Bis-octahydrophenanthrenecarboxamide and its protein conjugates

Abstract

Provided herein are compounds, compositions, and methods for the treatment of diseases and disorders associated with liver X receptors, comprising bis-octahydrophenanthrenecarboxamides and protein (e.g., antibody) drug conjugates thereof. [Selected figure] Figure 11

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit under 35 U.S.C. § 119 of U.S. Provisional Application No. 62 / 508,327, filed May 18, 2017, the contents of which are incorporated herein by reference in their entirety.

[0002] (Field) Provided herein are novel bis-octahydrophenanthrenecarboxamides and protein conjugates thereof, and methods of treating various diseases, disorders, and illnesses that involve administering the bis-octahydrophenanthrenecarboxamides and protein conjugates thereof. [Background technology]

[0003] (background) Antibody-drug conjugates (ADCs) are antibodies attached to bioactive small molecule drugs, thus combining the targeting specificity of antibodies with the mode of action and efficacy of small molecule drugs. The therapeutic utility of ADCs has been demonstrated in cancer treatment and is a major ongoing research focus. ADCETRIS® (bentruximab vedotin) and KADCYLA® (ado-trastuzumab emtansine) are two ADCs approved for the treatment of specific cancer types, and at least 40 ADCs are currently in clinical development.

[0004] Liver X receptors (LXRs) include LXRα and LXRβ, ligand-dependent transcription factors that regulate the expression of genes involved in cholesterol, lipid, and glucose homeostasis, inflammation, and innate immunity. LXRα is highly expressed in the liver, intestine, adipose tissue, and differentiated macrophages; LXRβ is widely expressed. LXRs have diverse biological functions, including (i) stimulating the expression of cholesterol transporters, such as ABCA1 and ABCG1 (both of which mediate cellular cholesterol efflux); and (ii) negatively regulating macrophage inflammatory gene expression through the suppression of NF-kB activation. LXRs have also been implicated in atherosclerosis, proliferative disorders, neurodegenerative disorders, and inflammation. Proliferative disorders 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, Crohn's disease, and arthritis (Anderson et al., 2011; Huang et al., 2015; Cui et al., 2012). Macrophage LXRs are known to have anti-atherogenic activity. LXR agonists are believed to be able to (i) inhibit the initiation and slow the progression of atherosclerosis; (ii) attenuate atherosclerosis and stabilize established atherosclerotic lesions; and (iii) reduce lesion macrophage content through apoptosis.

[0005] The therapeutic efficacy of small molecule LXR modulators is limited, for example, by undesired LXR modulation in non-target cells and / or low bioavailability. Modulation of LXR in non-target cells can result in undesirable side effects, and low bioavailability can manifest for a number of reasons, including, but not limited to, low solubility, which further exacerbates the inadequate therapeutic range of treatment. The development of ADCs containing LXR modulators would enable target-specific LXR modulation, thereby avoiding side effects caused by off-target modulation of LXR. Furthermore, such ADCs would provide improved modulation of biological targets, improved bioavailability, and an improved therapeutic range. Therefore, there remains a continuing need for effective treatment of, for example, metabolic diseases, using small molecule ADCs of LXR modulators. Summary of the Invention

[0006] (overview) Provided herein are compounds useful for treating metabolic disorders, including, but not limited to, dyslipidemia. Also provided herein are compounds useful for treating, for example, inflammation or neurodegenerative disorders. The compounds provided herein are according to Formula I.

[0007] In one embodiment, provided herein is a compound according to Formula I, or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof: [ka] (In the formula, Q 1 and Q 2 each independently represents -CH2-, -C(O)-, -C(H)(OH)-, -C(OH)2-, -SO2-, -SO-, -PO(OR 11 )-, -PO(NR 11 NR 12 )-, -NR 11 - or -N=; W comprises -CH2-, -N(H)-, or -O-; R1 -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 -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 includes the group consisting of alkylene, substituted alkylene (including oxo, i.e., =0), heteroalkylene, and substituted heteroalkylene (including oxo, i.e., =0); Z comprises a group consisting of -OH and -NH; R 5 includes alkyl, heterocycloalkyl, or substituted heterocycloalkyl, where each heterocycloalkyl or substituted heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, and contains at least one -OH or -CHOH, or at least one primary or secondary nitrogen; Each R 6 comprises, independently in each occurrence, —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 is a compound according to Formula I, or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof: [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 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 includes the group consisting of alkylene, substituted alkylene (including but not limited to, oxo substitution (i.e., ═O)), heteroalkylene, and substituted heteroalkylene (including but not limited to, oxo substitution (i.e., ═O)); Z comprises a group consisting of -OH and -NH; R 5includes alkyl, heterocycloalkyl, or substituted heterocycloalkyl, where each heterocycloalkyl or substituted heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, and contains at least one -OH or -CHOH substituent, or at least one primary or secondary nitrogen, e.g., O-glucose; Each R 6 comprises, independently in each occurrence, —H, an amino acid residue, an N-alkyl amino acid residue, a peptide, or an 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 is a linker-payload having a compound according to Formula I above.

[0010] In another embodiment, provided herein is an antibody-drug conjugate having a compound of Formula I above or a linker-payload attached to an antibody or antigen-binding fragment thereof.

[0011] In another embodiment, presented herein is a compound according to Formula A or a pharmaceutically acceptable salt, or stereoisomeric form thereof: [ka] (In the formula, L is a linker; BA is a binder; k is an integer from 1 to 30; Q 1 and Q 2 each 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, a peptide, or an 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 is a pharmaceutical composition comprising a compound, linker-payload, or antibody-drug conjugate described herein and a pharmaceutically acceptable excipient, carrier, or diluent.

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

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

[0015] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] Figure 1 1a-1i shows the synthetic chemistry schemes of 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] Figure 3, 3a-3e, shows 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 compounds, compositions, and methods useful for treating, for example, dyslipidemia, metabolic disorders, inflammation, or neurodegenerative disorders in a subject.

[0026] (definition) When referring to the compounds provided herein, the following terms have the following meanings unless otherwise indicated. Unless defined otherwise, all technical and scientific terms used herein 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 provided herein, these definitions prevail unless stated otherwise.

[0027] As used herein, "alkyl" refers to a monovalent and saturated hydrocarbon radical moiety. Alkyl is optionally substituted and can be linear, branched, or cyclic, i.e., cycloalkyl. Alkyl includes radicals having 1 to 20 carbon atoms, i.e., C 1-20 Alkyl; a radical having 1 to 12 carbon atoms, i.e., C 1-12 Alkyl; a radical having 1 to 8 carbon atoms, i.e., C1-8 Alkyl; a radical having 1 to 6 carbon atoms, i.e., C 1-6 alkyl; and radicals having 1 to 3 carbon atoms, i.e., C 1-3 Examples of alkyl moieties include, but are not limited to, alkyl. Examples of alkyl moieties include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, i-butyl, pentyl moieties, hexyl moieties, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of pentyl moieties include, but are not limited to, n-pentyl and i-pentyl. Examples of hexyl moieties include, but are not limited to, 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. Alkylene groups are optionally substituted as described herein for alkyl. In some embodiments, alkylene is unsubstituted.

[0029] As used herein, the terms "O-amino acid" or "HO-amino acid" refer to an amino acid in which the natural amino group at the N-terminus of the amino acid or amino acid sequence has been replaced with an oxygen or a hydroxyl group, respectively. For example, "O-AAAA" or "HO-AAAA" refers to an amino acid sequence (AAAA) in which the natural amino group at the N-terminus has been replaced with an oxygen or a hydroxyl group, respectively (e.g., [ka] , where each R is an amino acid side chain). Similarly, the term "O-amino acid residue" or "HO-amino acid residue" refers to the chemical moiety in a compound that remains after a chemical reaction. For example, "O-amino acid residue" or "HO-amino acid residue" refers to the product of amide or peptide coupling of an O-amino acid or an HO-amino acid with a suitable coupling partner; where, for example, a water molecule is displaced after amide or peptide coupling of the O-amino acid or the HO-amino acid, resulting in a product with the O-amino acid residue or the HO-amino acid residue incorporated therein.

[0030] A designation of an amino acid or amino acid residue without specifying its stereochemistry is intended to encompass L-amino acids, D-amino acids, or racemic mixtures thereof.

[0031] As used herein, "haloalkyl" refers to an alkyl, as defined above, wherein the alkyl contains at least one substituent selected from a halogen, e.g., fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Examples of haloalkyl include, but are not limited to, -CF, -CHCF, -CClF, and -CCl.

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

[0033] As used herein, "alkynyl" refers to a monovalent hydrocarbon radical moiety containing at least two carbon atoms and one or more carbon-carbon triple bonds. Alkynyl is optionally substituted and can be linear, branched, or cyclic. Alkynyl includes radicals having 2 to 20 carbon atoms, i.e., C 2-20 Alkynyl; a radical having 2 to 12 carbon atoms, i.e., C 2-12 Alkynyl; a radical having 2 to 8 carbon atoms, i.e., C 2-8 Alkynyl; a radical having 2 to 6 carbon atoms, i.e., C 2-6 alkynyl; and radicals having 2 to 4 carbon atoms, i.e., C 2-4 Examples of alkynyl moieties include, but are not limited to, ethynyl, propynyl, and butynyl.

[0034] As used herein, "alkoxy" refers to a monovalent and saturated hydrocarbon radical moiety, where the hydrocarbon contains a single bond to an oxygen atom and the radical is located on the oxygen atom, e.g., in the case of ethoxy, CH3CH2-O·. An alkoxy substituent is attached to the compound it substitutes through the oxygen atom of the alkoxy substituent. An alkoxy is optionally substituted and can be linear, branched, or cyclic, i.e., cycloalkoxy. Alkoxy includes those having 1 to 20 carbon atoms, i.e., C 1-20 Alkoxy; having 1 to 12 carbon atoms, i.e., C 1-12 Alkoxy; having 1 to 8 carbon atoms, i.e., C 1-8 Alkoxy; having 1 to 6 carbon atoms, i.e., C 1-6 Alkoxy; and those having 1 to 3 carbon atoms, i.e., C 1-3Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, i-butoxy, pentoxy moieties, hexoxy moieties, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy (i.e., cyclopentoxy, cyclohex ... [ka] ), but are not limited to these.

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

[0036] As used herein, "aryl" refers to a monovalent moiety that is a radical of an aromatic compound whose ring atoms are carbon atoms. Aryl is optionally substituted and can be monocyclic or polycyclic, e.g., bicyclic or tricyclic. Examples of aryl moieties include those having 6 to 20 ring carbon atoms, i.e., C 6-20 Aryl; having 6 to 15 ring carbon atoms, i.e., C 6-15 Aryl and those having 6 to 10 ring carbon atoms, i.e., C 6-10 Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, and pyrenyl.

[0037] As used herein, "arylalkyl" refers to a monovalent moiety that is a radical of an alkyl compound, where the alkyl compound is substituted with an aromatic substituent, i.e., the aromatic compound contains a single bond to the alkyl group and the radical is located on the alkyl group. An arylalkyl group is attached to the depicted chemical structure via the alkyl group. An arylalkyl group can be a group having a structure, e.g., [ka] (wherein B is an aromatic moiety, e.g., phenyl). Arylalkyl is optionally substituted, i.e., the aryl group and / or the alkyl group can be substituted as disclosed herein. Examples of arylalkyl include, but are not limited to, benzyl.

[0038] As used herein, "alkylaryl" refers to a monovalent moiety that is a radical of an aryl compound, where the aryl compound is substituted with an alkyl substituent, i.e., the aryl compound contains a single bond to an alkyl group and the radical is located on the aryl group. The alkylaryl group is attached to the depicted chemical structure via the aryl group. The alkylaryl is a group that can be represented by a structure, e.g., [ka] (wherein B is an aromatic moiety, e.g., phenyl). Alkylaryl is optionally substituted, i.e., the aryl group and / or the alkyl group can be substituted as disclosed herein. Examples of alkylaryl include, but are not limited to, toluyl.

[0039] As used herein, "aryloxy" refers to a monovalent moiety that is a radical of an aromatic compound whose ring atoms are carbon atoms and the ring is substituted with an oxygen radical, i.e., the aromatic compound contains a single bond to an oxygen atom and the radical is located on the oxygen atom, e.g., 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. Aryloxy refers to radicals having 6 to 20 ring carbon atoms, i.e., C 6-20Aryloxy; having 6 to 15 ring carbon atoms, i.e., C 6-15 aryloxy and those having 6 to 10 ring carbon atoms, i.e., C 6-10 Examples of aryloxy moieties include, but are not limited to, phenoxy, naphthoxy, and anthroxy.

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

[0041] As used herein, "arylene" refers to a divalent moiety of an aromatic compound in which the only ring atoms are carbon atoms. Arylenes are optionally substituted and can be monocyclic or polycyclic, e.g., bicyclic or tricyclic. Examples of aryl moieties include those having 6 to 20 ring carbon atoms, i.e., C 6-20 Arylene; having 6 to 15 ring carbon atoms, i.e., C 6-15 Arylene and those having 6 to 10 ring carbon atoms, i.e., C 6-10 Examples include, but are not limited to, arylene.

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

[0043] As used herein, "heteroaryl" refers to a monovalent moiety that is a radical of an aromatic compound whose ring atoms contain carbon atoms and at least one oxygen, sulfur, nitrogen, or phosphorus atom. Examples of heteroaryl moieties include, but are not limited to, those having 5 to 20 ring atoms; 5 to 15 ring atoms; and 5 to 10 ring atoms. Heteroaryls are optionally substituted.

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

[0045] As used herein, "heterocycloalkyl" refers to a cycloalkyl in which one or more carbon atoms are replaced with a heteroatom. Suitable heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur atoms. The heterocycloalkyl is optionally substituted. Examples of heterocycloalkyl moieties include, but are not limited to, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, dioxolanyl, dithiolanyl, oxanyl, or thianyl.

[0046] As used herein, "Lewis acid" refers to a molecule or ion that accepts a lone pair of electrons. The Lewis acids used in the methods described herein are other than protons. Lewis acids include, but are not limited to, non-metallic acids, metallic acids, hard Lewis acids, and soft Lewis acids. Lewis acids include, but are not limited to, Lewis acids of aluminum, boron, iron, tin, titanium, magnesium, copper, antimony, phosphorus, silver, ytterbium, scandium, nickel, and zinc. Exemplary Lewis acids include AlBr, AlCl, BCl, boron trichloride methyl sulfide, BF, boron trifluoride methyl ether, boron trifluoride methyl sulfide, boron trifluoride tetrahydrofuran, dicyclohexylboron trifluoromethanesulfonate, iron(III) bromide, iron(III) chloride, tin(IV) chloride, titanium(IV) chloride, titanium(IV) isopropoxide, Cu(OTf), CuCl, CuBr, zinc chloride, alkylaluminum halides (R n AlX 3-n , where R is hydrocarbyl), Zn(OTf), ZnCl, Yb(OTf), Sc(OTf), MgBr, NiCl, Sn(OTf), Ni(OTf), and Mg(OTf).

[0047] As used herein, "N-containing heterocycloalkyl" refers to a cycloalkyl in which one or more carbon atoms are replaced with a heteroatom, and at least one heteroatom is a nitrogen atom. Suitable heteroatoms other than nitrogen include, but are not limited to, oxygen and sulfur atoms. N-containing heterocycloalkyls are optionally substituted. Examples of N-containing heterocycloalkyl moieties include, but are not limited to, morpholinyl, piperidinyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, or thiazolidinyl.

[0048] As used herein, "optionally substituted," when used to describe a radical moiety, e.g., optionally substituted alkyl, means that such moiety is optionally bonded to one or more substituents. Examples of such substituents include halo, cyano, nitro, optionally substituted haloalkyl, azido, epoxy, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, [ka] (where R A , R B , and R C is independently at each occurrence a hydrogen atom, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, or R A and R B

[0049] Examples include, but are not limited to, the following: together with the atoms to which they are attached, form 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 certain embodiments, when the radical moiety is optionally substituted with an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, or an optionally substituted saturated or unsaturated carbocyclic ring, the substituents on the optionally substituted heteroaryl, the optionally substituted heterocycloalkyl, or the optionally substituted saturated or unsaturated carbocyclic ring, if substituted, are not substituted with a substituent that is further optionally substituted with a further substituent. In some embodiments, when a group described herein is optionally substituted, the substituents attached to the group are not substituted unless otherwise specified.

[0049] As used herein, "binding agent" refers to any molecule, e.g., a protein, that is capable of binding with specificity to a given binding partner, e.g., an antigen.

[0050] As used herein, "linker" refers to a divalent, trivalent, or multivalent moiety that covalently attaches a binding agent to one or more compounds described herein, e.g., payload compounds and enhancers.

[0051] As used herein, "amide synthesis conditions" refers to reaction conditions suitable for achieving amide formation, for example, by reaction of a carboxylic acid, an activated carboxylic acid, or an acyl halide with an amine. In some examples, "amide synthesis conditions" refers to reaction conditions suitable for achieving amide bond formation between a carboxylic acid and an amine. In some of these examples, the carboxylic acid is first converted to an activated carboxylic acid, and then the activated carboxylic acid is reacted with an amine to form an amide. Suitable conditions for achieving amide formation include, but are not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), and the like. Fluorophosphate (PyAOP), Bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium These include, but are not limited to, those that utilize reagents to achieve the reaction of carboxylic acids with amines, including 3-oxide hexafluorophosphate (HATU), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDC), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), and carbonyldiimidazole (CDI). In some instances, the carboxylic acid is first converted to an activated carboxylic ester, which is then treated with an amine to form an amide bond.In some embodiments, a carboxylic acid is treated with a reagent. The reagent activates the carboxylic acid by deprotonating the carboxylic acid and then forming a product complex with the deprotonated carboxylic acid as a result of nucleophilic attack by the deprotonated carboxylic acid on the protonated reagent. The activated carboxylic acid ester of the particular carboxylic acid is then more susceptible to nucleophilic attack by amines than before the carboxylic acid was activated. This results in amide bond formation. The carboxylic acid is therefore described as activated. Exemplary reagents include DCC and DIC.

[0052] As used herein, "positional isomer," "positional isomers," or "mixture of positional isomers" refers to the product of a 1,3-cycloaddition or strain-promoted alkyne-azide cycloaddition (SPAAC) reaction, otherwise known as a click reaction, derived from a suitable azide (e.g., an -N3, or PEG-N3 derivatized antibody) treated with a suitable alkyne. In certain embodiments, for example, positional isomers and mixtures of positional isomers are characterized by the click reaction products shown below: [ka] In certain embodiments, multiple suitable azides and multiple suitable alkynes can be utilized in a synthetic scheme en route to a product, where each azide-alkyne pair can participate in one or more independent Click reactions to generate a mixture of regioisomeric Click reaction products. For example, one skilled in the art will recognize that a first suitable azide can independently react with a first suitable alkyne, and a second suitable azide can independently react with a second suitable alkyne en route to a product, resulting in four possible Click reaction regioisomers or a mixture of four possible Click reaction regioisomers in a sample of an ADC described herein. As a further example, one skilled in the art will recognize that a first suitable azide can independently react with a first suitable alkyne, and a second suitable azide can independently react with a second suitable alkyne en route to a product, resulting in four possible Click reaction regioisomers or a mixture of four possible Click reaction regioisomers in a sample of an LP described herein.

[0053] As used herein, the term "residue" refers to the chemical moiety in a compound that remains after a chemical reaction. For example, the term "amino acid residue" or "N-alkylamino acid residue" refers to the product of amide or peptide coupling of an amino acid or an N-alkylamino acid with a suitable coupling partner; where, for example, a water molecule is displaced after amide or peptide coupling of the amino acid or the N-alkylamino acid, resulting in a product incorporating the amino acid residue or the N-alkylamino acid residue.

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

[0055] Certain groups, moieties, substituents, and atoms are depicted with a wavy line crossing the bond or bonds to indicate the atom to which the group, moiety, substituent, or atom is attached. For example, a propyl group depicted as follows: [ka] The phenyl group substituted with has the following structure: [ka] As used herein, a diagram showing a substituent attached to a cyclic group (e.g., aromatic, heteroaromatic, fused ring, and saturated or unsaturated cycloalkyl or heterocycloalkyl) via a bond between ring atoms is intended to indicate that the cyclic group can be substituted with that substituent at any ring position in the cyclic group or on any ring in a fused ring group in accordance with techniques described herein or known in the art to which this disclosure pertains. For example, a group in which the subscript q is an integer from 0 to 4 and the substituent R 1 The position of the bond is generally described, i.e., at any vertex of the bond line structure, i.e., at any position of a group that is not directly attached to a specific ring carbon atom. [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" refers to, e.g., [ka] (where RG is the reactive group and SP is the spacer group). As described herein, a reactive linker can contain multiple reactive groups and multiple spacer groups. A spacer group is any bivalent moiety that crosslinks a reactive group to another group, e.g., a payload. A reactive linker (RL), together with the payload to which it is attached, provides an intermediate ("linker-payload") useful as a synthetic precursor for the preparation of the antibody conjugates described herein. A reactive linker contains a reactive group ("RG"), which is a functional group or moiety that can react with another group, e.g., a reactive moiety of an antibody, modified antibody, or antigen-binding fragment thereof, or an enhancing group. The moiety resulting from the reaction of a reactive group with an antibody, modified antibody, or antigen-binding fragment thereof bearing a linking group includes the "binder linker" ("BL") portion of the conjugates described herein. In some embodiments, the "reactive group" is a functional group or moiety (e.g., maleimide or N-hydroxysuccinimide (NHS) ester) that reacts with a cysteine ​​or lysine residue of an antibody or antigen-binding fragment thereof. In some embodiments, the "reactive group" is a functional group or moiety that can undergo a click chemistry reaction (see, e.g., click chemistry, Huisgen, Proc. Chem. Soc. 1961; Wang et al., J. Am. Chem. Soc. 2003; and Agard et al., J. Am. Chem. Soc. 2004). In some click chemistry embodiments, the reactive group is an alkyne that can undergo a 1,3 cycloaddition reaction with an azide. Such suitable reactive groups include, but are not limited to, strained alkynes, such as those suitable for strain-promoted alkyne-azide cycloaddition (SPAAC), cycloalkynes, such as cyclooctynes, benz-annulated alkynes, and alkynes that can undergo 1,3 cycloaddition reactions with alkynes in the absence of a copper catalyst. Suitable alkynes include dibenzoazacyclooctynes ​​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: [ka] Linker-payloads containing such reactive groups are useful for conjugating antibodies functionalized with azide groups. Such functionalized antibodies include antibodies functionalized with azide-polyethylene glycol groups. In some embodiments, such functionalized antibodies are obtained by treating an antibody having at least one glutamine residue, for example, heavy chain Gln295, with a compound bearing an amino group and an azide group in the presence of the enzyme transglutaminase.

[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 reacts with an azide on the 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 an antibody or antigen-binding fragment thereof to form a bond therewith, e.g., [ka] (where Ab represents an antibody or antigen-binding fragment thereof, and S represents the S atom on a cysteine ​​residue through which the functional group is attached to the Ab). In some instances, the reactive group is a functional group, e.g., [ka] which reacts with lysine residues on an antibody or antigen-binding fragment thereof to conjugate therewith, e.g., [ka] (where Ab represents an antibody or antigen-binding fragment thereof, and NH represents the NH atom on a lysine side chain residue through which the functional group is attached to the Ab).

[0058] As used herein, the phrase "biodegradable moiety" refers to a moiety that degrades in vivo into non-toxic, biocompatible components that can be removed from the body by normal biological processes. In some embodiments, the biodegradable moiety completely or substantially degrades in vivo over a period of about 90 days or less, about 60 days or less, or about 30 days or less, where the degree of degradation is based on the percent mass loss of the biodegradable moiety, where complete degradation corresponds to 100% mass loss. Exemplary biodegradable moieties include, but are not limited to, aliphatic polyesters such as poly(ε-caprolactone) (PCL), poly(3-hydroxybutyrate) (PHB), poly(glycolic acid) (PGA), poly(lactic acid) (PLA), and its copolymers with glycolic acid (i.e., poly(D,L-lactide-coglycolide) (PLGA) (Vert M, Schwach G, Engel R, and Coudane J (1998) J Control Release 53(1-3):85-92; Jain RA (2000) Biomaterials 21(23):2475-2490; Uhrich KE, Cannizzaro SM, Langer RS, and Shakesheff KM (1999) Chemical Reviews 99(11):3181-3198; and Park TG (1995) Biomaterials 16(15):1123-1130).

[0059] As used herein, the phrases "effective amount," "physiologically effective amount," or "prophylactically effective amount" refer to an amount of a compound that is sufficient to effect treatment when administered to a subject in need of such treatment. A "physiologically effective amount" of an active substance refers to an effective amount of the active substance that has a noticeable, externally observable effect on a patient. Thus, a physiologically effective amount affects one or more characteristics (e.g., phenotype) of a patient without requiring special equipment to determine the effect. For example, a physiologically effective amount of a compound disclosed herein has a noticeable, externally observable effect on a patient's behavior by alleviating one or more symptoms of the disease being treated. Therefore, it can be determined whether an effective amount of an active substance has been administered by observing the patient and observing whether any changes have occurred in the patient due to the active substance.

[0060] As used herein, the phrase "binder linker" or "BL" refers to any divalent, trivalent, or polyvalent group or moiety that links, connects, or bonds a binder (e.g., an antibody or antigen-binding fragment thereof) to a payload compound (e.g., bis-octahydrophenanthrenecarboxamide) described herein, and optionally to one or more side chain compounds. Typically, a suitable binder linker for the antibody conjugates described herein is one that is sufficiently stable to take advantage of the circulating half-life of the antibody while simultaneously being able to release its payload after antigen-mediated internalization of the conjugate. Linkers can be cleavable or non-cleavable. A cleavable linker is a linker that is cleaved by intracellular metabolism after internalization, for example, by hydrolysis, reduction, or enzymatic cleavage. A non-cleavable linker is a linker that releases the attached payload by lysosomal degradation of the antibody after internalization. Suitable linkers include, but are not limited to, acid-labile linkers, hydrolysis-labile linkers, enzyme-cleavable linkers, reduction-labile linkers, self-immolative linkers, and non-cleavable linkers. Suitable linkers also include, but are not limited to, those that are or contain peptides, glucuronides, succinimide-thioethers, polyethylene glycol (PEG) units, hydrazones, maltocaproyl units, dipeptide units, valine-citrulline units, and para-aminobenzyl (PAB) units. In some embodiments, the binder linker (BL) comprises a moiety formed by reaction of the reactive group (RG) of the reactive linker (RL) with the reactive portion of a binder, such as an antibody, modified antibody, or antigen-binding fragment thereof.

[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. In some examples, BL is a bond to a cysteine ​​of the antibody or antigen-binding fragment thereof. [ka] where: [ka] is a bond to a lysine of an antibody or antigen-binding fragment thereof.

[0062] (Compounds and Payloads) In some instances, presented herein are compounds or pharmaceutically acceptable salts, solvates, or stereoisomeric forms having the structure of Formula (I): [ka] (In the formula, Q 1 and Q 2each 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 At the same time, -H is not; 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 selected from the group consisting of alkylene, substituted alkylene (including but not limited to, oxo-substituted, i.e., =0), heteroalkylene, and substituted heteroalkylene (including but not limited to, oxo-substituted (i.e., =0)); Z is selected from the group consisting of -OH and -NH; R 5 is alkyl, heterocycloalkyl, or substituted heterocycloalkyl, where each heterocycloalkyl or substituted heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, and contains at least one —OH and —CHOH substituent, or at least one primary or secondary nitrogen, e.g., O-glucose; Each R 6 is, in each occurrence, —H, an amino acid residue, an N-alkyl amino acid residue, a peptide, or an 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 nwhere each n is an integer from 0 to 3.

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

[0064] In certain embodiments of formula I, R 6 are, in each instance, independently an amino acid residue, an N-alkyl amino acid residue, or a peptide. Those skilled in the art will recognize that amino acid residues can be achiral or chiral, for example, L-amino acids or D-amino acids. An amino acid typically includes an amino acid side chain. The side chain can be the side chain of any amino acid known to those skilled in the art. In certain embodiments, the side chain is the side chain of histidine, alanine, isoleucine, arginine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, valine, ornithine, selenocysteine, serine, glycine, homoglycine (e.g., β-homoglycine), or tyrosine. Those skilled in the art will recognize that peptides can be achiral or chiral, including, for example, racemic DL-amino acids or non-racemic D- or L-amino acids and diastereomeric mixtures thereof. The side chains of the peptides are as described in the context of amino acids above. Those skilled in the art will recognize that N-alkyl amino acid residues contain an alkyl substituent, as defined herein, at the terminal amino group of the amino acid residue or the terminal amino group of the peptide. Examples include N-methyl amino acids and N-ethyl amino acids.

[0065] In certain embodiments, in 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 wherein each n is an integer from 0 to 3. In certain embodiments, the O-amino acid residues include HO-amino acid residues as defined above. In one embodiment, O-PEG n is when n=0. In another embodiment, O-PEG n is when n=1. In another embodiment, O-PEG n where n=2. In another embodiment, O-PEG n is for n=3.

[0066] In some instances, presented herein are compounds having the structure of Formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomeric form: [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 R 2 At the same time, -H is not; R 3 is -N(R 6 )2; R4 is -XYZ; X is selected from the group consisting of -O- and -N(H)-; Y is selected from the group consisting of alkylene, substituted alkylene (including but not limited to, oxo-substituted, i.e., =0), heteroalkylene, and substituted heteroalkylene (including but not limited to, oxo-substituted (i.e., =0)); Z is selected from the group consisting of -OH and -NH; R 5 is alkyl, heterocycloalkyl, or substituted heterocycloalkyl, where each heterocycloalkyl or substituted heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, and contains at least one —OH and —CHOH substituent, or at least one primary or secondary nitrogen, e.g., O-glucose; Each R 6 is, in each occurrence, —H, an amino acid residue, an N-alkyl amino acid residue, a peptide, or an 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 heterocycloalkyl or substituted heterocycloalkyl. Useful heterocycloalkyl groups include tetrahydropyranyl, glycosidyl, and piperazinyl. These groups can be substituted or unsubstituted. In some embodiments, they are unsubstituted. In some embodiments, they are substituted. Exemplary substituents include at least one hydroxyl, at least one primary nitrogen, or at least one secondary nitrogen.

[0068] In certain embodiments of Formula Ia, R 6are, in each instance, independently an amino acid residue, an N-alkyl amino acid residue, or a peptide. Those skilled in the art will recognize that amino acid residues can be achiral or chiral, e.g., L-amino acids or D-amino acids. An amino acid typically includes an amino acid side chain. The side chain can be the side chain of any amino acid known to those skilled in the art. In certain embodiments, the side chain is the side chain of histidine, alanine, isoleucine, arginine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, valine, ornithine, selenocysteine, serine, glycine, homoglycine (e.g., β-homoglycine), or tyrosine. Those skilled in the art will recognize that peptides can be achiral or chiral, including, for example, racemic DL-amino acids or non-racemic D- or L-amino acids and diastereomeric mixtures thereof. The side chains of the peptides are as described above in connection with amino acids. One skilled in the art will recognize that an N-alkyl amino acid residue contains an alkyl substituent, as defined herein, at the terminal amino group of the amino acid or peptide.

[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 residue, or O-PEG n wherein each n is an integer from 0 to 3. In certain embodiments, the O-amino acid residues include HO-amino acid residues as defined above. In one embodiment, O-PEG n is when n=0. In another embodiment, O-PEG n is when n=1. In another embodiment, O-PEG n where n=2. In another embodiment, O-PEG n is for n=3.

[0070] In one embodiment of Formula I or Ia, Q1 is -CH2- and Q 2 is —C(O)—. In another 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)- and 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 -CH2-. In another embodiment, Q 1 is -CH2- 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 another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -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 3In 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 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 In another embodiment, Q 1 is -CH2- and Q 2 is -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 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 -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)-, W is -CH2-, and R 1 is -OH and R 2 is —OH. In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -CH2-, and R1 is -OH 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 -OH 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 -OH 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 -OH 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 -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, 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, Q1 is -CH2- 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 -CH2- 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 -CH2- 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 -CH2- and Q 2 is -C(O)-, W is -CH2-, 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 -CH2-, and R 1 is -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 and R 2 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1is -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 -OR 5 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 —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)-, W is -CH2-, and R 1 is alkyl, 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 alkyl, and R 2 -OR 5 In another embodiment, Q 1 is -CH2- and Q 2is -C(O)-, W is -CH2-, 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)-, W is -CH2-, and R 1 is -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 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 -OP(O)(OR 6 )(OH) and R 2 is —H. In any one of the preceding embodiments of this paragraph, R 6 may be selected from the group consisting of hydroxyl and methyl.

[0073] In one embodiment of Formula I or Ia, Q 1 is -CH2- and Q 2 is -C(O)- and W is -O-. 1 is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is -H, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is -H, and R 2 is —OH. In another embodiment, Q 1 is -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 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 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 5 In another embodiment, 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)-, 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 1is -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 -OR 5 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 —OH. 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 —CH 2 NH 2 . 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 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 is R 5 In another embodiment, Q 1 is -CH2- and Q 2 is -C(O)-, W is -O-, 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 R1 is -OH 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 -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)-, W is -O-, and R 1 is -NH2 and R 2 is —OH. 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 —CH 2 NH 2 . 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 is -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 Q2 is -C(O)-, W is -O-, 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 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 , or -OR 5 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 —OH. 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 —CH 2 NH 2 . 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 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 4In 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 1 is -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is alkyl, 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 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)-, W is -O-, and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. In another embodiment, Q 1 is -CH2- 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 -CH2- and Q 2 is -C(O)-, W is -O-, and R 1 is -OP(O)(OR 6 )(OH) and R 2 is —H. In any one of the preceding embodiments of this paragraph, R 6 may be selected from the group consisting of hydroxyl and methyl.

[0075] In one embodiment of Formula I or Ia, Q 1 is -CH2- and Q 2 is -C(O)- and W is -NH-. 1 is -CH2- 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 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 —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 is R 3 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 R 4 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 R 5 In another embodiment, Q 1 is -CH2- and Q 2is -C(O)-, W is -NH-, and R 1 is -H, 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 -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 -NH-, 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)-, W is -NH-, and R 1 is -OH 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 -OH 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 -OH and R 2 is R 3 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 R 4 In another embodiment, Q1 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)-, 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, 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 -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)-, W is -NH-, and R 1 is -NH2 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 -NH2 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 -NH2 and R2 is R 3 In another embodiment, Q 1 is -CH2- 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 -CH2- 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 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 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 -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 -CH2- and Q 2 is -C(O)-, W is -NH-, and R 1 is alkyl, and R 2 is —OH. In another embodiment, Q 1 is -CH2- and Q2 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 -CH2- 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 -CH2- 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 -CH2- and Q 2 is -C(O)-, W is -NH-, and R 1 is alkyl, and 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 alkyl, 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 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)-, W is -NH-, and R 1 is -OH or -OP(O)(OR 6 )(OH) and R2 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)-, W is -NH-, and R 1 is -OP(O)(OR 6 )(OH) and R 2 is —H. In any one of the preceding embodiments of this paragraph, R 6 may be selected from the group consisting of hydroxyl and methyl.

[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 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 —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 —CH 2 NH 2 . In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R1 is -H, 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 -H, 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 -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 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 amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(H)(OH)- 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(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH and R 2is —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 is -C(H)(OH)- 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(H)(OH)- 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(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1is -NH2 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 -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 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 -NH2 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 -NH2 and R 2 -OR 5 In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R1 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 is -C(O)-, W is -CH2-, 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. 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 —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 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 4 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 5In 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 -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 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)-, W is -CH2-, and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OH and R 2 is -H. In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -OP(O)(OR 6 )(OH) and R 2 is —H. In any one of the preceding embodiments of this paragraph, R 6 may be selected from the group consisting of hydroxyl and methyl.

[0079] In one embodiment of Formula I or Ia, Q 1 is -C(H)(OH)- and Q 2is -C(O)- and W is -O-. 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -O-, and R 1 is -H, 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 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 -O-, and R 1 is -H, 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 -O-, and R 1 is -H, 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 -H, and R 2 is R 4 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 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 5In another embodiment, Q 1 is -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 is -C(O)-, W is -O-, 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(H)(OH)- and Q 2 is -C(O)-, W is -O-, and R 1 is -OH and R 2 is —OH. In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -O-, and R 1 is -OH and R 2 is —CH 2 NH 2 . In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -O-, and R 1 is -OH and R 2 is R 3 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 In another embodiment, Q 1 is -C(H)(OH)- and Q 2is -C(O)-, W is -O-, 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 -O-, and R 1 is -OH 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 -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 is -C(O)-, W is -O-, 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(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 is -C(H)(OH)- and Q 2 is -C(O)-, W is -O-, 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 -O-, and R 1 is -NH2 and R 2 is R3 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 R 4 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 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 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 amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(H)(OH)- 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 , or -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 —OH. In another embodiment, Q 1is -C(H)(OH)- and Q 2 is -C(O)-, W is -O-, and R 1 is alkyl, 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 -O-, and R 1 is alkyl, 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 alkyl, and R 2 is R 4 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 R 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 -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, dimethylamino, 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)-, W is -O-, and R 1is -OH or -OP(O)(OR 6 )(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 -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. In any one of the preceding embodiments of this paragraph, R 6 may be selected from the group consisting of hydroxyl and methyl.

[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-. 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 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 is —OH. 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 is —CH 2 NH 2 . In another embodiment, Q 1is -C(H)(OH)- 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(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 is -H, 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 -H, 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 -H, and R 2 -OR 5 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 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(H)(OH)- 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 -OR 5 In another embodiment, Q 1 is -C(H)(OH)- and Q 2is -C(O)-, W is -NH-, 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 -NH-, 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 -NH-, 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 -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)-, 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 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 amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of 1 is -C(H)(OH)- and Q2 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 -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 2 is 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 is -C(H)(OH)- 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 -C(H)(OH)- and Q2 is -C(O)-, 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 is -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 Q 2 is -C(O)-, W is -NH-, and R 1 is alkyl, 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 alkyl, 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 alkyl, and R 2 is R 3 In another embodiment, Q 1 is -C(H)(OH)- 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(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 is alkyl, and R2 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 alkyl, and R 2 -OR 5 In another embodiment, Q 1 is -C(H)(OH)- and Q 2 is -C(O)-, W is -NH-, and R 1 is alkyl, and R 2 is 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)-, W is -NH-, and R 1 is -OH or -OP(O)(OR 6 )(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 -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. In any one of the preceding embodiments of this paragraph, R 6 may be selected from the group consisting of hydroxyl and methyl.

[0083] In one embodiment of Formula I or Ia, Q 1is -C(O)- and Q 2 is -C(O)- and W is -CH2-. 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 -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)-, W is -CH2-, and R 1 is -H, 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 -H, 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 -H, 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 -H, and R 2 is R 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -H, and R 2 is R 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 -OR5 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, 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)-, 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 —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 -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 In another embodiment, Q 1 is -C(O)- and Q 2is -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)-, 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 1 is -NH2 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 -NH2 and R 2 is R 3In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is -NH2 and R 2 is R 4 In another embodiment, Q 1 is -C(O)- 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 is -C(O)- 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 -C(O)- 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 -C(O)- 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 -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -CH2-, and R 1 is alkyl, and R 2 is —OH. In another embodiment, Q 1 is -C(O)- and Q 2is -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, and R 2 is R 4 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 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)-, W is -CH2-, and R 1 is alkyl, and R 2 is amino, dimethylamino, hydroxyl, [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)-, W is -CH2-, and R 1 is -OH or -OP(O)(OR 6 )(OH) and R2 is -H. 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 -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 preceding embodiments of this paragraph, R 6 may be selected from the group consisting of hydroxyl and methyl.

[0085] In one embodiment of Formula I or Ia, Q 1 is -C(O)- and Q 2 is -C(O)- and W is -O-. 1 is -C(O)- and Q 2 is -C(O)-, W is -O-, and R 1 is -H, 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)-, W is -O-, and R 1 is -H, and R 2 is —OH. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, 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 -C(O)-, W is -O-, and R 1 is -H, and R2 is R 3 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 R 4 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 R 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 -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 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 -O-, 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)-, W is -O-, and R 1 is -OH and R 2 is —OH. In another embodiment, Q 1 is -C(O)- and Q 2is -C(O)-, W is -O-, 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(O)-, 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(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 is R 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 -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 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 -O-, and R 1 is -NH2 and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, W is -O-, 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 -O-, 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(O)-, 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 is -C(O)-, 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(O)-, 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 -C(O)-, W is -O-, and R 1 is -NH2 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 -NH2 and R 2 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of1 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 , or -OR 5 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 —OH. 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 —CH 2 NH 2 . 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 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 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 5 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 -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2is -C(O)-, W is -O-, and 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)-, W is -O-, and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. In another embodiment, Q 1 is -C(O)- and Q 2 is -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)-, W is -O-, and R 1 is -OP(O)(OR 6 )(OH) and R 2 is —H. In any one of the preceding embodiments of this paragraph, 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 -NH-. 1 is -C(O)- 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 5In 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 —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, 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)-, 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 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 -H, 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 -H, and R 2 is amino, dimethylamino, hydroxyl, [ka] In another embodiment, Q is selected from the group consisting of1 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 -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 —OH. 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 —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 -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 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 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 2is -C(O)-, 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(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 -C(O)- 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(O)- 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(O)- and Q 2 is -C(O)-, 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(O)-, 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(O)-, W is -NH-, and R 1 is -NH2 and R 2 is R 5In 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, Q 1 is -C(O)- and Q 2 is -C(O)-, 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 2 is -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(O)- and Q 2 is -C(O)-, 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 R1 is alkyl, 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 alkyl, 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 alkyl, 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 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)-, W is -NH-, and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(O)-, 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(O)-, W is -NH-, and R 1 is -OP(O)(OR 6 )(OH) and R 2is —H. In any one of the preceding embodiments of this paragraph, R 6 may be selected from the group consisting of hydroxyl and methyl.

[0089] In one embodiment of Formula I or Ia, Q 1 is -C(O)- and Q 2 is -CH2- and W is -CH2-. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -CH2-, and R 1 is -H, 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-, W is -CH2-, and R 1 is -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-, 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 R5 In another embodiment, 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 is -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-, 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 -CH2-, 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 -CH2-, W is -CH2-, and R 1 is -OH and R 2 is R 3 In another embodiment, Q 1 is -C(O)- and Q 2is -CH2-, 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 -CH2-, 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 -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 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 -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-, 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 2is —CH 2 NH 2 . 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 R 3 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 R 4 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 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 2 is -CH2-, 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 -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 -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2is -CH2-, 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, Q 1 is -C(O)- and Q 2 is -CH2-, 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 -CH2-, 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 -CH2-, W is -CH2-, 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, Q1 is -C(O)- and Q 2 is -CH2-, W is -CH2-, and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -CH2-, and R 1 is -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 -OP(O)(OR 6 )(OH) and R 2 is —H. In any one of the preceding embodiments of this paragraph, R 6 may be selected from the group consisting of hydroxyl and methyl.

[0091] In one embodiment of Formula I or Ia, Q 1 is -C(O)- and Q 2 is -CH2- and W is -O-. 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 is -H, 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-, W is -O-, and R 1 is -H, and R 2 is —OH. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 is -H, and R 2is —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 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 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, 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-, 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 -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2is -CH2-, W is -O-, 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 -O-, 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 -CH2-, 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 -CH2-, 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 is R 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, 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 -CH2-, W is -O-, 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 -CH2-, W is -O-, 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-, W is -O-, 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 -O-, 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 -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 is -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-, W is -O-, and R 1 is -NH2 and R 2 -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, 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 -CH2-, 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 -CH2-, W is -O-, 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 -O-, 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 -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 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 R1 is alkyl, and R 2 -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 is alkyl, and R 2 is 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-, W is -O-, and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 is -OH and R 2 is -H. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -O-, and R 1 is -OP(O)(OR 6 )(OH) and R 2 is —H. In any one of the preceding embodiments of this paragraph, 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-. 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is -H, and R2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is -H, and R 2 is —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 is R 3 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 R 4 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 R 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 -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is -H, and R 2 is amino, dimethylamino, hydroxyl, [ka] 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 -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 —OH. 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 —CH 2 NH 2 . In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is -OH and R 2 is R 3 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 4 In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is -OH and R 2 is R 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-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, 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 -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-, 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 -CH2-, 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 -CH2-, 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 -CH2-, W is -NH-, and R 1 is -NH2 and R 2 is R 4 In another embodiment, Q 1 is -C(O)- and Q 2is -CH2-, W is -NH-, and R 1 is -NH2 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 -NH2 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, 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 -OR 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 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 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 alkyl, and R 2 is R 3In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, 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 -CH2-, 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 another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and 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-, W is -NH-, and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R 1 is -OH and R 2 is -H. In another embodiment, Q 1 is -C(O)- and Q 2 is -CH2-, W is -NH-, and R1 is -OP(O)(OR 6 )(OH) and R 2 is —H. In any one of the preceding embodiments of this paragraph, R 6 may be selected from the group consisting of hydroxyl and methyl.

[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 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 is —OH. 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 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 -H, 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 -H, and R 2 is R 4 In another embodiment, Q 1is -C(O)- and Q 2 is -C(H)(OH)-, W is -CH2-, and R 1 is -H, and R 2 is R 5 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 -OR 5 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 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 -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(H)(OH)-, 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(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 R1 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 is -C(O)- and Q 2 is -C(H)(OH)-, 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(H)(OH)-, 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 -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(H)(OH)-, W is -CH2-, and R 1 is -NH2 and R 2is —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 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 -NH2 and R 2 is R 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 -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 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 -CH2-, and R 1is 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. 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 —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 alkyl, 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 alkyl, 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 alkyl, and R 2 is R 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 -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -CH2-, and R1 is alkyl, and R 2 is 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)-, W is -CH2-, and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -CH2-, 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 -CH2-, and R 1 is -OP(O)(OR 6 )(OH) and R 2 is —H. In any one of the preceding embodiments of this paragraph, R 6 may be selected from the group consisting of hydroxyl and methyl.

[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-. 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 is -H, and R 2 -OH, -CH2NH2, R 3 , R 4 , R 5 , or -OR 5In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 is -H, and R 2 is —OH. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 is -H, and R 2 is —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 -H, 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 -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, and 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 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 -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(H)(OH)-, W is -O-, and R 1 is -OH and R 2 is —OH. 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 —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 -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 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 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 -OR 5In 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 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 , or -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 is -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, 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 -O-, 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 -O-, and R 1 is -NH2 and R 2 is R 4 In another embodiment, Q 1 is -C(O)- and Q 2is -C(H)(OH)-, 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 -C(H)(OH)-, W is -O-, and R 1 is -NH2 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 -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 1 is alkyl, and R 2 is —OH. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 is alkyl, 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 -O-, and R 1 is alkyl, and R 2is R 3 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 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 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 -OR 5 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 amino, dimethylamino, 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)-, W is -O-, and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -O-, and R 1 is -OH and R 2 is -H. In another embodiment, Q 1is -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. In any one of the preceding embodiments of this paragraph, R 6 may be selected from the group consisting of hydroxyl and methyl.

[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-. 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 , 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 -H, and R 2 is —OH. 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 —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 -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 2is R 4 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 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, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, 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(H)(OH)-, W is -NH-, 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(H)(OH)-, W is -NH-, and R 1 is -OH and R 2 is —OH. 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 —CH 2 NH 2 . In another embodiment, Q 1 is -C(O)- and Q2 is -C(H)(OH)-, 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 is -C(H)(OH)-, W is -NH-, 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 -NH-, and R 1 is -OH and 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 -OH and R 2 -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 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 -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2 is -C(H)(OH)-, W is -NH-, and R1 is -NH2 and R 2 is —OH. 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 —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 is -C(O)- and Q 2 is -C(H)(OH)-, W is -NH-, and R 1 is -NH2 and R 2 -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 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. 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 —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 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 4 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 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 -OR 5 In another embodiment, Q 1 is -C(O)- and Q 2is -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)-, W is -NH-, and R 1 is -OH or -OP(O)(OR 6 )(OH) and R 2 is -H. In another embodiment, Q 1 is -C(O)- and Q 2 is -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. In any one of the preceding embodiments of this paragraph, R 6 may be selected from the group consisting of hydroxyl and methyl.

[0101] In some instances, presented herein are compounds or pharmaceutically acceptable salts, solvates, or stereoisomeric forms having the structure of Formula (Ib): [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 At the same time, -H is not; 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 selected from the group consisting of alkylene, substituted alkylene (including but not limited to, oxo-substituted (i.e., =0)), heteroalkylene, and substituted heteroalkylene (including but not limited to, oxo-substituted (i.e., =0)); Z is selected from the group consisting of -OH and -NH; R 5 is alkyl, heterocycloalkyl, or substituted heterocycloalkyl, where each heterocycloalkyl or substituted heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, and contains at least one —OH and —CHOH substituent, or at least one primary or secondary nitrogen, e.g., O-glucose; Each R 6 is, in each occurrence, —H, an amino acid residue, an N-alkyl amino acid residue, a peptide, or an 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 5is heterocycloalkyl or substituted heterocycloalkyl. Useful heterocycloalkyl groups include tetrahydropyranyl, glycosidyl, and piperazinyl. These groups can be substituted or unsubstituted. In some embodiments, they are unsubstituted. In some embodiments, they are substituted. Exemplary substituents include at least one hydroxyl, at least one primary nitrogen, or at least one secondary nitrogen.

[0103] In certain embodiments of Formula Ib, R 6 are, in each instance, independently an amino acid residue, an N-alkyl amino acid residue, or a peptide. Those skilled in the art will recognize that amino acid residues can be achiral or chiral, e.g., L-amino acids or D-amino acids. An amino acid typically includes an amino acid side chain. The side chain can be the side chain of any amino acid known to those skilled in the art. In certain embodiments, the side chain is the side chain of histidine, alanine, isoleucine, arginine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, valine, ornithine, selenocysteine, serine, glycine, homoglycine (e.g., β-homoglycine), or tyrosine. Those skilled in the art will recognize that peptides can be achiral or chiral, including, for example, racemic DL-amino acids or non-racemic D- or L-amino acids and diastereomeric mixtures thereof. The side chains of the peptides are as described above in connection with amino acids. One skilled in the art will recognize that an N-alkyl amino acid residue contains an alkyl substituent, as defined herein, at the terminal amino group of the amino acid or peptide.

[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 residue, or O-PEG nwherein each n is an integer from 0 to 3. In certain embodiments, the O-amino acid residues include HO-amino acid residues as defined above. In one embodiment, O-PEG n is when n=0. In another embodiment, O-PEG n is when n=1. In another embodiment, O-PEG n where 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 and R 2 is -O-(CH2) n -Z, where n is an integer from 1 to 4. In some embodiments, 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 is -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 some embodiments, R 1 is -OH and R 2 is -N(H)C(O)-(CH2) n -NH2 and n is 1. In some embodiments, R1 is -OH and R 2 is -N(H)C(O)-(CH2) n -NH2 and n is 2. In some embodiments, R 1 is -OH and 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 -NH, where each R is -H, -OH, or -CHOH, where n is an integer from 1 to 4. In some embodiments, R 1 is -OH and R 2 is -N(H)C(O)-(CRR) n -NH, each R is -H, and n is an integer from 1 to 4. In some embodiments, R 1 is -OH and R 2 is -N(H)C(O)-(CRR) n -NH, each R is -OH, and n is an integer from 1 to 4. In some embodiments, R 1 is -OH and R 2 is -N(H)C(O)-(CRR) n wherein R is —NH, each R is —CHOH, and n is an integer from 1 to 4. In any one of the preceding embodiments of 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 of this paragraph, n is 3. In any one of the preceding embodiments of this paragraph, n is 4.

[0108] In one embodiment of Formula Ib, R 1 is -OH and R 2is N-piperazinyl. In another embodiment, R 1 is -OH and R 2 is -N(R 6 )2. In another embodiment, R 1 is -OH and R 2 is N-serinyl. 1 is -OH and 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] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof.

[0111] (Conjugates / Antibody Drug Conjugates (ADCs)) Provided herein is a conjugate of Formula A or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof: [ka] (In the formula, L is a linker or XYZ, where X is -NH- or -O-; Y is an enzyme-cleavable moiety, a self-immolative group, an acid-labile moiety, PEG n , a sugar moiety, or an enhancing group; and Z is a binder linker (BL), where Z is covalently attached to BA; BA is a binder; k is an integer from 1 to 30; Q 1 and Q 2each 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, independently in each occurrence, —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 connection with Formula I). Exemplary enzyme-cleavable moieties include, but are not limited to, any dipeptide or tripeptide (e.g., VC-PAB and VA, as described elsewhere herein). Exemplary self-immolative groups are described elsewhere herein. Exemplary acid-labile moieties include, but are not limited to, alkoxyamines, ketoxyamines, carbonates, or phosphonates. Exemplary enhancing groups are described elsewhere herein. Exemplary reactive moieties are described elsewhere herein. In certain embodiments, Y is PEG. nIn certain embodiments, amino acids can be used to connect the payload, the enhancing group, and the antibody (each of which is described elsewhere herein) to one another, as described elsewhere herein and will be apparent. As will be understood by those skilled in the art, the connection of the payload, the enhancing group, and the antibody via an amino acid can be carried out by amide coupling reaction, thio-Michael addition, or phenol-O-alkylation. For example, the amino acid connecting the payload, the enhancing group, and the antibody is lysine. As a further example, in one embodiment, the amino acid connecting the payload, the enhancing group, and the antibody is D-lysine. As a further example, in one embodiment, the amino acid connecting the payload, the enhancing group, and the antibody is aspartic acid. As a further example, in one embodiment, the amino acid connecting the payload, the enhancing group, and the antibody is glutamic acid. As a further example, in one embodiment, the amino acid connecting the payload, the enhancing group, and the antibody is serine. As a further example, in one embodiment, the amino acid connecting the payload, the enhancing group, and the antibody is cysteine. By way of further example, in one embodiment, the amino acid connecting the payload, the enhancing group, and the antibody is a tyrosine.

[0112] Provided herein are conjugates of formula (A) or a pharmaceutically acceptable salt, solvate, or stereoisomeric form 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 , R7 , X, Y, and Z are as described in connection with 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 as described in connection with 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 connection with formula Ib. In certain embodiments, R is R 1 is.

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

[0116] In some embodiments, the binding agent is an antibody or an antigen-binding fragment thereof. The antibody can be in any form known to those skilled in the art. As used herein, the term "antibody" refers to any antigen-binding molecule or molecular complex that contains at least one complementarity-determining region (CDR) that specifically binds to or interacts with a particular antigen. The term "antibody" includes immunoglobulin molecules that contain four polypeptide chains, two heavy (H) chains and two light (L) chains, interconnected by disulfide bonds, and multimers thereof (e.g., IgM). Each heavy chain contains a heavy chain variable region (referred to herein as HCVR or V). H The heavy chain constant region comprises three domains: C H 1. C H 2, and C H Each light chain comprises a light chain variable region (herein LCVR or V L The light chain constant region comprises one domain (C L 1) V H and V L The regions can be further subdivided into regions of hypervariability called complementarity-determining regions (CDRs) interspersed with more conserved regions called framework regions (FRs). H and V Lis composed of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In various embodiments of the present invention, the FRs of antibodies (or antigen-binding portions thereof) suitable for the compounds herein may be identical to human germline sequences or may be naturally or artificially modified. An amino acid consensus sequence can be defined based on a comparative analysis of two or more CDRs. As used herein, the term "antibody" also includes antigen-binding fragments of an intact antibody molecule. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like include any naturally occurring, enzymatically obtained, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be obtained from intact antibody molecules using any suitable standard technique, such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable domains and, optionally, constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. The DNA can be sequenced and manipulated chemically or by using molecular biology techniques, for example, to place one or more variable and / or constant domains in a suitable configuration, or to introduce codons, generate cysteine ​​residues, modify, add, or delete amino acids, etc. Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues mimicking the hypervariable regions of an antibody (e.g., isolated CDRs such as CDR3 peptides), or constrained FR3-CDR3-FR4 peptides.Other engineered molecules, such as 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, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed by the term "antigen-binding fragment" as used herein. Antigen-binding fragments of antibodies typically contain at least one variable domain. A variable domain may be of any size or amino acid composition and typically contains at least one CDR adjacent to or in-frame with one or more framework sequences. H Domain is V L In the antigen-binding fragment associated with the domain, V H Domains and V L The domains may be in any suitable arrangement relative to each other. For example, the variable region may be a dimer and the V H -V H , V H -V L , or V L -V L Alternatively, the antigen-binding fragment of an antibody may contain a dimer of monomeric V H or V L In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary arrangements of variable and constant domains that may be found in an antigen-binding fragment of an antibody of the invention include: (i) a V H -C H 1;(ii)V H -C H 2;(iii)V H -C H 3;(iv)V H -C H 1-C H 2;(v)V H -C H 1-C H 2-C H 3;(vi)V H -C H 2-C H 3;(vii)VH -C L ;(viii)V L -C H 1;(ix)V L -C H 2;(x)V L -C H 3;(xi)V L -C H 1-C H 2;(xii)V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv)V L -C LIn any arrangement of variable and constant domains, including any of the exemplary arrangements described above, the variable and constant domains may be directly linked to each other or may be linked by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids that create a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Like intact antibody molecules, antigen-binding fragments may be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies typically contain at least two different variable domains, each capable of specifically binding to a different antigen or to a different epitope on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, can be adapted for use in connection with the antigen-binding fragments of antibodies of the invention using routine techniques available in the art. In certain embodiments described herein, the antibodies described herein are human antibodies. As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies of the invention may include, for example, amino acid residues in the CDRs, particularly CDR3, that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term "human antibody" as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. The term "human antibody" does not include naturally occurring molecules that typically exist in naturally occurring, unmodified organisms without modification or human intervention / manipulation. Antibodies of the invention may, in some embodiments, be recombinant human antibodies.As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, generated, or isolated by recombinant means, e.g., antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, generated, or isolated by any other means involving splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis when animals transgenic for human Ig sequences are used), thus altering the V of the recombinant antibody. H and V L The amino acid sequence of the region is human germline V H and V LThese sequences are derived from and related to the human antibody germline repertoire but may not naturally occur in vivo within the human antibody germline repertoire. Human antibodies can exist in two forms related to hinge heterogeneity. In one form, the immunoglobulin molecule contains a stable four-chain construct of approximately 150-160 kDa in which dimers are linked by interchain heavy chain disulfide bonds. In the second form, the dimers are not linked by interchain disulfide bonds, forming a molecule of approximately 75-80 kDa composed of covalently linked light and heavy chains (half antibodies). These forms are extremely difficult to separate, even after affinity purification. The frequency of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the antibody hinge region isotype. A single amino acid substitution in the hinge region of a human IgG4 hinge can significantly reduce the occurrence of the second form to the level normally observed with a human IgG1 hinge (Angal et al. (1993) Molecular Immunology 30:105). H 2 or C HThe present invention encompasses antibodies with one or more mutations in these three regions, which may be desirable, for example, to improve the yield of a desired antibody form during production. The antibodies described herein may be isolated antibodies. As used herein, "isolated antibody" refers to an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which it naturally occurs or is naturally produced, is an "isolated antibody" for purposes of the present invention. Isolated antibodies also include antibodies in situ within recombinant cells. Isolated antibodies are antibodies that have been subjected to at least one purification or isolation step. In some embodiments, isolated antibodies may be substantially free of other cellular material and / or chemicals. As used herein, antibodies may contain one or more amino acid substitutions, insertions, and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences from which the antibody was derived. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. The present invention includes antibodies and antigen-binding fragments thereof derived from any of the amino acid sequences disclosed herein, in which one or more amino acids in one or more framework and / or CDR regions have been mutated to the corresponding residue in the germline sequence from which the antibody was derived, or to the corresponding residue in another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue (such sequence changes are collectively referred to herein as "germline mutations"). Starting from the heavy and light chain variable region sequences disclosed herein, one skilled in the art can generate many antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof. In certain embodiments, V H and / or V LAll framework and / or CDR residues within the domain are mutated back to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only specific residues are mutated, e.g., only those residues found in the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or CDR1, Only the mutated residues found in CDR2 or CDR3 are mutated back to the original germline sequence. In other embodiments, one or more of the framework and / or CDR residues are mutated to the corresponding residue in a different germline sequence (i.e., a germline sequence different from the germline sequence from which the antibody was originally derived). Furthermore, antibodies of the present disclosure can contain any combination of two or more germline mutations within the framework and / or CDR regions, for example, where certain individual residues are mutated to the corresponding residue in a particular germline sequence, while certain other residues that differ from the original germline sequence are maintained or mutated to the corresponding residue in a different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be readily tested for one or more desired properties, such as, for example, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Antibodies and antigen-binding fragments obtained by this general method are encompassed within the scope of the present disclosure. Antibodies useful in the compounds herein also include antibodies comprising variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein with one or more conservative substitutions. The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule, known as the paratope. A single antigen may have multiple epitopes. Thus, different antibodies may bind to different portions of an antigen and have different biological effects. Epitopes can be either conformational or linear. Conformational epitopes arise from spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear epitopes arise from adjacent amino acid residues in a polypeptide chain. In some circumstances, an epitope 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 light chain. In certain embodiments, the light chain is a λ light chain. In certain embodiments, the antibody comprises a heavy chain. In some embodiments, the heavy chain is IgA. In some embodiments, the heavy chain is IgD. In some embodiments, the heavy chain is IgE. In some embodiments, the heavy chain is IgG. In some embodiments, the heavy chain is IgM. In some embodiments, the heavy chain is IgG1. In some embodiments, the heavy chain is IgG2. In some embodiments, the heavy chain is IgG3. In some embodiments, the heavy chain is IgG4. In some embodiments, the heavy chain is IgA1. In some embodiments, the heavy chain is IgA2.

[0118] In some embodiments, the antibody is an antibody fragment. In some embodiments, the antibody fragment is an Fv fragment. In some embodiments, the antibody fragment is a Fab fragment. In some embodiments, the antibody fragment is 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 some embodiments, 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.

[0121] The antibody can have binding specificity for any antigen deemed suitable by those skilled in the art. In some 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), macrophage receptor with collagen-like structure (MARCO), scavenger receptor with C-type lectin (SRCL), and scavenger receptor A-5 (SCARA5), class A scavenger receptors including COLEC12, class B macrophage scavenger receptors including CD36, LIMPII, SRBI, and SRBII, class D scavenger receptor CD68, and lysosomal membrane glycoprotein (LAMP), lectin-like oxidized low-density lipoprotein receptor 1. Class E scavenger receptors include LOX-1 and dectin-1; class F scavenger receptors containing endothelial cell-expressed scavenger receptor-I (SREC-I) and SREC-II and multiple epidermal growth factor (EGF)-like domains (MEGF) 10; class G scavenger receptor CXC chemokine ligand 16 (CXCL16); class H scavenger receptors including fasciclin, EGF-like, lamin-type EGF-like, and link domain-containing scavenger receptor-1 (FEEL-1) and -2 (FEEL-2); and class I scavenger receptor C. Examples of molecules that can be used include, but are not limited to, D163 and other C-type lectin superfamily members, including class J scavenger receptor for advanced glycation end products (RAGE), DEC205, CD206, Dectin-2, Mincle, DC-SIGN, and DNGR-1, as well as B7 family-related members, including V-set and Ig domain-containing 4 (VSIG4), colony-stimulating factor 1 receptor (CSF1R), asialoglycoprotein receptor (ASGPR), and other membrane proteins, such as amyloid-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 can be attached to a binder, for example, an antibody or antigen-binding molecule, via a bond at a specific amino acid in the antibody or antigen-binding molecule. Exemplary amino acid linkages that can be used in connection with this aspect of the disclosure include, for example, lysine (see, e.g., US 5,208,020; US 2010 / 0129314; Hollander et al., Bioconjugate Chem., 2008, 19:358-361; WO 2005 / 089808; US 5,714,586; US 2013 / 0101546; and US 2012 / 0585592), cysteine ​​(see, e.g., US 2007 / 0258987; WO 2013 / 055993; WO 2013 / 055990; WO 2013 / 053873; WO 2013 / 053872; WO Nos. 2011 / 130598; US 2013 / 0101546; and US 7,750,116), selenocysteine ​​(see, e.g., WO 2008 / 122039; and Hofer et al., Proc. Natl. Acad. Sci., USA, 2008, 105: 12451-12456), formylglycine (see, 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. Protocols, 2012, 10:1052-1067), unnatural amino acids (see, e.g., WO Examples of suitable linkers include amino acids (see, e.g., US 2008 / 0305497, WO 2014 / 065661, and Ryan et al., Food & Agriculture Immunol., 2001, 13: 127-130), and acidic amino acids (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 antigen-binding molecule, and the antibody is attached to the linker via a lysine residue. In some embodiments, the antibody or antigen-binding molecule is attached to the linker via a cysteine ​​residue.

[0124] Linkers can also be conjugated to one or more glutamine residues via transglutaminase-based chemical enzymatic conjugation (see, e.g., Dennler et al., Bioconjugate Chem. 2014, 25, 569-578 and WO 2017 / 147542). For example, one or more glutamine residues of an antibody can be coupled to a primary amine compound in the presence of transglutaminase. Briefly, in some embodiments, an antibody having a glutamine residue (e.g., Gln295 residue) is treated with a primary amine compound, described in more detail below, in the presence of the enzyme transglutaminase. Primary amine compounds include, for example, payloads or linker-payloads that directly provide antibody-drug conjugates via transglutaminase-mediated coupling. Primary amine compounds also include linkers and spacers that are functionalized with reactive groups that can be subsequently treated with additional compounds to synthesize antibody-drug conjugates. Antibodies containing glutamine residues can be isolated from natural sources or modified to contain one or more glutamine residues. Techniques for artificially creating glutamine residues in antibody polypeptide chains (glutaminyl-modified antibodies or antigen-binding molecules) are within the capabilities of those skilled in the art. In some embodiments, the antibodies are aglycosylated.

[0125] In certain embodiments, the antibody or glutaminyl-modified antibody or antigen-binding molecule comprises at least one glutamine residue in at least one polypeptide chain sequence. In certain embodiments, the antibody or glutaminyl-modified antibody or antigen-binding molecule comprises two heavy chain polypeptides, each having one Gln295 residue. In further embodiments, the antibody or glutaminyl-modified antibody or antigen-binding molecule comprises one or more glutamine residues at a site other than 295 in the heavy chain. Included herein are antibodies of this section that carry the Asn297Gln (N297Q) mutation described herein. Included herein are antibodies of this section that carry a Gln55 (Q55) residue.

[0126] (Primary amine compounds) Primary amine compounds useful for transglutaminase-mediated coupling of glutamine-containing antibodies (or antigen-binding compounds) can be any primary amine compound deemed useful by those skilled in the art. Typically, primary amine compounds have the formula HN-R, where R can be any group compatible with the antibody and reaction conditions. In certain embodiments, R is alkyl, substituted alkyl, heteroalkyl, or substituted heteroalkyl.

[0127] In some embodiments, the primary amine compound comprises a reactive group or a protected reactive group. Useful reactive groups include azides, alkynes, cycloalkynes, thiols, alcohols, ketones, aldehydes, acids, esters, hydrazides, anilines, and amines. In some embodiments, the reactive group is selected from the group consisting of azides, alkynes, sulfhydryls, cycloalkynes, aldehydes, and carboxyls.

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

[0129] In certain embodiments, the primary amine compound is according to one of the following formulas: H2N-(CH2) n -X; H2N-(CH2CH2O) n -(CH2) p -X; H2N-(CH2) n -N(H)C(O)-(CH2) m -X; H2N-(CH2CH2O) n -N(H)C(O)-(CH2CHO) m -(CH2) p -X; H2N-(CH2) n -C(O)N(H)-(CH2) m -X; H2N-(CH2CH2O) n -C(O)N(H)-(CH2CH2O) m -(CH2) p -X; H2N-(CH2) n -N(H)C(O)-(CH2CHO) m -(CH2) p -X; H2N-(CH2CH2O) n -N(H)C(O)-(CH2) m -X; H2N-(CH2) n -C(O)N(H)-(CH2CH2O) m -(CH2) p -X; and H2N-(CH2CH2O) n -C(O)N(H)-(CH2)m -X; (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 It may be optionally substituted with alkyl, methylformyl, or -SO3H. In some embodiments, 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 is a moiety, e.g., a bivalent moiety, that covalently links the binding agent to the payload compound described herein. In other examples, the linker L is a trivalent or multivalent moiety that covalently links the binding agent to the payload compound described herein. Suitable linkers can be found, for example, in Antibody-Drug Conjugates and Immunotoxins; Phillips, GL (ed.); Springer Verlag: New York, 2013; Antibody-Drug Conjugates; Ducry, L. (ed.); Humana Press, 2013; Antibody-Drug Conjugates; Wang, J., Shen, W.-C., and Zaro, JL (eds.); Springer International Publishing, 2015, the contents of each of which are incorporated herein by reference in their entirety. Payload compounds include compounds of Formulas I, Ia, and Ib above, and residues thereof after attachment to or incorporation by linker L. Those skilled in the art will recognize that certain functional groups on the payload moiety are convenient for attachment to a linker and / or binder. These groups include amines, hydroxyls, phosphates, and sugars.

[0134] In some embodiments, the linker is stable under physiological conditions. In some embodiments, the linker is cleavable, for example, in the presence of an enzyme or at a specific pH range or value, and can release at least the payload portion. In some embodiments, the linker comprises an enzyme-cleavable moiety. Exemplary enzyme-cleavable moieties include, but are not limited to, peptide bonds, ester bonds, hydrazones, and disulfide bonds. In some embodiments, the linker comprises a cathepsin-cleavable linker.

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

[0136] In some embodiments, suitable linkers include, but are not limited to, a single linker that is chemically coupled to two cysteine ​​residues of an antibody, such as an antibody that can mimic the disulfide bonds of an antibody that are disrupted as a result of the conjugation process.

[0137] In some embodiments, the linker comprises one or more amino acids. Suitable amino acids include natural, non-natural, standard, non-standard, proteinogenic, non-proteinogenic, and L- or D-α-amino acids. In some embodiments, the linker comprises alanine, valine, glycine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, 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, the linker comprises valine and citrulline. In some embodiments, the linker comprises lysine, valine, and citrulline. In some embodiments, the linker comprises lysine, valine, and alanine. In some embodiments, the linker comprises valine and alanine.

[0138] In some embodiments, the linker comprises a self-immolative group. The self-immolative group can be any such group known to those skilled in the art. In certain embodiments, the self-immolative group is p-aminobenzyl (PAB) or a derivative thereof. Useful derivatives include p-aminobenzyloxycarbonyl (PABC). Those skilled in the art will recognize that the self-immolative group can undergo a chemical reaction that releases the remaining atoms of the linker from the payload.

[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 A moiety that connects a moiety to a binding agent (BA) or to a reactive group residue attached to a BA. 1 The spacer may include, but is not limited to, alkylene or polyether, or both. The end of the spacer, for example, the portion of the spacer bound to the binding agent or AA, can be a moiety derived from a reactive moiety used for coupling the antibody or AA to the spacer during chemical synthesis of the conjugate. In some embodiments, n is 1, 2, 3, or 4. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4.

[0141] In some embodiments, SP 1 The spacer comprises an alkylene. In some embodiments, SP 1 The spacer is C 5-7 In some embodiments, SP 1 The spacer comprises a polyether. In some embodiments, SP 1 The spacer comprises a polymer 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 can be any reactive group known to those skilled in the art to be capable of forming one or more bonds with a binding agent. The reactive group RG is a moiety that contains a moiety in its structure that can react with a binding agent (e.g., with an antibody at its cysteine ​​or lysine residue, or with an azide moiety, e.g., with a PEG-N3 functionalized antibody at one or more glutamine residues) to form a compound of formula A, Aa, or Ab. After conjugation with a binding agent, the reactive group becomes a reactive group (RG'). Exemplary reactive groups include, but are not limited to, those containing a haloacetyl, isothiocyanate, succinimide, N-hydroxysuccinimide, or maleimide moiety that can react with a binding agent.

[0144] In some embodiments, the reactive group includes, but is not limited to, an alkyne. In some embodiments, the alkyne is an alkyne that can undergo 1,3-cycloaddition with azide in the absence of a copper catalyst, such as a strained alkyne. Strained alkynes are suitable for strain-promoted alkyne-azide cycloaddition (SPAAC), cycloalkynes, such as cyclooctynes, and benz-annulated alkynes. Suitable alkynes include dibenzoazacyclooctynes ​​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] and derivatives thereof. Particularly useful alkynes include, but are not limited to: [ka] Examples include:

[0145] In some embodiments, the binding agent is directly attached to RG'. In some embodiments, the binding agent is attached to a spacer below, e.g., SP 4 In certain embodiments, the binder is attached to RG' via a PEG spacer. As discussed in detail below, in certain embodiments, the binder is prepared by functionalizing one or more azide groups. Each azide group can react with RG to form RG'. In certain embodiments, the binder is derivatized with -PEG-N3 linked to a glutamine residue. Exemplary -N3-derivatized binders, methods for their preparation, and methods for their use in reacting with RG are provided herein. In certain embodiments, RG is an alkyne suitable for participation in 1,3-cycloaddition, and RG' is a 1,2,3-triazolyl moiety formed from the reaction of RG with the azide-functionalized binder. By way of further example, in certain embodiments, RG' is [ka] or linked to a binder as shown in the mixture of each positional isomer, where each R and R' are as described herein.

[0146] SP 2 The spacer is (AA)n A spacer is a moiety that connects the moiety to the payload. 1 Spacers include, but are not limited to, those described above. Additional suitable SPs 2 Spacers include, but are not limited to, those containing alkylene or polyether, or both. SP 2 The terminus of the spacer, e.g., the portion of the spacer directly attached to the payload or AA, is used to connect the payload or AA to the SP during chemical synthesis of the conjugate. 2 It can be a moiety derived from a reactive moiety used for the purpose of coupling to a spacer. In some instances, SP 2 The end of the spacer, e.g., SP directly linked to the payload or AA 2 The spacer portion can be the residue of a reactive moiety used for the purpose of coupling a payload or AA to the spacer during chemical synthesis of the conjugate.

[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 selected from the group consisting of 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 heterocycloalkylene or substituted heterocycloalkylene is selected from the groups -O-, -N(H)-, and -N(H)- available for attachment to the remainder of the molecule. [ka] 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, a p-aminobenzyloxycarbonyl residue (PABC). When a PABC is present, preferably only one PABC is present. Preferably, the PABC residue, if present, is proximal to the payload (AA). nThe AA is the terminal AA in the group. Suitable amino acids for each AA include natural, non-natural, standard, non-standard, proteinogenic, non-proteinogenic, and L- or D-α-amino acids. In some embodiments, the linker comprises alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, derivatives thereof, or combinations thereof. In certain embodiments, one or more side chains of the amino acid are linked to the side chain group described below. In some embodiments, n is 2. In some embodiments, (AA) n is valine-citrulline. In some embodiments, (AA) n is citrulline-valine. In some embodiments, (AA) n is valine-alanine. In some embodiments, (AA) n is alanine-valine. In some embodiments, (AA) n is valine-glycine. In some embodiments, (AA) n is glycine-valine. In some embodiments, n is 3. In some embodiments, the(AA) n is valine-citrulline-PABC. In some embodiments, (AA) n is citrulline-valine-PABC. In some embodiments, (AA) n is glutamic acid-valine-citrulline. In some embodiments, (AA) n is 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) nis glutamic acid-valine-citrulline-PAB. 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 has been shown to promote 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 the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, attachment to the binding agent can be direct or via a spacer, hi some embodiments, attachment to the binding agent is via a PEG spacer to a glutamine residue of the binding agent.

[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 the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, attachment to the binding agent can be direct or via a spacer, hi some embodiments, attachment to the binding agent is via a PEG spacer to a glutamine residue of the binding agent.

[0152] In any of the above embodiments, (AA) n The group may be modified with one or more enhancing groups. Advantageously, the enhancing groups are (AA) nThe enhancing group can be linked to the side chain of any amino acid in the nucleotide sequence. Useful amino acids for linking the enhancing group include lysine, asparagine, aspartic acid, glutamine, glutamic acid, and citrulline. The link to the enhancing group can be a direct bond to the amino acid side chain, or the link can be indirect via a spacer and / or a reactive group. Useful spacers and reactive groups include any of those described above. The enhancing group can be any group deemed useful by those skilled in the art. For example, the enhancing group can be any group that confers a beneficial effect on a compound, payload, linker-payload, or antibody conjugate, including, but not limited to, a biological effect, a biochemical effect, a synthetic effect, a solubilizing effect, an imaging effect, a detection effect, and a reactivity effect. In certain embodiments, the enhancing group is a hydrophilic group. In certain embodiments, the enhancing group is a cyclodextrin. In certain embodiments, the enhancing group is an alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid. The cyclodextrin can be any cyclodextrin known to those skilled in the art. In certain embodiments, the cyclodextrin is α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof. In certain embodiments, the cyclodextrin is α-cyclodextrin. In certain embodiments, the cyclodextrin is β-cyclodextrin. In certain embodiments, the cyclodextrin is γ-cyclodextrin. In certain embodiments, the enhancing group can improve the solubility of the remainder of the conjugate. In certain embodiments, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is substituted or unsubstituted. In certain embodiments, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) 1-5 SO3H, -(CH2) n -NH-(CH2) 1-5 SO3H, -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, -(CH2CH2O) m-C(O)NH-(CH2) 1-5 SO3H, -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, -(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, or -(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5, and m is 1, 2, 3, 4, or 5. In one embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) 1-5 In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n -NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2)1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, 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, attachment to the binding agent can be direct or via a spacer, hi some embodiments, attachment to the binding agent is via a PEG spacer to a glutamine residue of the binding agent.

[0153] SP 1 The spacer group is as described above. SP 2 The spacer groups are as described above. nThe groups are as described 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 Spacers include, but are not limited to, those containing alkylene or polyether, or both. SP 3 The end of the spacer, i.e., SP directly bonded to the enhancing group or AA 3 The spacer portion is a portion of the enhancer group or AA attached to SP during the chemical synthesis of the conjugate. 3 It can be a moiety derived from a reactive moiety used for the purpose of coupling to a spacer. In some instances, SP 3 The terminus of the spacer, i.e., the portion of the spacer directly attached to the enhancer group or AA, can be the residue of a reactive moiety used for the purpose of coupling the enhancer group or AA to the spacer during chemical synthesis of the conjugate. In certain embodiments, SP 3 is (AA) n In one embodiment, SP 3 The spacer is (AA) n is linked to the side chain of a lysine residue of

[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 bond to the enhancer; [ka] is (AA) n is a bond with; and a is an integer of 2 to 8.

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

[0157] In some embodiments, the reactive group includes, but is not limited to, an alkyne. In some embodiments, the alkyne is an alkyne that can undergo 1,3-cycloaddition with azide in the absence of a copper catalyst, such as a strained alkyne. Strained alkynes are suitable for strain-promoted alkyne-azide cycloaddition (SPAAC), cycloalkynes, such as cyclooctynes, and benz-annulated alkynes. Suitable alkynes include dibenzoazacyclooctynes ​​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] and derivatives thereof. Particularly useful alkynes include, but are not limited to: [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, attachment to the binding agent can be direct or via a spacer, hi some embodiments, attachment to the binding agent is via a PEG spacer to a glutamine residue of the binding agent.

[0159] In some embodiments, the linker is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof, or a mixture of positional isomers thereof, 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 the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, in one embodiment, ZZ is C 1-6 In some embodiments, the 1,3-cycloaddition or SPAAC regioisomer, or mixture of regioisomers, is derived from a PEG-N3 derivatized antibody that has been 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 positional isomer thereof, or a mixture of positional isomers thereof. [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof, or a mixture of positional isomers thereof. [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof, or a mixture of positional isomers thereof. As discussed above, the bond to the binder can be direct or via a spacer. In some embodiments, the bond to the binder is via a PEG spacer to the glutamine residue of the binder. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancer is a cyclodextrin. In some embodiments, the enhancer is an alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid. The cyclodextrin can be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin is α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof. In some embodiments, the cyclodextrin is α-cyclodextrin. In some embodiments, the cyclodextrin is β-cyclodextrin. In some embodiments, the cyclodextrin is γ-cyclodextrin. In some embodiments, 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 one embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) 1-5 In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n -NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, 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.

[0160] In some embodiments, the linker is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof, or a mixture of positional isomers thereof, 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 the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, the bond to the binder can be direct or via a spacer. In some embodiments, the bond to the binder is via a PEG spacer to the glutamine residue of the binder. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancer is a cyclodextrin. In some embodiments, the enhancer is an alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid. The cyclodextrin can be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin is α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof. In some embodiments, the cyclodextrin is α-cyclodextrin. In some embodiments, the cyclodextrin is β-cyclodextrin. In some embodiments, the cyclodextrin is γ-cyclodextrin. In some embodiments, 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 one embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) 1-5In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n -NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, 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.

[0161] In some embodiments, the linker is: [ka] TIFF0007728636000181.tif134170, or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof, or a mixture of positional isomers thereof, 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 the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, attachment to the binding agent can be direct or via a spacer, hi some embodiments, attachment to the binding agent is via a PEG spacer to a glutamine residue of the binding agent. In some embodiments, the linker is: [ka] TIFF0007728636000186.tif216170, or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof, or a mixture of positional isomers thereof, 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 the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, attachment to the binding agent can be direct or via a spacer, hi some embodiments, attachment to the binding agent is via a PEG spacer to a glutamine residue of the binding agent.

[0162] In some embodiments, the linker is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof, or a mixture of positional isomers thereof, 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 the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, the bond to the binder can be direct or via a spacer. In some embodiments, the bond to the binder is via a PEG spacer to the glutamine residue of the binder. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancer is a cyclodextrin. In some embodiments, the enhancer is an alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid. The cyclodextrin can be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin is α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof. In some embodiments, the cyclodextrin is α-cyclodextrin. In some embodiments, the cyclodextrin is β-cyclodextrin. In some embodiments, the cyclodextrin is γ-cyclodextrin. In some embodiments, 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 one embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) 1-5 In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n -NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, 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.

[0163] In some embodiments, the linker is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof, or a mixture of positional isomers thereof, 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 the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, the bond to the binder can be direct or via a spacer. In some embodiments, the bond to the binder is via a PEG spacer to the glutamine residue of the binder. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancer is a cyclodextrin. In some embodiments, the enhancer is an alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid. The cyclodextrin can be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin is α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof. In some embodiments, the cyclodextrin is α-cyclodextrin. In some embodiments, the cyclodextrin is β-cyclodextrin. In some embodiments, the cyclodextrin is γ-cyclodextrin. In some embodiments, 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 one embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) 1-5In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n -NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, 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.

[0164] In some embodiments, the linker is: [ka] TIFF0007728636000200.tif69170, or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof, or a mixture of positional isomers thereof, 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 the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, attachment to the binding agent can be direct or via a spacer, hi some embodiments, attachment to the binding agent is via a PEG spacer to a glutamine residue of the binding agent.

[0165] In some embodiments, the linker is: [ka] TIFF0007728636000205.tif98170, or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a positional isomer thereof, or a mixture of positional isomers thereof, 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 the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, attachment to the binding agent can be direct or via a spacer, hi some embodiments, attachment to the binding agent is via a PEG spacer to a glutamine residue of the binding agent.

[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 positional isomer thereof, wherein: 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 linked to one AA of the 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 described in connection with formula I; 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 the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, the bond to the binder can be direct or via a spacer. In some embodiments, the bond to the binder is via a PEG spacer to the glutamine residue of the binder. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancer is a cyclodextrin. In some embodiments, the enhancer is an alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid. The cyclodextrin can be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin is α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof. In some embodiments, the cyclodextrin is α-cyclodextrin. In some embodiments, the cyclodextrin is β-cyclodextrin. In some embodiments, the cyclodextrin is γ-cyclodextrin. In some embodiments, 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 one embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) 1-5In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n -NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where m is 1, 2, 3, 4, or 5. In certain embodiments, R is R 1 is.

[0168] In some embodiments, the conjugate is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or positional isomer thereof, wherein: 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 described in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, the bond to the binder can be direct or via a spacer. In some embodiments, the bond to the binder is via a PEG spacer to the glutamine residue of the binder. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancer is a cyclodextrin. In some embodiments, the enhancer is an alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid. The cyclodextrin can be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin is α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof. In some embodiments, the cyclodextrin is α-cyclodextrin. In some embodiments, the cyclodextrin is β-cyclodextrin. In some embodiments, the cyclodextrin is γ-cyclodextrin. In some embodiments, 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 one embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) 1-5In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n -NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where m is 1, 2, 3, 4, or 5. In certain embodiments, R is R 1 is.

[0169] In some embodiments, the conjugate is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or positional isomer thereof, wherein: 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 described in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. As discussed above, the bond to the binder can be direct or via a spacer. In some embodiments, the bond to the binder is via a PEG spacer to the glutamine residue of the binder. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancer is a cyclodextrin. In some embodiments, the enhancer is an alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid. The cyclodextrin can be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin is α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, or a mixture thereof. In some embodiments, the cyclodextrin is α-cyclodextrin. In some embodiments, the cyclodextrin is β-cyclodextrin. In some embodiments, the cyclodextrin is γ-cyclodextrin. In some embodiments, 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 one embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) 1-5In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n -NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where m is 1, 2, 3, 4, or 5. In certain embodiments, R is R 1 is.

[0170] In some embodiments, the conjugate is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or positional isomer thereof, wherein: 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 described in connection with formula I; 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 the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancer is a cyclodextrin. In some embodiments, the enhancer is an alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid. The cyclodextrin can be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin is an α-cyclodextrin, a β-cyclodextrin, or a γ-cyclodextrin, or a mixture thereof. In some embodiments, the cyclodextrin is an α-cyclodextrin. In some embodiments, the cyclodextrin is a β-cyclodextrin. In some embodiments, the cyclodextrin is a γ-cyclodextrin. In some embodiments, 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 one embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) 1-5 In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n -NH-(CH2) 1-5SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where m is 1, 2, 3, 4, or 5. In 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 positional isomer thereof, wherein: 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 described in connection with formula I; 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 the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancer is a cyclodextrin. In some embodiments, the enhancer is an alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid. The cyclodextrin can be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin is an α-cyclodextrin, a β-cyclodextrin, or a γ-cyclodextrin, or a mixture thereof. In some embodiments, the cyclodextrin is an α-cyclodextrin. In some embodiments, the cyclodextrin is a β-cyclodextrin. In some embodiments, the cyclodextrin is a γ-cyclodextrin. In some embodiments, 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 one embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) 1-5 In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n -NH-(CH2) 1-5SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where m is 1, 2, 3, 4, or 5. In certain embodiments, R is R 1 is.

[0172] In some embodiments, the conjugate comprises: [ka] TIFF0007728636000222.tif196170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or positional isomer thereof, wherein: 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 described in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, 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] TIFF0007728636000225.tif199170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or positional isomer thereof, wherein: 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 , R3 , R 4 , R 5 , R 6 , R 7 , X, Y, Z, and n are as described in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, 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 positional isomer thereof, wherein: 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 described in connection with formula I; 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 the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancer is a cyclodextrin. In some embodiments, the enhancer is an alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid. The cyclodextrin can be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin is an α-cyclodextrin, a β-cyclodextrin, or a γ-cyclodextrin, or a mixture thereof. In some embodiments, the cyclodextrin is an α-cyclodextrin. In some embodiments, the cyclodextrin is a β-cyclodextrin. In some embodiments, the cyclodextrin is a γ-cyclodextrin. In some embodiments, 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 one embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) 1-5 In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n -NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2)1-5 SO3H)2, where m is 1, 2, 3, 4, or 5. In 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 positional isomer thereof, wherein: 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 described in connection with formula I; 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 the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, in one embodiment, ZZ is C 1-6 It is heteroalkyl. In some embodiments, the enhancer is a hydrophilic group. In some embodiments, the enhancer is a cyclodextrin. In some embodiments, the enhancer is an alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid. The cyclodextrin can be any cyclodextrin known to those skilled in the art. In some embodiments, the cyclodextrin is an α-cyclodextrin, a β-cyclodextrin, or a γ-cyclodextrin, or a mixture thereof. In some embodiments, the cyclodextrin is an α-cyclodextrin. In some embodiments, the cyclodextrin is a β-cyclodextrin. In some embodiments, the cyclodextrin is a γ-cyclodextrin. In some embodiments, 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 one embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) 1-5 In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH) n -NH-(CH2) 1-5SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -C(O)NH-(CH2) 1-5 SO3H, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2CH2O) m -C(O)NH-(CH2) 1-5 SO3H, where m is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2) n -N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2) n -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is —(CH2CH2O) m -C(O)N((CH2) 1-5 C(O)NH(CH2) 1-5 SO3H)2, where m is 1, 2, 3, 4, or 5. In certain embodiments, R is R 1 is.

[0176] In some embodiments, the conjugate comprises: [ka] TIFF0007728636000234.tif83170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or positional isomer thereof, wherein: 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 described in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, 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] TIFF0007728636000237.tif90170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or positional isomer thereof, wherein: 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 , R3 , R 4 , R 5 , R 6 , R 7 , X, Y, Z, and n are as described in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, 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 conjugates can be prepared from azide-functionalized linking agents and their residues, as described in the sections below. For convenience, the triazole residues in some of the structures above are shown in parentheses. Those skilled in the art will recognize that the trazole can be formed from the azide group of an azide-derivatized linking agent and an alkyne of the linker payload LP.

[0179] In some embodiments, the conjugate comprises: [ka] TIFF0007728636000240.tif243170TIFF0007728636000241.tif246170TIFF0007728636000242.tif219170TIFF0007728636000243.tif200170TIFF0007728636000244.tif249170, or a positional isomer, stereoisomeric form, pharmaceutically acceptable salt, or solvate thereof. In the above embodiments, k is an integer of 1 to 30. In certain embodiments, k is an integer of 1 to 8. In certain embodiments, k is an integer of 1 to 4. In certain embodiments, k is 8, 7, 6, 5, 4, 3, 2, or 1. In certain embodiments, k is 4. In certain embodiments, k is 3. In some embodiments, k is 2. In some embodiments, k is 1.

[0180] (Reactive Linker-Payload) The conjugates provided herein can be prepared from a reactive linker-payload having the reactive group RG described above, which can be linked to an enhancing group and / or a binding agent according to the methods described below.

[0181] In some embodiments, the reactive linker-payload is: [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or positional isomer thereof, wherein: 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 described in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, 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 positional isomer thereof, wherein: 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 described in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, 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 positional isomer thereof, wherein: 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 described in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, 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 positional isomer thereof, wherein: 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 described in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, 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] TIFF0007728636000254.tif153170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or positional isomer thereof, wherein: R is -H, R 1 , or R 2and 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 described in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, 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] TIFF0007728636000257.tif155170 or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or positional isomer thereof, wherein: 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 described in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, 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 positional isomer thereof, wherein: 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 described in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6By way of further example, 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 positional isomer thereof, wherein: 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 described in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, 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 isomer thereof, wherein: 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 described in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, 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 isomer thereof, wherein: R is -H, R 1 , or R 2 and Q 1 , Q 2 , W, R 1 , R 2 , R 3 , R 4 , R5 , R 6 , R 7 , X, Y, Z, and n are as described in connection with formula I; Each R 9 is —CH or —(CH)N(H)C(O)NH; and Each A is -O-, -N(H)-, [ka] where ZZ is hydrogen or the side chain of an amino acid discussed elsewhere herein. For example, in one embodiment, ZZ is C 1-6 By way of further example, 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] TIFF0007728636000268.tif242170TIFF0007728636000269.tif247170TIFF0007728636000270.tif242170TIFF0007728636000271.tif246170, or positional isomers, stereoisomeric forms, pharmaceutically acceptable salts, and solvates thereof.

[0192] (Method for preparing compounds) The compounds provided herein can be prepared, isolated, or obtained by any method apparent to those skilled in the art. Exemplary preparation methods are described in detail in the following examples. In some embodiments, the compounds provided herein can be prepared according to Scheme A.

[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 defined as described in relation to 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 Q, for example by saponification and activation of the carboxylic acid moiety, 1 After amination, for example, by saponification and amidation of the carboxylic acid moiety, Q 2 and a second coupling partner is provided having Q 1 and Q 2 and then combining the coupling partners having R 1 and R 2 Deprotection of provides compounds of Formula I. Exemplary preparation methods are described in detail in the Examples below.

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

[0195] The linker-payloads described herein can be synthesized by a series of coupling steps. [ka] For example, the payload on the right can be coupled to SP via one or more standard coupling reactions. 2 In a preferred embodiment, the payload compounds described herein contain a free amino group available for coupling via amide synthesis conditions, as described herein. (AA) n The amino acid of the spacer SP can be added by amide synthesis conditions, for example, peptide synthesis conditions.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 contains a free amino or carboxyl group available for coupling via amide synthesis conditions, as described herein. If present, the spacer SP 3 via one or more standard coupling reactions (AA) n In a preferred embodiment, the SPs described herein can be linked to 3 and (AA) n The group contains a free amino or carboxyl group available for coupling via amide synthesis conditions, as described herein.

[0196] Spacer SP 3 When present, the reactive group RG terminates in a reactive group that can be linked to an enhancer EG via coupling conditions deemed suitable by those skilled in the art. In certain embodiments, the spacer SP 3 is linked to the enhancer EG via amide synthesis conditions. In some embodiments, the spacer SP 3 is linked to the enhancer EG via click chemistry. In these embodiments, the spacer SP 3 terminates in a reactive group suitable for a Click reaction, e.g., an azide or an alkyne, and the enhancer EG contains a complementary reactive group suitable for a Click reaction, e.g., an alkyne or an azide. In a preferred embodiment, SP 3 ends with a strained alkyne, EG contains an azide; or SP 3 is terminated with a carboxylic acid, and EG contains an amine. When EG is a cyclodextrin moiety, the cyclodextrin can contain an azide. Azidocyclodextrins can be prepared synthetically or obtained from commercial sources. When EG is a sulfonic acid moiety, one end of the EG terminates with a sulfonic acid group, and the other end terminates with a primary or secondary amine.

[0197] The conjugates described herein can be synthesized by coupling the linker-payloads described herein to a binder, e.g., an antibody, under standard conjugation conditions (see, e.g., Doronina et al., Nature Biotechnology 2003, 21, 7, 778, incorporated herein by reference in its entirety). When the binder is an antibody, the antibody can be coupled to the linker-payload through one or more cysteine ​​or lysine residues of the antibody. The linker-payload can be coupled to a cysteine ​​residue by, for example, subjecting the antibody to a reducing agent, e.g., dithiotheritol, to cleave the antibody's disulfide bonds, purifying the reduced antibody, e.g., by gel filtration, and then treating the antibody with a linker-payload containing a suitable reactive moiety, e.g., a maleimide group. Suitable solvents include, but are not limited to, water, DMA, DMF, and DMSO. A linker-payload containing a reactive group, such as an activated ester or acid halide group, can be coupled to the lysine residue of the antibody. Suitable solvents include, but are not limited to, water, DMA, DMF, and DMSO. The conjugate can be purified using known protein techniques, including, for example, size exclusion chromatography, dialysis, and ultrafiltration / diafiltration.

[0198] Binders, e.g., antibodies, can also be conjugated via click chemistry. In some click chemistry embodiments, the linker-payload comprises a reactive group, e.g., an alkyne, capable of undergoing a 1,3-cycloaddition reaction with azide. Suitable reactive groups are described above. The antibody includes an antibody comprising one or more azide groups. Such antibodies include, for example, antibodies functionalized with an azide-polyethylene glycol group. In some embodiments, such functionalized antibodies are derived by treating an antibody having at least one glutamine residue, e.g., heavy chain Gln295 or Gln55, with a primary amine compound in the presence of the enzyme transglutaminase. In some embodiments, such functionalized antibodies are derived by treating an antibody having at least one glutamine residue, e.g., heavy chain Gln297, with a primary amine compound in the presence of the enzyme transglutaminase. Such antibodies include Asn297Gln (N297Q) mutants. In some embodiments, such functionalized antibodies are derived by treating an antibody having at least two glutamine residues, e.g., heavy chain Gln295 and heavy chain Gln297, with a primary amine compound in the presence of the enzyme transglutaminase. Such antibodies include the Asn297Gln (N297Q) mutant. In some embodiments, the antibody has two heavy chains described in this paragraph for a total of two or four glutamine residues.

[0199] In some embodiments, the antibody contains a glutamine residue 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, Gln295, or Q295. Those skilled in the art will recognize that this is a conserved glutamine residue in the wild-type sequences of many antibodies. In other useful embodiments, the antibody can be modified to contain a glutamine residue. Techniques for modifying antibody sequences to contain a glutamine residue are within the capabilities of those skilled in the art (see, for example, Ausubel et al., Current Protoc. Mol. Biol.).

[0200] In some embodiments, the antibody contains two glutamine residues, one in each heavy chain. In certain embodiments, the antibody contains a Q295 residue in each heavy chain. In further embodiments, the antibody contains one, two, three, four, five, six, seven, eight, or more glutamine residues. These glutamine residues can be 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 or modified residues. The antibody can be prepared according to standard techniques.

[0201] Those skilled in the art will recognize that antibodies are often glycosylated at residue N297 near residue Q295 in the heavy chain sequence. Glycosylation at residue N297 can interfere with transglutaminase activity at residue Q295 (Dennler et al., supra). Thus, in a preferred embodiment, the antibody is aglycosylated. In certain embodiments, the antibody is deglycosylated or aglycosylated. In certain embodiments, the antibody heavy chain has an N297 mutation. In other words, the antibody has been mutated so that it no longer has an asparagine residue at position 297. In certain embodiments, the antibody heavy chain has an N297Q mutation. Such antibodies can be prepared by site-directed mutagenesis to remove or disable the glycosylation sequence or by site-directed mutagenesis to insert a glutamine residue into a site that does not abrogate antibody function or binding. In some embodiments, the antibody with Q295 residue and / or N297Q mutation contains one or more additional natural glutamine residues in its variable region that can be accessed by transglutaminase and therefore can be conjugated to a linker or linker-payload. An exemplary natural glutamine residue can be found, for example, at Q55 in the light chain. In such cases, the antibody conjugated via transglutaminase can have a larger DAR value than expected (e.g., a DAR greater than 4). Any such antibody can be isolated from natural or artificial sources.

[0202] The antibody without interfering glycosylation is then reacted with a primary amine compound. In some embodiments, the aglycosylated antibody is reacted with a primary amine compound to generate a glutaminyl-modified antibody. In some embodiments, the deglycosylated antibody is treated with a primary amine compound to generate a glutaminyl-modified antibody.

[0203] The primary amine can be any primary amine that can form a covalent bond with a glutamine residue in the presence of transglutaminase. Useful primary amines are described below. The transglutaminase can be any transglutaminase that is deemed suitable by those skilled in the art. In some embodiments, the transglutaminase is an enzyme that catalyzes the formation of an isopeptide bond between a free amine group on a primary amine compound and an acyl group on the side chain of a glutamine residue. Transglutaminase is also known as protein-glutamine-γ-glutamyltransferase. In certain embodiments, the transglutaminase is classified under EC 2.3.2.13. The transglutaminase can be derived from any source that is deemed suitable. In some embodiments, the transglutaminase is microbial. Useful transglutaminases have been isolated from Streptomyces mobaraense, Streptomyces cinnamoneum, Streptomyces griseo-carneum, Streptomyces lavendulae, and Bacillus subtilis. Non-microbial transglutaminases, including mammalian transglutaminases, can also be used. In certain embodiments, transglutaminases can be produced by any technique or obtained from any source deemed suitable by those skilled in the art. In certain embodiments, transglutaminases are obtained from commercially available sources.

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

[0205] In some embodiments, the glutaminyl-modified antibody is reacted or treated with a reactive linker-payload to form an antibody-payload conjugate. This reaction can proceed under conditions deemed suitable by those skilled in the art. In some embodiments, the glutaminyl-modified antibody is contacted with the reactive linker-payload compound under conditions suitable for forming a bond between the glutaminyl-modified antibody and the linker-payload 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 diseases, illnesses, or disorders, including, but not limited to, those associated with the antigens listed herein, comprising administering a therapeutically or prophylactically effective amount of one or more compounds disclosed herein, e.g., one or more compounds of the formulae provided herein.

[0208] The compounds described herein can be administered alone or together with one or more additional therapeutic agents. The one or more additional therapeutic agents can be administered immediately before, simultaneously with, or immediately after the administration of the compounds described herein. The present disclosure also includes pharmaceutical compositions comprising any of the compounds described herein in combination with one or more additional therapeutic agents, and methods of treatment comprising administering such a combination to a subject in need thereof.

[0209] Suitable additional therapeutic agents include, but are not limited to: a second glucocorticoid, an autoimmune therapeutic agent, a hormone, a biologic, or a monoclonal antibody. Suitable therapeutic agents also include, but are not limited to, any pharmaceutically acceptable salt, acid, or derivative of the compounds described herein.

[0210] In some embodiments of the methods described herein, multiple doses of a compound described herein (or a pharmaceutical composition comprising a compound described herein in combination with any of the additional therapeutic agents mentioned herein) can be administered to a subject over a defined time course. The method according to this aspect of the disclosure includes sequentially administering multiple doses of a compound described herein to a subject. As used herein, "sequentially administering" means that each dose of the compound is administered to a subject at a different time, for example, on different days separated by a predetermined interval (e.g., hour, day, week, or month). The disclosure includes methods comprising sequentially administering to a patient a single initial dose of a compound described herein, followed by one or more secondary doses of the compound, and optionally, subsequently, one or more tertiary doses of the compound.

[0211] The terms "initial dose," "secondary dose," and "tertiary dose" refer to the time sequence of administration of the compounds described herein. Thus, an "initial dose" is a dose administered at the beginning of a treatment regimen (also known as a "baseline dose"); a "secondary dose" is a dose administered after the initial dose; and a "tertiary dose" is a dose administered after the secondary dose. The initial dose, secondary dose, and tertiary dose may all contain the same amount of a compound described herein, but may differ from each other, typically in terms of frequency of administration. In some embodiments, the amount of compound contained in the initial dose, secondary dose, and / or tertiary dose varies from each other during the course of treatment (e.g., adjusted upward or downward as needed). In some embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered as "loading doses" at the beginning of a treatment regimen, followed by subsequent doses (e.g., "maintenance doses") administered at a less frequent frequency.

[0212] In certain exemplary embodiments of the present disclosure, each secondary and / or tertiary dose is administered 1 to 26 weeks (e.g., 1, 1 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, 4 1 / 2, 5, 5 1 / 2, 6, 6 1 / 2, 7, 7 1 / 2, 8, 8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2, 13, 13 1 / 2, 14, 14 1 / 2, 15, 15 1 / 2, 16, 16 1 / 2, 17, 17 1 / 2, 18, 18 1 / 2, 19, 19 1 / 2, 20, 20 1 / 2, 21, 21 1 / 2, 22, 22 1 / 2, 23, 23 1 / 2, 24, 24 1 / 2, 25, 251 / 2, 26, 26 1 / 2 weeks, or longer). As used herein, the phrase "immediately preceding dose" refers to the dose of a compound administered to a patient prior to the administration of the very next dose in a series of multiple doses, in a sequence with no intervening doses.

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

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

[0215] The present disclosure includes dosing regimens in which two to six loading doses are administered to a patient at a first frequency (e.g., once weekly, once every two weeks, once every three weeks, once monthly, once every two months, etc.), followed by two or more maintenance doses administered to the patient at a less frequent frequency. For example, according to this aspect of the disclosure, if the loading dose is administered monthly, the maintenance doses may be administered to the patient once every six weeks, once every two months, once every three months, etc.

[0216] The present disclosure includes pharmaceutical compositions of the compounds and / or conjugates described herein, e.g., compounds of Formula I, Ia, Ib, A, Aa, or Ab, e.g., compositions comprising the compounds described herein, their salts, stereoisomers, polymorphs, and pharmaceutically acceptable carriers, diluents, and / or excipients. Examples of suitable carriers, diluents, and excipients include, but are not limited to, buffers for maintaining an appropriate composition pH (e.g., citrate buffer, succinate buffer, acetate buffer, phosphate buffer, lactate buffer, oxalate buffer, etc.), carrier proteins (e.g., human serum albumin), saline, polyols (e.g., trehalose, sucrose, xylitol, sorbitol, etc.), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxolates, etc.), antimicrobial agents, and antioxidants.

[0217] In some instances, provided herein are methods for treating a disease, disorder, or condition, comprising administering to a patient having the disorder a therapeutically effective amount of a compound of Formula I, Ia, Ib, A, Aa, or Ab, or a pharmaceutical composition thereof.

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

[0219] In some instances, provided herein are methods for treating or preventing any disease, disorder, or condition responsive to modulation of LXR signaling. In some instances, the disease or disorder is associated with LXR function, LXR polymorphisms, LXR agonist activity, or LXR antagonist activity. In some instances, provided herein are methods for treating or preventing a disease, disorder, or condition selected from the group consisting of a proliferative disorder, a neurodegenerative disorder, an immunological disorder, an autoimmune disease, an inflammatory disorder, a skin disorder, a metabolic disorder, a cardiovascular disease, and a gastrointestinal disorder.

[0220] The proliferative disorder can be any proliferative disorder known to those of skill in the art. In certain embodiments, the proliferative disorder includes, but is not limited to, an oncology disorder, wherein the oncology disorder can be any cancer disorder known to those of skill in the art. In certain embodiments, provided herein is a method of treating or preventing melanoma. In certain embodiments, provided herein is a method of treating or preventing metastatic melanoma. In certain embodiments, provided herein is a method of treating or preventing lung cancer. In certain embodiments, provided herein is a method of treating or preventing EGFR-tyrosine kinase inhibitor-resistant lung cancer. In certain embodiments, provided herein is a method of treating or preventing oral cancer. In certain embodiments, provided herein is a method of treating or preventing oral squamous cell carcinoma. In certain embodiments, provided herein is a method of treating or preventing prostate cancer. In certain embodiments, provided herein is a method of treating or preventing Hodgkin's lymphoma. In certain embodiments, provided herein is a method of treating or preventing breast cancer.

[0221] The neurodegenerative disorder can be any neurodegenerative disorder known to one of skill in the art. In certain embodiments, provided herein is a method of treating or preventing Alzheimer's disease. In certain embodiments, provided herein is a method of treating or preventing Parkinson's disease. In certain embodiments, provided herein is a method of treating or preventing Huntington's disease. In certain embodiments, provided herein is a method of treating or preventing amyotrophic lateral sclerosis. In certain embodiments, provided herein is a method of treating or preventing myelin gene expression. In certain embodiments, provided herein is a method of treating or preventing a disease, disorder, or disorder of myelination and remyelination.

[0222] The immunological disorder can be any immunological disorder known to those skilled in the art. In certain embodiments, provided herein is a method for treating or preventing inflammatory bowel disease. In certain embodiments, provided herein is a method for treating or preventing ulcerative colitis. In certain embodiments, provided herein is a method for treating or preventing Crohn's disease.

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

[0224] The metabolic disease can be any metabolic disease known to those skilled in the art. In some embodiments, the metabolic disease is dyslipidemia. The dyslipidemia can be any dyslipidemia known to those skilled in the art. In some embodiments, the dyslipidemia is selected from the group consisting of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipoproteinemia, HDL deficiency, ApoA-I deficiency, and cardiovascular disease, for example, coronary artery disease (including, for example, the treatment and prevention of angina pectoris, myocardial infarction, and sudden cardiac death); atherosclerosis (including, for example, the treatment and prevention of atherosclerotic plaques resulting from medical procedures such as balloon angioplasty). In some embodiments, provided herein is a method for treating or preventing diabetes.

[0225] The cardiovascular disease can be any cardiovascular disease known to those skilled in the art. In certain embodiments, provided herein is a method for treating or preventing atherosclerosis. In certain embodiments, provided herein is a method for treating or preventing atherosclerosis resulting from abnormal macrophage processing. In certain embodiments, provided herein is a method for treating or preventing atherosclerosis resulting from the formation of oxidized low-density lipoprotein (oxLDL) when macrophages are unable to process oxLDL. In certain embodiments, provided herein is a method for treating or preventing ischemic heart disease. In certain embodiments, provided herein is a method for treating or preventing stroke. In certain embodiments, provided herein is a method for treating or preventing hypertensive heart disease. In certain embodiments, provided herein is a method for treating or preventing aortic aneurysm. In certain embodiments, provided herein is a method for treating or preventing endocarditis. In certain embodiments, provided herein is a method for treating or preventing peripheral arterial disease. In certain embodiments, provided herein is a method of treating or preventing any combination of the diseases provided in this paragraph.

[0226] In some instances, provided herein are methods of modulating the function of a nuclear receptor, where the function can be selected from, by way of non-limiting example, expression / secretion of inflammatory mediators (e.g., cytokines, chemokines), cholesterol regulation, cholesterol uptake, cholesterol efflux, cholesterol oxidation, migration, chemotaxis, apoptosis and necrosis, inflammatory activity, lipid regulation, 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 comprising administering the bis-octahydrophenanthrenecarboxamides and conjugates.

[0228] In some instances, the compound of formula (I) is a compound identified in Table 1. Table 1. List of payloads [Table 1] TIFF0007728636000275.tif249170TIFF0007728636000276.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, but are not limited to, those listed in Table 2 below. Table 2. Linker-payload list [Table 2] TIFF0007728636000281.tif209170TIFF0007728636000282.tif207170TIFF0007728636000283.tif230170TIFF0007728636000284.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, such as Sinopharm Chemical Reagent Co. (SCRC), Sigma-Aldrich, Alfa, or other suppliers.

[0233] 1 H NMR and other NMR spectra were recorded on a Bruker AVIII 400 or Bruker AVIII 500. Data were processed with Nuts or MestReNova software, and proton shifts were measured in parts per million (ppm) downfield from the internal 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 phases: 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 × 50 mm, 3.5 μm; column temperature: 50 °C; detectors: analog-to-digital converter (ADC), evaporative light scattering detector (ELSD), diode array detector (DAD) (214 nm and 254 nm), electrospray ionization-ambient ionization (ES-API).

[0236] Method B for HPLC-MS determination included the following mobile phases: A: water (10 mM NH4HCO3), B: acetonitrile; gradient phase: 5% to 95% B within 15 min; flow rate: 1.0 mL / min; column: XBridge C18, 4.6 × 50 mm, 3.5 μm; column temperature: 50 °C; detector: ADC ELSD, DAD (214 nm and 254 nm), mass selective detector (MSD) (ES-API).

[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 included the following equipment: WATERS 2767; Column: Two connected in series, Shimadzu Shim-Pack, PRC-ODS, 20 × 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: 1.8-2.3 mL / min; Column: SunFire C18, 4.6 × 50 mm, 3.5 μm; Column temperature: 50 °C; Detector: ADC ELSD, DAD (214 nm and 254 nm), ES-API.

[0239] Method B for LC-MS measurement included: equipment: Gilson GX-281; ​​column: Xbridge Prep C18 10 μm OBD, 19 × 250 mm; mobile phase: A: water (10 mM NH4HCO3), B: acetonitrile; gradient phase: 5% to 95% B within 3 min; flow rate: 1.8–2.3 mL / min; column: XBridge C18, 4.6 × 50 mm, 3.5 μm; column temperature: 50 °C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), MSD (ES-API).

[0240] Preparative high-pressure liquid chromatography (prep-HPLC) with acidic or basic solvent systems was performed on a Gilson GX-281 instrument. For the acidic solvent system, a Waters SunFire 10 μm C18 column (100 Å, 250 × 19 mm) was used; solvent A for preparative HPLC was water / 0.05% TFA, and solvent B was acetonitrile. The elution conditions were a linear gradient increase 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 mm) was used; solvent A for preparative HPLC was water / 10 mM ammonium bicarbonate (NH4HCO3), and solvent B was acetonitrile. The elution conditions were a linear gradient increase of solvent B from 5% to 100% over 20 min at a flow rate of 30 mL / min.

[0241] Flash chromatography was performed on a Biotage instrument using Agela flash column silica-CS cartridges; reversed-phase flash chromatography was performed on a Biotage instrument using Boston ODS or Agela C18 cartridges.

[0242] As used herein, the symbols and conventions used in these processes, schemes, and examples are consistent with those used in modern scientific literature, e.g., the Journal of the American Chemical Society or the Journal of Biological Chemistry, regardless of whether a particular abbreviation is specifically defined. Specifically, but not limited to, the following abbreviations may be used in the examples and throughout this specification: [Table 3] TIFF0007728636000286.tif245170TIFF0007728636000287.tif247170TIFF0007728636000288.tif110170

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

[0244] In Figure 1, the starting material, podocarpic acid 1, was originally discovered in plant resins in 1873 and later reported from several species of the genus Podocarpus (see, e.g., J. Chem. Soc. 1938, 1006-1013). The synthesis of compound 4 from podocarpic acid 1 has been previously reported (see, e.g., 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; activated ester 6b was prepared from the treatment of 4 with 5. Symmetrical imides 8a were synthesized from the treatment of amide 7a with acid chloride 6a or activated ester 6b, followed by hydrogenation-mediated debenzylation to give imide 9a. Similarly, unsymmetrical imides 8b–e and 8g were synthesized by coupling reactions of amides 7b–g with activated ester 6b or acid chloride 6a. The yields of unsymmetrical imides 8b–e and 8g from 6a were lower than those of symmetrical imide 8a, but the yields of 8b–e and 8g using activated ester 6b increased from 40% to 50–85%.

[0245] Imides 9a–e were obtained from 8a–e by deprotection of the corresponding protecting groups—Bn in 8a, TBS in 8b, or Boc in 8c, 8d, and 8e, respectively. The N,N-dimethylated analog 9f was obtained by hydrogenation of 8d in methanol, which simultaneously removed the benzyl group and N,N-dimethylated the aniline nitrogen; the N-Boc analog 9g was obtained by debenzylation of 8d. Compounds 9h–o were obtained by amide coupling reaction of 9d with amino acid derivatives in the presence of HATU and DIPEA, followed by deprotection of the Boc group with 10–25% TFA in DCM or deprotection of the Fmoc group with 20% piperidine in organic solvents. Amide coupling reaction of 9d with Fmoc-Gly-OH followed by Fmoc deprotection gave 9h; amide coupling reaction of 9d with Boc-β-Ala-OH followed by Boc deprotection gave 9i; amide coupling reaction of 9d with Boc-Ser-OH followed by Boc deprotection gave 9j; amide coupling reaction of 9d with Boc-Sar-OH followed by Boc deprotection gave 9k; amide coupling reaction of 9d with Boc-Lys(Boc)-OH followed by Boc deprotection gave 9l; amide coupling reaction of 9d with Boc-His-OH followed by Boc deprotection gave 9m; amide coupling reaction of 9d with Boc-Asp-OtBu followed by Boc and -OtBu deprotection gave 9n in one pot; The amide coupling reaction of 9d with Boc-Glu-OtBu, followed by deprotection of the Boc and -OtBu, afforded 9o in one pot. Compound 9p was synthesized from the amide coupling reaction of 7g with 6b in the presence of LiHMDS to form 8g, followed by Raney nickel-catalyzed reduction of the nitrile to an amine and debenzylation with boron tribromide (BBr). Compound 9q was obtained from the amide coupling reaction of 9d with glutaric anhydride. Compound 9r was obtained from the amide coupling reaction of 9d with Boc-iminodiacetic acid, followed by Boc deprotection.Compound 9t was obtained from the amide coupling reaction of 7d with the activated ester of dehydroabietic acid (Cas no. 1740-19-8) 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-octahydrophenanthrene-1-carboxylate (P1-2) [ka] To a solution of podocarpic acid (P1-1, 90 g, 0.33 mol) in methanol (200 mL) and toluene (600 mL) was added (trimethylsilyl)diazomethane (2 M in hexane, 200 mL). The reaction mixture was stirred at room temperature for 2 hours, after which time LCMS showed complete consumption of podocarpic acid. The volatiles were removed in vacuo, and the residue was triturated from petroleum ether (2 L) to give compound P1-2 (91 g, 96% yield) as a white solid. ESI m / z: 289 (M+H) + . [ka]

[0247] Methyl (1S,4aS,10aR)-1,4a-dimethyl-6-(trifluoromethanesulfonyloxy)-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (P1-3) [ka] To a solution of compound P1-2 (10 g, 35 mmol) in methylene chloride (200 mL) was added pyridine (3.3 g, 42 mmol) and DMAP (0.84 g, 6.9 mmol) under a nitrogen atmosphere. The mixture was cooled to −78° C. and trifluoromethanesulfonic anhydride (12 g, 42 mmol) was added. The resulting mixture was allowed to warm to 25° C. and stirred at 25° C. for an additional 4 h. The reaction mixture was diluted with DCM (500 mL), washed with water (100 mL), aqueous hydrochloric acid (1 N, 150 mL), and brine (100 mL), dried over sodium sulfate, and concentrated in vacuo to give crude compound P1-3 (14 g, 97% crude yield) as a viscous oil, which was sufficiently pure for the next step. The crude compound P1-3 was purified by flash chromatography (0-10% ethyl acetate in petroleum ether) to give 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] To a solution of compound P1-3 (14 g, 34 mmol) and tert-butyl carbamate (BocNH2, 7.9 g, 68 mmol) in tert-butanol (100 mL) was added cesium carbonate (22 g, 68 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 1.8 g, 2.0 mmol), and X-Phos (1.8 g, 4.0 mmol) sequentially at room temperature. The mixture was degassed and purged with argon three times and then stirred overnight at 80 °C under argon (balloon) until compound P1-3 was completely consumed, as monitored by TLC. 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 purified by silica gel column chromatography (0-6.25% ethyl acetate in petroleum ether) to give compound P1-4 (11 g, 82% yield) 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,9,10,10a-octahydrophenanthrene-1-carboxylic acid (P1-5) [ka] To a solution of compound P1-4 (4.9 g, 13 mmol) in DMSO was added potassium tert-butoxide (15 g, 0.13 mol) in one portion at room temperature. The reaction mixture was stirred under argon at 60 °C for 3 h until the reaction was complete by LCMS. After cooling to room temperature, the reaction mixture was poured into ice and slowly acidified to pH 5 with aqueous hydrochloric acid (0.5 M), while the temperature did not exceed 25 °C. The precipitate was collected by filtration and washed several times with water. The crude product was further purified by silica gel column chromatography (0-20% ethyl acetate in petroleum ether) to give compound P1-5 (4.5 g, 93% yield) as a white 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-octahydrophenanthrene-3-yl]carbamate (P1-6) [ka] To a solution of P1-5 (4.5 g, 12 mmol) and HATU (4.9 g, 13 mmol) in DMF (50 mL) was added diisopropylethylamine (20 mL, 0.12 mol), and the mixture was stirred at 25 °C for 1 hour. Ammonium chloride (16 g, 0.30 mol) was then added to the mixture, and the mixture was stirred at room temperature overnight. The resulting mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (0-20% ethyl acetate in petroleum ether) to give compound P1-6 (4.2 g, 94% yield) as a white solid. ESI m / z: 373.3 (M+1) + . [ka]

[0251] Methyl (1S,4aS,10aR)-6-(benzyloxy)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-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 stirred at 20-25° C. for 15 minutes. To the mixture, benzyl bromide (7.1 mL, 60 mmol) was added 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 give the title compound P1-8 (13 g, 89% yield) as a white solid. ESI m / z: 379 (M+H) + . [ka]

[0252] (1S,4aS,10aR)-6-(benzyloxy)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylic acid (P1-9) [ka] A mixture of compound P1-8 (11 g, 29 mmol) and potassium tert-butoxide (33 g, 0.29 mol) in DMSO (0.19 L) was stirred at 100 °C for 1 h until the methyl group was completely removed, as monitored by LCMS and TLC. After cooling to 25 °C, the mixture was quenched with aqueous hydrochloric acid (1 N) and extracted with ethyl acetate. The combined organic solution was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-24% ethyl acetate in petroleum ether) to give 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] To a solution of P1-9 (9.6 g, 26 mmol) in DMF (100 mL) were added DIPEA (14 mL, 79 mmol) and perfluorophenyl 2,2,2-trifluoroacetate (15 g, 53 mmol). The mixture was stirred at room temperature overnight and monitored by LCMS. The reaction mixture was then diluted with ether (200 mL) and washed with water (300 mL) and brine (200 mL). The organic solution was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (0-10% ethyl acetate in petroleum ether) to give compound P1-10 (12 g, 88% yield) as a white solid. ESI 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)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]carbamate (P1-11) [ka] To a solution of compound P1-6 (2.3 g, 6.2 mmol) in THF (20 mL), n-BuLi (2.5 M in hexane, 5.5 mL, 14 mmol) was added dropwise at -78 °C. The reaction was stirred at this temperature for 1 h. To the mixture, a solution of P1-10 (3.0 g, 5.6 mmol) in THF (20 mL) was added, and the resulting mixture was then stirred overnight at 10-20 °C until compound P1-10 was consumed, as monitored by LCMS. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic solution was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (0-30% ethyl acetate in petroleum ether) to give compound P1-11 (1.59 g, 51% yield) 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]formamido}carbonyl)-4b,8-dimethyl-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, purged with hydrogen, and stirred overnight at room temperature under a hydrogen balloon until P1-11 was completely consumed, 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 (0-55% ethyl acetate in petroleum ether) to give P1-12 (1.06 g, 61% yield) 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-octahydrophenanthrene-1-carbonyl]-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-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. The reaction mixture was stirred at room temperature for 1 hour until Boc was removed by LCMS. The volatiles were removed in vacuo, and the residue was purified by preparative HPLC (Method B) to give 9d (0.10 g, 70% yield) as a white solid.

[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% (in columns AD, AS, OD, and OJ).

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

[0263] Example 1b LP8 (Figure 1b) Synthesis of 1S,4aS,10aR)-6-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)-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-1-carboxamide (LP1-2) [ka] To a solution of 9d (53 mg, 0.10 mmol) in DMF (1 mL) were added Fmoc-Val-Ala-OH (41 mg, 0.10 mmol), HATU (38 mg, 0.1 mmol), and diisopropylethylamine (26 mg, 0.20 mmol) sequentially. After stirring at 25 °C for 24 h until 9d was consumed by LCMS, piperidine (0.1 mL) was added to the mixture, and the resulting solution was stirred at 25 °C for an additional 3 h. After filtration, the filtrate was directly purified by preparative HPLC (Method B) to give compound LP1-2 (45 mg, 64% yield) as a white solid. ESI 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,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-1-carboxamide (LP1-4) [ka] To a solution of compound LP1-3 (35 mg, 0.064 mmol) in DMF (1 mL) were added HATU (24 mg, 0.064 mmol) and compound LP1-2 (45 mg, 0.064 mmol) sequentially at room temperature. The mixture was stirred at room temperature for several minutes until it became homogeneous. Diisopropylethylamine (41 mg, 0.32 mmol) was added to the mixture via syringe at room temperature. The resulting mixture was stirred overnight (16 h) at room temperature until LP1-2 was almost consumed by LCMS. Then, piperidine (0.1 mL, excess) was added dropwise to the reaction mixture at room temperature, and the mixture was stirred for an additional 3 h until Fmoc was removed as monitored by LCMS. The reaction mixture was directly purified by reverse-phase flash chromatography or preparative HPLC (Method B, basic conditions) to give 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(hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29-dodecaoxaheptacyclo[26.2.2.2 3,6 .2 8,11 .2 13,16 .2 18,21 .2 23,26 ]dotetracontan-5-yl]methyl}-1H,4H,5H,6H,7H,8H,9H-cycloocta[d][1,2,3]triazol-4-yl)oxy]acetamido}hexanamido]-3-methylbutanamido]propanamido]-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-octahydrophenanthrene-1-carboxamide (LP1-5) [ka] To a solution of compound LP1-4 (30 mg, 30 μmol) in DMF (0.5 mL) was added a solution of CD-N3 (60 mg, 60 μmol) in DMF (0.5 mL) via syringe at room temperature. The mixture was stirred at 20-25 °C for 3 days. LCMS showed that compound LP1-4 was almost consumed. The reaction mixture was directly purified by preparative HPLC (Method B) to give compound LP1-5 (14 mg, 23% yield) 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-hexaen-10-yn-2-yl}-4-oxobutanamido)-N-[(1R)-1-{[(1S)-1-{[(1S)-1-{[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl]formamido}carbonyl)-4b,8-dimethyl-4b,5,6 ,7,8,8a,9,10-Octahydrophenanthrene-3-yl]carbamoyl}ethyl]carbamoyl}-2-methylpropyl]carbamoyl}-5-{2-[(1-{[31,32,33,34,35,36,37,38,39,40,41,42-dodecahydroxy-10,15,20,25,30-pentakis(hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29-dodecaoxaheptacyclo[26.2.2.2 3,6 .2 8,11 .2 13,16 .2 18,21 .2 23,26 ]dotetracontan-5-yl]methyl}-1H,4H,5H,6H,7H,8H,9H-cycloocta[d][1,2,3]triazol-4-yl)oxy]acetamido}pentyl]-3,6,9,12-tetraoxapentadecan-15-amide (LP8) [ka] To a solution of compound LP1-5 (14 mg, 7.4 μmol) and DIBAC-Suc-PEG4-OSu (6.5 mg, 10 μmol) in DMF (1 mL) was added triethylamine (2.0 mg, 20 μmol), and the mixture was stirred at 20-25 °C for 16 h. Most of the volatiles were removed in vacuo, and the residue was purified by preparative HPLC (Method B) to give compound LP8 (5.0 mg, 27% yield) 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-10,15,20,25,30,35,40-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,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-octahydrophenanthrene-1-yl]carbonyl}-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide (LP2-5) [ka] To a solution of compound LP1-4 (30 mg, 0.030 mmol) in DMF (2 mL) was added γCD-N3 (0.12 mg, 0.091 mmol). The mixture was stirred at RT for 16 hours and monitored by LCMS. The mixture was filtered through a membrane, and the filtrate was then purified by preparative HPLC (Method A) to give compound LP2-5 (40 mg, 57% yield) 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-hexaen-10-yn-2-yl}-4-oxobutanamido)-N-[(1R)-1-{[(1S)-1-{[(1S)-1-{[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl]formamido}carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahy 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56-hexadecahydroxy-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,7H,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) was added HATU (3.0 mg, 7.8 μmol). After stirring the mixture at 10° C. for 10 minutes, compound LP2-5 (15 mg, 6.5 μmol) and DIPEA (1.7 mg, 13 μmol) were added. The mixture was stirred at RT for 2 hours until LP2-5 was completely consumed, as monitored by LCMS. The mixture was filtered through a membrane, and the filtrate was purified by preparative HPLC (Method B) to give compound LP32 (6.0 mg, 32% yield) as a white solid. ESI m / z: 1424.2 (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)-2,4,7,9,12,14,17,19,22,24,27,29-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]-5-(carbamoylamino)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-octahydrophenanthren-1-yl]formamido}carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthren-3-yl]carbamoyl}-2-hydroxyethyl]carbamate (LP5-1) [ka] To a solution of compound LP15 (20 mg, 15 μmol) in DMF (1 mL) was added a solution of CD-N3 (46 mg, 45 μmol) in acetonitrile (2 mL) and water (2 mL) at RT. The mixture was stirred at 30° C. for 16 h. LCMS showed that compound LP15 was almost consumed. The reaction mixture was directly purified by preparative HPLC (Method B) to give 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-oxobutanamide)-3,6,9,12-tetraoxapentadecan-15-amido]-6-{2-[(1-{[31,32,33,34,35,36,37,38,39,40,41,42-dodecahydroxy-10,15,20,25,30-pentakis(hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29-dodecaoxaheptacyclo[26.2.2.2 3,6 .2 8,11 .2 13,16 .218,21 .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]-5-(carbamoylamino)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-octahydrophenanthren-1-yl]formamido}carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthren-3-yl]carbamoyl}-2-hydroxyethyl]carbamate (LP13) [ka] To a solution of DIBAC-PEG4-acid LP5-2 (4.3 mg, 7.8 μmol) in DMF (1 mL) was added HATU (3.0 mg, 3.6 μmol) and DIPEA (1.7 mg, 13 μmol) at RT. The resulting mixture was stirred at RT for 10 min. Then, LP5-1 (15 mg, 6.5 μmol) was added to the mixture. The reaction mixture was stirred at 30° C. for 2 h until the reaction was complete, as monitored by LCMS. The reaction mixture was filtered and purified by preparative HPLC (Method B) to give 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] To a solution of azido-PEG4-NHS (L6-1, 0.10 g, 0.26 mmol) in anhydrous DMF (4 mL), taurine (39 mg, 0.31 mmol) and DIPEA (15 mg, 0.52 mmol) were added. The mixture was stirred at 25 °C overnight. The mixture was filtered, and the filtrate was purified by preparative HPLC (Method A) to give compound LP6-2 (80 mg, 78% yield) as a colorless 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-octahydrophenanthrene-1-yl]formamide}carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3- yl]carbamoyl}-2-hydroxyethyl]carbamoyl}oxy)methyl]phenyl}carbamoyl)-4-(carbamoylamino)butyl]carbamoyl}-2-methylpropyl]carbamoyl}pentyl]carbamoyl}methoxy)-1H,4H,5H,6H,7H,8H,9H-cycloocta[d][1,2,3]triazol-1-yl]-3,6,9,12-tetraoxapentadecane-15-amido}ethane-1-sulfonic acid (LP6-3) [ka] To a solution of compound LP6-2 (20 mg, 50 μmol) in water (1 mL) was added saturated aqueous sodium bicarbonate solution dropwise at 0° C. until the pH was ∼7. Then, to the stirred solution, a solution of compound LP15 (28 mg, 21 μmol) in acetontrile (1 mL) was added via syringe. The mixture was stirred overnight at 25° C. The reaction mixture was monitored by LCMS until compound LP15 was completely consumed. The reaction mixture was filtered and purified by preparative HPLC (Method A) to give compound LP6-3 (15 mg, 41% yield) as a white 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-tetraoxapentadecan-15-amido]-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-octahydrophenanthren-1-yl]formamido}carbonyl)-4b,8-dimethyl-4 b,5,6,7,8,8a,9,10-Octahydrophenanthrene-3-yl]carbamoyl}-2-hydroxyethyl]carbamoyl}oxy)methyl]phenyl}carbamoyl)-4-(carbamoylamino)butyl]carbamoyl}-2-methylpropyl]carbamoyl}pentyl]carbamoyl}methoxy)-1H,4H,5H,6H,7H,8H,9H-cycloocta[d][1,2,3]triazol-1-yl]-3,6,9,12-tetraoxapentadecane-15-amido}ethane-1-sulfonic acid (LP36) [ka] To a solution of compound LP6-3 (15 mg, 8.8 μmol) and commercially available DIBAC-Suc-PEG4-OSu LP6-4 (5.7 mg, 8.8 μmol, CAS 1427004-19-0) in DMF (1 mL) was added DIPEA (2.3 mg, 18 μmol), and the mixture was stirred at RT for 2 h. Most of the volatiles were removed in vacuo, and the residue was purified by preparative HPLC (Method B) to give 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] To a solution of azido-PEG4-NHS (L18-1, 0.10 g, 0.26 mmol) in anhydrous DMF (4 mL), taurine (39 mg, 0.31 mmol) and DIPEA (15 mg, 0.52 mmol) were added. The mixture was stirred at 25 °C overnight. The mixture was filtered, and the filtrate was purified by preparative HPLC (Method A) to give compound LP18-2 (80 mg, 78% yield) 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-carbonylcarbamoyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3 -ylamino)-1-oxopropan-2-ylamino)-3-methyl-1-oxobutan-2-ylamino)-6-oxohexylamino)-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-18-sulfonic acid (LP18-3) [ka] To a solution of compound LP1-4 (40 mg, 40 μmol) in DMF (1 mL) was added azide LP18-2 (40 mg, 0.10 mmol) at RT. The reaction was stirred at RT for 16 h until completion was indicated by LCMS. The reaction 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-tetraoxapentadecan-15-amido]-5-{[(1S)-1-{[(1S)-1-{[(4bS,8S,8aR)-8-({[(1S,4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl]formamide}carbonyl)-4b,8-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]triazol-1-yl]-3,6,9,12-tetraoxapentadecane-15-amido}ethane-1-sulfonic acid (LP18) [ka] To a solution of compound LP18-3 (30 mg, 22 μmol) in DMF (1 mL) was added a solution of DIBAC-suc-PEG-OSu (LP18-4, 14 mg, 22 μmol) in DMF (1 mL) and DIPEA (4 mg, 32 μmol) sequentially at RT. The reaction mixture was stirred at RT for 2 h. The reaction mixture was directly purified by preparative HPLC (Method B) to give compound LP18 (15 mg, 37% yield) 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-hydroxypropanamido)-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-1-carboxamide (9j) [ka] To a solution of Fmoc-Ser-OH (33 mg, 0.1 mmol) in DMF (1 mL) was added HATU (38 mg, 0.1 mmol) and DIPEA (39 mg, 0.3 mmol) at 25° C. The resulting mixture was stirred at this temperature for 1 h. Then, 9d (30 mg, 0.06 mmol) was added to the mixture. The reaction mixture was stirred at 25° C. for 16 h. After 9d was completely consumed (as monitored by LCMS), piperidine (0.2 mL) was added to the mixture, which was stirred at room temperature for another 30 min. The residue was directly purified by preparative HPLC (Method B) to give 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-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]carbamoyl}butanoic acid; Trifluoroacetate (9o) [ka] To a solution of OtBu-N-Boc-Glu-OH (15 mg, 0.05 mmol) in DMF (1 mL) was added HATU (19 mg, 0.05 mmol) and DIPEA (13 mg, 0.1 mmol) at 25° C. The resulting mixture was stirred at this temperature for 1 h. 9d (14 mg, 0.026 mmol) was then added to the mixture. After stirring at 25° C. for 16 h and complete consumption of 9d (as monitored by LCMS), the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic solution was dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in DCM (1 mL), and TFA (0.1 mL) was slowly added to the solution at room temperature. The mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo, and the residue was purified by preparative HPLC (Method A) to give 9o (8 mg, 46% yield) 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-octahydrophenanthrene-1-carbonyl]-6-[(2S)-2,6-diaminohexanamido]-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide; Trifluoroacetate (9l) [ka] To a solution of Boc-Lys-OH (15 mg, 0.05 mmol) in DMF (1 mL) was added HATU (19 mg, 0.05 mmol) and DIPEA (13 mg, 0.1 mmol) at 25° C. The resulting mixture was stirred at this temperature for 1 h. Then, 9d (15 mg, 0.028 mmol) was added to the mixture. After stirring at 25° C. for 16 h and complete consumption of 9d (as monitored by LCMS), the reaction mixture was diluted with ethyl acetate and washed with 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 slowly added to the solution at room temperature. The mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo, and the residue was purified by preparative HPLC (Method A) to give 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)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-octahydrophenanthren-1-yl]formamido}carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthren-3-yl]carbamoyl}-2-hydroxyethyl]carbamate (LP4-2) [ka] To a solution of Fmoc-vc-PAB-PNP (LP4-1, 58 mg, 76 μmol) and 9j (36 mg, 58 μmol) in DMF (3 mL), HOBt (7.9 mg, 58 μmol) and DIPEA (15 mg, 0.12 mmol) were added, and the mixture was stirred at 30 °C for 16 h. After that, compound 9j was completely consumed by LCMS. To the resulting mixture, diethylamine (0.1 mL) was added, and the reaction was stirred at RT for 1 h until Fmoc was removed, as monitored by LCMS. After filtering the reaction, the filtrate was directly purified by preparative HPLC (Method B) to give compound LP4-2 (36 mg, 48% yield) 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)acetamido]hexanamido]-3-methylbutanamido]-5-(carbamoylamino)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-octahydrophenanthren-1-yl]formamido}carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthren-3-yl]carbamoyl}-2-hydroxyethyl]carbamate (LP15) [ka] To a solution of compound LP4-3 (24 mg, 44 μmol) in DMF (2 mL) were added HATU (17 mg, 44 μmol) and compound LP4-2 (35 mg, 34 μmol) sequentially at RT. The mixture was stirred at RT for several minutes until it became homogeneous. DIPEA (8.8 mg, 68 μmol) was added to the mixture via syringe at RT. The resulting mixture was stirred at RT for 2 hours until LP4-2 was almost consumed by LCMS. Diethylamine or piperidine (0.1 mL, excess) was then added dropwise to the reaction mixture at RT, and the mixture was stirred for 1 hour until the Fmoc group was removed as monitored by LCMS (Note: both diethylamine and piperidine were effective). The reaction mixture was directly purified by preparative HPLC (Method B) to give 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) was added HATU (0.24 g, 0.64 mmol) and DIPEA (0.15 g, 1.1 mmol) at RT. The resulting mixture was stirred at RT for 3 minutes. Then, payload 9d (0.20 g, 0.38 mmol) was added to the mixture. The reaction mixture was stirred at RT for 15 minutes until the reaction was complete, as monitored by LCMS. The reaction mixture was filtered and purified by preparative HPLC (Method B) to give 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-carbonyl]carbamoyl}-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 by LCMS. Volatiles were removed in vacuo. The residue was purified by reverse-phase flash chromatography (0-100% acetonitrile in aqueous ammonium bicarbonate (10 mM)) to give compound LP11-2 (77 mg, 86% yield) as a white solid. ESI m / z: 879 (M+1) + . [ka]

[0284] {4-[(2S)-2-[(2S)-2-[1-(4-{2-azatricyclo[10.4.0.04,9 ]hexadeca-1(12),4(9),5,7,13,15-hexaen-10-yn-2-yl}-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3-methylbutanamido]-5-(carbamoylamino)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-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 (LP11-3) [ka] To a mixture of compound LP11-2 (57 mg, 65 μmol) and compound LP9-5 (0.10 g, 96 μmol) in DMF (3 mL), HOBt (30 mg, 0.22 mmol) and DIPEA (0.11 g, 0.81 mmol) were added, and the mixture was stirred at RT for 1 h, which was monitored by LCMS. The reaction mixture was purified by reverse-phase flash chromatography (0-100% acetonitrile in aqueous ammonium bicarbonate (10 mM)) to give compound LP11-3 (97 mg, 81% yield) as a white solid. ESI m / z: 909 (M / 2+1). + .

[0285] {4-[(2S)-2-[(2S)-2-[1-(4-{2-azatricyclo[10.4.0.0 4,9]hexadeca-1(12),4(9),5,7,13,15-hexaen-10-yn-2-yl}-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3-methylbutanamido]-5-(carbamoylamino)pentanamido]phenyl}methyl N-[(1S)-5-amino-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}pentyl]carbamate (LP311) [ka] To a solution of compound LP11-3 (97 mg, 53 μmol) in DMF (3 mL) was added diethylamine (45 mg, 0.62 mmol). The mixture was stirred at RT for 2 h until Fmoc was removed by LCMS. The reaction mixture was directly purified by preparative HPLC (Method B) to give compound LP311 (40 mg, 47% yield) as a white solid. ESI m / z: 798 (M / 2+1) + . [ka]

[0286] Example 1j Synthesis of LP39 (Figure 1i) 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)-N-[(1S)-1-{[(1S)-4-(carbamoylamino)-1-{[4-(hydroxymethyl)phenyl]carbamoyl}butyl]carbamoyl}-2-methylpropyl]-3,6,9,12-tetraoxapentadecan-15-amide (LP9-3) [ka] To a solution of compound LP9-2 (0.30 g, 0.54 mmol) in DMF (10 mL), HATU (0.31 g, 0.81 mmol) and DIPEA (0.14 g, 1.1 mmol) were added sequentially at room temperature. The mixture was stirred at room temperature for 15 min. VC-PAB-OH (LP9-1, CAS: 159857-79-1, 0.21 g, 0.54 mmol) was added to the reaction solution at room temperature, and the resulting mixture was stirred at room temperature for 3 h; the reaction progress was monitored by LCMS. The reaction mixture was filtered through a membrane filter, and the filtrate was directly purified by reverse flash chromatography (0–100% acetonitrile in water (containing 10 mmol / L ammonium bicarbonate)) to give compound LP9-2 (0.30 g, 60% yield) as a white solid. ESI m / z: 617 (M+H). + .

[0287] {4-[(2S)-2-[(2S)-2-[1-(4-{2-azatricyclo[10.4.0.0 4,9 ]Hexadeca-1(12),4(9),5,7,13,15-hexaen-10-yn-2-yl}-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3-methylbutanamido]-5-(carbamoylamino)pentanamido]phenyl}methyl 4-nitrophenyl carbonate (LP9-5) [ka] To a solution of compound LP9-3 (0.15 g, 0.16 mmol) in DMF (10 mL), bis(4-nitrophenyl)carbonate (LP9-4, 0.15 g, 0.49 mmol) and DIPEA (63 mg, 0.49 mmol) were added sequentially at 0 °C. The mixture was then stirred at RT for 3 h until LP9-3 was almost consumed, as monitored by LCMS. The reaction mixture was filtered through a membrane filter, and the filtrate was directly purified by reverse flash chromatography (0–100% acetonitrile in water (containing 10 mmol / L ammonium bicarbonate)) to give compound LP9-5 (50 mg, 28% yield) as a white solid. ESI m / z: 1079 (M+H). + .

[0288] (4S)-4-{[({4-[(2S)-2-[(2S)-2-[1-(4-{2-azatricyclo[10.4.0.0 4,9 ]Hexadeca-1(12),4(9),5,7,13,15-hexaen-10-yn-2-yl}-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3-methylbutanamido]-5-(carbamoylamino)pentanamido]phenyl}methoxy)carbonyl]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-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-yl]carbamoyl}butanoic acid (LP39) [ka] To a mixture of compound 9o (50 mg, 76 μmol) and compound LP9-5 (0.10 g, 96 μmol) in DMF (1 mL), HOBt (16 mg, 0.12 mmol) and DIPEA (39 mg, 0.31 mmol) were added, and the mixture was stirred at RT for 1 h, which was monitored by LCMS. The reaction mixture was purified by preparative HPLC (Method B) to give compound LP39 (40 mg, 33% yield) as a white solid. ESI m / z: 799 (M / 2+1) + . [ka]

[0289] Example 2 This example shows a general method for making key intermediates 7b-7f. The chemical synthesis for making 7b-7e is shown in FIG.

[0290] Amide 7f was prepared from the HATU-catalyzed amide coupling reaction of 1 with NH4Cl. Intermediates 7b and 7c were prepared from phenol-O-alkylation of 7f with 10b and 10c, respectively. Intermediates 7d and 7e were synthesized starting from the conversion of phenol 2 to triflate 11, which was then subjected to Buchwald coupling conditions to introduce the masked amino functionality of 12d and 12e; acidic deprotection of 12d and 12e followed by basic hydrolysis to convert the esters to acids 13d and 13e, respectively; and finally, Boc-protection of 13d and 13e gave 14d and 14e, respectively, which were further carried forward in amide coupling reactions with ammonium salts to give 7d and 7e, respectively. Intermediate 7g was prepared from the amide coupling reaction of 1 with 2,4-dimethoxybenzylamine to form 7g-1, followed by conversion to the triflate analog 7g-2 with trifluoromethanesulfonic anhydride. The cyano analog 7g-3 was prepared by removal of the 2,4-dimethoxybenzyl moiety using zinc cyanide, with final deprotection achieved with TFA.

[0291] Alternatively, 13d was prepared starting from Boc-protection of podocarpic acid 1 to form E2, followed by conversion to triflate E3. Intermediate E3 was stable to purification by normal-phase column chromatography, and further treatment with diphenylmethanimine under Buchwald conditions afforded a mixture of E4-1, E4-2, E4-3, and 13d, which was hydrolyzed in one pot in aqueous HCl in THF (v / v = 1:1) to give 13d in 28% overall yield.

[0292] Example 3 This example illustrates a method for making intermediate 7a. This example refers to compounds numbered in FIG.

[0293] (Step 1:) Preparation of (1S,4aS,10aR)-methyl-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (2)

[0294] To a solution of podocarpic acid (1, 0.20 g, 0.73 mmol) in methanol (1.4 mL) and toluene (5.2 mL) was added (trimethylsilyl)diazomethane (2 M in hexane, 0.45 mL). The reaction mixture was stirred overnight at 10–25 °C. After complete consumption of the podocarpic acid based on LC-MS, the volatiles were removed in vacuo, and the residue was purified by flash chromatography (0–35% ethyl acetate in petroleum ether) to give compound 2 (0.21 g, 98% yield) as a white solid. ESI m / z: 289 (M+H). + . [ka]

[0295] (Step 2:) Preparation of (1S,4aS,10aR)-methyl 6-(benzyloxy)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (3)

[0296] To a solution of compound 2 (0.10 g, 0.35 mmol) in DMF (1.2 mL) was added cesium carbonate (0.12 g, 0.38 mmol), and the mixture was stirred at 20-25 °C for 15 min. Benzyl bromide (88 mg, 0.52 mmol) was then added to the mixture at rt, and the resulting mixture was stirred for an additional 4 h, then poured into water and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (10-35% ethyl acetate in petroleum ether) to give compound 3 (0.13 g, 99% yield) as a white solid. ESI m / z: 379 (M+H) + . [ka]

[0297] (Step 3:) Preparation of (1S,4aS,10aR)-6-(benzyloxy)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylic acid (4)

[0298] To a mixture of compound 3 (0.10 g, 0.26 mmol) in DMSO (1.7 mL), potassium tert-butoxide (0.30 g, 2.6 mmol) was added, and the mixture was stirred at 100 °C for 2 h until the reaction was complete, as monitored by LC-MS and TLC. After cooling the reaction to 25 °C, the mixture was quenched with aqueous hydrochloride (1 N) to pH 2 and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (20-35% ethyl acetate in petroleum ether) to give compound 4 (92 mg, 95% yield) as a white solid. ESI m / z: 365 (M+H) + . [ka]

[0299] (Step 4:) Preparation of (1S,4aS,10aR)-6-(benzyloxy)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonyl chloride (6a)

[0300] To a solution of compound 4 (0.10 g, 0.27 mmol) in 1,2-dichloroethane (DCE) (2 mL) was added thionyl chloride (0.20 mL), and the reaction was then stirred for 3 hours at 90° C. After the reaction was cooled to room temperature, the volatiles were removed in vacuo and the crude product was used in the next step without further purification.

[0301] (Alternative Step 4:) Preparation of (1S,4aS,10aR)-perfluorophenyl-6-(benzyloxy)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (6b)

[0302] To a solution of 4 (0.50 g, 1.4 mmol) in DMF (5 mL), DIPEA (0.51 g, 4.1 mmol) was added, followed by perfluorophenyl 2,2,2-trifluoroacetate 5 (0.77 g, 2.7 mmol). The mixture was stirred at 25 °C overnight and then diluted with ether (80 mL). The organic mixture was washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (0–15% ethyl acetate in petroleum ether) to give ester 6b (0.46 g, 63% yield) as a white solid. [ka]

[0303] (Step 5:) Preparation of (1S,4aS,10aR)-6-(benzyloxy)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide (7a)

[0304] A solution of compound 4 (50 mg, 0.14 mmol) and HATU (57 mg, 0.15 mmol) in DMF was stirred at 25° C. for 15 min. DIPEA (89 mg, 0.69 mmol) and ammonium chloride (25 mg, 0.48 mmol) were added to the solution at 25° C., and the resulting mixture was then stirred for an additional 4 h, poured into water, and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (0-35% ethyl acetate in petroleum ether) to give 7a (48 mg, 91% yield) as a white solid. ESI m / z: 364 (M+1) + . [ka]

[0305] Example 4 This example illustrates methods for making intermediates 7b-7g. This example refers to compounds numbered in FIG.

[0306] (1S,4aS,10aR)-6-Hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide (7f)

[0307] To a solution of podocarpic acid 1 (0.30 g, 1.1 mmol) in DMF (4 mL), HATU (0.46 g, 1.2 mmol), DIPEA (0.57 g, 4.4 mmol), and ammonium chloride (0.23 g, 4.4 mmol) were added, and the solution was stirred at 10-25 °C for 16 h. The mixture was poured into water and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (0-35% ethyl acetate in petroleum ether) to give the desired compound (0.77 g, 100% yield) as an oil. ESI m / z: 274.1 (M+1) + . [ka]

[0308] (1S,4aS,10aR)-6-(2-(tert-butyldimethylsilyloxy)ethoxy)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide (7b)

[0309] To a solution of 7f (0.33 g, 0.47 mmol) in DMF (2.5 mL) were added cesium carbonate (0.60 g, 1.8 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (10b, 0.45 g, 2.1 mmol). After stirring the reaction under nitrogen for 8 h, the mixture was poured into water (30 mL) and ethyl acetate (30 mL). The organics were separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (20-35% ethyl acetate in petroleum ether) to give compound 7b (0.21 g, 87% yield). ESI m / z: 432.2 (M+1). + . [ka]

[0310] tert-Butyl 2-((4bS,8S,8aR)-8-carbamoyl-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthren-3-yloxy)ethylcarbamate (7c)

[0311] Following the procedure for making 7b, 7c (60 mg, 40% yield) as a white solid was obtained from 7f treated with 10c. ESI m / z: 360.9 (M-55). + , 438.9 (M+23) + .

[0312] tert-Butyl-(4bS,8S,8aR)-8-carbamoyl-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-3-ylcarbamate (7d)

[0313] (Step 1:) Preparation of (1S,4aS,10aR)-methyl-1,4a-dimethyl-6-(trifluoromethylsulfonyloxy)-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (11)

[0314] To a solution of compound 2 (0.33 g, 1.1 mmol) in DCM (6 mL) were added 2,6-lutidine (0.15 g, 1.4 mmol) and DMAP (28 mg, 0.23 mmol). The mixture was cooled to -78 °C, and trifluoromethanesulfonic anhydride (0.39 g, 1.4 mmol) was added. The resulting mixture was allowed to warm to 25 °C and stirred at 25 °C for an additional 4 h. The reaction mixture was diluted with ethyl acetate (50 mL), and the organics were washed with water (6 mL), aqueous hydrochloride (1N, 10 mL), and brine (10 mL), then dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (0-10% ethyl acetate in petroleum ether) to give compound 11 (0.43 g, 89% yield) as a viscous oil. ESI m / z: 421.2 (M+1). + . [ka]

[0315] (Step 2:) Preparation of (1S,4aS,10aR)-6-amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylic acid (13d)

[0316] To a mixture of cesium carbonate (0.62 g, 1.9 mmol), X-phos (50 mg, 0.11 mmol), and Pd2(dba)3 (50 mg, 55 μmol) in tert-butanol (5 mL) under an argon atmosphere, a solution of compound 11 (0.40 g, 0.95 mmol) in tert-butanol (5 mL) was added, followed by diphenylmethanimine (0.26 g, 1.4 mmol). The reaction mixture was stirred at 100 °C under argon for 30 min. After that, the reaction mixture was cooled to room temperature, diluted with DCM, and filtered through Celite to remove insoluble residues. The filtrate was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. To the residue (crude 12d), hydrochloride salt (4 N, 2 mL) in methanol was added, and the resulting solution was stirred at 25 °C for 5 h. The volatiles were removed in vacuo and the residue was...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemical 1】 (In the formula, Q 1 and Q 2 each independently represents -CH 2 - or -C(O)-; W is —N(H)— or —O—; R 1 are independently -OH or -OP(O)(OR 6 ) 2 and R 2 are independently -CH 2 NH 2 , R 3 , R 4 , R 5 , or -OR 5 and R 3 is -N(R 6 ) 2 and R 4 is -XYZ; X is selected from the group consisting of -O- and -N(H)-; Y is C 1 -C 20 Alkylene, substituted C 1 -C 20 alkylene, 1-20 membered heteroalkylene, and substituted 1-20 membered heteroalkylene, wherein the substituents are C 1 -C 20 selected from the group consisting of alkyl, halo, cyano, nitro, hydroxyl, amino, oxo, carboxyl, and 5-20 membered heteroaryl; Z is -OH and -NH 2 selected from the group consisting of: R 5 is C 1-20 Alkyl, C 3-20 Heterocycloalkyl or substituted C 3-20 heterocycloalkyl, where each heterocycloalkyl or substituted heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, or at least one primary or secondary nitrogen; Each R 6 is, in each occurrence, independently hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide, or C 1-20 is alkyl, wherein the amino acid residue or N-alkylamino acid residue includes histidine, alanine, isoleucine, arginine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, valine, ornithine, selenocysteine, serine, glycine, homoglycine or β-homoglycine, or tyrosine. wherein the peptide comprises 2 to 10 amino acid residues; 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. 2. The compound of claim 1, wherein the compound is of formula Ia: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemistry 2】 。

3. Q 1 Ga-CH 2 - and Q 2 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is -C(O)-.

4. Q 1 is -C(O)- and Q 2 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is -C(O)-.

5. Q 1 is -C(O)- and Q 2 Ga-CH 2 3. The compound of claim 1 or 2, wherein: - or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

6. 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is -O-.

7. 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is -NH-.

8. R 1 is -OH and R 2 But R 3 , R 4 , R 5 , or -OR 5 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

9. 10. The compound of claim 1, wherein the compound is of formula Ib: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemistry 3】 。

10. R 1 The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is -OH.

11. R 2 -O-(CH 2 ) n -Z, and n is an integer from 1 to 4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to any one of claims 1 to 10.

12. R 2 -N(H)C(O)-(CH 2 ) n -NH 2 and n is an integer from 1 to 4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to any one of claims 1 to 10.

13. R 2 -N(H)C(O)-(CRR) n -NH 2 where each R is hydrogen, —OH, or —CH 2 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 39, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 12

14. R 2 The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is N-piperazinyl.

15. R 2 -N(R 6 ) 2 11. The compound according to any one of claims 1 to 10, wherein:

16. R 2 The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is N-serinyl.

17. R 1 -OP(O)(OR 6 )(OH) and R 2 Ga-NH 2 10. The compound according to any one of claims 1 to 7 or 9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

18. 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of: 【Chemistry 4】 【change】 。

19. a linker-payload selected from the group consisting of: 【Chemistry 5】 【change】 【change】 【change】 。

20. A compound of formula A or a pharmaceutically acceptable salt or stereoisomer thereof: 【Chemistry 6】 (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, (CH2CH2O) 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 binder; 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.

21. 21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or 20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

22. 21. The compound of claim 20 having the formula B, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a positional isomer thereof: 【Chemistry 7】 (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).

23. The SP 1 The spacer is 【Chemistry 8】 where RG′ is the reactive group residue after reaction of the reactive group RG with the binder; 【Chemistry 9】 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 【Chemistry 10】 and SP 2 is a bond or PABC; The SP 3 The spacer is 【Chemistry 11】 where RG′ is the reactive group residue after reaction of the reactive group RG with the enhancing group EG; 【Chemistry 12】 is a bond to EG; and 【Chemistry 13】 (AA) n 23. The compound of claim 22, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is a bond to:

24. 24. The compound of any one of claims 20, 22, or 23, 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 14】 (wherein each 【Chemistry 15】 is a direct or indirect bond via a PEG spacer to the binding agent).

25. 25. The compound of claim 24, 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 16】 (In the formula, 【Chemistry 17】 is a direct or indirect bond via a PEG spacer to the binding agent).

26. 25. The compound of claim 24, 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 18】 (In the formula, 【Chemistry 19】 is a direct or indirect bond via a PEG spacer to the binding agent).

27. 24. The compound of claim 22 or 23, wherein the compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is the following compound: 【Chemistry 20】 。

28. 24. The compound of claim 22 or 23, wherein the compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is the following compound: 【Chemical 21】 。

29. 24. The compound of claim 22 or 23, wherein the compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is the following compound: 【Chemical 22】 。

30. 28. The compound of claim 27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is an antibody or an antigen-binding fragment thereof.

31. 28. The compound of claim 27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein k is an integer from 1 to 4.

32. 28. The compound of claim 27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is an antibody or antigen-binding fragment thereof that binds to HER2.

33. 28. The compound according to claim 27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is an antibody or antigen-binding fragment thereof that binds to PRLR.

34. 28. The compound of claim 27, 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.

35. 28. The compound of claim 27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is an antibody or antigen-binding fragment thereof and conjugation is via two Q295 residues.

36. 28. The compound of claim 27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is N297Q antibody or an antigen-binding fragment thereof.

37. 28. The compound of claim 27, 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.

38. 28. The compound of claim 27, 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.

39. 21. The compound of claim 20, 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: ​ 【change】 (wherein k is an integer from 1 to 4).

40. 21. The compound of claim 20, or a regioisomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, comprising a BA linked to a compound selected from the group consisting of: 【Chemistry 24】 【change】 【change】 【change】 (wherein k is an integer from 1 to 4).

41. 21. The compound of claim 20, or a regioisomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of: 【Chemistry 25】 【change】 【change】 【change】 【change】 【change】 (wherein k is an integer from 1 to 4).

42. 42. The compound of any one of claims 39 to 41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein k is 2.

43. 42. The compound according to any one of claims 39 to 41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein k is 4.

44. 42. The compound of any one of claims 39 to 41, 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.

45. The compound according to any one of claims 39 to 41, 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.

46. The compound according to any one of claims 39 to 41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is an antibody or antigen-binding fragment thereof having binding specificity for Her2 or PRLR.

47. The compound according to any one of claims 39 to 41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein BA is an antibody or an antigen-binding fragment thereof having binding specificity for MSR1.

48. 42. The compound of any one of claims 39 to 41, 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.

49. 42. The compound of any one of claims 39 to 41, 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.

50. 10. The compound of claim 1, having the structure: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemical 26】 。

51. 10. The compound of claim 1, having the structure: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemical 27】 。

52. 10. The compound of claim 1, having the structure: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemical 28】 。

53. 10. The compound of claim 1, having the structure: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemical 29】 。

54. 10. A linker-payload comprising the compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having the structure: 【Chemistry 30】 。

55. 10. A linker-payload comprising the compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having the structure: 【Chemical 31】 。

56. 10. A linker-payload comprising the compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having the structure: 【Chemical 32】 。

57. 10. A linker-payload comprising the compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having the structure: 【Chemical 33】 。

58. 21. The compound of claim 20, having the structure: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemical 34】 where BA is a binder and k is an integer from 1 to 30.

59. 21. The compound of claim 20, having the structure: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemical 35】 where BA is a binder and k is an integer from 1 to 30.

60. 21. The compound of claim 20, having the structure: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemical 36】 where BA is a binder and k is an integer from 1 to 30.

61. 21. The compound of claim 20, having the structure: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemical 37】 where BA is a binder and k is an integer from 1 to 30.

62. 21. The compound of claim 20, or a regioisomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of: 【Chemical 38】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 (wherein k is an integer from 1 to 4).

63. 21. The compound of claim 20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, comprising BA linked via a linker L to a compound of the following formula: 【Chemical Formula 39】 。

64. 21. The compound of claim 20, having the formula: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemistry 40】 。

65. 10. Use of a compound according to any one of claims 1 to 18, 20 to 53 or 58 to 63, 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.

66. 64. Use of a compound according to any one of claims 1 to 18, 20 to 53 or 58 to 63, 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.

67. 10. Use of a compound according to any one of claims 1 to 18, 20 to 53 or 58 to 63, 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.

68. 21. The compound of claim 20, 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.

69. 69. The compound of claim 68, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein said primary amine compound comprises a divalent PEG group.

70. The primary amine compound is H 2 N-(CH 2 CH 2 O) 3 -(CH 2 ) 2 -N 3 70. The compound of claim 69, wherein: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

71.

41. A compound selected from the group consisting of:

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