(H)-, or -O-; R 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 where R 1 and R 2 is simultaneously has -H instead; 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 alkylene, substituted alkylene (including but not limited to oxo-substituted, i.e., ═O). ), heteroalkylene, and substituted heteroalkylene (including but not limited to, oxo-substituted (i.e., is selected from the group consisting of (including ═O); Z is selected from the group consisting of -OH and -NH; R 5 is alkyl, heterocycloalkyl, or substituted heterocycloalkyl, wherein each heterocycloalkyl or substituted heterocycloalkyl is selected from nitrogen and oxygen. and at least one -OH and -CH2OH group. containing a substituent, or at least one primary or secondary nitrogen, e.g., O-glucose; Each R 6 represents in each case -H, an amino acid residue, an N-alkyl amino acid residue, a peptide, or alkyl; and Each R 7 are independently halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O- Amino acid residues and O-PEG n where each n is an integer from 0 to 3.

[0063] In certain embodiments of Formula I, R 5 is a heterocycloalkyl or substituted heterocycloalkyl Useful heterocycloalkyl groups include tetrahydropyranyl, glycopyranyl, and the like. These groups may be substituted or unsubstituted. In some embodiments, they are unsubstituted. Exemplary substituents include at least one hydroxyl group. , at least one primary nitrogen, or at least one secondary nitrogen.

[0064] In certain embodiments of formula I, R 6 is, in each occurrence, independently an amino acid residue, an N-alkyl Those skilled in the art will recognize that amino acid residues are either achiral or chiral. It will be recognized that the amino acid may be, for example, an L-amino acid or a D-amino acid. Typically, the amino acid side chain is the side chain of any amino acid known to those skilled in the art. In some embodiments, the side chain is selected from the group consisting of histidine, alanine, isoleucine, and the like. , arginine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine Inosin, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, Phosphorus, ornithine, selenocysteine, serine, glycine, homoglycine (e.g., β-phosphoric acid, Those skilled in the art will appreciate that the peptide may be, for example, racemic DL- Contains amino acids or non-racemic D- or L-amino acids and their diastereomeric mixtures It will be recognized that the side chains of the peptides may be achiral or chiral. As described in the context of the amino acids listed above, those skilled in the art will recognize that N-alkyl amino acid residues are The terminal amino group of the amino acid residue or the terminal amino group of the peptide is It will be recognized that alkyl groups such as N-methylamino are included in the alkyl groups. Examples include N-amino acids and N-ethyl amino acids.

[0065] In certain embodiments of Formula I, each R 7 Ha, Halo, C 1-6 Alkyl, C 1-6 Alkoxy, - CN, O-glucose, O-amino acid residue, or O-PEG n where each n is an integer from 0 to 3. In certain embodiments, the O-amino acid residue is an HO-amino acid, as defined above. In one embodiment, the O-PEG residue n is for the case where n=0. O-PEG n is when n=1. In another embodiment, O-PEG n is n=2 In another embodiment, O-PEG n is for n=3.

[0066] In some instances, provided herein are compounds or pharmaceuticals having the structure of Formula (Ia): A pharmaceutically acceptable salt, solvate, or stereoisomeric form of: [ka] (In the formula, Q 1 and Q 2 each is independently —CH—, —C(O)—, —C(H)(OH)—, or —C(OH)—; W is -CH2-, -N(H)-, or -O-; R 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 where R 1 and R2 is simultaneously has -H instead; 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 alkylene, substituted alkylene (including but not limited to oxo-substituted, i.e., ═O). ), heteroalkylene, and substituted heteroalkylene (including but not limited to, oxo-substituted (i.e., is selected from the group consisting of (including ═O); Z is selected from the group consisting of -OH and -NH; R 5 is alkyl, heterocycloalkyl, or substituted heterocycloalkyl, wherein each heterocycloalkyl or substituted heterocycloalkyl is selected from nitrogen and oxygen. and at least one -OH and -CH2OH group. containing a substituent, or at least one primary or secondary nitrogen, e.g., O-glucose; Each R 6 represents in each case -H, an amino acid residue, an N-alkyl amino acid residue, a peptide, or alkyl; and Each R 7 are independently halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O- Amino acid residues and O-PEG n where each n is an integer from 0 to 3.

[0067] In certain embodiments of Formula Ia, R 5 is a heterocycloalkyl or substituted heterocycloalkyl Useful heterocycloalkyl groups include tetrahydropyranyl, glycopyranyl, and the like. These groups may be substituted or unsubstituted. In some embodiments, they are unsubstituted. Exemplary substituents include at least one hydroxyl group. , at least one primary nitrogen, or at least one secondary nitrogen.

[0068] In certain embodiments of Formula Ia, R 6 is, in each occurrence, independently an amino acid residue, an N-alkyl Those skilled in the art will recognize that amino acid residues are either achiral or chiral. It will be recognized that the amino acid may be, for example, an L-amino acid or a D-amino acid. Typically, the amino acid side chain is the side chain of any amino acid known to those skilled in the art. In some embodiments, the side chain is selected from the group consisting of histidine, alanine, isoleucine, and the like. , arginine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine Inosin, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, Phosphorus, ornithine, selenocysteine, serine, glycine, homoglycine (e.g., β-phosphoric acid, Those skilled in the art will appreciate that the peptide may be, for example, racemic DL- Amino acids or non-racemic D- or L-amino acids, including their diastereomeric mixtures It will be recognized that the side chains of the peptide may be achiral or chiral. in connection with amino acids. Those skilled in the art will recognize that N-alkylamino acids The residue is a nucleotide as defined herein at the terminal amino group of the amino acid or at the terminal amino group of the peptide. It will be recognized that the term "alkyl" includes alkyl substituents that may be present.

[0069] In certain embodiments of Formula Ia, R 7 Ha, Halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O -glucose, O-amino acid residues, or O-PEG n where each n is an integer from 0 to 3. In certain embodiments, the O-amino acid residue is an HO-amino acid residue as defined above. In one embodiment, O-PEG n is for n=0. In another embodiment , O-PEG n is when n=1. In another embodiment, O-PEG n is the case of n=2 In another embodiment, O-PEG n is for n=3.

[0070] In one embodiment of Formula I or Ia, Q 1 is -CH2- and Q 2 is -C(O)-. In an embodiment, Q 1 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 is -C(H)(OH)-.

[0071] In one embodiment of Formula I or Ia, Q 1 is -CH2- and Q 2 is -C(O)- and W is -CH 2-. In another embodiment, Q 1 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 Another reality In the embodiment, Q 1 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 is -CH2- and Q 2 is -C(O)- W is -CH2-, and R 1 is -H, and R 2 is —CH 2 NH 2 . In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -H, and R 2 is R 3 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- and W is , -CH2-, and R 1 is -H, and R 2 is R 4 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -H, and R 2 is R 5 It is. In the embodiment of the present invention, Q 1 is -CH2- and Q 2is -C(O)-, W is -CH2-, and R 1 is -H, and R 2 -OR 5 In another embodiment, Q 1 is -CH2- and Q 2 teeth, -C(O)-, W is -CH2-, and R 1 is -H, and R 2 are amino, dimethylamino, Droxil, [ka] In another embodiment, Q is selected from the group consisting of 1 is -CH2- and Q 2 is -C(O)- W is -CH2-, and R 1 is -OH and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or - OR 5 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- and W is -C 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 is -CH2NH2 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- and W is -CH2- , R 1 is -OH and R 2 is R 3 In another embodiment, Q1 is -CH2- and Q 2 teeth , -C(O)-, W is -CH2-, and R 1 is -OH and R 2 is R 4 Another embodiment In Q 1 is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH R 2 is R 5 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- , W is -CH2-, and R 1 is -OH and R 2 -OR 5 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH and R 2 Is, A amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -CH2- and Q 2 is -C(O)- W is -CH2-, and R 1 is -NH2 and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- and W is - CH2- and R 1is -NH2 and R 2 is —OH. In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -NH2 and R 2 is -CH2NH2 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- and W is -CH2- Yes, R 1 is -NH2 and R 2 is R 3 In another embodiment, Q 1 is -CH2- , Q 2 is -C(O)-, W is -CH2-, and R 1 is -NH2 and R 2 is R 4 Another reality In the embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 teeth,- NH2 and R 2 is R 5 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- W is -CH2-, and R 1 is -NH2 and R 2 -OR 5 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -NH2 , R 2 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -CH2- and Q 2 is -C(O)- 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 -CH2- and Q 2 is -C(O)- and W is -CH2- and R 1 is alkyl, and R 2 is —OH. In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is alkyl, and R 2 is —CH 2 NH 2 . In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is alkyl, and R 2 is R 3 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is alkyl, and R 2 is R 4 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- and W is -CH2- and R 1 is alkyl, and R 2 is 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 -O -R 5 In another embodiment, Q 1 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] is selected from the group consisting of:

[0072] In another embodiment of Formula I or Ia, Q 1 is -CH2- and Q 2 is -C(O)- and W is - CH2- and R 1 -OH or -OP(O)(OR 6 )(OH) and R 2 is —H. In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH, R 2 is -H. In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- and W is , -CH2-, and R 1 is -OP(O)(OR 6 )(OH) and R 2 is -H. In any one of the embodiments, R 6 may be selected from the group consisting of hydroxyl and methyl. do.

[0073] In one embodiment of Formula I or Ia, Q 1 is -CH2- and Q 2 is -C(O)- and W is -O- In another embodiment, Q 1 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 Another implementation In an embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is -H Yes, R 2 is —OH. In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- W is -O- and R 1 is -H, and R 2 is —CH 2 NH 2 . In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is -H, and R 2 is R 3 in In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- and W is -O- R 1 is -H, and R 2 is R 4 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is -H, and R 2 is R 5In another embodiment, Hey, Q 1 is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is -H, and R 2 -OR 5 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- and W is -CH2- and R 1 is -H, and R 2 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -CH2- and Q 2 is -C(O)- 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 -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- Ri, Q 2 is -C(O)-, W is -O-, and R 1 is -OH and R 2 is -CH2NH2. In the embodiment of the present invention, Q 1 is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 teeth , -OH, and R2 is R 3 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O )-, W is -O-, and R 1 is -OH and R 2 is R 4 In another embodiment, , Q 1 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 is -CH2- and Q 2 is -C(O)- and W is -O- and R 1 is -OH and R 2 -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 Amino, humidifier ethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -CH2- and Q 2 is -C(O)- W is -O- and R 1 is -NH2 and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -O -R 5 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- and W is -O- and R 1 is -NH2 and R 2 is —OH. In another embodiment, Q 1 is -CH2- Ri, Q 2 is -C(O)-, W is -O-, and R 1 is -NH2 and R 2 is -CH2NH2. In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is -NH2 and R 2 is R 3 In another embodiment, Q 1 is -CH2- and Q 2 teeth,- C(O)-, W is -O-, and R 1 is -NH2 and R 2 is R 4 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is -NH2 and R 2 is R 5 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- and W is , -O-, and R 1 is -NH2 and R 2 -OR 5 In another embodiment, Q 1 -C H2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -NH2 and R 2 is Amino , dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -CH2- and Q 2 is -C(O)- W is -O- and R 1 is alkyl, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 ,also HA-OR 5 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- and W is , -O-, and 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 2NH2. In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- and W is -O - and R 1 is alkyl, and R 2 is R 3 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is alkyl, and R 2 is R 4 is In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is alkyl, and R 2 is R 5 In another embodiment, Q 1is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is alkyl, and R 2 -OR 5 Another In one embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 teeth , alkyl, and R 2 is amino, dimethylamino, hydroxyl, [ka] is selected from the group consisting of:

[0074] In another embodiment of Formula I or Ia, Q 1 is -CH2- and Q 2 is -C(O)- and W is - O- and R 1 -OH or -OP(O)(OR 6 )(OH) and R 2 is —H. In another embodiment Te, Q 1 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 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. In any one of them, R 6 may be selected from the group consisting of hydroxyl and methyl.

[0075] In one embodiment of Formula I or Ia, Q1 is -CH2- and Q 2 is -C(O)- and W is -NH In another embodiment, Q 1 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 Another reality In the embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -NH-, and R 1 -H and R 2 is —OH. In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- W is -NH- and R 1 is -H, and R 2 is —CH 2 NH 2 . In another embodiment , Q 1 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 is -CH2- and Q 2 is -C(O)- and W is -NH- and R 1 is -H, and R 2 is R 4 In another embodiment, Q 1 is -CH2- , Q 2 is -C(O)-, W is -NH-, and R 1 is -H, and R 2 is R 5 Another implementation In an embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -NH-, and R 1 is -H Yes, R 2 -OR 5 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- W is -CH2- and R 1 is -H, and R 2 are amino, dimethylamino, hydroxy Lu, [ka] In another embodiment, Q is selected from the group consisting of 1 is -CH2- and Q 2 is -C(O)- 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 -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- Ri, Q 2 is -C(O)-, W is -NH-, and R 1 is -OH and R 2 is -CH2NH2. In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -NH-, and R 1 is -OH and R2 is R 3 In another embodiment, Q 1 is -CH2- and Q 2 -C (O)-, W is -NH-, and R 1 is -OH and R 2 is R 4 In another embodiment, Te, Q 1 is -CH2- and Q 2 is -C(O)-, W is -NH-, and R 1 is -OH and R 2 is R 5 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- and W is -NH- and R 1 is -OH and R 2 -OR 5 In another embodiment, Q 1 is -CH2 - and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH and R 2 is amino, di Methylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -CH2- and Q 2 is -C(O)- W is -NH- and R 1 is -NH2 and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or - OR 5 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- and W is -N H- and R 1 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 is -NH2 and R 2 is -CH2NH2 In another embodiment, Q 1 is -CH2- and Q 2 is —C(O)—, W is —NH—, R 1 is -NH2 and R 2 is R 3 In another embodiment, Q 1 is -CH2- and Q 2 teeth , -C(O)-, W is -NH-, and R 1 is -NH2 and R 2 is R 4 Another embodiment In Q 1 is -CH2- and Q 2 is -C(O)-, W is -NH-, and R 1 is -NH2 R 2 is R 5 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- , W is -NH-, and R 1 is -NH2 and R 2 -OR 5 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -NH2 and R 2 teeth, Amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -CH2- and Q 2 is -C(O)- 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 -CH2- and Q 2 is -C(O)- and W is -NH- and R 1 is alkyl, and R 2 is —OH. In another embodiment, Q 1 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 is -CH2- and Q 2 is -C(O)- and W is -NH- and R 1 is alkyl, and R 2 is R 3 In another embodiment, Q 1 teeth , -CH2-, and Q 2 is -C(O)-, W is -NH-, and R 1 is alkyl, and R 2 teeth, R 4 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- and W is -NH- and R 1 is alkyl, and R 2 is R 5In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -NH-, and R 1 is alkyl, and R 2 -OR 5 in In another embodiment, Q 1 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] is selected from the group consisting of:

[0076] In another embodiment of Formula I or Ia, Q 1 is -CH2- and Q 2 is -C(O)- and W is - NH- and R 1 -OH or -OP(O)(OR 6 )(OH) and R 2 is —H. In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -NH-, and R 1 is -OH and R 2 is -H. In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)- and W is , -NH-, and R 1 is -OP(O)(OR 6 )(OH) and R 2 is -H. In any one of the embodiments, R 6 may be selected from the group consisting of hydroxyl and methyl. do.

[0077] In one embodiment of Formula I or Ia, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- and W is , -CH2-. 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 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 in In another embodiment, Q 1 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 is -C(H)(OH)- and Q 2 is -C(O)- and W is -CH2- and R 1 is -H, and R 2 is R 3 In another embodiment, Q 1 is -C(H)(OH)- Yes, Q 2 is -C(O)-, W is -CH2-, and R 1 is -H, and R 2 is R 4 Another In one embodiment, Q 1 is -C(H)(OH)- and Q 2is —C(O)—, W is —CH—, R 1 is -H, and R 2 is R 5 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 -OR 5 Another implementation In an embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 teeth , -H, R 2 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(H)(OH)- and Q 2 -C (O)-, W is -CH-, and R 1 is -OH and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , -OR 5 In another embodiment, Q 1 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 is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH and R 2 is —CH 2 NH 2 . In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- W is -CH2- and R 1 is -OH and R 2 is R 3 In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH and R 2 is R 4 In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH and R 2 is R 5 In another embodiment, Q 1 teeth,- C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH and R 2 -O -R 5 In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- and W is , -CH2-, and R 1 is -OH and R 2 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(H)(OH)- and Q 2 -C (O)-, W is -CH-, and R 1 is -NH2 and R 2-OH, -CH2NH2, R 3 , R 4 , R 5 , -OR 5 In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- W is -CH2-, and R 1 is -NH2 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 -NH2 and R 2 is —CH 2 NH 2 . In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- W is -CH2- and R 1 is -NH2 and R 2 is R 3 In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -NH2, R 2 is R 4 In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- , W is -CH2-, and R 1 is -NH2 and R 2 is R 5 In another embodiment, Q 1 teeth , -C(H)(OH)-, and Q 2 is -C(O)-, W is -CH2-, and R 1 is -NH2 and R 2 teeth , -OR 5 In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- , W is -CH2-, and R 1 is -NH2 and R 2 are amino, dimethylamino, and hydroxyl , [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(H)(OH)- and Q 2 -C (O)-, W is -CH-, and 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(H)(OH)- and Q 2 is -C(O)- W is -CH2-, and R 1 is alkyl, and R 2 is —OH. Hey, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 Is, Al Kill and R 2 is —CH 2 NH 2 . In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is alkyl, and R 2 is R 3 Another In one embodiment, Q 1 is -C(H)(OH)- and Q2 is —C(O)—, W is —CH—, R 1 is alkyl, and R 2 is R 4 In another embodiment, Q 1 is -C(H)(OH)- Ri, Q 2 is -C(O)-, W is -CH2-, and R 1 is alkyl, and R 2 is R 5 is. In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- and W is -CH2- R 1 is alkyl, and R 2 -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, A amino, dimethylamino, hydroxyl, [ka] is selected from the group consisting of:

[0078] In another embodiment of Formula I or Ia, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- and W is -CH2- and R 1 -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. In regards to 1 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 teeth,- C(O)-, W is -CH-, and R 1 is -OP(O)(OR 6 )(OH) and R 2 is -H. In any one of the preceding embodiments of the paragraph, R 6 consists of hydroxyl and methyl It may be selected from the group:

[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 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 is. 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)-, W is -O-, and R 1 is -H, and R 2 is -CH2NH2. In the embodiment, Q 1 is -C(H,OH)- and Q 2 is -C(O)-, W is -O-, and R1 teeth , -H, R 2 is R 3 In another embodiment, Q 1 is -C(H,OH)- and Q 2 teeth,- C(O)-, W is -O-, and R 1 is -H, and R 2 is R 4 In another embodiment, Te, Q 1 is -C(H,OH)- and Q 2 is -C(O)-, W is -O-, and R 1 is -H, and R 2 is R 5 In another embodiment, Q 1 is -C(H,OH)- and Q 2 is -C(O)-, W is -O- and R 1 is -H, and R 2 -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] In another embodiment, Q is selected from the group consisting of 1 is -C(H)(OH)- and Q 2 -C (O)-, W is -O-, and R 1 is -OH and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 ,also HA-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 teeth, -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)- and W is -O- and R 1 is -OH and R 2 is R 3 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 Yes In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- and W is -O- Yes, R 1 is -OH and R 2 is R 5 In another embodiment, Q 1 is -C(H)(OH)- Yes, Q 2 is -C(O)-, W is -O-, and R 1 is -OH and R 2 -OR 5 It is. In the embodiment of the present invention, 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] In another embodiment, Q is selected from the group consisting of 1 is -C(H)(OH)- and Q 2 -C (O)-, W is -O-, and R 1 is -NH2 and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 ,also HA-OR 5 In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- , W is -O-, and R 1 is -NH2 and R 2 is —OH. In another embodiment, Q 1 teeth , -C(H)(OH)-, and Q 2 is -C(O)-, W is -O-, and R 1 is -NH2 and R 2 teeth, In another embodiment, Q is —CH 2 NH 2 . 1 is -C(H)(OH)- and Q 2 is -C(O)- , W is -O-, and R 1 is -NH2 and R 2 is R 3 In another embodiment, Q 1 teeth, -C(H)(OH)-, and Q 2 is -C(O)-, W is -O-, and R 1 is -NH2 and R 2 is R 4 In another embodiment, Q 1 is -C(H)(OH)- and Q 2is -C(O)- and W is - O- and R 1 is -NH2 and R 2 is R 5 In another embodiment, Q 1 is -C(H)(OH )- and Q 2 is -C(O)-, W is -O-, and R 1 is -NH2 and R 2 -OR 5 Yes In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- and W is -O- Yes, R 1 is -NH2 and R 2 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(H)(OH)- and Q 2 -C (O)-, W is -O-, and 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(H)(OH)- and Q 2 is -C(O)- W is -O- and R is 1 is alkyl, and R 2 is —OH. Te, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -O-, and R 1 is an alkyl Yes, R 2is —CH 2 NH 2 . In another embodiment, Q 1 is -C(H)(OH)- and Q 2 teeth,- C(O)-, W is -O-, and R 1 is alkyl, and R 2 is R 3 Another embodiment In Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -O-, and R 1 Is, Al Kill and R 2 is R 4 In another embodiment, Q 1 is -C(H)(OH)- and Q 2 teeth, -C(O)-, W is -O-, and R 1 is alkyl, and R 2 is R 5 Another embodiment In Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -O-, and R 1 Is, Al Kill and R 2 -OR 5 In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -O-, and R 1 is alkyl, and R 2 is amino, dimethyl amino, hydroxyl, [ka] is selected from the group consisting of:

[0080] In another embodiment of Formula I or Ia, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- and W is -O- and R 1 -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. In Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -O-, and R 1 is -OH and R 2 is -H. In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O )-, W is -O-, and R 1 is -OP(O)(OR 6 )(OH) and R 2 is -H. This paragraph In any one of the foregoing embodiments, R 6 is selected from the group consisting of hydroxyl and methyl can be selected from:

[0081] In one embodiment of Formula I or Ia, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- and W is , -NH-. In another embodiment, Q 1 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 is In another embodiment, Q 1 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 is -C(H)(OH)- Yes, Q 2 is -C(O)-, W is -NH-, 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 -NH- R 1 is -H, and R 2 is R 3 In another embodiment, Q 1 is -C(H)(OH)- , Q 2 is -C(O)-, W is -NH-, and R 1 is -H, and R 2 is R 4 Another implementation In an embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 teeth , -H, R 2 is R 5 In another embodiment, Q 1 is -C(H)(OH)- and Q 2 teeth, -C(O)-, W is -NH-, and R 1 is -H, and R 2 -OR 5 In another embodiment, Hey, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -H Yes, R 2 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of1 is -C(H)(OH)- and Q 2 -C (O)-, W is -NH-, and R 1 is -OH and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 ,also HA-OR 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 —OH. In another embodiment, Q 1 teeth , -C(H)(OH)-, and Q 2 is -C(O)-, W is -NH-, and R 1 is -OH and R 2 teeth, In another embodiment, Q is —CH 2 NH 2 . 1 is -C(H)(OH)- and Q 2 is -C(O)- , W is -NH-, and R 1 is -OH and R 2 is R 3 In another embodiment, Q 1 teeth, -C(H)(OH)-, and Q 2 is -C(O)-, W is -NH-, and R 1 is -OH and R 2 is R 4 In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- and W is - NH- and R 1 is -OH and R 2 is 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 -OR 5 Yes In another embodiment, Q 1 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] In another embodiment, Q is selected from the group consisting of 1 is -C(H)(OH)- and Q 2 -C (O)-, W is -NH-, and R 1 is -NH2 and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , -OR 5 In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- W is -NH- and R 1 is -NH2 and R 2 is —OH. In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -NH2 and R 2 is —CH 2 NH 2 . In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- W is -NH- and R 1 is -NH2 and R 2is R 3 In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -NH2 and R 2 is R 4 In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH- and R 1 is -NH2 and R 2 is R 5 In another embodiment, Q 1 teeth,- C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -NH2 and R 2 -O -R 5 In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- and W is , -NH-, and R 1 is -NH2 and R 2 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(H)(OH)- and Q 2 -C (O)-, W is -NH-, and 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(H)(OH)- and Q2 is -C(O)- W is -NH- and R 1 is alkyl, and R 2 is —OH. Te, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 is an alkyl and R 2 is —CH 2 NH 2 . In another embodiment, Q 1 is -C(H)(OH)- and Q 2 teeth , -C(O)-, W is -NH-, and R 1 is alkyl, and R 2 is R 3 Another implementation In an embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 teeth , alkyl, and R 2 is R 4 In another embodiment, Q 1 is -C(H)(OH)-, Q 2 is -C(O)-, W is -NH-, and R 1 is alkyl, and R 2 is R 5 Another In one embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 is alkyl, and R 2 -OR 5 In another embodiment, Q 1 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] is selected from the group consisting of:

[0082] In another embodiment of Formula I or Ia, Q 1 is -C(H)(OH)- and Q 2 is -C(O)- and W is -NH- and R 1 -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. In Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -OH and R 2 is -H. In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O )-, W is -NH-, and R 1 is -OP(O)(OR 6 )(OH) and R 2 is -H. This paragraph In any one of the foregoing embodiments, R 6 is selected from the group consisting of hydroxyl and methyl can be selected from:

[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 H2- and R 1 is -H, and R 2 -OH, -CH2NH2, R3 , R 4 , R 5 , or -OR 5 Another In one embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 teeth , -H, R 2 is —OH. In another embodiment, Q 1 is -C(O)- and Q 2 is -C( O)—, W is —CH—, and R 1 is -H, and R 2 is —CH 2 NH 2 . In another embodiment, Hey, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -H , R 2 is 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 is R 4 In another embodiment, Q 1 -C (O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -H, and R 2 is R 5 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 -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, dimethylamino No, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -C(O)- W is -CH2-, and R 1 is -OH 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 is -OH 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 -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 is 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 is R 4 Another embodiment In regards to 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH and R 2 is R 5 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 -OR 5 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 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -C(O)- W is -CH2-, and R 1 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 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 1is -NH2 and R 2 is -CH2NH2 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- and W is -CH2- and R 1 is -NH2 and R 2 is R 3 In another embodiment, Q 1 is -C(O)- Ri, Q 2 is -C(O)-, W is -CH2-, and R 1 is -NH2 and R 2 is R 4 Another In one embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 teeth , -NH2, and R 2 is R 5 In another embodiment, Q 1 is -C(O)- and Q 2 -C (O)-, W is -CH-, and R 1 is -NH2 and R 2 -OR 5 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] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -C(O)- 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 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 —CH 2 NH 2 . 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 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is alkyl, R 2 is R 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- and W is -CH2- and R 1 is alkyl, and R 2 is 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 -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- and W is -CH2- and R 1 is alkyl, and R 2 are amino, dimethylamino, hydroxy Lu, [ka] is selected from the group consisting of:

[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 -OH or -OP(O)(OR 6 )(OH) and R 2 is —H. Hey, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH R 2 is -H. 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 is -H. In any one of the embodiments, R 6 is selected from the group consisting of hydroxyl and methyl It can be done.

[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 Another reality In the embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -O-, and R 1 -H and R 2 is —OH. 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 is —CH 2 NH 2 . In another embodiment, Te, 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 is R 4 In another embodiment, Q 1 is -C(O)- Ri, Q 2 is -C(O)-, W is -O-, and R 1 is -H, and R 2 is R 5 Another implementation In an embodiment, Q 1 is -C(O)- and Q 2is -C(O)-, W is -O-, and R 1 is -H Yes, R 2 -OR 5 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 are amino, dimethylamino, hydroxy Lu, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -C(O)- 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)- Ri, Q 2 is -C(O)-, W is -O-, and R 1 is -OH and R 2 is -CH2NH2. In the embodiment of the present invention, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -O-, and R 1 teeth , -OH, and R 2 is R 3 In another embodiment, Q 1is -C(O)- and Q 2 is -C( O)-, W is -O-, and R 1 is -OH and R 2 is R 4 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 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 -OR 5 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 Amino, humidifier ethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -C(O)- W is -O- and R 1 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 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 is -NH2 and R 2 is -CH2NH2 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -O-, R 1 is -NH2 and R 2 is R 3 In another embodiment, Q 1 is -C(O)- and Q 2 teeth , -C(O)-, W is -O-, and R 1 is -NH2 and R 2 is R 4 In another embodiment, Hey, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -O-, and R 1 is -NH2 , R 2 is R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -O- and R 1 is -NH2 and R 2 -OR 5 In another embodiment, Q 1 teeth , -C(O)-, and Q 2 is -C(O)-, W is -O-, and R 1 is -NH2 and R 2 Ami No, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -C(O)- W is -O- and R 1 is alkyl, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 ,also HA-OR 5 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 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 -C H2NH2. 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 is 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 is R 4 in 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 R 5 In another embodiment, Q 1 is -C(O)- Ri, Q 2 is -C(O)-, W is -O-, and R 1 is alkyl, and R 2 -OR 5 is In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -O-, R 1 is alkyl, and R 2 is amino, dimethylamino, hydroxyl, [ka] is selected from the group consisting of:

[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 -OH or -OP(O)(OR 6 )(OH) and R 2 is —H. 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 is -H. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- and W is , -O-, and R 1 is -OP(O)(OR 6 )(OH) and R 2 is -H. In any one of the above, R 6 may 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 H-. 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 Another reality In the embodiment, 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)- W is -NH- and R 1 is -H, and R 2 is —CH 2 NH 2 . In another embodiment, Te, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -H, and R 2 is R 3 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 is R 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -H, and R 2is R 5 It is. In the embodiment of the present invention, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -H, and R 2 -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 teeth , -C(O)-, W is -NH-, and R 1 is -H, and R 2 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -C(O)- 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 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 is 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 is R 4 Another embodiment In Q 1 is -C(O)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -OH R 2 is 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 -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, A amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -C(O)- W is -NH- and R 1 is -NH2 and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or - OR 5 In another embodiment, Q 1is -C(O)- and Q 2 is -C(O)- and W is - NH- and R 1 is -NH2 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 -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 is -NH2 and R 2 is R 3 In another embodiment, Q 1 is -C(O)-, Q 2 is -C(O)-, W is -NH-, and R 1 is -NH2 and R 2 is R 4 Another implementation In an embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -NH 2 and R 2 is R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- W is -NH- and R 1 is -NH2 and R 2 -OR 5 In another embodiment, Te, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -NH2 and R 2is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -C(O)- 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 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 —CH 2 NH 2 . 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 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 is R 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- and W is , -NH-, and R1 is alkyl, and R 2 is 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,- OR 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] is selected from the group consisting of:

[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 -OH or -OP(O)(OR 6 )(OH) and R 2 is —H. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -OH, R 2 is -H. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)- and W is -NH- and R 1 is -OP(O)(OR 6 )(OH) and R 2 is -H. In any one of the embodiments, 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 Another reality In the embodiment, 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 is -CH2- W is -CH2-, and R 1 is -H, and R 2 is —CH 2 NH 2 . In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -CH2-, and R 1 is -H, and R 2 is R 3 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 is 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 is R 5 It is. In the embodiment of the present invention, Q 1 is -C(O)- and Q 2 is -CH2-, W is -CH2-, and R 1 is -H, and R 2 -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 teeth , -CH2-, W is -CH2-, and R 1 is -H, and R 2 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -CH2- W is -CH2-, and R 1 is -OH 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 -C H2- and R 1 is -OH 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 -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 is 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 is R 4 Another embodiment In regards to 1 is -C(O)- and Q 2 is -CH2-, W is -CH2-, and R 1 is -OH Yes, R 2 is 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 -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] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -CH2- W is -CH2-, and R 1 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 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 is -NH2 and R 2 is -CH2NH2 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2- and W is -CH2- Yes, R 1 is -NH2 and R 2 is R 3 In another embodiment, Q 1 is -C(O)- , Q 2 is -CH2-, W is -CH2-, and R 1 is -NH2 and R 2 is R 4 Another reality In the embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -CH2-, and R 1 teeth,- NH2 and R 2 is R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2- W is -CH2-, and R 1 is -NH2 and R 2 -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2is -CH2-, W is -CH2-, and R 1 is -NH2 , R 2 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -CH2- 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 is -CH2- and W 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 —CH 2 NH 2 . 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 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 is 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 is 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 -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] is selected from the group consisting of:

[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 -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 -CH2-, and R 1 is -OH, R 2 is -H. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2- and W is , -CH2-, and R 1 is -OP(O)(OR 6)(OH) and R 2 is -H. In any one of the embodiments, R 6 may be selected from the group consisting of hydroxyl and methyl. do.

[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 Another implementation In an embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 is -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 —CH 2 NH 2 . 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 R 3 in In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2- and W is -O- R 1 is -H, and R2 is 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 is R 5 In another embodiment, Hey, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 is -H, and R 2 -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2- and W is -O- and R 1 is -H, and R 2 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -CH2- 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)- Ri, Q 2 is -CH2-, W is -O-, and R 1is -OH and R 2 is -CH2NH2. In the embodiment of the present invention, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 teeth , -OH, and R 2 is R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH 2-, W is -O-, and R 1 is -OH and R 2 is R 4 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, 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 -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 is amino, dimethyl Amino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -CH2- W is -O- and R 1 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 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 is -NH2 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 -NH2 and R 2 is R 3 In another embodiment, Q 1 is -C(O)- and Q 2 teeth, -CH2-, W is -O-, and R 1 is -NH2 and R 2 is R 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 is -NH2 and R 2 is R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2- and W is , -O-, and R 1 is -NH2 and R 2 -OR 5 In another embodiment, Q 1 -C (O)- and Q 2 is -CH2-, W is -O-, and R 1 is -NH2 and R 2 is Amino, Dimethylamino, Hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -CH2- W is -O- and R 1 is alkyl, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 ,also HA-OR 5 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 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 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 is 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 is R 4 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 is 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 -OR 5 Another In one embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 teeth, alkyl, and R 2 is amino, dimethylamino, hydroxyl, [ka] is selected from the group consisting of:

[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 -OH or -OP(O)(OR 6 )(OH) and R 2 is —H. In another embodiment Te, 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. In any one of them, R 6 may 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 Another reality In the embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 -H 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 -H, and R 2 is —CH 2 NH 2 . 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 is 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 is R 5 Another embodiment In regards to 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is -H R 2 -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 are amino, dimethylamino, and hydroxyl , [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -CH2- 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 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 is R 3 In another embodiment, Q 1 is -C(O)- and Q 2 teeth,- CH2-, W is -NH-, and R 1 is -OH and R 2 is R 4 In another embodiment, Te, Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is -OH and R 2 is 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 -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 is amino, di Methylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -CH2- W is -NH- and R1 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 -N H- and R 1 is -NH2 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 -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 is -NH2 and R 2 is R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is -NH2 and R 2 is R 4 Another embodiment In Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is -NH2 R 2 is R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2- , W is -NH-, and R 1 is -NH2 and R 2 -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, A amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -CH2- 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 -CH2- and W 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 is -CH2- and W is -NH- and R 1 is alkyl, and R 2 is R 3 In another embodiment, Q 1 teeth , -C(O)-, and 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 is R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is alkyl, and R 2 -OR 5 in 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] is selected from the group consisting of:

[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 -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 -NH-, and R 1 is -OH and R 2 is -H. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2- and W is , -NH-, and R 1 is -OP(O)(OR 6 )(OH) and R 2 is -H. In any one of the embodiments, R 6 may be selected from the group consisting of hydroxyl and methyl. do.

[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 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 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 is -CH2NH2 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 R 3 In another embodiment, Q 1is -C(O)- Ri, Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 is -H, and R 2 is R 4 It is. In the embodiment of the present invention, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- and W is -CH2- , R 1 is -H, and R 2 is R 5 In another embodiment, Q 1 is -C(O)- and Q 2 teeth , -C(H)(OH)-, W is -CH2-, and R 1 is -H, and R 2 -OR 5 Another reality In the embodiment, 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] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -C(H)( OH)—, W is —CH—, and 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 —CH 2 NH 2 . 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 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 is R 4 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 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 -O -R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- and W is , -CH2-, and R 1 is -OH and R 2 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -C(H)( OH)—, W is —CH—, and R 1 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 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 is -NH2 and R 2 is —CH 2 NH 2 . In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- W is -CH2- and R 1 is -NH2 and R 2 is R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 is -NH2, R 2 is R 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- , W is -CH2-, and R 1is -NH2 and R 2 is R 5 In another embodiment, Q 1 teeth , -C(O)-, and Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 is -NH2 and R 2 teeth , -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- , W is -CH2-, and R 1 is -NH2 and R 2 are amino, dimethylamino, and hydroxyl , [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -C(H)( OH)—, W is —CH—, and 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)- W is -CH2-, and R 1 is alkyl, and R 2 is —OH. Hey, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 Is, Al Kill and R 2 is —CH 2 NH 2 . In another embodiment, Q 1is -C(O)- and Q 2 teeth , -C(H)(OH)-, W is -CH2-, and R 1 is alkyl, and R 2 is R 3 Another In one embodiment, Q 1 is -C(O)- and Q 2 is —C(H)(OH)—, W is —CH—, R 1 is alkyl, and R 2 is 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 is R 5 is. 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 -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 is alkyl, and R 2 Is, A amino, dimethylamino, hydroxyl, [ka] is selected from the group consisting of:

[0096] In another embodiment of Formula I or Ia, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- and W is -CH2- and R 1-OH or -OP(O)(OR 6 )(OH) and R 2 is -H. In regards to 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 teeth, -OH and R 2 is -H. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H) (OH)-, W is -CH-, and R 1 is -OP(O)(OR 6 )(OH) and R 2 is -H. In any one of the preceding embodiments of the paragraph, R 6 consists of hydroxyl and methyl It may 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 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 is. 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 is -CH2NH2. In one 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 R 3 In another embodiment, Q 1 is -C(O)- and Q 2 -C (H)(OH)-, W is -O-, and R 1 is -H, and R 2 is 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 is 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 -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] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q2 is -C(H)( OH)—, W is —O—, and R 1 is -OH and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 ,also HA-OR 5 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 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 2NH2. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- and W is -O- and R 1 is -OH and R 2 is 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 is R 4 Yes 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 is 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 -OR 5 It is. In the embodiment of the present invention, Q 1 is -C(O)- and Q 2 is —C(H)(OH)—, W is —O—, R 1 is -OH and R 2 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -C(H)( OH)—, W is —O—, and R 1 is -NH2 and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 ,also HA-OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- , W is -O-, and R 1 is -NH2 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 -NH2 and R 2 teeth, In another embodiment, Q is —CH 2 NH 2 . 1 is -C(O)- and Q 2 is -C(H)(OH)- , W is -O-, and R 1 is -NH2 and R 2 is R 3In another embodiment, Q 1 teeth, -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 is -NH2 and R 2 is R 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- and W is - O- and R 1 is -NH2 and R 2 is R 5 In another embodiment, Q 1 is -C(O)- Yes, Q 2 is -C(H)(OH)-, W is -O-, and R 1 is -NH2 and R 2 -OR 5 Yes In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- and W is -O- Yes, R 1 is -NH2 and R 2 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -C(H)( OH)—, W is —O—, and 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)- W is -O- and R is 1 is alkyl, and R 2 is —OH. Te, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 is an alkyl Yes, R 2 is —CH 2 NH 2 . In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H) (OH)-, W is -O-, and R 1 is alkyl, and R 2 is R 3 Another embodiment In Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 Is, Al Kill and R 2 is R 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H )(OH)-, W is -O-, and R 1 is alkyl, and R 2 is R 5 Another embodiment In Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 Is, Al Kill and R 2 -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 teeth,- C(H)(OH)-, W is -O-, and R 1 is alkyl, and R 2 is amino, dimethyl amino, hydroxyl, [ka] is selected from the group consisting of:

[0098] In another embodiment of Formula I or Ia, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- and W is -O- and R 1 -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. In Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 is -OH and R 2 is -H. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH )-, W is -O-, and R 1 is -OP(O)(OR 6 )(OH) and R 2 is -H. This paragraph In any one of the foregoing embodiments, R 6 is selected from the group consisting of hydroxyl and methyl can be selected from:

[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 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 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 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 is 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 is R 4 Another implementation In an embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -NH-, and R 1 teeth , -H, R 2 is R 5 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 -OR 5 In another embodiment, Hey, Q 1is -C(O)- and Q 2 is -C(H)(OH)-, W is -NH-, and R 1 is -H Yes, R 2 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -C(H)( OH)—, W is —NH—, and R 1 is -OH and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 ,also HA-OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 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)-, and Q 2 is -C(H)(OH)-, W is -NH-, and R 1 is -OH and R 2 teeth, In another embodiment, Q is —CH 2 NH 2 . 1 is -C(O)- and Q 2 is -C(H)(OH)- , W is -NH-, and R 1 is -OH and R 2 is 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 is 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 is 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 -OR 5 Yes 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] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2 is -C(H)( OH)—, W is —NH—, and R 1 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 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 is -NH2 and R 2 is —CH 2 NH 2 . In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- W is -NH- and R 1 is -NH2 and R 2 is R 3 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -NH-, and R 1 is -NH2 and R 2 is R 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -NH- and R 1 is -NH2 and R 2 is R 5 In another embodiment, Q 1 teeth,- C(O)- and Q 2 is -C(H)(OH)-, W is -NH-, and R 1 is -NH2 and R 2 -O -R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- and W is , -NH-, and R 1 is -NH2 and R 2 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(O)- and Q 2is -C(H)( OH)—, W is —NH—, and 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)- W is -NH- and R 1 is alkyl, and R 2 is —OH. Te, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -NH-, and R 1 is an alkyl and R 2 is —CH 2 NH 2 . 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 R 3 Another embodiment In regards to 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -NH-, and R 1 teeth, alkyl, and R 2 is R 4 In another embodiment, Q 1 is -C(O)- and Q 2 teeth, -C(H)(OH)-, W is -NH-, and R 1 is alkyl, and R 2 is R 5 Another reality In the embodiment, Q 1 is -C(O)- and Q 2is -C(H)(OH)-, W is -NH-, and R 1 is alkyl, and R 2 -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] is selected from the group consisting of:

[0100] In another embodiment of Formula I or Ia, Q 1 is -C(O)- and Q 2 is -C(H)(OH)- and W is -NH- and R 1 -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. In Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -NH-, and R 1 is -OH and R 2 is -H. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH )-, W is -NH-, and R 1 is -OP(O)(OR 6 )(OH) and R 2 is -H. This paragraph In any one of the foregoing embodiments, R 6 is selected from the group consisting of hydroxyl and methyl can be selected from:

[0101] In some instances, provided herein are compounds or pharmaceuticals having the structure of Formula (Ib): A pharmaceutically acceptable salt, solvate, or stereoisomeric form of: [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 where R 1 and R 2 is simultaneously has -H instead; 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 alkylene, substituted alkylene (including but not limited to, oxo-substituted (i.e., ═O) ), heteroalkylene, and substituted heteroalkylene (including but not limited to, oxo-substituted (i.e., is selected from the group consisting of (including ═O); Z is selected from the group consisting of -OH and -NH; R 5 is alkyl, heterocycloalkyl, or substituted heterocycloalkyl, wherein each heterocycloalkyl or substituted heterocycloalkyl is selected from nitrogen and oxygen. and at least one -OH and -CH2OH group. containing a substituent, or at least one primary or secondary nitrogen, e.g., O-glucose; Each R6 represents in each case -H, an amino acid residue, an N-alkyl amino acid residue, a peptide, or alkyl; and Each R 7 are independently halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O- Amino acid residues and O-PEG n where each n is an integer from 0 to 3.

[0102] In certain embodiments of Formula Ib, R 5 is a heterocycloalkyl or substituted heterocycloalkyl Useful heterocycloalkyl groups include tetrahydropyranyl, glycopyranyl, and the like. These groups may be substituted or unsubstituted. In some embodiments, they are unsubstituted. Exemplary substituents include at least one hydroxyl group. , at least one primary nitrogen, or at least one secondary nitrogen.

[0103] In certain embodiments of Formula Ib, R 6 is, in each occurrence, independently an amino acid residue, an N-alkyl Those skilled in the art will recognize that amino acid residues are either achiral or chiral. It will be recognized that the amino acid may be, for example, an L-amino acid or a D-amino acid. Typically, the amino acid side chain is the side chain of any amino acid known to those skilled in the art. In some embodiments, the side chain is selected from the group consisting of histidine, alanine, isoleucine, and the like. , arginine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine Inosin, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, Phosphorus, ornithine, selenocysteine, serine, glycine, homoglycine (e.g., β-phosphoric acid, Those skilled in the art will appreciate that the peptide may be, for example, racemic DL- Amino acids or non-racemic D- or L-amino acids, including their diastereomeric mixtures It will be recognized that the side chains of the peptide may be achiral or chiral. in connection with amino acids. Those skilled in the art will recognize that N-alkylamino acids The residue is a nucleotide as defined herein at the terminal amino group of the amino acid or at the terminal amino group of the peptide. It will be recognized that the term "alkyl" includes alkyl substituents that may be present.

[0104] In certain embodiments of Formula Ib, R 7 Ha, Halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O -glucose, O-amino acid residues, or O-PEG n where each n is an integer from 0 to 3. In certain embodiments, the O-amino acid residue is an HO-amino acid residue as defined above. In one embodiment, O-PEG n is for n=0. In another embodiment , O-PEG n is when n=1. In another embodiment, O-PEG n is the case of n=2 In another embodiment, O-PEG n is for 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 from 1 to 4. , R 1 is -OH and R 2 is -O-(CH2) n -Z and n is 1. In some embodiments, R 1 is -OH and R 2 is -O-(CH2) n -Z and n is 2. In some embodiments, R 1 teeth, -OH and R 2 is -O-(CH2) n -Z and n is 3. In some embodiments, 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, where 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 some embodiments, R 1 is -OH and R 2 teeth , -N(H)C(O)-(CH2) n -NH2 and n is 2. In some embodiments, R 1 is -OH , R 2 is -N(H)C(O)-(CH2) n -NH2 and n is 3. In some embodiments, R 1 is -OH and R 2 is -N(H)C(O)-(CH2) n -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 an embodiment, R 1 is -OH and R 2 is -N(H)C(O)-(CRR) n -NH2, and each R is -H, and n is an integer from 1 to 4. In some embodiments, R 1 is -OH and R 2 -N (H)C(O)-(CRR) n -NH2, each R is -OH, and n is an integer from 1 to 4. In an embodiment, R 1 is -OH and R 2 is -N(H)C(O)-(CRR) n -NH2 and each R is -CH2 OH and n is an integer from 1 to 4. In any one of the preceding embodiments in this paragraph, n is 1. In any one of the preceding embodiments of this paragraph, n is 2. In any one of the preceding embodiments, n is 3. In one of them, n is 4.

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

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

[0110] In some embodiments, provided herein are: [ka] a compound according to any of formulas I, Ia, and Ib, or a medicament thereof, which may be selected from the group consisting of: and its acceptable salt, solvate, or stereoisomeric form.

[0111] (Conjugates / Antibody Drug Conjugates (ADCs)) Provided herein is a conjugate of formula A or a pharmaceutically acceptable salt thereof: Solvates or stereoisomeric forms: [ka] (In the formula, L is a linker or XYZ, where X is -NH- or -O-; Y is an enzyme-cleavable moiety, self-destructive group, acid-labile moiety, PEG n , a sugar moiety, or an enhancing group; and Z is a linking agent linker. linker (BL), where Z is covalently bonded to BA; BA is a binder; k is an integer from 1 to 30; Q 1 and Q 2 each is independently —CH—, —C(O)—, —C(H)(OH)—, or —C(OH)—; W is -CH2-, -N(H)-, or -O-; R is -H, -OR 6 , -OH, -NH2, alkyl, or -OP(O)(OR 6 )2; Each R 6 is, in each occurrence, independently -H, an amino acid residue, a peptide, or an alkyl. and where R 1 , R 2 , R 3 , R 4 , and R 5 is as described in relation to Formula I) . Exemplary enzyme-cleavable moieties include any dipeptide or tripeptide (e.g., These include, but are not limited to, VC-PAB and VA (as described elsewhere in this document). Exemplary self-immolative groups are described elsewhere herein. Exemplary acid-labile moieties The component may be an alkoxyamine, a ketoxyamine, a carbonate, or a phosphonate. Exemplary enhancing groups include, but are not limited to, those described elsewhere herein. Exemplary reactive moieties are described elsewhere herein. In the above, Y is PEG n In some embodiments, amino acids are used to As described elsewhere herein and as will be apparent, payloads, enhancing groups, and antibodies (each (each described elsewhere herein) can be connected to one another. As will be understood, the connection of the payload, the enhancing group, and the antibody via an amino acid is This can be achieved by thio-Michael addition, phenol-O-alkylation, or by cycloaddition. For example, the amino acids connecting the payload, the enhancing group, and the antibody can be lysine. By way of further example, in one embodiment, the payload, enhancing group, and antibody are The connecting amino acid is D-lysine. The amino acid connecting the load, the enhancer group, and the antibody is aspartic acid. Thus, in one embodiment, the amino acids connecting the payload, the enhancing group, and the antibody are As a further example, in one embodiment, the payload, enhancer, and The amino acid connecting the antibody is serine. The amino acid connecting the payload, the enhancing group, and the antibody is a cysteine. In one embodiment, the amino acid connecting the payload, the enhancing group, and the antibody is It is tyrosine.

[0112] Provided herein is a conjugate of formula (A) or a pharmaceutically acceptable salt thereof , solvates, or stereoisomeric forms of: [ka] (In the formula, L is a linker; BA is a binder; k is an integer from 1 to 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 as described in relation to Formula I In certain embodiments, R is R 1 is.

[0113] Provided herein are compounds of formula (Aa) or a pharmaceutically acceptable salt thereof: [ka] (In the formula, L is a linker; BA is a binder; k is an integer from 1 to 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 written in relation to Formula Ia. In some embodiments, R is R 1 is.

[0114] Provided herein is a compound of formula (Ab) or a pharmaceutically acceptable salt thereof: [ka] (In the formula, L is a linker; BA is a binder; k is an integer from 1 to 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 as described in relation to formula Ib In some embodiments, R is R 1 is.

[0115] (binder) Suitable binding agents for any of the conjugates provided in this disclosure include These include antibodies, lymphokines, hormones, growth factors, viral receptors, interleukins, or any other cell-binding or peptide-binding molecule or substance, Not limited to these.

[0116] In some embodiments, the binding agent is an antibody or an antigen-binding fragment thereof. The antibody can be of any form known to those of skill in the art. The term "antigen" refers to a small molecule that specifically binds to or interacts specifically with a particular antigen. "Antigen" refers to any antigen-binding molecule or molecular complex that contains at least one complementarity-determining region (CDR). The term "antibody" refers to two heavy (H) chains and two ribosomal (R) chains interconnected by disulfide bonds. Immunoglobulin molecules, including four polypeptide chains of light (L) chains, and their multimers (e.g., IgM Each heavy chain comprises a heavy chain variable region (HCVR or V H and heavy chain constant region The heavy chain constant region contains three domains: C H 1. C H 2, and C H 3. Each light chain comprises: The light chain variable region (referred to herein as LCVR or V L The light chain constant region is , one domain (C L 1) V H and V L The region is called the framework region (FR). It is further subdivided into hypervariable regions called complementarity-determining regions (CDRs), which are interspersed with conserved regions. Each V can be divided H and V LIt consists of three CDRs and four FRs, and From the carboxy terminus to the carboxy terminus, the order is: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 In various embodiments of the present invention, the compounds herein are suitable for use as anti- The FRs of the antibody (or antigen-binding portion thereof) may be identical to human germline sequences or may be naturally occurring. Alternatively, the amino acid consensus sequence may be a sequence of two or more CDRs. The term "antibody" as used herein can be defined based on a ratio analysis. It also includes antigen-binding fragments of an intact antibody molecule. As used herein, the term "antigen-binding portion" of an antibody The term "antigen-binding fragment" of an antibody and the like refers to any fragment that specifically binds to an antigen to form a complex. Any naturally occurring, enzymatically obtained, synthetic, or genetically modified polypeptide. Antigen-binding fragments of antibodies can be isolated using any suitable standard technique, e.g., Proteolytic digestion or manipulation of DNA encoding antibody variable domains and optionally constant domains These can be derived from intact antibody molecules using recombinant genetic engineering techniques involving the creation and expression of antibodies. Such DNA is known and / or can be obtained, for example, from commercial sources, DNA libraries (e.g., Antibody libraries (including phage-antibody libraries) or can be synthesized. DNA can be sequenced and identified chemically or using molecular biology techniques. by manipulating the polypeptides, for example by placing one or more variable and / or constant domains in a suitable arrangement. and / or codons are introduced to generate cysteine ​​residues, modify or add amino acids, if Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) A minimal recognition unit consisting of amino acid residues that mimic the hypervariable region of an antibody (e.g., a CDR3 peptide) Other modified molecules include isolated CDRs such as FR3-CDR3-FR4 peptides, or constrained FR3-CDR3-FR4 peptides. For example, domain-specific antibodies, single domain antibodies, domain deleted antibodies, chimeric antibodies, CDR Grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, small modular immunotherapeutics (SMIPs), and small Variable IgNAR domains are also encompassed by the term "antigen-binding fragment" as used herein. An antigen-binding fragment of an antibody typically contains at least one variable domain. can be of any size or amino acid composition and typically contains one or more framework sequences V H Domain is V L In the antigen-binding fragment associated with the domain, V H Domains and V L The domain is The variable regions may be in any suitable configuration relative to each other. For example, the variable regions may be dimeric or TsuV H -V H , V H -V L , or V L -V L Alternatively, the antibody may comprise an antigen-binding fragment of an antibody. is the V of the monomer H or V L In some embodiments, the antibody may contain an anti- A native binding fragment comprises at least one variable domain covalently linked to at least one constant domain. The variable and constant domains that may be found in the antigen-binding fragments of the antibodies of the present invention may also contain Non-limiting exemplary configurations of in include: (i) V H -C H 1;(ii)V H -C H 2;(iii)V H -C H 3;(iv)V H -C H 1 -C H 2;(v)V H -C H 1-C H 2-C H 3;(vi)V H -C H 2-C H 3;(vii)V H -C L ;(viii)V L -C H 1;(ix)V L -C H 2;(x)V L -C H 3;(xi)V L -C H 1-C H 2;(xii)V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv) V L -C L The following are mentioned: Any arrangement of variable and constant domains, including any of the exemplary arrangements above, may be used. In the present invention, the variable and constant domains may be directly linked to each other or may be completely Alternatively, they may be connected by a partial hinge or linker region. The regions are flexible regions between adjacent variable and / or constant domains in a single polypeptide molecule. At least two (e.g., 5, 10, 15, 20, 40) flexible or semi-flexible connections are formed. 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). A multispecific antigen-binding fragment of the antibody typically comprises at least two different variable domains, where each variable domain is specific for a separate antigen or a different epitope on the same antigen. Exemplary bispecific antibody formats disclosed herein are Any multispecific antibody format, including those described herein, can be synthesized using routine techniques available in the art. and can be adapted for use in connection with antigen-binding fragments of antibodies of the present invention. In certain embodiments described herein, the antibodies described herein are human antibodies. As used herein, the term "human antibody" refers to an antibody derived from human germline immunoglobulin sequences. The human antibodies of the present invention are intended to include antibodies having variable and constant regions derived from the human antibodies of the present invention. For example, in the CDRs, particularly CDR3, there are sequences not encoded by human germline immunoglobulin sequences. Amino acid residues (e.g., by in vitro random or site-directed mutagenesis) These may include mutations introduced by somatic mutation or in vivo. However, the term "human antibody" as used herein refers to antibodies derived from other mammals, such as mice. Antibodies in which CDR sequences derived from the germline of a particular species are grafted onto human framework sequences are also included. The term "human antibody" generally refers to antibodies that have not undergone any modification or human intervention / manipulation. and does not include naturally occurring molecules present in naturally occurring, unmodified organisms. The antibody may, in some embodiments, be a recombinant human antibody. The term "recombinant human antibody" as used herein refers to an antibody prepared, expressed, and produced by recombinant means. All human antibodies, whether isolated or produced, are expressed in recombinant form, for example, by transfection into host cells. Antibodies expressed using recombinant expression vectors (described further below), recombinant combinatorial Antibodies isolated from human antibody libraries (described further below), human immunoglobulins Antibodies isolated from animals (e.g., mice) transgenic for the phosphogene (See, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or human immunodeficiency virus (HIV)-associated antigens. By any other means involving splicing of globulin gene sequences to other DNA sequences. It is intended to include antibodies that are prepared, expressed, engineered, or isolated. Such recombinant human antibodies contain variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are In vitro mutagenesis (or use of animals transgenic for human Ig sequences) In this case, the recombinant antibody is subjected to in vivo somatic mutagenesis (in vivo somatic mutagenesis), thus H and V L territory The amino acid sequence of the region is similar to that of the human germline V H and V L Derived from and related to the sequence, but These sequences may not naturally occur within the human antibody germline repertoire in vivo. The body can exist in two forms, which are related to the heterogeneity of the hinge. In one form, Immunoglobulin molecules consist of approximately 15 heavy chain dimers held together by interchain disulfide bonds. The second form contains a stable four-chain construct of 0-160 kDa. The dimer is held together by interchain disulfide bonds. Approximately 75-80 kD, composed of unlinked, covalently linked light and heavy chains (half antibody) These forms are extremely difficult to separate, even after affinity purification. The frequency of the second form in various intact IgG isotypes is limited. This is due to structural differences associated with antibody hinge region isotypes. Single amino acid substitutions in the hinge region of IgG4 hinges are commonly observed using human IgG1 hinges. The occurrence of the second form can be significantly reduced to levels that are comparable to those observed in the control group (Angal et al., 2011). 993) Molecular Immunology 30:105). The present disclosure relates to a method for the preparation of a medicament for the treatment of rhesus erythrocytes. H 2 or C H More than one in three areas The present invention also encompasses antibodies with mutations that, for example, may result in a desired antibody morphology in production. It may be desirable to improve the yield of the isolated antibodies described herein. As used herein, an "isolated antibody" refers to an antibody that has been identified and It refers to an antibody that has been separated and / or recovered from at least one component of its natural environment. For example, from at least one component of an organism or in which the antibody is naturally occurring or naturally produced An antibody that has been separated or removed from a tissue or cell containing the antibody is referred to as an "isolated" antibody for purposes of the present invention. An isolated antibody also includes an antibody in situ within a recombinant cell. The antibody is an antibody that has been subjected to at least one purification or isolation step. Thus, an isolated antibody is one that is substantially free of other cellular material and / or chemicals. As used herein, an antibody may be a polypeptide that is a homolog of a specific amino acid sequence relative to the corresponding germline sequence from which the antibody is derived. In comparison, one or more amino acids in the framework and / or CDR regions of the heavy and light chain variable domains Such mutations may include amino acid substitutions, insertions, and / or deletions. The amino acid sequences disclosed in the above can be compared with the available genetic sequences from, for example, public antibody sequence databases. This can be readily confirmed by comparing the sequence of the sequence. The antibody may be derived from a recombinant human genomic DNA fragment, or from a recombinant human genomic DNA fragment. to the corresponding residue in another human germline sequence, or to the corresponding germline residue The amino acid sequence of the present invention has been mutated to a conservative amino acid substitution (such sequence changes are referred to herein as Any of the amino acid sequences disclosed herein may contain a germline mutation (collectively referred to as a "germline mutation"). Those skilled in the art will recognize that the heavy chains disclosed herein include antibodies and antigen-binding fragments thereof derived therefrom. and light chain variable region sequences, and one or more individual germline mutations or combinations thereof Many antibodies and antigen-binding fragments can be produced, including those containing V. H Reach and / or V L All framework and / or CDR residues within the domain are mutated to produce antibodies In other embodiments, a particular residues found only in the first eight amino acids of FR1 or the last eight amino acids of FR4. Only the mutated residues listed, or CDR1, Only the mutation residues found in CDR2 or CDR3 were mutated to obtain the original germline sequence. In other embodiments, one or more of the framework and / or CDR residues are realigned with a different a germline sequence that differs from the germline sequence from which the antibody was originally derived Furthermore, antibodies of the present disclosure may be mutated, for example, by mutating specific individual residues is mutated to the corresponding residue in a particular germline sequence, while the original germline Certain other residues that differ from the sequence may be maintained or may differ from the corresponding residues in the germline sequence. Two or more germline mutations within the framework and / or CDR regions that are mutated Once obtained, a gene may contain one or more germline mutations. Antibodies and antigen-binding fragments that exhibit, for example, improved binding specificity, increased binding affinity, modified one or more of the following: improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Antibodies obtained by this general method can be readily tested for the above desired properties. Antibodies and antigen-binding fragments thereof are encompassed within the scope of the present disclosure. is an HCVR, LCVR, and / or CDR amino acid sequence disclosed herein with one or more conservative substitutions. Also included are antibodies containing any variant of the amino acid sequence. The antigenic determinants interact with specific antigen-binding sites in the variable region of the antibody molecule known as the polypeptide. A single antigen can have multiple epitopes. Therefore, different antibodies can Epitopes can bind to different parts of a molecule and have different biological effects. Conformational epitopes can be either conformational or linear. Conformational epitopes are epitopes that occur at different positions in a linear polypeptide chain. A linear epitope is formed by spatially juxtaposed amino acids from different segments. In some situations, the amino acid residues are formed by adjacent amino acid residues in a peptide chain. A pitope may comprise a saccharide, phosphoryl, or sulfonyl moiety on an antigen.

[0117] In certain embodiments, the antibody comprises a light chain. In certain embodiments, the light chain is a κ In certain embodiments, the light chain is a λ light chain. The antibody comprises a heavy chain. In some embodiments, the heavy chain is IgA. In some embodiments, the heavy chain is IgD. In some embodiments, the heavy chain is IgE. In some embodiments, the heavy chain is IgG. In some embodiments, the heavy chain is IgM. In some embodiments, the heavy chain is IgG1. In some embodiments, the 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. The antibody fragment is an Fv fragment. In some embodiments, the antibody fragment is a Fab fragment. In some embodiments, the antibody fragment is a F(ab')2 fragment. In some embodiments, the antibody fragment is a Fab' fragment. In some embodiments, the antibody fragment is an scFv (sFv ) fragment. In some embodiments, the antibody fragment is an scFv-Fc fragment.

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

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

[0121] The antibody may have binding specificity for any antigen deemed suitable by one of skill in the art. In certain embodiments, the antigen is a transmembrane molecule (e.g., a receptor) or a growth factor. Exemplary antigens include scavenger receptor A (SR-A or MSR1), collagen, and the like. Macrophage receptor with a C-type lectin-like structure (MARCO), a scavenger Class A scavenger receptors, including SRCL (Scavenger Receptor A-5) and COLEC12 (SCARA5), are also involved. Class B macrophage scavenger receptors, including CD36, LIMPII, SRBI, and SRBII -receptor, class D scavenger receptor CD68, and lysosomal membrane glycoprotein (LAMP), Class E scavengers containing lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) and dectin-1 scavenger receptor, endothelial cell-expressed scavenger receptor-I (SREC-I) and SREC Class F scavenger receptor containing -II and multiple epidermal growth factor (EGF)-like domains (MEGF) 10 Body, class G scavenger receptor CXC chemokine ligand 16 (CXCL16), fasciclin, 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 receptor for advanced glycation end products (RAGE), DEC205, CD206, and Dectin Other C-type lectin superfamily members, including DNGR-1, MINCL, DC-SIGN, and DNGR-1, members, and B7 family-related members, including V-set and Ig domain-containing 4 (VSIG4), Colony-stimulating factor 1 receptor (CSF1R), asialoglycoprotein receptor (ASGPR), and amyloglycoprotein receptor (AGP) Other molecules include membrane proteins such as idiopathic beta precursor-like protein 2 (APLP-2), In some embodiments, the antigen is PRLR or HER2. In some embodiments, the antibody is an anti-PRLR or anti-HER2 antibody.

[0122] The binder linker binds the antibody or antigen-binding molecule via a bond at a specific amino acid. The antibody or antigen-binding molecule can be attached to the antibody or antigen-binding molecule. Exemplary amino acid linkages that can be used in the linkage include, for example, lysine (e.g., See, for example, US 5,208,020; US 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 / 0585592), cysteine ​​(see, e.g., US 2007 / 0258987; WO 2013 / 055993; WO 201 3 / 055990; WO 2013 / 053873; WO 2013 / 053872; WO 2011 / 130598; US 2013 / 010154 No. 6; and US Pat. No. 7,750,116), selenocysteine ​​(see, e.g., WO 2008 / 122039; and Hof (See er et al., Proc. Natl. Acad. Sci., USA, 2008, 105: 12451-12456), formyl Glycine (e.g., Carrico et al., Nat. Chem. Biol., 2007, 3:321-322; Agarwal et al., Proc. Natl. Acad. Sci., USA, 2013, 110:46-51, and Rabuka et al., Nat. Pro Tocols, 2012, 10:1052-1067), unnatural amino acids (see, for example, WO 2013 / 068874 and WO 2012 / 166559), as well as acidic amino acids (see, for example, WO 2012 / 05982). The linker is conjugated to the antigen-binding protein via a bond to the carbohydrate. (See, e.g., US 2008 / 0305497, WO 2014 / 065661, and Ryan et al., Food & Agriculture Immunol., 2001, 13: 127-130).

[0123] In some instances, the binding agent is an antibody or an antigen-binding molecule, and the antibody is a lysine In some embodiments, the antibody or antigen-binding The molecule is attached to the linker via a cysteine ​​residue.

[0124] The linker is conjugated via transglutaminase-based chemoenzymatic conjugation. Alternatively, the hydroxylase may be conjugated to one or more glutamine residues (see, e.g., Dennler et al., (See Bioconjugate Chem. 2014, 25, 569-578 and WO 2017 / 147542). In the presence of glutaminase, one or more glutamine residues of the antibody are converted to a primary amine. Briefly, in some embodiments, Antibodies containing glutamine residues (e.g., Gln295 residue) are subjected to transglutaminase in the presence of the enzyme In the presence of a primary amine compound, the primary amine compound is treated with a primary amine compound, which is described in more detail below. The compounds include, for example, antibody drug conjugates via transglutaminase-mediated coupling. It includes a payload or linker-payload that directly provides the gate. The compound can be subsequently treated with additional compounds for the synthesis of antibody drug conjugates. Also included are linkers and spacers that are functionalized with reactive groups that can be bonded to glutamine residues. Antibodies containing the group may be isolated from a natural source or modified to contain one or more glutamine residues. Glutamine residues in the antibody polypeptide chain (glutaminyl-modified antibodies or Techniques for engineering original binding molecules are within the capabilities of those skilled in the art. Thus, the antibody is aglycosylated.

[0125] In certain embodiments, the antibody or glutaminyl-modified antibody or antigen-binding molecule At least one polypeptide chain sequence contains at least one glutamine residue. In an embodiment, the antibody or glutaminyl-modified antibody or antigen-binding molecule each has one G In a further embodiment, the antibody or The glutaminyl-modified antibody or antigen-binding molecule has one or more glutaminyl residues at a site other than 295 of the heavy chain. Included herein are the Asn297Gln (N297Q) mutations described herein. Antibodies of this section bearing the Gln55 (Q55) residue are included herein. The antibody in this section.

[0126] (Primary amine compounds) Transglutaminase-mediated coupling of glutamine-containing antibodies (or antigen-binding compounds) The primary amine compounds useful in the method include any primary amine compounds that are deemed useful by those skilled in the art. Typically, the primary amine compound has the formula HN-R, where R is It can be any group that is compatible with the antibody and reaction conditions. In some embodiments, R is , alkyl, substituted alkyl, heteroalkyl, or substituted heteroalkyl.

[0127] In some embodiments, the primary amine compound has a reactive group or a protected reactive group. Useful reactive groups include azides, alkynes, cycloalkynes, thiols, alcohols, and the like. These include aldehydes, ketones, aldehydes, acids, esters, hydrazides, anilines, and amines. In certain embodiments, the reactive group is an azide, alkyne, sulfhydryl, cycloalkenyl, or cycloalkenyl. The alkyl group is selected from the group consisting of alkylene, aldehyde, and carboxyl.

[0128] In certain embodiments, the primary amine compound is according to the formula HN-LL-X, wherein: LL is a divalent spacer and X is a reactive group or a protected reactive group. In some embodiments, LL is a divalent polyethylene glycol (PEG) group. , X is selected from the group consisting of -SH, -N3, alkyne, aldehyde, and tetrazole. In certain embodiments, X is -N3.

[0129] In certain embodiments, the primary amine compound is according to one of the following formulas: R: H2N-(CH2) n -X; H2N-(CH2CH2O) n -(CH2) p -X; H2N-(CH2) n -N(H)C(O)-(CH2) m -X; H2N-(CH2CH2O) n -N(H)C(O)-(CH2CHO) m -(CH2) p -X; H2N-(CH2) n -C(O)N(H)-(CH2) m -X; H2N-(CH2CH2O) n -C(O)N(H)-(CH2CH2O) m -(CH2) p -X; H2N-(CH2) n -N(H)C(O)-(CH2CHO) m -(CH2) p -X; H2N-(CH2CH2O) n -N(H)C(O)-(CH2) m -X; H2N-(CH2) n -C(O)N(H)-(CH2CH2O) m -(CH2) p -X; and H2N-(CH2CH2O) n -C(O)N(H)-(CH2) m -X; (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:

[0130] In the above, any of the alkyl (i.e., -CH2-) groups may be, for example, C 1-8 Alkyl , methylformyl, or —SO3H. In one embodiment, The alkyl group is unsubstituted

[0131] In some embodiments, the primary amine compound is: [ka] is selected from the group consisting of:

[0132] In certain embodiments, the primary amine compound is [ka] Exemplary conditions for the above reaction are provided in the Examples below.

[0133] (Linker) The linker L portion of the conjugates described herein can be used to link a binding agent to a conjugate described herein. In another example, the compound is a moiety, e.g., a bivalent moiety, that covalently attaches the compound to a payload compound. The linker L is a trivalent linker that covalently attaches the binding agent to a payload compound described herein. Suitable linkers are, for example, those described herein, the contents of each of which are fully incorporated by reference. Antibody-Drug Conjugates and Immunotoxins, as incorporated herein by reference, es and Immunotoxins); Phillips, GL (ed.); Springer Verlag: New York, 2013; Antibody-Drugs Antibody-Drug Conjugates; edited by Ducry, L.; Humana Press, 2013; Antibodies - 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 compounds of formula I, Ia, and Ib above, and a bond or bonded to a linker L or a bond or bonded to a linker L. Those skilled in the art will appreciate that a particular functional group on the payload moiety may be incorporated into the linker. and / or linking agents. , amine, hydroxyl, phosphate, and sugar.

[0134] In certain embodiments, the linker is stable under physiological conditions. Thus, the linker is cleavable, e.g., in the presence of an enzyme or at a particular pH range or value. In some embodiments, the receptor can release at least the payload portion. The anchor comprises an enzyme-cleavable moiety. Exemplary enzyme-cleavable moieties include a peptide bond, an endonucleaser, an enantiomer, an amino acid ... These include, but are not limited to, ester linkages, hydrazone linkages, and disulfide linkages. In some embodiments, the linker comprises a cathepsin-cleavable linker.

[0135] In some embodiments, the linker comprises a non-cleavable moiety. In the embodiment, the non-cleavable linker is [ka] or a residue thereof. In some embodiments, the non-cleavable linker-payload Do is [ka] or a positional isomer thereof. In some embodiments, the non-cleavable linker is [ka] or a residue thereof. In some embodiments, the non-cleavable linker-payload Do is [ka] or a positional isomer thereof. In one embodiment, the linker is maleimidocyclohexyl cyclohexanecarboxylate or 4-(N-maleimidomethyl)cyclohexanecarboxylic acid (MCC) In the structure, [ka] represents a bond with a binder. In some examples, [ka] shows, for example, click chemistry residues obtained by reaction of a binder with a linker payload. vinegar.

[0136] In some embodiments, suitable linkers include a single binding agent, e.g., an antibody. These include, but are not limited to, those chemically linked to two cysteine ​​residues in Such linkers do not bind to antibodies that are destroyed as a result of the conjugation process. The disulfide bonds in the hydroxylase may act to mimic the disulfide bonds in the hydroxylase.

[0137] In some embodiments, the linker comprises one or more amino acids. Acids include natural, unnatural, standard, non-standard, proteinogenic, and non-proteinogenic. and L- or D-α-amino acids. In some embodiments, the linker is , alanine, valine, glycine, leucine, isoleucine, methionine, tryptophan , phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagus Gin, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, a derivative thereof, or a combination thereof. In some embodiments, one or more side chains of the amino acid are linked to a side chain group as described below. In some embodiments, the linker comprises valine and citrulline. The anchors include lysine, valine, and citrulline. The anchors include lysine, valine, and alanine. Car contains valine and alanine.

[0138] In some embodiments, the linker comprises a self-immolative group. In certain embodiments, the self-immolative group is p- p-aminobenzyl (PAB) or its derivatives. Useful derivatives include p-aminobenzyl Those skilled in the art will appreciate that the self-immolative group can separate the payload from the remainder of the linker. You will be aware that chemical reactions can occur that release atoms.

[0139] In some embodiments, the linker is: [ka] where: SP 1 is a spacer; SP 2 is a spacer; [ka] is one or more bonds with a binding agent; [ka] is one or more bindings with the payload; each AA is an amino acid; and n is an integer from 1 to 10.

[0140] SP 1 The spacer is (AA) n The moiety is connected to the binding agent (BA) or to a reactive group residue attached to the BA. This is the part that is suitable for SP 1 The spacer may be an alkylene or polyether, or The terminus of the spacer, e.g., For example, the spacer moiety attached to the binding agent or AA may be attached to the antibody during chemical synthesis of the conjugate. or derived from the reactive moiety used for the purpose of coupling AA to the spacer. In certain embodiments, n is 1, 2, 3, or 4. In certain embodiments, n is 2. In certain embodiments, n is 3. In this example, n is 4.

[0141] In some embodiments, SP 1 The spacer comprises an alkylene. In one embodiment, SP 1 The spacer is C 5-7 In some embodiments, the alkylene , SP 1 The spacer comprises a polyether. In some embodiments, SP 1 Spacer includes polymers of ethylene oxide, for example, polyethylene glycol.

[0142] In some embodiments, SP 1 Spacers are: [ka] where: RG′ is the reactive group residue after reaction of the reactive group RG with the binder; [ka] is the bond with the binding agent; [ka] is (AA) n is a bond with; and b is an integer of 2 to 8.

[0143] The reactive group RG is known to those skilled in the art to be capable of forming one or more bonds with a binding agent. The reactive group RG can be any reactive group that reacts with a binding agent (e.g., with an antibody). , functionalizing antibodies at their cysteine ​​or lysine residues, or at azide moieties, e.g., PEG-N3 at one or more glutamine residues) to form a compound of formula A, Aa, or Ab After conjugation with the binding agent, the reactive group is a moiety that contains in its structure a moiety that The reactive group (RG') is an exemplary reactive group such as a haloacetate that can react with a linking agent. ethyl, isothiocyanate, succinimide, N-hydroxysuccinimide, or maleic acid Examples include, but are not limited to, those containing a mido moiety.

[0144] In certain embodiments, reactive groups include, but are not limited to, alkynes. In certain embodiments, the alkyne undergoes 1,3-cycloaddition with an azide in the absence of a copper catalyst. An alkyne that can undergo a reaction, for example, a strained alkyne. Sulfate-promoted alkyne-azide cycloaddition (SPAAC), cycloalkynes, e.g., cyclooctyne, and Suitable alkynes include dibenzoazacyclooctamethyl and benzannulated alkynes. Chin or [ka] , dibenzocyclooctyne or [ka] , biarylazacyclooctynone or [ka] , difluorinated cyclooctyne or [ka] , substituted, for example, fluorinated alkynes, aza-cycloalkynes, bicycle[6.1.0]nonynes or [ka] Particularly useful alkynes include, but are not limited to, Well, [ka] Examples include:

[0145] In some embodiments, the binding agent is directly bound to RG'. The binder is attached to the lower spacer, e.g., SP 4 In certain embodiments, In this embodiment, the binding agent is attached to RG' via a PEG spacer. In certain embodiments, the binding agent is functionalized with one or more azide groups, as shown in Each azide group can react with RG to form RG'. In an embodiment, the binding agent is derivatized with -PEG-N3 linked to a glutamine residue. Exemplary -N3 derivatized binders, their methods of preparation, and their use in reactions with RG are: In certain embodiments, RG is suitable for participating in 1,3-cycloaddition. and RG' is a 1,2,3-trimethylsilyl group formed from the reaction of RG with an azide-functionalized linking agent. By way of further example, in certain embodiments, RG′ is [ka] or a mixture of each positional isomer. As described in the specification.

[0146] SP 2 The spacer is (AA) n A suitable spacer is a part that connects the part to the payload. Then, SP 1 Spacers include, but are not limited to, those described above. Further suitable SP 2 The spacer may be an alkylene or polyether, or SP includes, but is not limited to, those containing both. 2 The end of the spacer For example, the portion of the spacer directly attached to the payload or AA may be During chemical synthesis, the payload or AA is 2 Used for coupling to spacers In some instances, the SP 2 Spa The end of the sensor, for example, SP directly linked to a payload or AA 2 The spacer part is The payload or AA is coupled to the spacer during the chemical synthesis of the conjugate. It can be the residue of a reactive moiety used for that purpose.

[0147] In some embodiments, SP 2 The spacer is -O-, -N(R 6 )-, -R 4' -, -R 5' -, -OR 5' -, and -OP(O)(OR 6 )O—, wherein: R 4' is -Z'-YX-; X is selected from the group consisting of -O- and -N(H)-; Y is alkylene, substituted alkylene (including but not limited to oxo-substituted, i.e., ═O). ), heteroalkylene, and substituted heteroalkylene; Z' is selected from the group consisting of -O- and -N(H)-; R 5' is heterocycloalkylene or substituted heterocycloalkylene, where each Each heterocycloalkylene or substituted heterocycloalkylene is a heterocyclic group having a substituted or unsubstituted heterocycloalkylene. -O-, -N(H)-, and -N(H)- are useful for bonding [ka] one selected from nitrogen and oxygen, comprising at least two moieties selected from the group consisting of , 2, or 3 heteroatoms; and Each R 6 is -H, an amino acid residue, a peptide, or an alkyl).

[0148] In one embodiment, SP 2 The spacer is -O-, -N(H)-, [ka] In some embodiments, each of [ka] is the combination with the payload, and each [ka] is (AA) n It is a combination with.

[0149] In the above formula, each AA is an amino acid or, optionally, p-aminobenzyloxycarbonyl If a PABC is present, preferably only one PABC is present. Preferably, the PABC residue, if present, is proximal to the payload (AA) n At the terminal AA in the group Suitable amino acids for each AA include natural, non-natural, standard, non-standard, protein-specific, and These include proteinogenic, non-proteinogenic, and L- or D-α-amino acids. In embodiments, the linker is selected from the group consisting of alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, Tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine The present invention includes citrulline, histidine, or citrulline, derivatives thereof, or combinations thereof. In certain embodiments, one or more side chains of the amino acids are linked to the following side chain groups: In some embodiments, n is 2. In some embodiments, (AA) n Ha, ballin- In some embodiments, (AA) is citrulline. n is citrulline-valine. In some embodiments, (AA) n is valine-alanine. (AA) n is alanine-valine. In some embodiments, (AA) n Is, Ba In some embodiments, (AA) n 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 In some embodiments, (AA) is valine-PABC. n is glutamic acid-valine-cytosine In some embodiments, (AA) n Glutamine-Valine-Citrulline In some embodiments, (AA) n is lysine-valine-alanine. In some embodiments, (AA) n is lysine-valine-citrulline. In some embodiments, n is 4. In some embodiments, (AA) n Glutamate-Bali In some embodiments, (AA) n is glutamine-valine- Citrulline-PABC. Those skilled in the art will recognize PABC as having the following structure: [ka] The PABC residue is a p-aminobenzyloxycarbonyl residue. Groups have been shown to facilitate cleavage of certain linkers in vitro and in vivo.

[0150] In some embodiments, the linker is: [ka] where: Each [ka] is the bond with the binder; Each [ka] is the binding with the payload; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, the attachment to the binding agent can be direct or via a spacer. In some embodiments, the binding to the binding agent can be achieved by binding the glutamic acid of the binding agent. The linker is a PEG spacer between the PEG and PEG residues.

[0151] In some embodiments, the linker is: [ka] where: Each [ka] is the bond with the binder; Each [ka] is the binding with the payload; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, the attachment to the binding agent can be direct or via a spacer. In some embodiments, the binding to the binding agent can be achieved by binding the glutamic acid of the binding agent. The linker is a PEG spacer between the PEG and PEG residues.

[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 in Useful amino acids for linking the enhancing group include lysine, asparagine, aspartic acid, and thiamin Examples of the linking group include glutamic acid, glutamine, glutamic acid, and citrulline. can be a direct bond to the amino acid side chain, or the linkage can be a spacer and / or Useful spacers and reactive groups include Examples of enhancing groups include any of those described above. The enhancing groups may be any group deemed useful by those skilled in the art. For example, the enhancing group can be any group that enhances a biological effect, including, but not limited to: , biochemical effects, synthesis effects, solubilization effects, imaging effects, detection effects, and reactivity effects. a compound, payload, linker-payload, or antibody conjugate having a beneficial effect, In some embodiments, the enhancing group is a hydrophilic group. In some embodiments, the enhancing group is a cyclodextrin. wherein the enhancing group is alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl. The cyclodextrin may be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin is alpha cyclodextrin. cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof. In some embodiments, the cyclodextrin is alpha cyclodextrin. In some embodiments, the cyclodextrin is a beta cyclodextrin. In one embodiment, the cyclodextrin is gamma cyclodextrin. In some embodiments, the enhancing group can improve the solubility of the remainder of the conjugate. In some embodiments, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyls may be used. The sulfonic acid may be substituted or unsubstituted. In certain embodiments, the alkyl , heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acids are —(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 SO3H2, where n is 1, 2, 3, 4, or 5 and m is 1, 2, 3, 4, or 5. In one embodiment, The alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH 2) 1-5 In another embodiment, alkyl, heteroalkyl, alkylenyl, Or heteroalkylenyl sulfonic acid is -(CH2) n -NH-(CH2) 1-5 SO3H, where n is In another embodiment, the alkyl, heteroalkyl, alkyl Heteroalkylenyl or heteroalkylenyl sulfonic acids are -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, wherein n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroaryl, The alkyl, 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, The alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n - N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where n is 1, 2, 3, 4, or 5. In embodiments, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl Sulfonic acid is -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where n is 1, In another embodiment, the alkyl, heteroalkyl, alkylenyl, The alkyl or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where m is 1, 2, 3, 4, or 5. In some embodiments, The linker is: [ka] where: SP 1 is a spacer; SP 2 is a spacer; SP 3 is (AA) n a spacer linked to one AA of [ka] is one or more bonds with a binding agent; [ka] is one or more bindings with the payload; [ka] is one or more bonds to the enhancing group EG; each AA is an amino acid; and n is an integer from 1 to 10. As discussed above, the attachment to the binding agent can be direct or via a spacer. In some embodiments, the binding to the binding agent can be achieved by binding the glutamic acid of the binding agent. The linker is a PEG spacer between the PEG and PEG residues.

[0153] SP 1 The spacer group is as described above. SP 2The spacer groups are as described above. (AA) n The groups are as defined above.

[0154] SP 3 The spacer is (AA) n A suitable SP is a moiety that connects the SP moiety to the enhancer group (EG). 3 Spacer Examples of the alkylene-containing polyether include those containing alkylene or polyether, or both. , but not limited to: SP 3 The end of the spacer, i.e., the enhancer group or AA, is directly bonded to the Combined SP 3 The spacer portion is a portion of the enhancer group or AA attached to SP during the chemical synthesis of the conjugate. 3 Spa The moiety is derived from a reactive moiety used for the purpose of coupling to the enzyme. In some instances, SP 3 At the end of the spacer, i.e., at the enhancer group or AA The directly attached spacer moiety is a group that is attached to an enhancer group or AA during the chemical synthesis of the conjugate. a residue of a reactive moiety used for the purpose of coupling to the spacer In one embodiment, SP 3 is (AA) n With a spacer linked to only one AA of In one embodiment, SP 3 The spacer is (AA) n is linked to the side chain of a lysine residue in .

[0155] to In some embodiments, SP 3 Spacers are: [ka] where: RG′ is the reactive group residue after reaction of the reactive group RG with the enhancer EG; [ka] is the conjugate with the enhancer; [ka] is (AA) n is a bond with; and a is an integer of 2 to 8.

[0156] The reactive group RG is known to those skilled in the art to be capable of forming one or more bonds with the enhancer. The reactive group RG can be any reactive group that reacts with a binding agent (e.g., with an antibody). , reacted at its cysteine ​​or lysine residue, or at the azide moiety), to form a compound of formula A, Aa, or Ab The moiety is a moiety that contains in its structure a moiety that can form a compound of the formula: After conjugation, the reactive group becomes a reactive group residue (RG'). The reactive group RG can be reacted with any of the above reactions. Exemplary reactive groups include halo groups that can react with the linking agent. Cetyl, isothiocyanate, succinimide, N-hydroxysuccinimide, or maleic acid Examples include, but are not limited to, those containing an imide moiety.

[0157] In certain embodiments, reactive groups include, but are not limited to, alkynes. In certain embodiments, the alkyne undergoes 1,3-cycloaddition with an azide in the absence of a copper catalyst. An alkyne that can undergo a reaction, for example, a strained alkyne. Sulfate-promoted alkyne-azide cycloaddition (SPAAC), cycloalkynes, e.g., cyclooctyne, and Suitable alkynes include dibenzoazacyclooctamethyl and benzannulated alkynes. Chin or [ka] , dibenzocyclooctyne or [ka] , biarylazacyclooctynone or [ka] , difluorinated cyclooctyne or [ka] , substituted, for example, fluorinated alkynes, aza-cycloalkynes, bicycle[6.1.0]nonynes or [ka] Particularly useful alkynes include, but are not limited to, Well, [ka] Examples include:

[0158] In some embodiments, the linker is: [ka] where: RG′ is the reactive group residue after reaction of the reactive group RG with the binder; PEG is PEG3; SP 2 is a spacer; SP 3 is (AA) n a spacer linked to one AA of [ka] is one or more bonds with a binding agent; [ka] is one or more bindings with the payload; [ka] is one or more bonds to the enhancing group EG; each AA is an amino acid; and n is an integer from 1 to 10. As discussed above, the attachment to the binding agent can be direct or via a spacer. In some embodiments, the binding to the binding agent can be achieved by binding the glutamic acid of the binding agent. The linker is a PEG spacer between the PEG and PEG residues.

[0159] In some embodiments, the linker is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a compound thereof positional isomers, or mixtures of these positional isomers, wherein: Each [ka] is the bond with the binder; Each [ka] is the binding with the payload; Each [ka] is the conjugation with the enhancer; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 In some embodiments, 1,3- Cycloaddition or SPAAC regioisomers, or a mixture of regioisomers, can be treated with a suitable alkyne. For example, in one embodiment, the linker is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a compound thereof As a further example, the linker is : [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a compound thereof As a further example, in one embodiment, wherein the linker is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a compound thereof It is a positional isomer or a mixture of these positional isomers. As discussed above, the attachment to the binding agent can be direct or via a spacer. In some embodiments, the binding to the binding agent can be achieved by binding the glutamic acid of the binding agent. In some embodiments, the enhancer is attached to the parent In some embodiments, the enhancer is a cyclodextrin. In such embodiments, the enhancing group is an alkyl, heteroalkyl, alkylenyl, or heteroalkylene. The cyclodextrin may be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin is alpha cyclodextrin. cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof In some embodiments, the cyclodextrin is alpha cyclodextrin. In some embodiments, the cyclodextrin is a beta cyclodextrin. In some embodiments, the cyclodextrin is gamma cyclodextrin. and the 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 where n is 1, 2, 3, 4, or 5 and m is 1, 2, 3, 4, or 5. In the above, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Phosphoric acid is -(CH2) 1-5 In another embodiment, alkyl, heteroalkyl, aryl, Alkylenyl or heteroalkylenyl sulfonic acids are -(CH2) n -NH-(CH2) 1-5 SO3H, wherein n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroaryl, The alkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n -C(O)NH-(CH2) 1-5 S OH, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl , heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acids are -(CH2CH2O) m - C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, In the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where n is 1, 2, 3, 4, or 5 In another embodiment, alkyl, heteroalkyl, alkylenyl, or hetero Alkylenylsulfonic acids are -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where and n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroalkyl , alkylenyl, or heteroalkylenyl sulfonic acids are -(CH2CH2O) m -C(O)N((CH2) 1-5C( O)NH(CH2) 1-5 SO3H2, where m is 1, 2, 3, 4, or 5.

[0160] In some embodiments, the linker is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a compound thereof positional isomers, or mixtures of these positional isomers, wherein: Each [ka] is the bond with the binder; Each [ka] is the conjugation with the enhancer; Each [ka] is the binding with the payload; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, the attachment to the binding agent can be direct or via a spacer. In some embodiments, the binding to the binding agent can be achieved by binding the glutamic acid of the binding agent. In some embodiments, the enhancer is attached to the parent In some embodiments, the enhancer is a cyclodextrin. In such embodiments, the enhancing group is an alkyl, heteroalkyl, alkylenyl, or heteroalkylene. The cyclodextrin may be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin is alpha cyclodextrin. cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof In some embodiments, the cyclodextrin is alpha cyclodextrin. In some embodiments, the cyclodextrin is a beta cyclodextrin. In some embodiments, the cyclodextrin is gamma cyclodextrin. and the 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 where n is 1, 2, 3, 4, or 5 and m is 1, 2, 3, 4, or 5. In the above, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Phosphoric acid is -(CH2) 1-5 In another embodiment, alkyl, heteroalkyl, aryl, Alkylenyl or heteroalkylenyl sulfonic acids are -(CH2) n -NH-(CH2) 1-5 SO3H, wherein n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroaryl, The alkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n -C(O)NH-(CH2) 1-5 S OH, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl , heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acids are -(CH2CH2O) m - C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, In the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where n is 1, 2, 3, 4, or 5 In another embodiment, alkyl, heteroalkyl, alkylenyl, or hetero Alkylenylsulfonic acids are -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where and n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroalkyl , alkylenyl, or heteroalkylenyl sulfonic acids are -(CH2CH2O) m -C(O)N((CH2) 1-5 C( O)NH(CH2) 1-5 SO3H2, where m is 1, 2, 3, 4, or 5.

[0161] In some embodiments, the linker is: [ka] TIFF2023113639000182.tif134170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or or a mixture of these positional isomers, wherein: Each [ka] is the bond with the binder; Each [ka] is the binding with the payload; R 9 is —CH or —(CH)N(H)C(O)NH; and A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, the attachment to the binding agent can be direct or via a spacer. In some embodiments, the binding to the binding agent can be achieved by binding the glutamic acid of the binding agent. The linker is a PEG spacer between the PEG and PEG residues. In some embodiments, the linker is: [ka] TIFF2023113639000187.tif216170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or or a mixture of these positional isomers, wherein: Each [ka] is the bond with the binder; Each [ka] is the binding with the payload; R 9 is —CH or —(CH)N(H)C(O)NH; and A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, the attachment to the binding agent can be direct or via a spacer. In some embodiments, the binding to the binding agent can be achieved by binding the glutamic acid of the binding agent. The linker is a PEG spacer between the PEG and PEG residues.

[0162] In some embodiments, the linker is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a compound thereof positional isomers, or mixtures of these positional isomers, wherein: Each [ka] is the bond with the binder; Each [ka] is the binding with the payload; Each [ka] is the bond to the enhancer group; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, the attachment to the binding agent can be direct or via a spacer. In some embodiments, the binding to the binding agent can be achieved by binding the glutamic acid of the binding agent. In some embodiments, the enhancer is attached to the parent In some embodiments, the enhancer is a cyclodextrin. In such embodiments, the enhancing group is an alkyl, heteroalkyl, alkylenyl, or heteroalkylene. The cyclodextrin may be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin is alpha cyclodextrin. cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof In some embodiments, the cyclodextrin is alpha cyclodextrin. In some embodiments, the cyclodextrin is a beta cyclodextrin. In some embodiments, the cyclodextrin is gamma cyclodextrin. and the 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 where n is 1, 2, 3, 4, or 5 and m is 1, 2, 3, 4, or 5. In the above, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Phosphoric acid is -(CH2) 1-5 In another embodiment, alkyl, heteroalkyl, aryl, Alkylenyl or heteroalkylenyl sulfonic acids are -(CH2) n -NH-(CH2) 1-5 SO3H, wherein n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroaryl, The alkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n -C(O)NH-(CH2) 1-5 S OH, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl , heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acids are -(CH2CH2O) m - C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, In the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where n is 1, 2, 3, 4, or 5 In another embodiment, alkyl, heteroalkyl, alkylenyl, or hetero Alkylenylsulfonic acids are -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where and n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroalkyl , alkylenyl, or heteroalkylenyl sulfonic acids are -(CH2CH2O) m -C(O)N((CH2) 1-5 C( O)NH(CH2) 1-5 SO3H2, where m is 1, 2, 3, 4, or 5.

[0163] In some embodiments, the linker is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a compound thereof positional isomers, or mixtures of these positional isomers, wherein: Each [ka] is the bond with the binder; Each [ka] is the binding with the payload; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, the attachment to the binding agent can be direct or via a spacer. In some embodiments, the binding to the binding agent can be achieved by binding the glutamic acid of the binding agent. In some embodiments, the enhancer is attached to the parent In some embodiments, the enhancer is a cyclodextrin. In such embodiments, the enhancing group is an alkyl, heteroalkyl, alkylenyl, or heteroalkylene. The cyclodextrin may be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin is alpha cyclodextrin. cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof In some embodiments, the cyclodextrin is alpha cyclodextrin. In some embodiments, the cyclodextrin is a beta cyclodextrin. In some embodiments, the cyclodextrin is gamma cyclodextrin. and the 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 where n is 1, 2, 3, 4, or 5 and m is 1, 2, 3, 4, or 5. In the above, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Phosphoric acid is -(CH2) 1-5 In another embodiment, alkyl, heteroalkyl, aryl, Alkylenyl or heteroalkylenyl sulfonic acids are -(CH2) n -NH-(CH2) 1-5 SO3H, wherein n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroaryl, The alkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n -C(O)NH-(CH2) 1-5 S OH, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl , heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acids are -(CH2CH2O) m - C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, In the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where n is 1, 2, 3, 4, or 5 In another embodiment, alkyl, heteroalkyl, alkylenyl, or hetero Alkylenylsulfonic acids are -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where and n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroalkyl , alkylenyl, or heteroalkylenyl sulfonic acids are -(CH2CH2O) m -C(O)N((CH2) 1-5 C( O)NH(CH2) 1-5 SO3H2, where m is 1, 2, 3, 4, or 5.

[0164] In some embodiments, the linker is: [ka] TIFF2023113639000201.tif69170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or or a mixture of these positional isomers, wherein: Each [ka] is the bond with the binder; Each [ka] is the binding with the payload; R 9 is —CH or —(CH)N(H)C(O)NH; and A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, the attachment to the binding agent can be direct or via a spacer. In some embodiments, the binding to the binding agent can be achieved by binding the glutamic acid of the binding agent. The linker is a PEG spacer between the PEG and PEG residues.

[0165] In some embodiments, the linker is: [ka] TIFF2023113639000206.tif98170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or or a mixture of these positional isomers, wherein: Each [ka] is the bond with the binder; Each [ka] is the binding with the payload; R 9 is —CH or —(CH)N(H)C(O)NH; and A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, the attachment to the binding agent can be direct or via a spacer. In some embodiments, the binding to the binding agent can be achieved by binding the glutamic acid of the binding agent. The linker is a PEG spacer between the PEG and PEG residues.

[0166] The above linkers are useful to provide the following conjugates:

[0167] In some embodiments, the conjugate comprises: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or the position thereof isomers, where: BA is a binder; Each SP 1 , SP 2 , and SP 3 is the spacer group as defined above, where SP 3 is (AA) n brain Connected to one AA; EG is an enhancer; k is an integer from 1 to 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 as defined in relation to Formula I. As listed; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A, at each occurrence, is independently -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, the attachment to the binding agent can be direct or via a spacer. In some embodiments, the binding to the binding agent can be achieved by binding the glutamic acid of the binding agent. In some embodiments, the enhancer is attached to the parent In some embodiments, the enhancer is a cyclodextrin. In such embodiments, the enhancing group is an alkyl, heteroalkyl, alkylenyl, or heteroalkylene. The cyclodextrin may be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin is alpha cyclodextrin. cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof In some embodiments, the cyclodextrin is alpha cyclodextrin. In some embodiments, the cyclodextrin is a beta cyclodextrin. In some embodiments, the cyclodextrin is gamma cyclodextrin. and the 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 where n is 1, 2, 3, 4, or 5 and m is 1, 2, 3, 4, or 5. In the above, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Phosphoric acid is -(CH2) 1-5 In another embodiment, alkyl, heteroalkyl, aryl, Alkylenyl or heteroalkylenyl sulfonic acids are -(CH2) n -NH-(CH2) 1-5 SO3H, wherein n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroaryl, The alkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n -C(O)NH-(CH2) 1-5 S OH, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl , heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acids are -(CH2CH2O) m - C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, In the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where n is 1, 2, 3, 4, or 5 In another embodiment, alkyl, heteroalkyl, alkylenyl, or hetero Alkylenylsulfonic acids are -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where and n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroalkyl , alkylenyl, or heteroalkylenyl sulfonic acids are -(CH2CH2O) m -C(O)N((CH2) 1-5 C( O)NH(CH2) 1-5 SO3H2, where m is 1, 2, 3, 4, or 5. And R is R 1 is.

[0168] In some embodiments, the conjugate is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or the position thereof isomers, where: BA is a binder; each RG′ is a residue of a reactive group described herein; EG is an enhancer; k is an integer from 1 to 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 as defined in relation to Formula I. As listed; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, the attachment to the binding agent can be direct or via a spacer. In some embodiments, the binding to the binding agent can be achieved by binding the glutamic acid of the binding agent. In some embodiments, the enhancer is attached to the parent In some embodiments, the enhancer is a cyclodextrin. In such embodiments, the enhancing group is an alkyl, heteroalkyl, alkylenyl, or heteroalkylene. The cyclodextrin may be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin is alpha cyclodextrin. cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof In some embodiments, the cyclodextrin is alpha cyclodextrin. In some embodiments, the cyclodextrin is a beta cyclodextrin. In some embodiments, the cyclodextrin is gamma cyclodextrin. and the 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 where n is 1, 2, 3, 4, or 5 and m is 1, 2, 3, 4, or 5. In the above, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Phosphoric acid is -(CH2) 1-5 In another embodiment, alkyl, heteroalkyl, aryl, Alkylenyl or heteroalkylenyl sulfonic acids are -(CH2) n -NH-(CH2) 1-5 SO3H, wherein n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroaryl, The alkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n -C(O)NH-(CH2) 1-5 S OH, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl , heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acids are -(CH2CH2O) m - C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, In the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where n is 1, 2, 3, 4, or 5 In another embodiment, alkyl, heteroalkyl, alkylenyl, or hetero Alkylenylsulfonic acids are -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where and n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroalkyl , alkylenyl, or heteroalkylenyl sulfonic acids are -(CH2CH2O) m -C(O)N((CH2) 1-5 C( O)NH(CH2) 1-5 SO3H2, where m is 1, 2, 3, 4, or 5. And R is R 1 is.

[0169] In some embodiments, the conjugate is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or the position thereof isomers, where: BA is a binder; each RG′ is a residue of a reactive group described herein; EG is an enhancer; k is an integer from 1 to 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 as defined in relation to Formula I. As listed; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, the attachment to the binding agent can be direct or via a spacer. In some embodiments, the binding to the binding agent can be achieved by binding the glutamic acid of the binding agent. In some embodiments, the enhancer is attached to the parent In some embodiments, the enhancer is a cyclodextrin. In such embodiments, the enhancing group is an alkyl, heteroalkyl, alkylenyl, or heteroalkylene. The cyclodextrin may be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin is alpha cyclodextrin. cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof In some embodiments, the cyclodextrin is alpha cyclodextrin. In some embodiments, the cyclodextrin is a beta cyclodextrin. In some embodiments, the cyclodextrin is gamma cyclodextrin. and the 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 where n is 1, 2, 3, 4, or 5 and m is 1, 2, 3, 4, or 5. In the above, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Phosphoric acid is -(CH2) 1-5 In another embodiment, alkyl, heteroalkyl, aryl, Alkylenyl or heteroalkylenyl sulfonic acids are -(CH2) n -NH-(CH2) 1-5 SO3H, wherein n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroaryl, The alkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n -C(O)NH-(CH2) 1-5 S OH, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl , heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acids are -(CH2CH2O) m - C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, In the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where n is 1, 2, 3, 4, or 5 In another embodiment, alkyl, heteroalkyl, alkylenyl, or hetero Alkylenylsulfonic acids are -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where and n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroalkyl , alkylenyl, or heteroalkylenyl sulfonic acids are -(CH2CH2O) m -C(O)N((CH2) 1-5 C( O)NH(CH2) 1-5 SO3H2, where m is 1, 2, 3, 4, or 5. And R is R 1 is.

[0170] In some embodiments, the conjugate is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or the position thereof isomers, where: BA is a binder; k is an integer from 1 to 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 as defined in relation to Formula I. As listed; Each [ka] is the bond to the enhancer group; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancing group is alkyl, heteroalkyl, or cyclodextrin. , alkylenyl, or heteroalkylenyl sulfonic acids. It can be any cyclodextrin known to those skilled in the art. Cyclodextrin can be α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin. dextrin, or a mixture thereof. In some embodiments, the cyclodextrin In some embodiments, the cyclodextrin is a β-cyclodextrin. In some embodiments, the cyclodextrin is gamma cyclodextrin. In some embodiments, alkyl, heteroalkyl, alkylenyl, or Heteroalkylenyl sulfonic acids are -(CH2) 1-5 SO3H, -(CH2) 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 SO3H2, where n is 1, 2, 3, 4, or 5, and m is In one embodiment, alkyl, heteroalkyl, alkyl Heteroalkylenyl or heteroalkylenyl sulfonic acids are -(CH2) 1-5 In another embodiment, In the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In some embodiments, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyls may be used. Sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroaromatic groups are Alkylenylsulfonic 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, alkylenyl The alkyl or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 wherein n is 1, 2, 3, 4, or 5. In another embodiment, The alkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n -C(O)N((CH2 ) 1-5 C(O)NH(CH2) 1-5 SO3H2, where n is 1, 2, 3, 4, or 5. In the above, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Phosphoric acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where m is 1, 2 , 3, 4, or 5. In certain embodiments, R is R 1 is.

[0171] In some embodiments, the conjugate comprises: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or the position thereof isomers, where: BA is a binder; k is an integer from 1 to 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 as defined in relation to Formula I. As listed; Each [ka] is the bond to the enhancer group; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancing group is alkyl, heteroalkyl, or cyclodextrin. , alkylenyl, or heteroalkylenyl sulfonic acids. It can be any cyclodextrin known to those skilled in the art. Cyclodextrin can be α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin. dextrin, or a mixture thereof. In some embodiments, the cyclodextrin In some embodiments, the cyclodextrin is a β-cyclodextrin. In some embodiments, the cyclodextrin is gamma cyclodextrin. In some embodiments, alkyl, heteroalkyl, alkylenyl, or Heteroalkylenyl sulfonic acids are -(CH2) 1-5 SO3H, -(CH2) 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 SO3H2, where n is 1, 2, 3, 4, or 5, and m is In one embodiment, alkyl, heteroalkyl, alkyl Heteroalkylenyl or heteroalkylenyl sulfonic acids are -(CH2) 1-5 In another embodiment, In the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In some embodiments, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyls may be used. Sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroaromatic groups are Alkylenylsulfonic 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, alkylenyl The alkyl or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 wherein n is 1, 2, 3, 4, or 5. In another embodiment, The alkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n -C(O)N((CH2 ) 1-5 C(O)NH(CH2) 1-5 SO3H2, where n is 1, 2, 3, 4, or 5. In the above, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Phosphoric acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where m is 1, 2 , 3, 4, or 5. In certain embodiments, R is R 1 is.

[0172] In some embodiments, the conjugate comprises: [ka] TIFF2023113639000223.tif196170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or positional isomers, where: BA is a binder; k is an integer from 1 to 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 as defined in relation to Formula I. As listed; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. In certain embodiments, R is R 1 is.

[0173] In some embodiments, the conjugate comprises: [ka] TIFF2023113639000226.tif199170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or positional isomers, where: BA is a binder; k is an integer from 1 to 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 as defined in relation to Formula I. As listed; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. In certain embodiments, R is R 1 is.

[0174] In some embodiments, the conjugate comprises: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or the position thereof isomers, where: BA is a binder; k is an integer from 1 to 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 as defined in relation to Formula I. As listed; Each [ka] is the bond to the enhancer group; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancing group is alkyl, heteroalkyl, or cyclodextrin. , alkylenyl, or heteroalkylenyl sulfonic acids. It can be any cyclodextrin known to those skilled in the art. Cyclodextrin can be α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin. dextrin, or a mixture thereof. In some embodiments, the cyclodextrin In some embodiments, the cyclodextrin is a β-cyclodextrin. In some embodiments, the cyclodextrin is gamma cyclodextrin. In some embodiments, alkyl, heteroalkyl, alkylenyl, or Heteroalkylenyl sulfonic acids are -(CH2) 1-5 SO3H, -(CH2) 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 SO3H2, where n is 1, 2, 3, 4, or 5, and m is In one embodiment, alkyl, heteroalkyl, alkyl Heteroalkylenyl or heteroalkylenyl sulfonic acids are -(CH2) 1-5 In another embodiment, In the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In some embodiments, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyls may be used. Sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroaromatic groups are Alkylenylsulfonic 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, alkylenyl The alkyl or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2)1-5 C(O)NH(CH2) 1-5 SO3H)2 wherein n is 1, 2, 3, 4, or 5. In another embodiment, The alkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n -C(O)N((CH2 ) 1-5 C(O)NH(CH2) 1-5 SO3H2, where n is 1, 2, 3, 4, or 5. In the above, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Phosphoric acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where m is 1, 2 , 3, 4, or 5. In certain embodiments, R is R 1 is.

[0175] In some embodiments, the conjugate comprises: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or the position thereof isomers, where: BA is a binder; k is an integer from 1 to 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 as defined in relation to Formula I. As listed; Each [ka] is the bond to the enhancer group; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancing group is alkyl, heteroalkyl, or cyclodextrin. , alkylenyl, or heteroalkylenyl sulfonic acids. It can be any cyclodextrin known to those skilled in the art. Cyclodextrin can be α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin. dextrin, or a mixture thereof. In some embodiments, the cyclodextrin In some embodiments, the cyclodextrin is a β-cyclodextrin. In some embodiments, the cyclodextrin is gamma cyclodextrin. In some embodiments, alkyl, heteroalkyl, alkylenyl, or Heteroalkylenyl sulfonic acids are -(CH2) 1-5 SO3H, -(CH2) 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 SO3H2, where n is 1, 2, 3, 4, or 5, and m is In one embodiment, alkyl, heteroalkyl, alkyl Heteroalkylenyl or heteroalkylenyl sulfonic acids are -(CH2) 1-5 In another embodiment, In the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In some embodiments, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyls may be used. Sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, alkyl, heteroalkyl, alkylenyl, or heteroaromatic groups are Alkylenylsulfonic 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, alkylenyl The alkyl or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2 wherein n is 1, 2, 3, 4, or 5. In another embodiment, The alkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n -C(O)N((CH2 ) 1-5 C(O)NH(CH2) 1-5 SO3H2, where n is 1, 2, 3, 4, or 5. In the above, alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfo Phosphoric acid is -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H2, where m is 1, 2 , 3, 4, or 5. In certain embodiments, R is R 1 is.

[0176] In some embodiments, the conjugate comprises: [ka] TIFF2023113639000235.tif83170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or positional isomers, where: BA is a binder; k is an integer from 1 to 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 as defined in relation to Formula I. As listed; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. In certain embodiments, R is R 1 is.

[0177] In some embodiments, the conjugate comprises: [ka] TIFF2023113639000238.tif90170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or positional isomers, where: BA is a binder; k is an integer from 1 to 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 as defined in relation to Formula I. As listed; Each R 9is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. In certain embodiments, R is R 1 is.

[0178] In each of the above embodiments, the conjugate may be a compound selected from the group consisting of: , and can be prepared from a linking agent functionalized with an azide group, and a residue thereof. Additionally, the triazole residue in some of the structures above is shown in parentheses. The trazole is bonded to the azide group of the azide-derivatized binder and the linker payload LP. It will be appreciated that it can be formed from an alkyne.

[0179] In some embodiments, the conjugate comprises: [ka] TIFF2023113639000241.tif243170TIFF2023113639000242.tif246170TIFF2023113639000243.tif219170TIFF2023113639000244.tif200170TIFF2023113639000245.tif249170 or positional isomers, stereoisomeric forms, pharmaceutically acceptable salts, and solvates thereof. In the above embodiment, k is an integer of 1 to 30. In one embodiment, k is an integer from 1 to 8. In some embodiments, k is an integer from 1 to 4. In the formula, k is 8, 7, 6, 5, 4, 3, 2, or 1. In some embodiments, k is 4. In some embodiments, k is 3. In some embodiments, k is 2. In an embodiment, k is 1.

[0180] (Reactive Linker-Payload) The conjugates provided herein comprise a reactive linker-peptide having a reactive group RG as described above. The reactive linker payload can be prepared from erode according to the following method: and linked to an enhancing group and / or a binding agent.

[0181] In some embodiments, the reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or the position thereof isomers, where: each RG is a reactive group as defined 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 as defined in relation to Formula I. As listed; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. In certain embodiments, R is R 1 is.

[0182] In some embodiments, the reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or the position thereof isomers, where: each RG is a reactive group as defined 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 as defined in relation to Formula I. As listed; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. In certain embodiments, R is R 1 is.

[0183] In some embodiments, the reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or the position thereof isomers, where: 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 as defined in relation to Formula I. As listed; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. In certain embodiments, R is R 1 is.

[0184] In some embodiments, the reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or the position thereof isomers, where: 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 as defined in relation to Formula I. As listed; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. In certain embodiments, R is R 1 is.

[0185] In some embodiments, the reactive linker-payload is: [ka] TIFF2023113639000255.tif153170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or positional isomers, where: 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 as defined in relation to Formula I. As listed; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. In certain embodiments, R is R 1 is.

[0186] In some embodiments, the reactive linker-payload is: [ka] TIFF2023113639000258.tif155170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or positional isomers, where: 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 as defined in relation to Formula I. As listed; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. In certain embodiments, R is R 1 is.

[0187] In some embodiments, the reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or the position thereof isomers, where: 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 as defined in relation to Formula I. As listed; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. In certain embodiments, R is R 1 is.

[0188] In some embodiments, the reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or the position thereof isomers, where: 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 as defined in relation to Formula I. As listed; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. In certain embodiments, R is R 1 is.

[0189] In some embodiments, the reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or positional isomers, where: 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 as defined in relation to Formula I. As listed; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. In certain embodiments, R is R 1 is.

[0190] In some embodiments, the reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or positional isomers, where: 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 as defined in relation to Formula I. As listed; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or a side group of an amino acid as discussed elsewhere herein. For example, in one embodiment, ZZ is a C 1-6 Further examples include alkyl. In one embodiment, ZZ is C 1-6 It is heteroalkyl. In certain embodiments, R is R 1 is.

[0191] In some embodiments, the reactive linker-payload is: [ka] TIFF2023113639000269.tif242170TIFF2023113639000270.tif247170TIFF2023113639000271.tif242170TIFF2023113639000272.tif246170 or positional isomers, stereoisomeric forms, pharmaceutically acceptable salts, and solvates thereof. It is selected.

[0192] (Method for preparing compounds) The compounds provided herein may be prepared and isolated by any method apparent to one of skill in the art. Exemplary preparation methods are described in detail in the Examples below. In certain embodiments, the compounds provided herein are prepared according to Scheme A. It is possible.

[0193] Scheme A. Exemplary Preparation Scheme [ka] In the exemplary preparation scheme, Q 1 , Q 2 , R 1 , R 2 , R 7 , W, and n are, in the context of formula (I), After the initial esterification, R 1 Protection of and / or R 1 followed by either amination of R 2 P occurs. R 1 After protection of, for example, the carboxylic acid moiety By saponification and activation of Q 1 A first coupling partner is provided having the formula: After oxidation, for example, by saponification and amidation of the carboxylic acid moiety, Q 2 A second cup with Ring partners are provided. 1 and Q 2Coupling partners having Combine them into one, then R 1 and R 2 Deprotection of the compound of formula I provides Exemplary preparation methods are described in detail in the Examples below.

[0194] In certain embodiments, one or more protection or deprotection steps may be carried out in the manner described in Scheme A above. It may also be included in the preparation method.

[0195] The linker-payloads described herein are synthesized by a series of coupling steps. It is possible. [ka] For example, the payload on the right can be coupled to SP via one or more standard coupling reactions. 2 Connected to In a preferred embodiment, the payload compounds described herein are , a free amino group available for coupling via amide synthesis conditions as described herein Includes (AA) n The amino acid is added under amide synthesis conditions, e.g., peptide synthesis conditions. Spacer SP 2 via one or more standard coupling reactions (AA) n In a preferred embodiment, the SPs described herein can be linked to 2 and (AA ) n The group is a free alkyl group available for coupling via amide synthesis conditions as described herein. Contains an amino or carboxyl group. If present, the spacer SP 3 is one or more standard cups via the pulling reaction (AA) n In a preferred embodiment, the present invention SP as described in the details 3 and (AA) n The group is capable of coupling with amide synthesis conditions as described herein. It contains a free amino or carboxyl group available for binding.

[0196] Spacer SP 3 When present, the reactive group RG terminates. This reactive group may be any suitable group suitable to those skilled in the art. The compound can be linked to the enhancer EG via coupling conditions that are considered to be In an embodiment, the spacer SP 3 is linked to the enhancer EG via amide synthesis conditions. In one embodiment, the spacer SP 3 is linked to the enhancer EG via click chemistry In these embodiments, the spacer SP 3 is a reactive group suitable for Click reaction, e.g. , azide, or alkyne, and the enhancer EG has a complementary reactive group suitable for a Click reaction, e.g., Examples include alkynes or azides. In a preferred embodiment, SP 3 ends with a strained alkyne EG contains azide; or SP 3 ends in a carboxylic acid and EG contains an amine. When is a cyclodextrin moiety, the cyclodextrin may contain an azide. Azidocyclodextrins can be prepared synthetically or are commercially available. When EG is a sulfonic acid moiety, one end of the EG is One end is terminated with a sulfonic acid group, and the other end is terminated with a primary or secondary amine.

[0197] The conjugates described herein may comprise a linker-payload as described herein. is coupled to a binding agent, e.g., an antibody, under standard conjugation conditions. (See, for example, the references herein incorporated by reference in their entirety.) (See Doronina et al., Nature Biotechnology 2003, 21, 7, 778). the antibody is linked to the linker- The linker-payload can be coupled to the antibody. The antibody may be subjected to a reducing agent, such as dithiotheritol, to reduce the disulfides of the antibody. The peptide bond is cleaved and the reduced antibody is purified, for example, by gel filtration. The antibody is treated with a suitable reactive moiety, e.g., a linker-payload containing a maleimide group. By using a solvent such as cyclohexane, the cysteine ​​residue can be coupled to the cysteine ​​residue. , water, DMA, DMF, and DMSO. The linker-payload containing a functionalized ester or acid halide group is linked to the lysine residue of the antibody. Suitable solvents include water, DMA, DMF, and DMSO. Conjugates can be used, for example, by size exclusion chromatography. The protein may be purified using known protein techniques, including filtration, dialysis, and ultrafiltration / diafiltration. This can be done.

[0198] Binding agents, e.g., antibodies, can also be conjugated via click chemistry reactions In some embodiments of the click chemistry reaction, the linker-payload is an azido Reactive groups that can undergo 1,3-cycloaddition reactions with alkyl groups include, for example, alkynes. Such suitable reactive groups are described above. The antibody may contain one or more azide groups. Such antibodies include, for example, antibodies functionalized with azido-polyethylene glycol groups. In certain embodiments, such functionalized antibodies include antibodies having at least one Antibodies having glutamine residues, for example, heavy chain Gln295 or Gln55, can be synthesized by the enzyme transglutaminase. It is induced by treatment with a primary amine compound in the presence of aminease. In embodiments, such functionalized antibodies contain at least one glutamine residue, e.g., An antibody having heavy chain Gln297 is subjected to transglutaminase enzyme transglutaminase to convert the heavy chain Gln297 into a primary amine. Such antibodies include those containing the Asn297Gln (N297Q) mutation. In certain embodiments, such functionalized antibodies include at least two groups. Antibodies having glutamine residues, for example, heavy chain Gln295 and heavy chain Gln297, can be synthesized by the enzyme transglutaminase. It is induced by treatment with a primary amine compound in the presence of aminease. Such antibodies include an Asn297Gln (N297Q) mutation. The two overlapping sequences described in this paragraph are used for a total of two or four glutamine residues. It has a chain.

[0199] In certain embodiments, the antibody comprises a group A at one or more heavy chain positions numbered 295 in the EU numbering system. In the present disclosure, this position is referred to as glutamine 295 or Gln295 or Q295 Those skilled in the art will recognize that this is the conserved glutamine residue in the wild-type sequence of many antibodies. In other useful embodiments, the antibody is The antibody sequence can be modified to include glutamine residues. Techniques for doing so are within the capabilities of those skilled in the art (see, for example, Ausubel et al., Current Protocols. Molecular Biology, 1999). l. Biol.).

[0200] In certain embodiments, the antibody contains two glutamine residues, one in each heavy chain. In certain embodiments, the antibody comprises a Q295 residue in each heavy chain. The antibody may contain one, two, three, four, five, six, seven, eight, or more glutamic acid residues. These glutamine residues may be present in the heavy chain, the light chain, or both the heavy and light chains. Exemplary glutamine residues include Q55. These glutamine residues can be wild-type residues or modified residues. The antibodies are prepared according to standard techniques. It is possible.

[0201] Those skilled in the art will recognize that the antibody is glycosylated at residue N297, which is near residue Q295 in the heavy chain sequence. Glycosylation at residue N297 is associated with a glycosylation at residue Q295. This can interfere with transglutaminase (Dennler et al., supra). Thus, in a preferred embodiment, the antibody is aglycosylated. Thus, the antibody is aglycosylated or aglycosylated. In other words, the antibody has an N297 mutation at position 297. It has been mutated so that it no longer has a paragine residue. In the antibody heavy chain, the antibody heavy chain has a N297Q mutation. Such antibodies also have glycosylation sequences removed. or by site-directed mutagenesis to abolish or nullify the function or binding of the antibody. Prepared by site-directed mutagenesis to insert glutamine residues at sites that do not cause cleavage. In some embodiments, the Q295 residue and / or the N297Q mutation can be The antibody is accessible to transglutaminase and therefore has a linker or linker structure. anchor - one or more additional naturally occurring glutamines that can be conjugated to a payload Residues contained in the variable region include, for example, Q5 of the light chain. 5. In such cases, conjugation occurs via transglutaminase. The resulting antibodies may have a DAR value greater than expected (e.g., a DAR greater than 4). Any such antibody can be isolated from natural or artificial sources.

[0202] The antibody, which does not have interfering glycosylation, is then reacted with a primary amine compound. In some embodiments, the aglycosylated antibody is reacted with a primary amine compound to form a glutaminyl-modified antibody. In one embodiment, the deglycosylated antibody is purified by cleaving the deglycosylated antibody with a primary amine compound. Treated to generate glutaminyl-modified antibodies.

[0203] Primary amines form covalent bonds with glutamine residues in the presence of transglutaminase The primary amine can be any primary amine capable of reacting with the amine. Useful primary amines are listed below. The transglutaminase may be any suitable transglutaminase as deemed suitable by those skilled in the art. In some embodiments, the transglutaminase Aminoase reacts with the free amine group on the primary amine compound and the acyl group on the side chain of the glutamine residue. Transglutaminase is an enzyme that catalyzes the formation of isopeptide bonds between proteins. Also known as protein-glutamine-γ-glutamyltransferase. In the same way, transglutaminase is classified as EC 2.3.2.13. The taminase can be from any source deemed suitable. In some embodiments, the transglutaminase is microbial. Glutaminase is a enzyme produced by Streptomyces mobaraense, ... Streptomyces cinnamoneum, Streptomyces grisea Streptomyces griseo-carneum, Streptomyces lavendulae It has been isolated from Bacillus subtilis, Bacillus lavendulae, and Bacillus subtilis. Non-microbial transglutaminases may also be used, including transglutaminases from In one embodiment, the transglutaminase can be produced by any technique. or may be obtained from any source deemed suitable by one skilled in the art. In certain embodiments, the transglutaminase is obtained from a commercial source.

[0204] In certain embodiments, the primary amine compound is further In these embodiments, the glutaminyl-modified antibody comprises a reactive group capable of reacting with the React with or react with a reactive payload compound or reactive linker-payload compound. These can be treated to form antibody-payload conjugates. In an embodiment, the primary amine compound comprises an azide.

[0205] In one embodiment, the glutaminyl-modified antibody is reacted with a reactive linker-payload. The antibody is then reacted with or treated with a hydroxybenzoate to form the antibody-payload conjugate. The reaction may proceed under conditions deemed suitable by one skilled in the art. In the method, a glutaminyl-modified antibody is combined with the glutaminyl-modified antibody and a linker-payload. and the reactive linker-payload compound under conditions suitable to form a bond between the compound. Suitable reaction conditions are well known to those skilled in the art.

[0206] Exemplary reactions are provided in the Examples below.

[0207] Pharmaceutical Compositions and Methods of Treatment Provided herein are methods for treating and preventing a disease, illness, or disorder, comprising: One or more of the compounds disclosed herein, for example, one or more of the compounds of the formula provided herein The method comprises administering a therapeutically or prophylactically effective amount of the disease, disorder, and / or condition. Diseases include, but are not limited to, those associated with the antigens listed herein.

[0208] The compounds described herein may be administered alone or in combination with one or more additional therapeutic agents. The one or more additional therapeutic agents may be administered immediately prior to the administration of the compounds described herein. , or can be administered simultaneously with or immediately after the administration of the same. in combination with one or more additional therapeutic agents; and methods of treatment comprising administering such combinations to a subject in need thereof. .

[0209] Suitable additional therapeutic agents include: a second glucocorticoid, an autoimmune agent, a hormone These include, but are not limited to, anti-cancer drugs, biologics, or monoclonal antibodies. Suitable therapeutic agents include any pharmaceutically acceptable salts of the compounds described herein. These include, but are not limited to, salts, acids, or derivatives thereof.

[0210] In some embodiments of the methods described herein, multiple doses of the methods described herein are administered. a compound described herein (or a compound described herein and an additional therapeutic agent referred to herein) administering to a subject a pharmaceutical composition comprising any combination of The method according to this aspect of the disclosure can involve administering to a subject multiple doses of a compound described herein. As used herein, "sequentially administering" includes administering each compound sequentially. Different doses of the compound may be administered at different times, e.g., at predetermined intervals (e.g., hours, days, weeks, or The present disclosure provides a method for administering a single dose to a patient on different days separated by a single month. one initial dose of a compound described herein, followed by one or more secondary doses of the compound, and and optionally thereafter sequentially administering one or more tertiary doses of the compound.

[0211] The terms "primary dose," "secondary dose," and "tertiary dose" are used herein. The "initial dose" refers to the time sequence of administration of a compound. Thus, the "initial dose" refers to the dose administered at the beginning of a treatment regimen. a "secondary dose" is a dose given after the initial dose (also known as the "baseline dose"); a "tertiary dose" is a dose administered after the secondary dose. The first, second, and third doses may all contain the same amount of a compound described herein. In some embodiments, the initial dose, secondary dose, and secondary doses may differ from each other, typically with respect to frequency of administration. The amounts of compounds contained in the doses, and / or tertiary doses may vary relative to one another during the course of treatment (e.g. In some embodiments, two or more (e.g., For example, doses 2, 3, 4, or 5) are administered as "loading doses" at the start of a treatment regimen. and then as subsequent doses (e.g., "maintenance doses") administered less frequently. can be.

[0212] In certain exemplary embodiments of the present disclosure, each secondary and / or tertiary dose is administered in a dose that is greater than or equal to the dose immediately preceding the immediately preceding dose. doses from 1 to 26 weeks (e.g., 1, 1 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, 4 1 / 2, 5, 5 1 / 2, 6, 6 1 / 2, 7 , 7 1 / 2, 8, 8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2, 13, 13 1 / 2, 14, 14 1 / 2 , 15, 15 1 / 2, 16, 16 1 / 2, 17, 17 1 / 2, 18, 18 1 / 2, 19, 19 1 / 2, 20, 20 1 / 2, 21, 21 1 / 2, 2 2, 22 1 / 2, 23, 23 1 / 2, 24, 24 1 / 2, 25, 25 1 / 2, 26, 26 1 / 2 weeks or longer) As used herein, the phrase "immediately preceding dose" refers to a series of multiple doses. In the administration of a compound, a compound administered to a patient before the administration of the very next dose in a sequence with no intervening doses is The compound dose is referred to as the dose of the compound.

[0213] The method according to this aspect of the disclosure can include administering to the patient any number of secondary and / or tertiary doses of a compound. For example, in some embodiments, only a single secondary dose may be administered to a patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) Similarly, in some embodiments, a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7) doses are administered to the patient. , 8, or more) tertiary doses are administered to the patient. The dosing regimen may be tailored to the specific subject. Lifelong, indefinitely, or until such treatment is no longer therapeutically necessary can be carried out until it is no longer beneficial.

[0214] In embodiments comprising multiple secondary doses, each secondary dose is administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to a patient 1 to 2 weeks or more after the immediately preceding dose. may be administered 1 to 2 months later. Similarly, in embodiments involving multiple tertiary doses, each Each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose The dose may be administered to the patient 2 to 12 weeks after the immediately preceding dose. In this case, the frequency with which secondary and / or tertiary doses are administered to a patient may vary over the course of the treatment regimen. The frequency of administration may also vary depending on the individual patient's needs after clinical testing, as determined by the physician. may be adjusted during the course of treatment.

[0215] The present disclosure provides that 2-6 loading doses are administered at a first frequency (e.g., once weekly, once every two weeks, once every 3 weeks, once a month, once every 2 months, etc.) and then administered to patients in two or more maintenance doses. For example, this aspect of the disclosure includes a dosing regimen in which a patient receives a less frequent dose of According to the study, if the loading dose is administered once a month, the maintenance dose is administered once every six weeks. It may be administered to the patient once every two months, once every three months, etc.

[0216] The present disclosure relates to compounds and / or conjugates described herein, e.g., compounds of Formula I, Ia, Pharmaceutical compositions of compounds of formula Ib, A, Aa, or Ab, such as compounds described herein, salts, stereoisomers, polymorphs, and pharmaceutically acceptable carriers, diluents, and / or excipients. Suitable carriers, diluents, and excipients include those that are useful for maintaining the appropriate pH of the composition. Buffers for retention (e.g., citrate buffer, succinate buffer, acetate buffer) buffers, phosphate buffers, lactate buffers, oxalate buffers, etc.), body proteins (e.g., human serum albumin), saline, polyols (e.g., trehalose sugar, sucrose, xylitol, sorbitol, etc.), surfactants (e.g., polysorbate polysorbate 20, polysorbate 80, polyoxolates, etc.), antibacterial agents, and antioxidants However, the present invention is not limited to these.

[0217] In some instances, provided herein are methods for treating a disease, disorder, or illness. a compound of Formula I, Ia, Ib, A, Aa, or Ab, or a compound thereof, The method comprises administering a therapeutically effective amount of the pharmaceutical composition of the present invention.

[0218] In some instances, provided herein are methods for preventing a disease, disorder, or condition. a compound of Formula I, Ia, Ib, A, Aa, or Ab, or a compound thereof, The method comprises administering a prophylactically effective amount of the pharmaceutical composition of the present invention.

[0219] In some instances, provided herein are antibodies that are responsive to modulation of LXR signaling. In some instances, the method comprises treating or preventing any disease, disorder, or illness. The disease or disorder may involve an association with LXR function, LXR polymorphisms, LXR agonist activity, or LXR antagonist activity. In some instances, provided herein are methods for treating proliferative disorders, neurodegenerative disorders, and the like. , 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 of skill in the art. In this context, proliferative disorders include, but are not limited to, oncology disorders. wherein the oncological disorder can be any cancer disorder known to those skilled in the art. In embodiments, provided herein are methods of treating or preventing melanoma. In certain embodiments, provided herein are methods for treating or preventing metastatic melanoma. In certain embodiments, provided herein are methods for treating or preventing lung cancer. In one embodiment, provided herein is a method for preventing EGFR-tyrosine In one embodiment, the present invention provides a method for treating or preventing kinase inhibitor-resistant lung cancer. Provided herein are methods for treating or preventing oral cancer. Provided herein are methods for treating or preventing oral squamous cell carcinoma. In certain embodiments, provided herein are methods for treating or preventing prostate cancer. In some embodiments, provided herein are methods for treating or preventing Hodgkin's lymphoma. In some embodiments, provided herein are methods for treating or preventing breast cancer. is a preventative method.

[0221] The neurodegenerative disorder can be any neurodegenerative disorder known to those of skill in the art. In accordance with the present invention, provided herein are methods for treating or preventing Alzheimer's disease. In certain embodiments, provided herein are methods for treating or preventing Parkinson's disease. In some embodiments, provided herein are methods for treating Huntington's disease. In one embodiment, provided herein are methods for treating or preventing muscle atrophy. In one embodiment, the method comprises administering to a subject a compound provided herein, the compound being administered to a subject ... Provided are methods for treating or preventing myelin gene expression. Provided herein are methods for treating or preventing diseases, disorders, or disorders of myelination and remyelination. It is a preventative method.

[0222] The immunological disorder can be any immunological disorder known to those of skill in the art. In accordance with the present invention, provided herein are methods for treating or preventing inflammatory bowel disease. In certain embodiments, provided herein are methods for treating or preventing ulcerative colitis. In certain embodiments, provided herein are methods for treating or preventing Crohn's disease. It is a way to prevent this.

[0223] The inflammatory disorder can be any inflammatory disorder known to those of skill in the art. In one embodiment, provided herein is a method for treating or preventing arthritis. In accordance with the present invention, provided herein are methods for treating or preventing rheumatoid arthritis.

[0224] The metabolic disorder can be any metabolic disorder known to those of skill in the art. In the present invention, the metabolic disorder is dyslipidemia. Dyslipidemia can be any lipid abnormality known to those skilled in the art. In some embodiments, the dyslipidemia can be hyperlipidemia, hypercholesterolemia, or cholesterolemia, hypertriglyceridemia, hyperlipoproteinemia, HDL deficiency, ApoA-I deficiency, and cardiovascular diseases, such as coronary artery disease (e.g., angina pectoris, myocardial infarction, and sudden cardiac death). including the treatment and prevention of atherosclerosis; and prevention); and restenosis (e.g., as a result of medical procedures such as balloon angioplasty). and (including the treatment or prevention of atherosclerotic plaques resulting from the In certain embodiments, provided herein are methods for treating or preventing diabetes. It is the law.

[0225] The cardiovascular disease can be any cardiovascular disease known to those of skill in the art. Provided herein is a method for treating or preventing atherosclerosis, In certain embodiments, provided herein are methods for treating abnormal macrophage processes. The present invention is a method for treating or preventing atherosclerosis resulting from vasoconstriction. In the present invention, a method for treating oxLDL in macrophages is provided. Atherosclerosis resulting from the formation of oxidized low-density lipoprotein (oxLDL) that cannot be oxidized In one embodiment, provided herein is a method for treating or preventing a deficiency. In one embodiment, the method for treating or preventing ischemic heart disease is a method for treating or preventing ischemic heart disease. In one embodiment, the method provided herein is for treating or preventing stroke. Contemplated is a method for treating or preventing hypertensive heart disease. Provided herein are methods for treating or preventing aortic aneurysms. Provided herein are methods for treating or preventing endocarditis. In accordance with the present invention, provided herein is a method for treating or preventing peripheral arterial disease. In embodiments, provided herein are methods for treating any of the diseases provided in this paragraph. The present invention is a method for treating or preventing any of the above-mentioned combinations.

[0226] In some instances, provided herein are methods for modulating the function of a nuclear receptor, By way of non-limiting example, the function may be to inhibit the production of inflammatory mediators (e.g., cytokines, chemokine expression / secretion, cholesterol regulation, cholesterol uptake, cholesterol flux Egress, cholesterol oxidation, migration, chemotaxis, apoptosis and necrosis, inflammatory activity, lipid regulation, The effect may be selected from apoptosis, migration, chemotaxis, gene transcription, and protein expression. [Example]

[0227] (Example) Provided herein are novel bis-octahydrophenanthrenecarboxamides , protein conjugates thereof, and methods of treating diseases, disorders, and conditions By administering the bis-octahydrophenanthrene carboxamides and conjugates and

[0228] In some instances, the compound of formula (I) is a compound identified in Table 1. Table 1. List of payloads [Table 1] TIFF2023113639000276.tif249170TIFF2023113639000277.tif183170

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

[0230] Examples of linker-payloads of the present disclosure include those listed in Table 2 below. However, it is not limited to these. Table 2. Linker-payload list [Table 2] TIFF2023113639000282.tif209170TIFF2023113639000283.tif207170TIFF2023113639000284.tif230170TIFF2023113639000285.tif207170

[0231] Certain embodiments of the present invention are illustrated by the following non-limiting examples.

[0232] Unless otherwise expressly stated, reagents and solvents were obtained from commercial sources, e.g., Sinopharm Chemical Reagent Co. (SCRC), Sigma-Aldrich, Alfa, or other suppliers.

[0233] 1 1 H NMR and other NMR spectra were recorded on a Bruker AVIII 400 or Bruker AVIII 500. The data were processed using Nuts software or MestReNova software, and the proton shifts were calculated internally. Measured in parts per million (ppm) downfield from the standard tetramethylsilane (TMS).

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

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

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

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

[0238] Method A for LC-MS measurement includes: WATERS 2767; Column: Two columns connected in series. Shimadzu Shim-Pack, PRC-ODS, 20 x 250 mm, 15 μm; Mobile phase: A: water (0.01% TFA), B: Acetonitrile (0.01% TFA); Gradient phase: 5% B increased to 95% B within 3 min; Flow rate: 1 0.8~2.3mL / min; Column: SunFire C18, 4.6×50mm, 3.5μm; Column temperature: 50℃; Detector: AD C ELSD, DAD (214 nm and 254 nm), and ES-API were included.

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

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

[0241] Flash chromatography was performed using Agela Flash Column Silica-CS cartridges. reversed-phase flash chromatography was performed on a Boston ODS or Agel a Performed on a Biotage instrument using a C18 cartridge.

[0242] As used herein, the terms used in these processes, schemes, and examples are The symbols and conventions are used in modern science, regardless of whether a particular abbreviation is specifically defined. Literature, e.g., the Journal of the American Chemical Society or the Journal of Bio Consistent with those used in logical chemistry. Specifically, but not limited to: The following abbreviations may be used in the examples and throughout the specification: [Table 3] TIFF2023113639000287.tif245170TIFF2023113639000288.tif247170TIFF2023113639000289.tif110170

[0243] (Preparation method) Example 1 This example describes a general method for synthesizing podocarpic acid derivatives 9a-9r, 9t, and 9u in Table 1 above. This example refers to compounds numbered 1 through 9a-p in FIG.

[0244] In Figure 1, the starting material podocarpic acid 1 was originally discovered in plant resins in 1873. and later reported from some species of Podocarpus (e.g., J. Chem. Soc. 1 938, 1006-1013). The synthesis of compound 4 from podocarpic acid 1 has been reported previously (e.g. For example, Bioorg. Med. Chem. Lett. 2005, 15, 2824; Bioorg. Med. Chem. Lett. 2005, 15 , 4574). Acyl chloride 6a was prepared from the treatment of 4 with thionyl chloride; The symmetric imide 6b was prepared from the treatment of 4 with 5. The symmetric imide 8a was prepared from the acid chloride 6a or the activated ester. It is synthesized from the treatment of amide 7a with amide 6b, which is then subjected to debenzylation by hydrogenation. Similarly, unsymmetrical imides 8b-e and 8g were obtained by reacting amides 7b-g with activated esters. Unsymmetric imides 8b were synthesized from 6a by coupling reactions with ter 6b or acid chloride 6a. The yields of e and 8g were lower than those of the symmetric imide 8a, but the activated ester 6b was used. The yields of 8b-e and 8g increased from ~40% to 50-85%.

[0245] Imides 9a-e are prepared by reacting with the corresponding protecting groups—Bn in 8a, TBS in 8b, or 8c, 8d, and The N,N-dimethylated analog 9f was obtained from 8a-e by deprotection of the Boc group in 8e. Hydrogenation of 8d in methanol simultaneously removes methyl and N,N-dimethylates the aniline nitrogen. The N-Boc analog 9g was obtained from debenzylation of 8d. Compounds 9h-o were obtained from HATU and Amide coupling reaction of 9d with amino acid derivatives in the presence of methyl methylpropional and DIPEA, followed by cleavage in DCM. Deprotection of the Boc group with 10-25% TFA or deprotection of Fm with 20% piperidine in organic solvents The amide coupling reaction of 9d with Fmoc-Gly-OH was carried out. and subsequent Fmoc deprotection gave 9h; amide coupling of 9d with Boc-β-Ala-OH Coupling reaction followed by deprotection of the Boc group gave 9i; amide coupling of 9d with Boc-Ser-OH gave 9i. Ring-binding reaction followed by deprotection of the Boc group gives 9j; the amide of 9d with Boc-Sar-OH Coupling reaction and subsequent deprotection of the Boc group gave 9k; 9d and Boc-Lys(Boc)-OH were then reacted to give 9k. The amide coupling reaction of 9d with Boc-His-O gave 9l; Amide coupling reaction with H followed by deprotection of the Boc group gave 9m; Amide coupling reaction with p-OtBu followed by deprotection of Boc and -OtBu afforded 9n. obtained in one pot; amide coupling reaction of 9d with Boc-Glu-OtBu followed by Boc and -Ot Deprotection of Bu afforded 9o in one pot. Compound 9p was obtained in the presence of LiHMDS to form 8g. Amide coupling reaction of 7g with 6b in the presence of HCl followed by Raney cleavage of the nitrile to the amine. Compound 9q was synthesized by nickel-catalyzed reduction and debenzylation with boron tribromide (BBr3). Compound 9r was obtained by the amide coupling reaction of 9d with glutaric anhydride. It was obtained by amide coupling reaction with Boc-iminodiacetic acid followed by Boc deprotection. Compound 9t is the amide carboxylate of 7d with the activated ester of dehydroabietic acid (Cas. No. 1740-19-8). This was obtained by coupling 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 podocarpic acid (P1-1, 90 g, 0.33 mol) in methanol (200 mL) and toluene (600 mL) To the reaction mixture was added (trimethylsilyl)diazomethane (2M in hexane, 200 mL). The mixture was stirred at room temperature for 2 hours, after which time the podocarpic acid was completely consumed by LCMS. The effervescent material was removed in vacuo and the residue was triturated from petroleum ether (2 L) to give compound P1-2 (91 g, 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] A solution of compound P1-2 (10 g, 35 mmol) in methylene chloride (200 mL) was added with 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 trifluoromethane was added. methylmethanesulfonic anhydride (12 g, 42 mmol) was added and the resulting mixture was warmed to 25°C. The reaction mixture was diluted with DCM (500 mL), water (100 mL), aqueous sodium chloride (100 mL), and stirred for an additional 4 h at 25° C. Wash with acid (1N, 150 mL) and brine (100 mL), dry over sodium sulfate, and in vacuo Concentration gave crude compound P1-3 (14 g, 97% crude yield) as a viscous oil, which The crude compound P1-3 was purified by flash chromatography ( Purification with 0-10% ethyl acetate in petroleum ether gave the pure product as a viscous oil. 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 (14 g, 34 mmol) and tert-butyl carbamate (BocNH2, 7.9 g, 68 mmol) -butanol (100 mL) solution of cesium carbonate (22 g, 68 mmol), tris(dibenzylidene acetone) Dipalladium(0) (Pd2(dba)3, 1.8 g, 2.0 mmol) and X-Phos (1.8 g, 4.0 mmol) were added at room temperature. The mixture was degassed and purged with argon three times, and then monitored by TLC. The mixture was stirred overnight at 80 °C under argon (balloon) until compound P1-3 was 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 in vacuo and the residue was applied to a silica gel column. Purification by column chromatography (0-6.25% ethyl acetate in petroleum ether) revealed Compound P1-4 (11 g, 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] To a DMSO solution of compound P1-4 (4.9 g, 13 mmol), potassium tert-butoxide (15 g, 0.13 mol) was added. The reaction mixture was stirred under argon for 60 minutes until the reaction was complete by LCMS. After cooling to room temperature, the reaction mixture was poured onto ice and added with aqueous hydrochloric acid (0.5 M). The mixture was slowly acidified to pH 5 with 250 ml of water, while the temperature did not exceed 25°C. The precipitate was removed by filtration. The crude product was purified by silica gel column chromatography (petroleum ether). Further purification by elution with 0-20% ethyl acetate in ether gave compound P1-5 (4.5 g, 93% yield). Obtained as a colored solid. 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-octyl] Trihydrophenanthrene-3-yl]carbamate (P1-6) [ka] A solution of P1-5 (4.5 g, 12 mmol) and HATU (4.9 g, 13 mmol) in DMF (50 mL) was added with diisopropyl ether. Dimethylamine (20 mL, 0.12 mol) was added and the mixture was stirred at 25° C. for 1 hour. Then, ammonium chloride (16 g, 0.30 mol) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and purified. The residue was purified by flash chromatography (0-20% ethyl acetate in petroleum ether). Purification by HCl afforded compound P1-6 (4.2 g, 94% yield) as a white solid. 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-octamethyl Hydrophenanthrene-1-carboxylate (P1-8) [ka] A mixture of compound P1-2 (12 g, 40 mmol) and cesium carbonate (14 g, 44 mmol) in DMF (100 mL) was added for 20 min. The mixture was stirred for 15 minutes at 25° C. To the mixture was added benzyl bromide (7.1 mL, 60 mmol) at room temperature. After stirring at room temperature for 4 hours, the resulting mixture was poured into cold water and extracted with ethyl acetate. The combined organic solution was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (0-10% ethyl acetate in petroleum ether). ) to afford the title compound P1-8 (13 g, 89% yield) as a white solid. 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] DMSO (0.19 L) was added until the methyl group was completely removed, as monitored by LCMS and TLC. A mixture of compound P1-8 (11 g, 29 mmol) and potassium tert-butoxide (33 g, 0.29 mol) was added to The mixture was stirred at 00° C. for 1 hour. After cooling to 25° C., the mixture was quenched with aqueous hydrochloric acid (1N) and acetic acid The combined organic solution was washed with brine, dried over sodium sulfate, and extracted with ethyl acetate. The residue was purified by silica gel column chromatography (0.5% ethanol in petroleum ether). Purification with 24% ethyl acetate gave compound P1-9 (7.5 g, 71% yield) as a white solid. 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) was added with DIPEA (14 mL, 79 mmol) and perfluorophenyl To the mixture was added 2,2,2-trifluoromethyl-2,2,2-trifluoroacetate (15 g, 53 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was stirred and monitored by LCMS. The reaction mixture was then diluted with ether (200 mL). The organic solution was dried over sodium sulfate and washed with water (300 mL) and brine (200 mL). The residue was concentrated in vacuo and purified by flash chromatography (0-10% acetic acid in petroleum ether). Purification by ethyl acetate gave compound P1-10 (12 g, 88% yield) 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-octahydrophenanthrene-1-yl]formamide}carbonyl)-4 b,8-Dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]carbamate (P 1-11) [ka] A solution of compound P1-6 (2.3 g, 6.2 mmol) in THF (20 mL) was treated with n-BuLi (2.5 M in hexane, 5.5 mL, 14 mmHg). The reaction mixture was stirred at this temperature for 1 hour. To the mixture was added P1-10 (3.0 g, 5.6 A solution of 10 mmol) in THF (20 mL) was added, and then compound P1-10 was obtained as monitored by LCMS. The resulting mixture was stirred overnight at 10-20°C until the mixture was consumed. The mixture was quenched with ammonium hydroxide and extracted with ethyl acetate. The combined organic solution was washed with water and brine. The residue was purified by flash chromatography. Purification by filtration (0–30% ethyl acetate in petroleum ether) gave compound P1-11 (1.59 g, 51 % 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-octahydrophenanthrene-1-yl]formamide}carbonyl)-4b,8-di Methyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]carbamate (P1-12) [ka] To a solution of P1-11 (2.0 g, 2.78 mmol) in ethyl acetate (40 mL), wet palladium on carbon (10% Pd, 0.9 g) 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 a hydrogen balloon, which was monitored by LCMS. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography. Purification by chromatography (0-55% ethyl acetate in petroleum ether) gave P1-12 (1.06 g, 61% Yield: 1.03 g / m₂O. The compound 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-octadecanoate Hydrophenanthrene-1-carbonyl]-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10 α-Octahydrophenanthrene-1-carboxamide (9d) [ka] To a solution of compound P1-12 (0.17 g, 0.27 mmol) in DCM (10 mL) was added TFA (3 mL) dropwise at room temperature. LCMS The reaction mixture was stirred at room temperature for 1 hour until Boc was removed by HCl. The volatiles were removed in vacuo. The residue was purified by preparative HPLC (Method B) to give 9d (0.10 g, 70% yield) 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 min, Purity: 99.4%. Chiral HPLC: >99.9% (Columns AD, AS, OD) , and in 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-octahydrophenanthrene (1-carbonyl)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene- Synthesis of 1-carboxamides (LP1-2) [ka] A solution of 9d (53 mg, 0.10 mmol) in DMF (1 mL) was added to Fmoc-Val-Ala-OH (41 mg, 0.10 mmol), HATU (38 mg , 0.1 mmol), and diisopropylethylamine (26 mg, 0.20 mmol) were added sequentially. After stirring at 25°C for 24 hours until 9d was consumed, the mixture was added with piperidine (0.1 mL) and The resulting solution was stirred for an additional 3 hours at 25° C. After filtration, the filtrate was subjected to preparative HPLC (Method B). Direct purification gave 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-(cyclooct-2-ynyloxy) Acetamido)hexanamido)-3-methylbutanamido)propanamido)-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-carbohydrate Voxamide (LP1-4) [ka] A solution of compound LP1-3 (35 mg, 0.064 mmol) in DMF (1 mL) was added 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 at room temperature until it became homogeneous. The mixture was stirred at room temperature for several minutes. Diisopropylethylamine (41 mg, 0.32 mmol) was added to the mixture. The resulting LP1-2 was added by syringe at room temperature until it was almost consumed by LCMS. The mixture was stirred at room temperature overnight (16 hours). Then, piperidine (0.1 mL, (excess) was added dropwise at room temperature and the mixture was stirred until Fmoc was removed as monitored by LCMS. The reaction mixture was stirred for an additional 3 hours. Direct purification by Method B (basic conditions) gave compound LP1-4 (30 mg, 47% yield) as a white solid. 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(hydrogen Oxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29-dodecaoxaheptacyclo[26.2.2.2 3,6 .2 8,11 .2 13,16 .2 18,21 .2 23,26 ]dotetracontan-5-yl]methyl}-1H,4H,5H,6H,7H,8H,9H -cycloocta[d][1,2,3]triazol-4-yl)oxy]acetamido}hexanamido]-3 -Methylbutanamido]propanamido]-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydro -6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,1 0a-Octahydrophenanthrene-1-carboxamide (LP1-5) [ka] A solution of compound LP1-4 (30 mg, 30 μmol) in DMF (0.5 mL) was added to CD-N3 (60 mg, 60 μmol) in DMF (0.5 mL). The solution was added via syringe at room temperature. The mixture was stirred at 20-25°C for 3 days. Compound LP1-4 was almost consumed. The reaction mixture was directly purified 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 -yn-2-yl}-4-oxobutanamido)-N-[(1R)-1-{[(1S)-1-{[(4bS,8S,8aR)-8 -({[(1S,4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrofuran phenanthrene-1-yl]formamide}carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-o hexahydrophenanthrene-3-yl]carbamoyl}ethyl]carbamoyl}-2-methylpropyl 31,32,33,34,35,36,37,38,39,40,41,42-dodecahydroxycarbamoyl}-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-do Decaoxaheptacyclo[26.2.2.2 3,6 .2 8,11 .2 13,16 .2 18,21 .2 23,26 ]Dotetracontane-5 -yl]methyl}-1H,4H,5H,6H,7H,8H,9H-cycloocta[d][1,2,3]triazol-4-yl)o oxy]acetamido}pentyl]-3,6,9,12-tetraoxapentadecan-15-amide (LP8) [ka] Compound LP1-5 (14 mg, 7.4 μmol) and DIBAC-Suc-PEG4-OSu (6.5 mg, 10 μmol) were dissolved in DMF (1 mL). To the solution, triethylamine (2.0 mg, 20 μmol) was added, and the mixture was stirred at 20-25°C for 16 hours. Most of the volatiles were removed in vacuo and the residue was purified by preparative HPLC (Method B) to give the compound Compound LP8 (5.0 mg, 27% yield) was obtained as a white solid. ESI m / z: 1261 (M / 2+1) + . [ka]

[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-heptakis 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 ]he {1H,4H,5H,6H,7H,8H,9H-cycloocta[d][1,2,3]trimethyl}-1H,4H,5H,6H,7H,8H,9H-cycloocta[d][1,2,3]trimethyl thiazol-4-yl)oxy]acetamido}hexanamido]-3-methylbutanamido]pro Panamido]-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] To a solution of compound LP1-4 (30 mg, 0.030 mmol) in DMF (2 mL), γCD-N3 (0.12 mg, 0.091 mmol) was added. The mixture was stirred at RT for 16 h, which was monitored by LCMS. The filtrate was then purified by preparative HPLC (Method A) to give compound LP2-5 (40 mg, 5 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 -yn-2-yl}-4-oxobutanamido)-N-[(1R)-1-{[(1S)-1-{[(4bS,8S,8aR)-8 -({[(1S,4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrofuran phenanthrene-1-yl]formamide}carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-o hexahydrophenanthrene-3-yl]carbamoyl}ethyl]carbamoyl}-2-methylpropyl 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56-hexafluorophenyl]carbamoyl}-5-{2-[(1-{[ ... 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]triazol-4-yl)oxy]acetamido}pentyl]- 3,6,9,12-Tetraoxapentadecan-15-amide (LP32) [ka] To a solution of compound LP2-6 (4.3 mg, 7.8 μmol) in anhydrous DMF (1 mL), HATU (3.0 mg, 7.8 μmol) was added. The mixture was stirred at 10°C for 10 minutes, and then compound LP2-5 (15 mg, 6.5 μmol) and DIPEA (1.7 mg , 13 μmol) was added. The reaction mixture was monitored by LCMS until LP2-5 was completely consumed. The mixture was stirred at RT for 2 h. The mixture was filtered through a membrane and the filtrate was purified by preparative HPLC (Method B). After further 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 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 ]Do tetracontan-5-yl]methyl}-1H,4H,5H,6H,7H,8H,9H-cycloocta[d][1,2,3]triazol- hexanamide]-3-methylbutanamide]-5-(methyl-4-yl)oxy)acetamido} ... bamoylamino)pentanamido]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-octahydrophenanthrene 4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrobenzoyl [Irophenanthrene-3-yl]carbamoyl}-2-hydroxyethyl]carbamate (LP5-1) [ka] A solution of compound LP15 (20 mg, 15 μmol) in DMF (1 mL) was diluted with C in acetonitrile (2 mL) and water (2 mL). A solution of D-N3 (46 mg, 45 μmol) was added at RT. The mixture was stirred at 30° C. for 16 h. The reaction mixture was purified directly by preparative HPLC (Method B). The purification afforded compound LP5-1 (20 mg, 57% yield) 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-yn-2-yl}-4-oxobutanamido)-3,6,9,12-tetramethyl Oxapentadecan-15-amido]-6-{2-[(1-{[31,32,33,34,35,36,37,38,39,40,41,42-de Decahydroxy-10,15,20,25,30-pentakis(hydroxymethyl)-2,4,7,9,12,14,17,19,2 2,24,27,29-dodecaoxaheptacyclo[26.2.2.2 3,6 .2 8,11 .2 13,16 .2 18,21 .2 23,26 ]Dote cycloocta[d][1,2,3]triazo[1H,4H,5H,6H,7H,8H,9H- ... hexanamido]-3-methylbutanamido]-5-(carbamoyl-4-yl)oxy]acetamido} ... 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 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) was treated with HATU (3.0 mg, 3.6 μmol) and DIPEA (1.7 mg, 13 μmol) was added at RT. The resulting mixture was stirred at RT for 10 min. To the mixture was added LP5-1 (15 mg, 6.5 μmol). The reaction was monitored by LCMS. The reaction mixture was stirred at 30° C. for 2 hours until the reaction was complete. The reaction mixture was filtered and purified by preparative HPLC ( Purification by method B) gave 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-Azido-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecane-18-sulfonic acid (L6-2) [ka] A solution of azide-PEG-NHS (L6-1, 0.10 g, 0.26 mmol) in anhydrous DMF (4 mL) was diluted with taurine (39 mg, 0.3 1 mmol) and DIPEA (15 mg, 0.52 mmol) were added. The mixture was stirred at 25° C. overnight. The mixture The mixture was filtered, and the filtrate was purified by preparative HPLC (Method A) to give compound LP6-2 (80 mg, 78% yield). Obtained as a colored oil. ESI m / z: 399.1 (M+H) + . [ka]

[0272] 2-{1-[4-({[(5R)-5-amino-5-{[(1S)-1-{[(1S)-1-({4-[({[(1S)-1-{[(4bS,8S,8aR)-8-({[ (1S,4aS,10aR)-6-Hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophena 4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octabenzoxazole Hydrophenanthrene-3-yl]carbamoyl}-2-hydroxyethyl]carbamoyl}oxy )methyl]phenyl}carbamoyl)-4-(carbamoylamino)butyl]carbamoyl}-2-methyl (1H,4H,5H,6H,7H,8H,9H-trimethylpropyl)carbamoyl}pentyl]carbamoyl}methoxy)-1H,4H,5H,6H,7H,8H,9H-trimethylpropyl Chloocta[d][1,2,3]triazol-1-yl]-3,6,9,12-tetraoxapentadecan-15-a {Imid}ethane-1-sulfonic acid (LP6-3) [ka] A solution of compound LP6-2 (20 mg, 50 μmol) in water (1 mL) was added to saturated aqueous sodium bicarbonate solution to pH ~7. The solution was added dropwise at 0° C. Then, to the stirred solution, compound LP15 (28 mg, 21 μmol) in acetone was added. Acetontrile (1 mL) solution was added via syringe, and the mixture was stirred at 25° C. overnight. The reaction mixture was monitored by LCMS until compound LP15 was completely consumed. The mixture was filtered and purified by preparative HPLC (Method A) to give compound LP6-3 (15 mg, 41% yield) as a white solid. Obtained as a colored solid. ESI m / z: 856.5 (M / 2+1) + .

[0273] 2-{1-[4-({[(5R)-5-[1-(4-{2-azatricyclo[10.4.0.0 4,9 ]Hexadeca-1(12),4(9),5,7, 13,15-Hexaen-10-yn-2-yl}-4-oxobutanamido)-3,6,9,12-tetraoxapene tadecan-15-amido]-5-{[(1S)-1-{[(1S)-1-({4-[({[(1S)-1-{[(4bS,8S,8aR)-8-({[(1S,4 aS,10aR)-6-Hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene 4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydro- ... Phenantren-3-yl]carbamoyl}-2-hydroxyethyl]carbamoyl}oxy)methyl (phenyl)phenyl}carbamoyl)-4-(carbamoylamino)butyl]carbamoyl}-2-methylpropyl propyl]carbamoyl}pentyl]carbamoyl}methoxy)-1H,4H,5H,6H,7H,8H,9H-cyclo Octa[d][1,2,3]triazol-1-yl]-3,6,9,12-tetraoxapentadecan-15-amide }Ethane-1-sulfonic acid (LP36) [ka] Compound LP6-3 (15 mg, 8.8 μmol) and commercially available DIBAC-Suc-PEG-OSu LP6-4 (5.7 mg, 8.8 μmol) To a solution of 1,3-dimethyl-2,4-diphenyldiazomethane (CAS 1427004-19-0) in DMF (1 mL) was added DIPEA (2.3 mg, 18 μmol), and the mixture was stirred at RT. Stirred for 2 h. Most of the volatiles were removed in vacuo and the residue was purified by preparative HPLC (Method B). The purification afforded LP36 (6.0 mg, 30% yield) as a white solid. ESI m / z: 1123.8 (M / 2+H ) + , 749.5(M / 3+H) + . [ka]

[0274] Example 1f Synthesis of LP18 (Figure 1f) 1-Azido-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecane-18-sulfonic acid (L18-2 ) [ka] A solution of azide-PEG-NHS (L18-1, 0.10 g, 0.26 mmol) in anhydrous DMF (4 mL) was diluted with taurine (39 mg, 0. 31 mmol) and DIPEA (15 mg, 0.52 mmol) were added. The mixture was stirred at 25° C. overnight. was filtered, and the filtrate was purified by preparative HPLC (Method A) to give compound LP18-2 (80 mg, 78% yield). Obtained as a colorless oil. ESI m / z: 399.1 (M+H) + . [ka]

[0275] 1-(4-(2-((R)-5-amino-6-((S)-1-((S)-1-((4bS,8S,8aR)-8-((1S,4aS,10aR)-6-hydroxy 1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonylcarbonyl bamoyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-ylamine (1-oxopropan-2-ylamino)-3-methyl-1-oxobutan-2-ylamino)-6-oxo (isohexylamino)-2-oxoethoxy)-4,5,6,7,8,9-hexahydro-1H-cycloocta[d][ 1,2,3]triazol-1-yl)-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecane-1 8-Sulfonic acid (LP18-3) [ka] A solution of compound LP1-4 (40 mg, 40 μmol) in DMF (1 mL) was added with azide LP18-2 (40 mg, 0.10 mmol) at RT. The reaction was stirred at RT for 16 h until LCMS showed the reaction was complete. The mixture was directly purified by preparative HPLC to give compound LP18-3 (43 mg, 77% yield) as a white solid. ESI m / z: 695.4 (M / 2+H) + .

[0276] 2-{1-[4-({[(5R)-5-[1-(4-{2-azatricyclo[10.4.0.0 4,9 ]Hexadeca-1(12),4(9),5,7, 13,15-Hexaen-10-yn-2-yl}-4-oxobutanamido)-3,6,9,12-tetraoxapene Tadecane-15-amido]-5-{[(1S)-1-{[(1S)-1-{[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-hydro [Oxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-yl]form (4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene) -3-yl]carbamoyl}ethyl]carbamoyl}-2-methylpropyl]carbamoyl}pentyl ]carbamoyl}methoxy)-1H,4H,5H,6H,7H,8H,9H-cycloocta[d][1,2,3]triazole- 1-yl]-3,6,9,12-tetraoxapentadecane-15-amido}ethane-1-sulfonic acid (LP18) [ka] A solution of compound LP18-3 (30 mg, 22 μmol) in DMF (1 mL) was added to DMF (1 mL) and DIPEA (4 mg, 32 μmol). A solution of DIBAC-suc-PEG-OSu (LP18-4, 14 mg, 22 μmol) was added sequentially at RT. The mixture was stirred at RT for 2 h. The reaction mixture was directly purified by preparative HPLC (Method B) to give compound The product LP18 (15 mg, 37% yield) was obtained as a white solid. ESI m / z: 642 (M / 3+H) + . [ka]

[0277] Example 1g Synthesis of Payload 9j, Payload 9o, and Payload 9l [ka] [Table 4] Payload 9j (1S,4aS,10aR)-6-((S)-2-amino-3-hydroxypropanamide)-N-((1S,4aS,10aR)-6-hydroxypropanamide) Hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonyl (I)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide Do (9j) [ka] A solution of Fmoc-Ser-OH (33 mg, 0.1 mmol) in DMF (1 mL) was treated with HATU (38 mg, 0.1 mmol) and DIPEA (39 mg , 0.3 mmol) was added at 25°C. The resulting mixture was stirred at this temperature for 1 hour. To the mixture was added 9d (30 mg, 0.06 mmol). The reaction mixture was stirred at 25° C. for 16 hours, and (LCMS After 9d was completely consumed (as monitored by HPLC), piperidine (0.2 mL) was added to the mixture. This was stirred at room temperature for an additional 30 minutes. The residue was directly purified by preparative HPLC (Method B). This afforded 9j (18 mg, 51% yield) as a white solid. ESI m / z: 616 (M+1) + . [ka]

[0278] Payload 9o (4S)-4-amino-4-{[(4bS,8S,8aR)-8-{[(1S,4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2, 3,4,4a,9,10,10a-Octahydrophenanthrene-1-carbonyl]carbamoyl}-4b,8-dimethyl ethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]carbamoyl}butanoic acid; Trifluoroacetate (9o) [ka] A solution of OtBu-N-Boc-Glu-OH (15 mg, 0.05 mmol) in DMF (1 mL) was treated with HATU (19 mg, 0.05 mmol) and DIP EA (13 mg, 0.1 mmol) was added at 25° C. The resulting mixture was stirred at this temperature for 1 hour. Then, 9d (14 mg, 0.026 mmol) was added to the mixture. The mixture was stirred at 25° C. for 16 hours, and the resulting mixture was After 9d was completely consumed, the reaction mixture was diluted with ethyl acetate and added with water and The organic solution was dried over sodium sulfate and concentrated in vacuo. The residue was The mixture was dissolved in DCM (1 mL) and TFA (0.1 mL) was added slowly to the solution at room temperature. The mixture was stirred at rt for 2 h. The volatiles were removed in vacuo and the residue was purified by preparative HPLC (Method A). 9o (8 mg, 46% yield) was obtained as a white solid. ESI m / z: 658.3 (M+1) + . [ka]

[0279] Payload 9L (1S,4aS,10aR)-N-[(1S,4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-o hexahydrophenanthrene-1-carbonyl]-6-[(2S)-2,6-diaminohexanamide]-1,4a- Dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide; Trif Luoroacetate (9L) [ka] A solution of Boc-Lys-OH (15 mg, 0.05 mmol) in DMF (1 mL) was treated with HATU (19 mg, 0.05 mmol) and DIPEA (13 mg , 0.1 mmol) was added at 25°C. The resulting mixture was stirred at this temperature for 1 hour. To the mixture was added 9d (15 mg, 0.028 mmol). The mixture was stirred at 25°C for 16 hours and the resulting mixture was After 9d was completely consumed, the reaction mixture was diluted with ethyl acetate and added water and brine. The organic solution was dried over sodium sulfate and concentrated in vacuo. The residue (Boc-9l) was dissolved in DCM (1 mL), and TFA (0.1 mL) was added slowly to the solution at room temperature. The mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo and the residue was purified by preparative HPLC (Method A). This gave 9l (9 mg, 49% yield) as a white solid. ESI m / z: 657.5 (M+1). + . [ka]

[0280] Example 1h Synthesis of LP15 (Figure 1g) {4-[(2S)-2-[(2S)-2-amino-3-methylbutanamido]-5-(carbamoylamino)penta[amino] [mido]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-octahydrophenanthrene-1-yl]formamide carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl] Carbamoyl}-2-hydroxyethyl]carbamate (LP4-2) [ka] A solution of Fmoc-vc-PAB-PNP (LP4-1, 58 mg, 76 μmol) and 9j (36 mg, 58 μmol) in DMF (3 mL) was added with HO. Bt (7.9 mg, 58 μmol) and DIPEA (15 mg, 0.12 mmol) were added, and the mixture was stirred at 30° C. for 16 hours. After that, compound 9j was completely consumed by LCMS. Add amine (0.1 mL) and refrigerate the reaction mixture until Fmoc is removed, as monitored by LCMS. The reaction mixture was stirred at RT for 1 hour. After filtering the reaction mixture, the filtrate was directly purified by preparative HPLC (Method B). Compound LP4-2 (36 mg, 48% yield) was obtained as a pale yellow solid. ESI m / z: 1021 (M+1 ) + . [ka]

[0281] {4-[(2S)-2-[(2S)-2-[(2R)-2-amino-6-[2-(cyclooct-2-yn-1-yloxy)acetate Amido]hexanamido]-3-methylbutanamido]-5-(carbamoylamino)pentanamido do]phenyl}methyl N-[(1S)-1-{[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-hydroxy-1,4a -dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-yl]formamide (carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]ca {rubamoyl}-2-hydroxyethyl]carbamate (LP15) [ka] A solution of compound LP4-3 (24 mg, 44 μmol) in DMF (2 mL) was added with HATU (17 mg, 44 μmol) and compound LP4-2 (35 mg, 34 μmol) was added successively at RT. The mixture was stirred at RT for several minutes until it became homogeneous. To this mixture was added DIPEA (8.8 mg, 68 μmol) via syringe at RT. LCMS The resulting mixture was stirred at RT for 2 hours until LP4-2 was almost consumed. To this reaction mixture, diethylamine or piperidine (0.1 mL, excess) was added dropwise at RT, and LCMS showed The mixture was stirred for 1 hour until the Fmoc group was removed (note: diethyl (Both amines and piperidine were effective.) The reaction mixture was purified by preparative HPLC (Method B). Direct purification gave compound LP15 (15 mg, 33% yield) as a white solid. ESI m / z: 1313.6(M+H) + . [ka]

[0282] Example 1i Synthesis of LP311 (Figure 1h) tert-Butyl N-[(1S)-1-{[(4bS,8S,8aR)-8-{[(1S,4aS,10aR)-6-hydroxy-1,4a-dimethyl {1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonyl]carbamoyl}-4b, 8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]carbamoyl}-5- {[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}pentyl]carbamate (LP11-1) [ka] To a solution of N-Boc-N'-Fmoc-L-lysine (0.21 g, 0.45 mmol) in DMF (2 mL), HATU (0.24 g, 0.64 mmol) was added. and DIPEA (0.15 g, 1.1 mmol) were added at RT. The resulting mixture was stirred at RT for 3 min. After that, payload 9d (0.20 g, 0.38 mmol) was added to the mixture. The reaction mixture was then stirred at RT for 15 min until the reaction was complete. Purification by preparative HPLC (Method B) gave compound LP11-1 (0.10 g, 27% yield) as a white solid. ESI m / z: 979(M+1) + .

[0283] 9H-Fluoren-9-ylmethyl N-[(5S)-5-amino-5-{[(4bS,8S,8aR)-8-{[(1S,4aS,10aR)-6 -Hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbohydrate 4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene -3-yl]carbamoyl}pentyl]carbamate (LP11-2) [ka] To a solution of compound LP11-1 (0.10 g, 0.10 mmol) in DCM was added TFA (2 mL) at RT. The resulting mixture was stirred at RT for 1 h until complete removal of Boc. Volatiles were removed in vacuo...

Claims

1. A compound of formula A or a pharmaceutically acceptable salt or stereoisomer thereof: 【Chemistry 1】 (In the formula, L is a linker or XYZ, where X is -NH- or -O-; Y is an enzyme-cleavable moiety selected from a dipeptide, tripeptide, or peptide, a self-immolative group selected from p-aminobenzyl (PAB), p-aminobenzyloxycarbonyl (PABC) or derivatives thereof, an acid-labile moiety selected from an alkoxyamine, a ketoxyamine, a carbonate, or a phosphonate, (CH 2 CH 2 O) n , a sugar moiety, or an enhancing group selected from an alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid and / or a cyclodextrin; and Z is a binder linker (BL), where Z is covalently attached to BA; BA is a binding agent selected from an antibody, an antigen-binding fragment of an antibody, a lymphokine, a hormone, a growth factor, a viral receptor, or an interleukin; k is an integer from 1 to 30; Q 1 and Q 2 each independently represents -CH 2 - or -C(O)-; W is —N(H)— or —O—; R is independently -OH or -OP(O)(OR 6 )(OH); Each R 6 is, in each occurrence, independently hydrogen or C 1-20 is alkyl; Each R 7 are independently halo, C 1-6 Alkyl, C 1-6 alkoxy, -CN, O-glycosyl, O-amino acid residue, or O-PEG; and Each n is independently an integer from 0 to 3.

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

3. 10. The compound of claim 1 having the 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 is a spacer group, where SP 3 is (AA) n linked to one AA of; Each AA is an amino acid; n is an integer from 1 to 10; and EG is an enhancing group).

4. The SP 1 The spacer is 【Transformation 3】 where RG′ is the reactive group residue after reaction of the reactive group RG with the binder; 【Chemistry 4】 is a direct bond to the binding agent or an indirect bond via a PEG spacer, and b is an integer from 1 to 4; (AA) n but 【Transformation 5】 and SP 2 is a bond or PABC; The SP 3 The spacer is 【Transformation 6】 where RG′ is the reactive group residue after reaction of the reactive group RG with the enhancing group EG; 【Transformation 7】 is a bond to EG; and 【Transformation 8】 (AA) n or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, of claim 3, wherein

5. 5. The compound of any one of claims 1, 3 or 4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is selected from the group consisting of: 【Chemistry 9】 (wherein each 【Chemistry 10】 is a direct or indirect bond via a PEG spacer to the binding agent).

6. 6. The compound of claim 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound 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】 is a direct or indirect bond via a PEG spacer to the binding agent).

7. 6. The compound of claim 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound 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】 is a direct or indirect bond via a PEG spacer to the binding agent).

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

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

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

11. 11. The compound of any one of claims 1 or 3 to 10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is an antibody or an antigen-binding fragment of an antibody.

12. 12. The compound of any one of claims 1 or 3 to 11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is an antigen-binding fragment of an antibody.

13. 13. The compound of claim 12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the antigen-binding fragment of the antibody is selected from a Fab fragment, a F(ab')2 fragment, a Fd fragment, a Fv fragment, a single-chain Fv (scFv), a dAb fragment, a minimal recognition unit consisting of amino acid residues that mimic a hypervariable region of an antibody, or a constrained FR3-CDR3-FR4 peptide.

14. 12. The compound of claim 11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the antibody or antigen-binding fragment of an antibody is selected from a domain-specific antibody, a single domain antibody, a domain-deleted antibody, a chimeric antibody, a CDR-grafted antibody, a diabody, a triabody, a tetrabody, a minibody, a nanobody, a small modular immunopharmaceutical (SMIP), and a shark variable IgNAR domain.

15. 12. The compound of claim 11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the antibody or antigen-binding fragment of the antibody is selected from a monoclonal antibody and a polyclonal antibody.

16. 16. The compound of any one of claims 1 or 3 to 15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein k is an integer from 1 to 4.

17. 9. The compound according to claim 8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is an antibody that binds to HER2 or an antigen-binding fragment thereof.

18. 9. The compound according to claim 8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is an antibody that binds to PRLR or an antigen-binding fragment thereof.

19. 9. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is an antibody or an antigen-binding fragment thereof and the conjugation is via at least one Q295 residue.

20. 9. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is an antibody or an antigen-binding fragment thereof and conjugation is via two Q295 residues.

21. 9. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is N297Q antibody or an antigen-binding fragment thereof.

22. 9. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is an N297Q antibody or an antigen-binding fragment thereof, and conjugation is via at least one Q295 residue and at least one Q297 residue.

23. 9. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is an N297Q antibody or an antigen-binding fragment thereof, and conjugation is via two Q295 residues and two Q297 residues.

24. 10. The compound of claim 1, or a regioisomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, comprising BA linked via a linker L to a compound selected from the group consisting of: [Chemistry 18] 【change】 【change】 (wherein k is an integer from 1 to 4).

25. 10. The compound of claim 1, or a regioisomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, comprising a BA linked to a compound selected from the group consisting of: 【Chemistry 19】 【change】 【change】 【change】 【change】 (wherein k is an integer from 1 to 4).

26. 10. The compound of claim 1, or a regioisomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of: 【Chemistry 20】 【change】 【change】 【change】 【change】 【change】 【change】 (wherein k is an integer from 1 to 4).

27. 27. The compound of any one of claims 24 to 26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein k is 2.

28. 27. The compound of any one of claims 24 to 26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein k is 4.

29. 27. The compound of any one of claims 24 to 26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is an antibody or antigen-binding fragment thereof having binding specificity for an antigen selected from the group consisting of scavenger receptor classes A to J.

30. The compound of any one of claims 24 to 26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the BA is an antibody or an antigen-binding fragment thereof having binding specificity for an antigen selected from the group consisting of MSR1, MARCO, SRCL, SCARA5, COLEC12, CD36, LIMPII, SRBI, SRBII, CD68, LAMP, LOX-1, Dectin-1, SREC-I, SREC-II, MEGF, CXCL16, fasciclin, FEEL-1, FEEL-2, CD163, RAGE, C-type lectin superfamily members, DEC205, CD206, Dectin-2, Mincle, DC-SIGN, DNGR-1, VSIG4, CSF1R, ASGPR, and APLP-2.

31. 27. The compound of any one of claims 24 to 26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the BA is an antibody or antigen-binding fragment thereof having binding specificity for Her2 or PRLR.

32. 27. The compound of any one of claims 24 to 26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is an antibody or antigen-binding fragment thereof having binding specificity for MSR1.

33. 27. The compound of any one of claims 24 to 26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is an antibody or antigen-binding fragment thereof linked via one or more N295 residues.

34. 22. The compound of any one of claims 19 to 21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is an antibody or antigen-binding fragment thereof linked via one or more of residues N295 and N297Q.

35. 10. The compound of claim 1, having the structure: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemistry 21】 where BA is a binder and k is an integer from 1 to 30.

36. 10. The compound of claim 1, having the structure: 【Chemistry 22】 where BA is a binder and k is an integer from 1 to 30.

37. 10. The compound of claim 1, having the structure: 【Chemistry 23】 where BA is a binder and k is an integer from 1 to 30.

38. 10. The compound of claim 1, having the structure: 【Chemistry 24】 【change】 where BA is a binder and k is an integer from 1 to 30.

39. 10. The compound of claim 1, or a regioisomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of: 【Chemistry 25】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 (wherein k is an integer from 1 to 4).

40. 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, comprising BA linked via a linker L to a compound of the following formula: 【Chemistry 26】 。

41. 10. The compound of claim 1, having the formula: 【Chemistry 27】 。

42. 42. Use of a compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a metabolic disorder in a subject.

43. 42. Use of a compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of inflammation in a subject.

44. 42. Use of a compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a neurodegenerative disease in a subject.

45. 2. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is an antibody or antigen-binding fragment thereof conjugated to a primary amine compound at a glutamine residue, and L is bound to BA via the primary amine compound.

46. 46. ​​The compound of claim 45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein said primary amine compound comprises a divalent PEG group.

47. The primary amine compound is H 2 N-(CH 2 CH 2 O) 3 -(CH 2 ) 2 -N 3 47. The compound of claim 46, wherein:

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