Bcl-xl degrader antibody conjugates and uses thereof

Abstract

The invention provides protein-degrader antibody conjugate compositions of Formula (I) comprising an antibody linked by conjugation to one or more Bcl-xL target protein binder and VHL ligand (TPI-Sp-VHL) moieties. The invention also provides TPI-Sp-VHL derivative intermediate compositions comprising a reactive functional group. Such intermediate compositions are suitable substrates for formation of the degrader antibody conjugates through a linker or linking moiety. The invention further provides methods of treating diseases and disorders such as cancer with the degrader antibody conjugates.

Description

[0001]15077.006WO2 BCL-XL DEGRADER ANTIBODY CONJUGATES AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATIONS 5 This non-provisional application claims the benefit of priority to U.S. Provisional Applications No.63 / 665,421, filed 28 June 2024, and No.63 / 696,072, filed on 18 September 2024, each of which are incorporated by reference in their entirety. FIELD OF THE INVENTION The disclosure relates generally to antibody conjugate compositions, intermediates for 10 their manufacture, and methods of their use. The compositions are useful for facilitating intracellular degradation of target proteins. BACKGROUND OF THE INVENTION The ubiquitin proteasome system can be manipulated to conduct targeted degradation of specific proteins. Promoting the targeted degradation of pathogenic proteins using small 15 molecule degraders is a new modality in the treatment of diseases, including redirecting the activity of E3 ligases such as cereblon (CRBN) or VHL. Proteolysis targeting chimera compounds called PROTAC (Sakamoto, K. M., et al. (2001) Proc. Natl. Acad. Sci. USA 98:8554–8559; Sun, X. et al. (2019) Signal Transduct. Target. Ther.4:64; Schapira, M., et al (2019) Nat. Rev. Drug Discov.18:949–963) and “molecular glue” compounds (Yang, Z., et al 20 (2021) Cell Research 31:1315–1318; Tan, X. et al. (2007) Nature 446:640–645; Han, T. et al. (2017) Science 356, eaal3755) are two modes of TPD. PROTAC comprise three parts, including a ligand for binding a target protein, another ligand for recruiting an E3 ligase, and a linker to help anchor the target protein to the E3 ubiquitin ligase to promote its ubiquitination and subsequent proteasomal degradation. Similar to PROTAC, molecular glues can also cause 25 ubiquitination and degradation of a target protein. In contrast to PROTAC, molecular glues are small molecular weight compounds that trigger a compact protein–protein interaction between a target protein and an E3 ubiquitin ligase. Molecular glues are typically smaller than PROTAC and may have better pharmacological properties, higher membrane permeability, better cellular uptake, and better penetration of the blood-brain barrier. Molecular glues promote the poly- 30 ubiquitination and proteasomal degradation of various disease-associated protein targets (Chamberlain, P., et al (2019) Drug Disc. Today: Tech.31:29-34; WO 2022 / 152821). The molecular glue molecules bind to both the E3 ligase and the target protein, thereby mediating an alteration of the ligase surface and enabling an interaction with the target protein. Examples 1 15077.006WO2 include the IMiD (immunomodulatory imide drug) class including thalidomide, lenalidomide and pomalidomide, each approved for use in treating hematological cancers. More efficient targeting strategies are still required. The Von Hippel-Lindau (VHL) protein is among the most widely recruited E3 ligases for 5 protein degradation. Many potent small-molecule VHL binders feature a (R)- hydroxyproline motif (Buckley, D. L.; et al. J. Am. Chem. Soc. (2012) 134 (10):4465−4468; Galdeano, C.; et al J. Med. Chem. (2014) 57 (20), 8657−8663; Testa, A.; et al J. Am. Chem. Soc. (2018) 140 (29), 9299−9313; Han, X.; et al J. Med. Chem. (2019) 62 (24), 11218−11231) which forms an interaction with Ser110 in the HIF1α binding site of VHL but limits passive transport 10 across the cell membrane (Klein, V. G.; et al ACS Med. Chem. Lett. (2020) 11 (9), 1732−1738; Han, X.; et al Cell Rep. Phys. Sci. (2022) 3 (10):101062; Shah, R. R.; et al Bioorg. Med. Chem. (2020) 28 (5), 115326; Diehl, C. J. et al Chem. Soc. Rev. (2022) 51 (19):8216). Protein degraders which ligand the E3 ligase in a covalent manner offer potential advantages over their reversible counterparts by transforming the ternary complex into a simple binary interaction 15 between modified E3 and the substrate The Bcl-2 family includes more than 20 members of pro-survival and pro-apoptotic proteins. Bcl-2, Bcl-xL, Mcl-1, and Bcl-W are pro-survival proteins which promote cell survival by inhibiting their pro-apoptotic counterparts. Members in the pro-survival subgroup have four BH (Bcl-2 Homology) domains (BH1～BH4), except that Mcl-1 only has BH 1, 2, 3 domains 20 (Li M. et al (2020) Pharm. Res.151:104547). Another subgroup of Bcl-2 family is pro-apoptotic proteins and can be further classified as BH domain proteins (Bax, Bak, and Bok) , which contain three BH domains (BH1～BH3) and function as effectors of apoptosis; the other is BH3- only proteins (Bad, Bid, Bim, Noxa, PUMA, Bmf, Hrk, and Bik) which are the initiators of apoptosis. Bcl-2 family members work cooperatively to govern cell fate, as in healthy condition, 25 the pro-survival members bind to Bax and Bak to restrict the oligomerization of Bax / Bak, impairing their ability to induce apoptotic pores formation and permeabilization of the outer mitochondrial membrane. BH3-only proteins, as induced transcriptionally or post- transcriptionally by apoptotic stimuli, promote apoptosis by binding competitively to pro- survival Bcl-2 family members to release Bax / Bak or by directly activating these effector 30 proteins (Hata, Engelman et al.2015) . Dysregulation of apoptosis, usually caused by the imbalance between pro-survival and pro-apoptotic proteins in the Bcl-2 family, leads to uncontrolled cell growth and tumor development. Pro-survival protein Bcl-xL (B-cell lymphoma-extra large), one of the key regulators of the intrinsic pathway, (Boise, Gonzalez-Garcia et al. (1993) Cell 74(4):597-608), shares 44% 35 homology in amino acid sequence with Bcl-2 and has a similar structural domain to Bcl-2. A 2 15077.006WO2 hydrophobic pocket formed by the BH1–BH3 domains of Bcl-xL interacts with the BH3 domain of the pro-apoptotic proteins to form a heterodimer. In addition, the BH4 domain of Bcl-xL is involved in its anti-apoptotic activity (Lewis, Hayashi et al.2014, Lee and Fairlie 2019). Since Bcl-xL is the most common Bcl-2 family member overexpressed in solid tumors, as well as in 5 some subsets of leukemia and lymphoma, it is highly desirable to develop a therapeutic strategy that can retain the benefit of targeting Bcl-xL. Given the importance of Bcl-xL in regulating apoptosis, there remains a need for therapies that inhibit Bcl-xL activity, particularly selectively, as an approach towards the treatment of diseases in which apoptosis is dysregulated via expression or over-expression of anti-apoptotic Bcl-2 family proteins, such as Bcl-xL. Targeted 10 therapeutic agents to treat hyperproliferative disorders like cancer, and other disease are of interest. SUMMARY OF THE INVENTION One aspect of the invention is a Bcl-xL degrader antibody conjugate (DAC) composition comprising a target protein binder and VHL ligand moiety (TPI-Sp-VHL) covalently attached to 15 an antibody by an antibody linker, wherein the antibody binds to a tumor-associated antigen or cell-surface receptor and the target protein binder of the TPI-Sp-VHL binds to Bcl-xL. The DAC composition has Formula I: Ab−[L−(TPI−Sp−VHL)]pI or a pharmaceutically acceptable salt thereof, 20 wherein: Ab is the antibody; L is the antibody linker; TPI-Sp-VHL is the Bcl-xL target protein binder and VHL ligand moiety wherein the target protein binder is covalently attached to the VHL ligand by a spacer unit Sp; and 25 p is an integer from 1 to 12. The VHL ligand has Formula Ia: 3 15077.006WO2 wherein the substituents are defined herein. The target protein binder TPI has Formula Id: d 5 wherein the substituents are defined herein and the asterisk * is the attachment site to the spacer unit Sp. Another aspect of the invention is a Bcl-xL TPI-Sp-VHL compound (BXV). Another aspect of the invention is a Bcl-xL TPI-Sp-VHL linker compound (BXV-L). Another aspect of the invention is the DAC composition prepared by conjugation of a 10 cysteine amino acid of an antibody with a Bcl-xL TPI-Sp-VHL linker compound (BXV-L). Another aspect of the invention is a process for preparing the DAC composition comprising reacting a cysteine amino acid of an antibody with a BXV-L compound. Another aspect of the invention is a pharmaceutical composition comprising a therapeutically effective amount of the DAC composition, and one or more pharmaceutically 15 acceptable diluent, vehicle, carrier or excipient. Another aspect of the invention is a method for treating cancer comprising administering a therapeutically effective amount of the pharmaceutical composition to a patient in need thereof, Another aspect of the invention is a use of the DAC composition in the manufacture of 20 a medicament for the treatment of cancer in a mammal. 4 15077.006WO2 Another aspect of the invention is the DAC composition for use in a method for treating cancer. DESCRIPTION OF THE DRAWINGS Figure 1 shows a plot of tumor growth inhibition over time, post-dosing by the 5 intravenous administration of HER2+ (positive) HCC1569 xenograft tumor bearing CB17 SCID mice with: (1) vehicle, (2) trastuzumab at 20 mg / kg, and an anti-HER2-Bcl-xL degrader antibody conjugate, DAC-BXV-8, at (3) 2.5 mg / kg, (4) 5 mg / kg, and (5) 10 mg / kg. Figure 2 shows a plot of body weight change post-dosing by the intravenous administration of HER2+ HCC1569 xenograft tumor bearing CB17 SCID mice with: (1) 10 vehicle, (2) trastuzumab at 20 mg / kg, and an anti-HER2-Bcl-xL degrader antibody conjugate, DAC-BXV-8, at (3) 2.5 mg / kg, (4) 5 mg / kg, and (5) 10 mg / kg. DETAILED DESCRIPTION OF THE INVENTION Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will 15 be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to 20 those described herein, which could be used in the practice of the present invention. The invention is in no way limited to the methods and materials described. DEFINITIONS The terms “antibody” or “antibody construct” refer to a polypeptide comprising an antigen binding region (including the complementarity determining region (CDRs)) from an 25 immunoglobulin gene or fragments thereof. The term “antibody” specifically encompasses monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments that exhibit the desired biological activity. An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair 30 having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa) connected by disulfide bonds. Each chain is composed of structural domains, which are referred to as immunoglobulin domains. These domains are classified into different categories by size and function, e.g., variable domains or regions on the light and heavy chains (VLand VH, 5 15077.006WO2 respectively) and constant domains or regions on the light and heavy chains (CL and CH, respectively). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids, referred to as the paratope, primarily responsible for antigen recognition, i.e., the antigen binding domain. Light chains are classified as either kappa or lambda. Heavy chains 5 are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively. IgG antibodies are large molecules of about 150 kDa composed of four peptide chains. IgG antibodies contain two identical class γ heavy chains of about 50 kDa and two identical light chains of about 25 kDa, thus a tetrameric quaternary structure. The two heavy chains are linked to each other and to a light chain each by 10 disulfide bonds. The resulting tetramer has two identical halves, which together form the Y-like shape. Each end of the fork contains an identical antigen binding domain. There are four IgG subclasses (IgG1, IgG2, IgG3, and IgG4) in humans, named in order of their abundance in serum (i.e., IgG1 is the most abundant). Typically, the antigen binding domain of an antibody will be most critical in specificity and affinity of binding to cancer cells. 15 “Bispecific” antibodies (bsAbs) are antibodies that bind two distinct epitopes to cancer (Suurs F.V. et al (2019) Pharmacology & Therapeutics 201:103-119). Bispecific antibodies may engage immune cells to destroy tumor cells, deliver TPI-Sp-VHL moieties to tumors, and / or block tumor signaling pathways. An antibody that targets a particular antigen includes a bispecific or multispecific antibody with at least one antigen binding region that targets the 20 particular antigen. In some embodiments, the targeted monoclonal antibody is a bispecific antibody with at least one antigen binding region that targets tumor cells. Such antigens include but are not limited to: mesothelin, prostate specific membrane antigen (PSMA), HER2, HER3, TROP2, CEA, CEACAM5, EGFR, 5T4, Nectin4, CCL-1, CCR7, CD19, CD20, CD22, CD30, CD33, CD70, CD79b, CD123, CDH3, B7H3, B7H4 (also known as 08E), Integrin-beta6, 25 protein tyrosine kinase 7 (PTK7), glypican-3, GPC-1, LIV-1, Folate receptor alpha, Claudin18.2, RG1, fucosyl-GMl, tissue factor (CD142), cKit (CD117), Axl, , GC-C, CTLA-4, and CD44 (WO 2017 / 196598). In some embodiments, the antibody construct is an antigen-binding antibody “fragment,” which comprises at least an antigen-binding region of an antibody, alone or with other 30 components that together constitute the antibody construct. Many different types of antibody “fragments” are known in the art, including, for instance, (i) a Fab fragment, which is a monovalent fragment consisting of the VL, VH, CL, and CH1 domains, (ii) a F(ab’)2 fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, (iii) a Fv fragment consisting of the VL and VH domains of a single arm of an 35 antibody, (iv) a Fab’ fragment, which results from breaking the disulfide bridge of an F(ab’)2 6 15077.006WO2 fragment using mild reducing conditions, (v) a disulfide-stabilized Fv fragment (dsFv), and (vi) a single chain Fv (scFv), which is a monovalent molecule consisting of the two domains of the Fv fragment (i.e., VLand VH) joined by a synthetic linker which enables the two domains to be synthesized as a single polypeptide chain. In some embodiments, the antibody construct is an 5 antibody or a fusion protein comprising (i) an antigen binding domain and (ii) an Fc domain. The antibody or antibody fragment can be part of a larger construct, for example, a conjugate or fusion construct of the antibody fragment to additional regions. For instance, in some embodiments, the antibody fragment can be fused to an Fc region as described herein. In other embodiments, the antibody fragment (e.g., a Fab or scFv) can be part of a chimeric antigen 10 receptor or chimeric T-cell receptor, for instance, by fusing to a transmembrane domain (optionally with an intervening linker or “stalk” (e.g., hinge region)) and optional intercellular signaling domain. For instance, the antibody fragment can be fused to the gamma and / or delta chains of a t-cell receptor, so as to provide a T-cell receptor like construct that binds PD-L1. In yet another embodiment, the antibody fragment is part of a bispecific T-cell engager (BiTEs) 15 comprising a CD1 or CD3 binding domain and linker. In some embodiments, the antibody construct comprises an Fc domain. In certain embodiments, the antibody construct is a fusion protein. The antigen binding domain can be a single-chain variable region fragment (scFv). A single-chain variable region fragment (scFv), which is a truncated Fab fragment including the variable (V) domain of an antibody heavy chain 20 linked to a V domain of a light antibody chain via a synthetic peptide, can be generated using routine recombinant DNA technology techniques. Similarly, disulfide-stabilized variable region fragments (dsFv) can be prepared by recombinant DNA technology. The antibody construct or antigen binding domain may comprise one or more variable regions (e.g., two variable regions) of an antigen binding domain of an anti-CEA antibody, each variable region comprising a 25 CDR1, a CDR2, and a CDR3. “Cysteine-mutant antibody” or “Cysteine-engineered antibody” refer to an antibody in which one or more amino acid residues of an antibody are substituted with cysteine residues. A cysteine-mutant antibody may be prepared from the parent antibody by antibody engineering methods (Junutula, J. et al., (2008b) Nature Biotech., 26(8):925-932; Dornan et al. (2009) Blood 30 114(13):2721-2729; US 7521541; US 7723485; US 2012 / 0121615; WO 2009 / 052249). Cysteine residues provide for site-specific conjugation of a TPI-Sp-VHL compound to the antibody through the reactive cysteine thiol groups at the mutated / engineered cysteine sites but do not perturb immunoglobulin folding and assembly or alter antigen binding and effector functions. Cysteine-mutant antibodies can be conjugated to the TPI-Sp-VHL-linker compound with 35 uniform stoichiometry of the antibody conjugate (e.g., up to two TPI-Sp-VHL moieties per 7 15077.006WO2 antibody in an antibody that has a single engineered, mutant cysteine site). The TPI-Sp-VHL- linker compound has a reactive electrophilic group to react specifically with the free cysteine thiol groups of the cysteine-mutant antibody. A modified antibody or fragment can have two or more cysteine substitutions, and these substitutions can be used in combination with other 5 antibody modification and conjugation methods as described herein. Methods for inserting cysteine at specific locations of an antibody are known in the art, see, e.g., Lyons et al, (1990) Protein Eng., 3:703-708, WO 2011 / 005481, WO2014 / 124316, WO 2015 / 138615. “Epitope” means any antigenic determinant or epitopic determinant of an antigen to which an antigen binding domain binds (i.e., at the paratope of the antigen binding domain). 10 Antigenic determinants usually consist of chemically active surface groupings of molecules, such as amino acids or sugar side chains, and usually have specific three dimensional structural characteristics, as well as specific charge characteristics. The terms “Fc receptor” or “FcR” refer to a receptor that binds to the Fc region of an antibody. There are three main classes of Fc receptors: (1) FcγR which bind to IgG, (2) FcαR 15 which binds to IgA, and (3) FcεR which binds to IgE. The FcγR family includes several members, such as FcγI (CD64), FcγRIIA (CD32A), FcγRIIB (CD32B), FcγRIIIA (CD16A), and FcγRIIIB (CD16B). The Fcγ receptors differ in their affinity for IgG and also have different affinities for the IgG subclasses (e.g., IgG1, IgG2, IgG3, and IgG4). Nucleic acid or amino acid sequence “identity,” as referenced herein, can be determined 20 by comparing a nucleic acid or amino acid sequence of interest to a reference nucleic acid or amino acid sequence. The percent identity is the number of nucleotides or amino acid residues that are the same (i.e., that are identical) as between the optimally aligned sequence of interest and the reference sequence divided by the length of the longest sequence (i.e., the length of either the sequence of interest or the reference sequence, whichever is longer). Alignment of 25 sequences and calculation of percent identity can be performed using available software programs. Examples of such programs include CLUSTAL-W, T-Coffee, and ALIGN (for alignment of nucleic acid and amino acid sequences), BLAST programs (e.g., BLAST 2.1, BL2SEQ, BLASTp, BLASTn, and the like) and FASTA programs (e.g., FASTA3x, FASTM, and SSEARCH) (for sequence alignment and sequence similarity searches). Sequence alignment 30 algorithms also are disclosed in, for example, Altschul et al., J. Molecular Biol., 215(3): 403-410 (1990), Beigert et al., Proc. Natl. Acad. Sci. USA, 106(10): 3770-3775 (2009), Durbin et al., eds., Biological Sequence Analysis: Probalistic Models of Proteins and Nuclei A ids, Cambridge University Press, Cambridge, UK (2009), Soding, Bioinformatics, 21(7): 951-960 (2005), Altschul et al., Nucleic Acids Res., 25(17): 3389-3402 (1997), and Gusfield, Algorithms 35 on Strings, Trees and Sequences, Cambridge University Press, Cambridge UK (1997)). Percent 8 15077.006WO2 (%) identity of sequences can be also calculated, for example, as 100 x [(identical positions) / min(TGA, TGB)], where TGAand TGBare the sum of the number of residues and internal gap positions in peptide sequences A and B in the alignment that minimizes TGAand TGB. See, e.g., Russell et al., J. Mol Biol., 244: 332-350 (1994). 5 The “antibody construct” or “binding agent” comprises Ig heavy and light chain variable region polypeptides that together form the antigen binding site. Each of the heavy and light chain variable regions are polypeptides comprising three complementarity determining regions (CDR1, CDR2, and CDR3) connected by framework regions. The antibody construct can be any of a variety of types of binding agents known in the art that comprise Ig heavy and light 10 chains. For instance, the binding agent can be an antibody, an antigen-binding antibody “fragment,” or a T-cell receptor. “Amino acid” refers to any monomeric unit that can be incorporated into a peptide, polypeptide, or protein. Amino acids include naturally-occurring α-amino acids and their stereoisomers, as well as unnatural (non-naturally occurring) amino acids and their 15 stereoisomers. “Stereoisomers” of a given amino acid refer to isomers having the same molecular formula and intramolecular bonds but different three-dimensional arrangements of bonds and atoms (e.g., an L-amino acid and the corresponding D-amino acid). The amino acids can be glycosylated (e.g., N-linked glycans, O-linked glycans, phosphoglycans, C-linked glycans, or glypication) or deglycosylated. Amino acids may be referred to herein by either the 20 commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Naturally-occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Naturally-occurring α-amino acids include, without limitation, alanine (Ala), 25 cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), arginine (Arg), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), and combinations thereof. Stereoisomers of naturally-occurring α-amino acids include, without limitation, D-alanine (D-Ala), D-cysteine (D-Cys), D-aspartic30 acid (D-Asp), D-glutamic acid (D-Glu), D-phenylalanine (D-Phe), D-histidine (D-His), D- isoleucine (D-Ile), D-arginine (D-Arg), D-lysine (D-Lys), D-leucine (D-Leu), D-methionine (D- Met), D-asparagine (D-Asn), D-proline (D-Pro), D-glutamine (D-Gln), D-serine (D-Ser), D- threonine (D-Thr), D-valine (D-Val), D-tryptophan (D-Trp), D-tyrosine (D-Tyr), and combinations thereof. 9 15077.006WO2 Naturally-occurring amino acids include those formed in proteins by post-translational modification, such as citrulline (Cit). Unnatural (non-naturally occurring) amino acids include, without limitation, amino acid analogs, amino acid mimetics, synthetic amino acids, N-substituted glycines, and N-methyl 5 amino acids in either the L- or D-configuration that function in a manner similar to the naturally- occurring amino acids. For example, “amino acid analogs” can be unnatural amino acids that have the same basic chemical structure as naturally-occurring amino acids (i.e., a carbon that is bonded to a hydrogen, a carboxyl group, an amino group) but have modified side-chain groups or modified peptide backbones, e.g., homoserine, norleucine, methionine sulfoxide, and 10 methionine methyl sulfonium. “Amino acid mimetics” refer to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally-occurring amino acid. “Linker” refers to a functional group that covalently bonds two or more moieties in an antibody conjugate compound. For example, the linking moiety can serve to covalently bond a 15 drug TPI-Sp-VHL moiety to an antibody in an antibody conjugate composition. Useful bonds for connecting linking moieties to proteins and other materials include, but are not limited to, amides, amines, esters, carbamates, ureas, thioethers, thiocarbamates, thiocarbonates, and thioureas. “Divalent” refers to a chemical moiety that contains two points of attachment for linking 20 two functional groups; polyvalent linking moieties can have additional points of attachment for linking further functional groups. Divalent radicals may be denoted by the suffix “diyl”. For example, divalent linking moieties include divalent polymer moieties such as divalent poly(ethylene glycol), divalent cycloalkyl, divalent heterocycloalkyl, divalent aryl, and divalent heteroaryl group. A “divalent cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group” refers to a 25 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group having two points of attachment for covalently linking two moieties in a molecule or material. Cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups can be substituted or unsubstituted. Cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups can be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido acyl, nitro, cyano, alkoxy, and others. 30 A wavy line (“ ”) and one or more asterisks (*) represents a point of attachment ofthe specifi d chemical moiety to another moiety. If the specified chemical moiety has two wavy lines (“ ”) present, it will be understood that the chemical moiety can be used bilaterally, i.e.,as read from left to ht or from right to left. In some embodiments, a specified moiety having two wavy lines (“ ”) present is considered to be used as read from left to right.10 15077.006WO2 “Alkyl” refers to a straight (linear) or branched, saturated, aliphatic radical having the number of carbon atoms indicated. Alkyl can include any number of carbons, for example from one to six, one to eight, one to twelve, one to twenty, or one to forty. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n- 5 propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, - CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, - CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, - CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl- 2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-10 CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (- CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (- CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (- CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (- C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (- 15 C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, 1-heptyl, 1-octyl, and the like. Alkyl groups can be substituted or unsubstituted. “Substituted alkyl” groups can be substituted with one or more groups selected from halo, hydroxy, amino, oxo (=O), alkylamino, amido, acyl, nitro, cyano, and alkoxy. The term “alkyldiyl” refers to a divalent alkyl radical. Examples of alkyldiyl groups20 include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (- CH2CH2CH2-), and the like. An alkyldiyl group may also be referred to as an “alkylene” group. “Alkenyl” refers to a straight (linear) or branched, unsaturated, aliphatic radical having the number of carbon atoms indicated and at least one carbon-carbon double bond, sp2. Alkenyl can include from two to about 12 or more carbons atoms. Alkenyl groups are radicals having 25 “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. Examples include, but are not limited to, ethylenyl or vinyl (-CH=CH2), allyl (-CH2CH=CH2). butenyl, pentenyl, and isomers thereof. Alkenyl groups can be substituted or unsubstituted. “Substituted alkenyl” groups can be substituted with one or more groups selected from halo, hydroxy, amino, oxo (=O), alkylamino, amido, acyl, nitro, cyano, and alkoxy. 30 The terms “alkenylene” or “alkenyldiyl” refer to a linear or branched-chain divalent hydrocarbon radical. Examples include, but are not limited to, ethylenylene or vinylene (- CH=CH-), allyl (-CH2CH=CH-), and the like. “Alkynyl” refers to a straight (linear) or branched, unsaturated, aliphatic radical having the number of carbon atoms indicated and at least one carbon-carbon triple bond, sp. Alkynyl 35 can include from two to about 12 or more carbons atoms. For example, C2-C6alkynyl includes, 11 15077.006WO2 but is not limited to ethynyl (-C^CH), propynyl (propargyl, -CH2C^CH), butynyl, pentynyl, hexynyl, and isomers thereof Alkynyl groups can be substituted or unsubstituted. “Substituted alkynyl” groups can be substituted with one or more groups selected from halo, hydroxy, amino, oxo (=O), alkylamino, amido, acyl, nitro, cyano, and alkoxy. 5 The term “alkynylene” or “alkynyldiyl” refer to a divalent alkynyl radical. "Heteroalkyl" or “heteroalkylene” refer to a monovalent, straight or branched chain alkyl group, as defined above, comprising at least one heteroatom including but not limited to Si, N, O, P or S within the alkyl chain or at a terminus of the alkyl chain. In some embodiments, a heteroatom is within the alkyl chain. In other embodiments, a 10 heteroatom is at a terminus of the alkylene and thus serves to join the alkyl to the remainder of the molecule. In some embodiments, a heteroalkyl group may have 1 to 12 carbon atoms (C1-C12 heteroalkyl). In some embodiments, a heteroalkyl group may have 1 to 24 carbon atoms (C1-C24 heteroalkyl). In some embodiments, a heteroalkyl group may have 1 to 40 carbon atoms (C1-C40heteroalkyl) or 1-60 carbon atoms (C1-C60heteroalkyl). 15 Unless stated otherwise specifically in the specification, a heteroalkyl group is optionally substituted. For example, heteroalkyl groups can be substituted with 1-6 fluoro (F) substituents, for example, on the carbon backbone (as −CHF− or −CF2−) or on terminal carbons of straight chain or branched heteroalkyls (such as −CHF2 or −CF3). Examples of heteroalkyl groups include, but are not limited to, −CH2CH2OCH3, −CH2CH2NHCH3, −20 CH2CH2N(CH3)2, −C(=O)NHCH2CH2NHCH3, −C(=O)N(CH3)CH2CH2N(CH3)2, − C(=O)NHCH2CH2NHC(=O)CH2CH3, −C(=O)N(CH3)CH2CH2N(CH3)C(=O)CH2CH3, − OCH2CH2CH2NH(CH3), −OCH2CH2CH2N(CH3)2, −OCH2CH2CH2NHC(=O)CH2CH3, − OCH2CH2CH2N(CH3)C(=O)CH2CH3, −CH2CH2CH2NH(CH3), −OCH2CH2CH2N(CH3)2, −CH2CH2CH2NHC(=O)CH2CH3, −CH2CH2CH2N(CH3)C(=O)CH2CH3, −CH2SCH2CH3,25 −CH2CH2S(O)CH3, −NHCH2CH2NHC(=O)CH2CH3, −CH2CH2S(O)2CH3, − CH2CH2OCF3, −S(O)2CH3, −S(O)2NHCH3, and −Si(CH3)3. Up to two heteroatoms may be consecutive, such as, for example, −CH2NHOCH3and −CH2OSi(CH3)3. A terminal polyethylene glycol (PEG) moiety is a type of heteroalkyl group. Exemplary heteroalkyl groups also include ethylene oxide (e.g., polyethylene oxide), propylene oxide, amino acid 30 chains (i.e., short to medium length peptides such as containing 1-15 amino acids), and alkyl chains connected via a variety of functional groups such as amides, disulfides, ketones, phosphonates, phosphates, sulfates, sulfones, sulfonamides, esters, ethers, -S-, 12 15077.006WO2 carbamates, ureas, thioureas, anhydrides, or the like (including combinations thereof). In some embodiments, a heteroalkyl group includes a polyamino acid having 1-10 amino acids. In some embodiments, a heteroalkyl group includes a polyamino acid having 1-5 amino acids. 5 Heteroalkyl groups include a solubilizing unit comprising one or more groups of polyglycine, polysarcosine, polyethyleneoxy (PEG), and a glycoside, or combinations thereof. "Heteroalkenyl" refers to a heteroalkyl group, as defined above, that contains at least one carbon-carbon double bond. "Heteroalkynyl" refers to a heteroalkyl group, as 10 defined above, that contains at least one carbon-carbon triple bond. “Heteroalkyldiyl” refers to a divalent form of a heteroalkyl group as defined above. In some embodiments, a heteroalkyldiyl group may have 1 to 12 carbon atoms (C1- C12 heteroalkyldiyl). In some embodiments, a heteroalkyldiyl group may have 1 to 24 carbon atoms (C1-C24 heteroalkyldiyl). In some embodiments, a heteroalkyldiyl group 15 may have 1 to 40 carbon atoms (C1-C40 heteroalkyldiyl) or 1-60 carbon atoms (C1-C60 heteroalkyldiyl). Examples of heteroalkyldiyl groups include, but are not limited to, − CH2CH2OCH2−, −CH2CH2OCF2−, −CH2CH2NHCH2−, −CH2OC(=O)NH−, −CH2OP(=O)(OH)OCH2−, −C(=O)NHCH2CH2NHCH2−, −C(=O)N(CH3)CH2CH2N(CH3)CH2−, −C(=O)NHCH2CH2NHC(=O)CH2CH2−, − 20 C(=O)N(CH3)CH2CH2N(CH3)C(=O)CH2CH2−, −OCH2CH2OCH2CH2−, − OCH2CH2OCH2C(=O)−, −OCH2CH2OCH2CH2C(=O)−, −OCH2CH2NHCH2−, − OCH2CH2N(CH3)CH2−, −OCH2CH2CH2NHCH2−, −OCH2CH2CH2N(CH3)CH2−, − OCH2CH2CH2NHC(=O)CH2CH2−, −OCH2CH2CH2N(CH3)C(=O)CH2CH2−, − CH2CH2CH2NHCH2−-, −CH2CH2CH2N(CH3)CH2−, −CH2CH2CH2NHC(=O)CH2CH2−,25 −CH2CH2CH2N(CH3)C(=O)CH2CH2−, −CH2CH2NHC(=O)−, −CH2CH2N(CH3)CH2−, − CH2CH2N+(CH3)2−, −NHCH2CH2(NH2)CH2−, −NHCH2CH2(NHCH3)CH2−, − S(O)2CH2CH2−, −S(O)2NHCH2CH2−, −S(O)2CH2CH2CH2−, and − S(O)2NHCH2CH2CH2−. A divalent polyethylene glycol (PEG) moiety with one to about 50 units of −OCH2CH2− is a type of heteroalkyldiyl group. “Heteroalkenyldiyl” refers to a 30 divalent form of a heteroalkenyl group. “Heteroalkynyldiyl” refers to a divalent form of a heteroalkynyl group. 13 15077.006WO2 The terms “carbocycle”, “carbocyclyl”, “carbocyclic ring” and “cycloalkyl” refer to a saturated or partially unsaturated, monocyclic, fused bicyclic, bridged polycyclic ring, or linked by a bond to form a bicyclic assembly containing from 3 to 20 ring carbon atoms, or the number of carbon atoms indicated. Saturated monocyclic carbocyclic rings include, for example, 5 cyclopropyl (−CH(CH2CH2)), cyclobutyl (−CH(CH2CH2CH2), cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. Saturated bicyclic and polycyclic carbocyclic rings include, for example, norbornyl, [2.2.2] bicyclooctanyl, decahydronaphthalyl and adamantyl. Carbocyclic groups can also be partially unsaturated, having one or more double or triple bonds in the ring. Representative carbocyclic groups that are partially unsaturated include, but are not limited to, 10 cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl (1,3- and 1,4-isomers), cycloheptenyl, cycloheptadienyl, cyclooctenyl, cyclooctadienyl (1,3-, 1,4- and 1,5-isomers), norbornenyl, and norbornadienyl. The term “cycloalkyldiyl” refers to a divalent cycloalkyl radical. “Aryl” refers to a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms (C6− 15 C20) derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biaryl group. Representative aryl groups include phenyl, naphthyl and biphenyl. Other aryl groups include benzyl, having a methylene linking group. Some aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other 20 aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. The terms “arylene” or “aryldiyl” mean a divalent aromatic hydrocarbon radical of 6-20 carbon atoms (C6−C20) derived by the removal of two hydrogen atom from a two carbon atoms of a parent aromatic ring system. Some aryldiyl groups are represented in the exemplary structures as “Ar”. Aryldiyl includes bicyclic radicals comprising an aromatic ring fused to a 25 saturated, partially unsaturated ring, or aromatic carbocyclic ring. Typical aryldiyl groups include, but are not limited to, radicals derived from benzene (phenyldiyl), substituted benzenes, naphthalene, anthracene, biphenylene, indenylene, indanylene, 1,2-dihydronaphthalene, 1,2,3,4- tetrahydronaphthyl, and the like. Aryldiyl groups are also referred to as “arylene”, and are optionally substituted with one or more substituents described herein. 30 The terms “heterocycle,” “heterocyclyl” and “heterocyclic ring” are used interchangeably herein and refer to a saturated or a partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) carbocyclic radical of 3 to about 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms being C, where one or more ring atoms is optionally substituted 35 independently with one or more substituents described below. Heterocycles can be monocyclic, 14 15077.006WO2 fused to form bicyclic or tricyclic groups, or linked by a bond to form a biheterocyclic such as the 4-(piperidin-4-yl)piperazine group: A heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 5 1 to 4 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), for example: a bicyclo [4,5], [5,5], [5,6], or [6,6] system. Heterocycles are described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John 10 Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. “Heterocyclyl” also includes radicals where heterocycle radicals are fused with a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, morpholin-4- yl, piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one, pyrrolidin-1-yl, 15 thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, azocan-1-yl, azetidin-1-yl, octahydropyrido[1,2-a]pyrazin-2-yl, [1,4]diazepan-1-yl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 20 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl, 3- azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl quinolizinyl and N-pyridyl ureas. Spiro heterocyclyl moieties are also included within the scope of this definition. 25 Examples of spiro heterocyclyl moieties include azaspiro[2.5]octanyl and azaspiro[2.4]heptanyl. Examples of a heterocyclic group wherein 2 ring atoms are substituted with oxo (=O) moieties are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The heterocycle groups herein are optionally substituted independently with one or more substituents described herein. The term “heterocyclyldiyl” refers to a divalent, saturated or a partially unsaturated (i.e., 30 having one or more double and / or triple bonds within the ring) carbocyclic radical of 3 to about 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms being C, where one or more ring atoms is optionally substituted independently with one or more substituents as described. Examples of 5- membered and 6-membered heterocyclyldiyls include morpholinyldiyl, piperidinyldiyl, 15 15077.006WO2 piperazinyldiyl, pyrrolidinyldiyl, dioxanyldiyl, thiomorpholinyldiyl, and S- dioxothiomorpholinyldiyl. The term “heteroaryl” refers to a monovalent aromatic radical of 5-, 6-, or 7-membered rings, and includes fused ring systems (at least one of which is aromatic) of 5-20 atoms, 5 containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heteroaryls can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biheteroaryl such as the 4-(pyrazol-3-yl)pyridine group: Examples of heteroaryl groups are pyridinyl (including, for example, 2-10 hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4- hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, 15 thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, imidazo[1,2-a]pyridinyl, furopyridinyl, benzothiazolyl, thiazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, thiazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyridazinyl, dihydrobenzothiazolyl, tetrahydrobenzothiazolyl, dihydrothiazolopyridinyl, 20 dihydrothiazolopyridinyl, dihydroimidazopyridinyl, dihydrothiazolopyridinyl, dihydrothiazolopyridinyl, dihydroimidazopyrazinyl, and dihydroimidazopyridazinyl. Heteroaryl groups are optionally substituted independently with one or more substituents described herein. The term “heteroaryldiyl” refers to a divalent aromatic radical of 5-, 6-, or 7-membered rings, and includes fused ring systems (at least one of which is aromatic) of 5-20 atoms, 25 containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryldiyl include divalent version of the heteroaryl groups examples listed above, including but not limited to: pyridyldiyl, imidazolyldiyl, pyrimidinyldiyl, pyrazolyldiyl, triazolyldiyl, pyrazinyldiyl, tetrazolyldiyl, furyldiyl, thienyldiyl, isoxazolyldiyldiyl, thiazolyldiyl, oxadiazolyldiyl, oxazolyldiyl, isothiazolyldiyl, imidazo[1,2-a]pyridindiyl, and 30 pyrrolyldiyl. The heterocycle or heteroaryl groups may be carbon (carbon-linked), or nitrogen (nitrogen-linked) bonded where such is possible. By way of example and not limitation, carbon bonded heterocycles or heteroaryls are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 16 15077.006WO2 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an 5 azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. By way of example and not limitation, nitrogen bonded heterocycles or heteroaryls are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3- 10 pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindolinone, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline. The terms “halo” and “halogen,” by themselves or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom. The term “carbonyl,” by itself or as part of another substituent, refers to C(=O) or – 15 C(=O)–, i.e., a carbon atom double-bonded to oxygen and bound to two other groups in the moiety having the carbonyl. As used herein, the phrase “quaternary ammonium salt” refers to a tertiary amine that has been quaternized with an alkyl substituent (e.g., a C1-C4 alkyl such as methyl, ethyl, propyl, or butyl). 20 The term “fused” refers to a ring which is joint to an adjacent ring and share two adjacent ring atoms that form a covalent bond. The term “bridged” refers to a ring fusion wherein non-adjacent atoms on a ring are joined by a divalent substituent, such as alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged 25 ring systems. The term or prefix “spiro” refers to a ring substituent which is joined by two bonds at the same carbon atom. Examples of spiro groups include 1,1 -diethylcyclopentane, dimethyl- dioxolane, and 4-benzyl-4- methylpiperidine, wherein the cyclopentane and piperidine, respectively, are the spiro substituents. 30 The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen. “Optionally substituted” may be zero to 35 the maximum number of possible substitutions, and each occurrence is independent. When the 17 15077.006WO2 term “substituted” is used, then that substitution is required to be made at a substitutable hydrogen atom of the indicated substituent. An optional substitution may be the same or different from a (required) substitution. The term "chiral" refers to molecules which have the property of non-superimposability 5 of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner. The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereochemical definitions and conventions used herein generally follow S. P. Parker, 10 Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that the compounds of the invention include all stereoisomeric forms of, including but not limited to, diastereomers, 15 enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, and form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate 20 the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is 25 referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose 30 molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography. "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable 35 mirror images of one another. 18 15077.006WO2 The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by 5 reorganization of some of the bonding electrons. The term "salt" refers to acid or base salts of the compounds of the disclosed herein. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, 10 and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Pharmaceutically acceptable salts of the acidic compounds disclosed herein are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts. 15 Similarly acid addition salts, such as of mineral acids, organic carboxylic and organic sulfonic acids, e.g., hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as pyridyl, constitutes part of the structure. The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the 20 various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure. Any compound or Formula given herein, is intended to represent unlabeled forms as well as isotopically labeled forms of the compounds (i.e., "isotopic analogs"). Isotopically labeled 25 compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine, such as2H,3H,11C,13C,14C,13N, 15N,15O,17O,18O,31P,32P,35S,18F,36Cl,123I and125I, respectively. Various isotopically labeled 30 compounds of the present disclosure, for example those into which radioactive isotopes such as 3H,13C and14C are incorporated. Such isotopically labeled compounds may be useful for enhanced therapeutic activity, in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive 35 treatment of patients. 19 15077.006WO2 The disclosure also includes "deuterated analogs" of compounds described herein in which from 1 to n hydrogens attached to a carbon atom is / are replaced by deuterium (2H), in which n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when 5 administered to a mammal, particularly a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci.5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium. Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug 10 metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and / or an improvement in therapeutic index. An18F,3H, or11C labeled compound may be useful for PET or SPECT or other imaging studies. Isotopically 15 labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein. The concentration of such a heavier isotope, specifically deuterium, 20 may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a 25 deuterium (D) is meant to represent deuterium. The terms “treat,” “treatment,” and “treating” refer to any indicia of success in the treatment or amelioration of an injury, pathology, condition (e.g., cancer), or symptom (e.g., cognitive impairment), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology, or condition 30 more tolerable to the patient; reduction in the rate of symptom progression; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of the symptom. The treatment or amelioration of symptoms can be based on any objective or subjective parameter, including, for example, the result of a physical examination. The terms “cancer,” “neoplasm,” and “tumor” are used herein to refer to cells which 35 exhibit autonomous, unregulated growth, such that the cells exhibit an aberrant growth 20 15077.006WO2 phenotype characterized by a significant loss of control over cell proliferation. Cells of interest for detection, analysis, and / or treatment in the context of the invention include cancer cells (e.g., cancer cells from an individual with cancer), malignant cancer cells, pre-metastatic cancer cells, metastatic cancer cells, and non-metastatic cancer cells. Cancers of virtually every tissue are 5 known. The phrase “cancer burden” refers to the quantum of cancer cells or cancer volume in a subject. Reducing cancer burden accordingly refers to reducing the number of cancer cells or the cancer cell volume in a subject. The term “cancer cell” as used herein refers to any cell that is a cancer cell (e.g., from any of the cancers for which an individual can be treated, e.g., isolated from an individual having cancer) or is derived from a cancer cell, e.g., clone of a cancer cell. 10 For example, a cancer cell can be from an established cancer cell line, can be a primary cell isolated from an individual with cancer, can be a progeny cell from a primary cell isolated from an individual with cancer, and the like. In some embodiments, the term can also refer to a portion of a cancer cell, such as a sub-cellular portion, a cell membrane portion, or a cell lysate of a cancer cell. Many types of cancers are known to those of skill in the art, including solid 15 tumors such as carcinomas, sarcomas, glioblastomas, melanomas, lymphomas, and myelomas, and circulating cancers such as leukemias. As used herein, the term “cancer” includes any form of cancer, including but not limited to, solid tumor cancers (e.g., skin, lung, prostate, breast, gastric, bladder, colon, ovarian, pancreas, kidney, liver, glioblastoma, medulloblastoma, leiomyosarcoma, head & neck 20 squamous cell carcinomas, melanomas, and neuroendocrine) and liquid cancers (e.g., hematological cancers); carcinomas; soft tissue tumors; sarcomas; teratomas; melanomas; leukemias; lymphomas; and brain cancers, including minimal residual disease, and including both primary and metastatic tumors. The phrases “effective amount” and “therapeutically effective amount” refer to a dose or 25 amount of a substance such as an antibody conjugate that produces therapeutic effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); Goodman & 30 Gilman’s The Pharmacological Basis of Therapeutics, 11thEdition (McGraw-Hill, 2006); and Remington: The Science and Practice of Pharmacy, 22ndEdition, (Pharmaceutical Press, London, 2012)). In the case of cancer, the therapeutically effective amount of the antibody conjugate may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow 35 to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; 21 15077.006WO2 and / or relieve to some extent one or more of the symptoms associated with the cancer. To the extent the antibody conjugate may prevent growth and / or kill existing cancer cells, it may be cytostatic and / or cytotoxic. For cancer therapy, efficacy can, for example, be measured by assessing the time to disease progression (TTP) and / or determining the response rate (RR) 5 “Recipient,” “individual,” “subject,” “host,” and “patient” are used interchangeably and refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired (e.g., humans). “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, camels, etc. In certain embodiments, the mammal is 10 human. As used herein, the term “administering” refers to parenteral, intravenous, intraperitoneal, intramuscular, intratumoral, intralesional, intranasal, or subcutaneous administration, oral administration, administration as a suppository, topical contact, intrathecal administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to the 15 subject. The terms “about” and “around,” as used herein to modify a numerical value, indicate a close range surrounding the numerical value. Thus, if “X” is the value, “about X” or “around X” indicates a value of from 0.9X to 1.1X, e.g., from 0.95X to 1.05X or from 0.99X to 1.01X. A reference to “about X” or “around X” specifically indicates at least the values X, 0.95X, 0.96X, 20 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Accordingly, “about X” and “around X” are intended to teach and provide written description support for a claim limitation of, e.g., “0.98X.” ANTIBODIES The degrader antibody conjugate (DAC) compositions of the invention comprise an 25 antibody. Included in the scope of the antibody embodiments of the invention are functional variants of the antibody constructs or antigen binding domain described herein. The term “functional variant” as used herein refers to an antibody construct having an antigen binding domain with substantial or significant sequence identity or similarity to a parent antibody construct or antigen binding domain, which functional variant retains the biological activity of 30 the antibody construct or antigen binding domain of which it is a variant. Functional variants encompass, for example, those variants of the antibody constructs or antigen binding domain described herein (the parent antibody construct or antigen binding domain) that retain the ability to recognize target cells expressing a tumor-associated antigen or cell surface receptor to a 22 15077.006WO2 similar extent, the same extent, or to a higher extent, as the parent antibody construct or antigen binding domain. In reference to the antibody construct or antigen binding domain, the functional variant can, for instance, be at least about 30%, about 50%, about 75%, about 80%, about 85%, about 5 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or more identical in amino acid sequence to the antibody construct or antigen binding domain. A functional variant can, for example, comprise the amino acid sequence of the parent antibody construct or antigen binding domain with at least one conservative amino acid 10 substitution. Alternatively, or additionally, the functional variants can comprise the amino acid sequence of the parent antibody construct or antigen binding domain with at least one non- conservative amino acid substitution. In this case, it is preferable for the non-conservative amino acid substitution to not interfere with or inhibit the biological activity of the functional variant. The non-conservative amino acid substitution may enhance the biological activity of the 15 functional variant, such that the biological activity of the functional variant is increased as compared to the parent antibody construct or antigen binding domain. A functional variant can, for example, comprise the amino acid sequence of the parent antibody construct or antigen binding with at least one non-canonical amino acid (ncAA) substitution (L Wang, et al, (2001) Science , 292(5516):498-500, CC Liu, PG Schultz, (2010) 20 Annu Rev Biochem.79:413-44). The antibodies comprising the degrader antibody conjugate (DAC) compositions of the invention include Fc engineered mutant variants are described in: Dall’Acqua, W.F. (2006) J. Biol. Chem.281(33):23514-23524; US 2016 / 0145350; US 2021 / 0139603; US 2024 / 0018259; US 8969526; US 8775090; US 7658921; US 7416726; US 7083784; US 5624821; WO 25 2022 / 097065, which are hereby incorporated by reference in their entireties herein. In some embodiments, the mutations in the Fc region that result in modulated binding to one or more Fc receptors can include one or more of the following mutations: YTE (M252Y / S254T / T256E), LALAPA (L234A / L235A / P329A), LALAPG (L234A / L235A / P329G), SD (S239D), LALASKPA (L234A, L235A, S267K, P329A), SDIE (S239D / I332E), SE (S267E), SELF 30 (S267E / L328F), SDIE (S239D / I332E), SDIEAL (S239D / I332E / A330L), GA (G236A), ALIE (A330L / I332E), GASDALIE (G236A / S239D / A330L / I332E), V9 (G237D / P238D / P271G / A330R), and V11 (G237D / P238D / H268D / P271G / A330R), and / or one or more mutations at the following amino acids: E345R, E345R / E430G, E345K, E233, G237, P238, H268, P271, L328 and A330. 23 15077.006WO2 The antibodies comprising the antibody conjugate compositions of the invention include glycan variants, such as afucosylation. In some embodiments, the Fc region of the binding agents are modified to have an altered glycosylation pattern of the Fc region compared to the native non-modified Fc region. 5 In some embodiments, the antibodies in the antibody conjugate compositions contain a modified Fc region, wherein the modification modulates the binding of the Fc region to one or more Fc receptors. In some embodiments, the antibodies in the antibody conjugate contain one or more modifications (e.g., amino acid insertion, deletion, and / or substitution) in the Fc region that 10 results in modulated binding (e.g., increased binding or decreased binding) to one or more Fc receptors (e.g., FcγRI (CD64), FcγRIIA (CD32A), FcγRIIB (CD32B), FcγRIIIA (CD16a), and / or FcγRIIIB (CD16b)) as compared to the native antibody lacking the mutation in the Fc region. In some embodiments, the antibodies in the antibody conjugate compositions contain one or more modifications (e.g., amino acid insertion, deletion, and / or substitution) in the Fc 15 region that reduce the binding of the Fc region of the antibody to FcγRIIB. In some embodiments, the antibodies in the antibody conjugate compositions contain one or more modifications (e.g., amino acid insertion, deletion, and / or substitution) in the Fc region of the antibody that reduce the binding of the antibody to FcγRIIB while maintaining the same binding or having increased binding to FcγRI (CD64), FcγRIIA (CD32A), and / or FcRγIIIA (CD16a) as 20 compared to the native antibody lacking the mutation in the Fc region. In some embodiments, the antibodies in the antibody conjugate compositions contain one of more modifications in the Fc region that increase the binding of the Fc region of the antibody to FcγRIIB. In some embodiments, the modulated binding is provided by mutations in the Fc region of the antibody relative to the native Fc region of the antibody. The mutations can be in a CH2 25 domain, a CH3 domain, or a combination thereof. A “native Fc region” is synonymous with a “wild-type Fc region” and comprises an amino acid sequence that is identical to the amino acid sequence of an Fc region found in nature or identical to the amino acid sequence of the Fc region found in the native antibody (e.g., cetuximab). Native sequence human Fc regions include a native sequence human IgG1 Fc region, native sequence human IgG2 Fc region, native 30 sequence human IgG3 Fc region, and native sequence human IgG4 Fc region, as well as naturally occurring variants thereof. Native sequence Fc includes the various allotypes of Fcs (Jefferis et al., (2009) mAbs, 1(4):332-338). In some embodiments, the Fc region of the antibodies of the antibody conjugate compositions are modified to have an altered glycosylation pattern of the Fc region compared to 35 the native non-modified Fc region. Human immunoglobulin is glycosylated at the Asn297 24 15077.006WO2 residue in the Cγ2 domain of each heavy chain. This N-linked oligosaccharide is composed of a core heptasaccharide, N-acetylglucosamine4Mannose3 (GlcNAc4Man3). Removal of the heptasaccharide with endoglycosidase or PNGase F is known to lead to conformational changes in the antibody Fc region, which can significantly reduce antibody-binding affinity to activating 5 FcγR and lead to decreased effector function. The core heptasaccharide is often decorated with galactose, bisecting GlcNAc, fucose, or sialic acid, which differentially impacts Fc binding to activating and inhibitory FcγR. Additionally, it has been demonstrated that α2,6-sialyation enhances anti-inflammatory activity in vivo, while afucosylation leads to improved FcγRIIIa binding and a 10-fold increase in antibody-dependent cellular cytotoxicity and antibody- 10 dependent phagocytosis. Specific glycosylation patterns, therefore, can be used to control inflammatory effector functions. In some embodiments, the modification to alter the glycosylation pattern is a mutation. For example, a substitution at Asn297. In some embodiments, Asn297 is mutated to glutamine (N297Q). Methods for controlling immune response with antibodies that modulate FcγR- 15 regulated signaling are described, for example, in US 7416726, US 2007 / 0014795 and US 2008 / 0286819, which are hereby incorporated by reference in their entireties. In some embodiments, the antibodies of the antibody conjugate compositions are modified to contain an engineered Fab region with a non-naturally occurring glycosylation pattern. For example, hybridomas can be genetically engineered to secrete afucosylated mAb, 20 desialylated mAb or deglycosylated Fc with specific mutations that enable increased FcRγIIIa binding and effector function. In some embodiments, the antibodies of the antibody conjugate compositions are engineered to be afucosylated or glycosylated. In some embodiments, the antibodies in the antibody conjugate compositions are a cysteine-engineered antibody which provides for site-specific conjugation of an adjuvant, label, 25 or drug moiety to the antibody through cysteine substitutions at sites where the engineered cysteines are available for conjugation but do not perturb immunoglobulin folding and assembly or alter antigen binding and effector functions (Junutula, et al., (2008) Nature Biotech., 26(8):925-932; Dornan et al. (2009) Blood 114(13):2721-2729; US 7521541; US 7723485; US 2012 / 0121615; WO 2009 / 052249). A “cysteine engineered antibody” or “cysteine engineered 30 antibody variant” is an antibody in which one or more residues of an antibody are substituted with cysteine residues. Cysteine-engineered antibodies can be conjugated to the TPI-Sp-VHL moiety with uniform stoichiometry (e.g., up to two TPI-Sp-VHL moieties per antibody in an antibody that has a single engineered cysteine site). In some embodiments, the cysteine-engineered antibodies have a cysteine residue 35 introduced at the 239-serine (HC S239C), 246-lysine (HC K246C) and / or 375-serine (HC 25 15077.006WO2 S375C) sites of the heavy chain according to EU numbering. In other embodiments, cysteine- engineered antibodies are used to prepare antibody conjugate compositions with a reactive cysteine thiol residue introduced at a site on the light chain, such as the 149-lysine site (LC K149C), or on the heavy chain such as the 122-serine site (HC S122C), as numbered by Kabat 5 numbering. In other embodiments, the cysteine-engineered antibodies have a cysteine residue introduced at the 118-alanine site (EU numbering) of the heavy chain (HC A118C). This site is alternatively numbered 121 by Sequential numbering or 114 by Kabat numbering. In other embodiments, the cysteine-engineered antibodies have a cysteine residue introduced in: (i) the light chain at G64C, R142C, K188C, L201C, T129C, S114C, or E105C according to Kabat 10 numbering; (ii) the heavy chain at D101C, V184C, T205C, or S122C according to Kabat numbering; or (iii) other cysteine-mutant antibodies, and as described in Bhakta, S. et al, (2013) “Engineering THIOMABs for Site-Specific Conjugation of Thiol-Reactive Linkers”, Laurent Ducry (ed.), Antibody-Drug Conjugates, Methods in Molecular Biology, vol.1045, pages 189- 203; WO 2011 / 156328; US 9000130. 15 In some embodiments, the antibody is a full-length antibody. In certain embodiments, the antibody is an antigen binding fragment. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody or Fc fusion protein is selected from: abagovomab, abatacept (also known as ORENCIA®), abciximab (also known as REOPRO®), c7E3 Fab), 20 adalimumab (also known as HUMIRA®), adecatumumab, alemtuzumab (also known as CAMPATH®), MabCampath or Campath-1H), altumomab, afelimomab, panitumumab, mafenatox, anrukizumab, apolizumab, arcitumomab, aselizumab, atlizumab, atorolimumab, bapineuzumab, basiliximab (also known as SIMULECT®), bavituximab, bectumomab (also known as LYMPHOSCAN®), belimumab (also known as LYMPHO-STAT-B®), bertilimumab, 25 besilesomab, bevacizumab (also known as AVASTIN®), biciromab brallobarbital, bivatuzumab mertansine, campath, canakinumab (also known as ACZ885), cantuzumab mertansine, capromab (also known as PROSTASCINT®), catumaxomab (also known as REMOVAB®), cedelizumab (also known as CIMZIA®), certolizumab pegol, cetuximab (also known as ERBITUX®), clenoliximab, dacetuzumab, dacliximab, daclizumab (also known as ZENAPAX®), 30 datopotamab, denosumab (also known as AMG 162), detumomab, dorlimomab aritox, dorlixizumab, duntumumab, durimulumab, durmulumab, ecromeximab, eculizumab (also known as SOLIRIS®), edobacomab, edrecolomab (also known as Mab17-1A, PANOREX®), efalizumab (also known as RAPTIVA®), efungumab (also known as MYCOGRAB®), elsilimomab, enapotamab, enfortumab, enlimomab pegol, epitumomab cituxetan, efalizumab, 35 epitumomab, epratuzumab, erlizumab, ertumaxomab (also known as REXOMUN®), etanercept 26 15077.006WO2 (also known as ENBREL®), etaracizumab (also known as etaratuzumab, VITAXIN®, ABEGRIN®), exbivirumab, fanolesomab (also known as NEUTROSPEC®), faralimomab, felvizumab, fontolizumab (also known as HUZAF®), galiximab, gantenerumab, gavilimomab (also known as ABXCBL®), gemtuzumab ozogamicin (also known as MYLOTARG®), 5 golimumab (also known as CNTO 148), gomiliximab, ibalizumab (also known as TNX-355), ibritumomab tiuxetan (also known as ZEVALIN®), igovomab, imciromab, indusatumab, infliximab (also known as REMICADE®), inolimomab, inotuzumab ozogamicin, ipilimumab (also known as MDX-010, MDX-101), iratumumab, keliximab, labetuzumab, ladiratuzumab, lemalesomab, lebrilizumab, lerdelimumab, lexatumumab (also known as, HGS-ETR2, ETR2- 10 ST01), lexitumumab, libivirumab, lintuzumab, loncastuximab, losatuxizumab, lucatumumab, lumiliximab, mapatumumab (also known as HGSETR1, TRM-1), maslimomab, matuzumab (also known as EMD72000), mepolizumab (also known as BOSATRIA®), metelimumab, milatuzumab, miltuximab, minretumomab, mirvetuximab, mitumomab, morolimumab, motavizwnab (also known as NUMAX®), muromonab (also known as OKT3), nacolomab 15 tafenatox, naptumomab estafenatox, natalizumab (also known as TYSABRI®, ANTEGREN®), nebacumab, nerelimomab, nimotuzumab (also known as THERACIM hR3®, THERA-CIM- hR3®, THERALOC®), nofetumomab merpentan (also known as VERLUMA®), ocrelizumab, odulimomab, ofatumumab, omalizumab (also known as XOLAIR®), oregovomab (also known as OVAREX®), otelixizumab, pagibaximab, palivizumab (also known as SYNAGIS®), 20 panitumumab (also known as ABX-EGF, VECTIBIX®), pascolizumab, pemtumomab (also known as THERAGYN®), pertuzumab (also known as 2C4, OMNITARG®), pexelizumab, pinatuzumab, pintumomab, polatuzumab, priliximab, pritumumab, ranibizumab (also known as LUCENTIS®), raxibacumab, regavirumab, reslizumab, rituximab (also known as RITUXAN®, MabTHERA®), rovelizumab, ruplizumab, sacituzumab, satumomab, sevirumab, sibrotuzumab, 25 siplizumab (also known as MEDI-507), sontuzumab, stamulumab (also known as MYO-029), sulesomab (also known as LEUKOSCAN®), tacatuzumab tetraxetan, tadocizumab, talizumab, taplitumomab paptox, tefibazumab (also known as AUREXIS®), telimomab aritox, teneliximab, teplizumab, ticilimumab, tocilizumab (also known as ACTEMRA®), tisotumab, toralizumab, tositumomab, trastuzumab (also known as HERCEPTIN®), tremelimumab (also known as CP- 30 675,206), tucotuzumab celmoleukin, tusamitamab, tuvirumab, urtoxazumab, ustekinumab (also known as CNTO 1275), vapaliximab, veltuzumab, vepalimomab, visilizumab (also known as NUVION®), volociximab (also known as M200), votumumab (also known as HUMASPECT®), zalutumumab, zanolimumab (also known as HuMAX-CD4), ziralimumab, zolimomab aritox, daratumumab, elotuxumab, obintunzumab, olaratumab, brentuximab vedotin, 27 15077.006WO2 afibercept, abatacept, belatacept, afibercept, etanercept, romiplostim, SBT-040 (sequences listed in US 2017 / 0158772. In some embodiments, the antibody is rituximab. In an exemplary embodiment, the degrader antibody conjugate composition of the invention comprises an antibody construct that comprises an antigen binding domain that 5 specifically recognizes and binds CEA (carcinoembryonic antigen). In certain embodiments, the degrader antibody conjugate composition comprises an anti-CEA antibody. to CEACAM antigens. Specifically CEACAM targeting, degrader antibody conjugates of the invention bind to: (i) CEACAM5; (ii) CEACAM6; or (iii) to both CEACAM5 and CEACAM6. CEACAM5, CEACAM6, or both CEACAM5 and CEACAM6 specific antibodies comprise embodiments of 10 the degrader antibody conjugates of the invention for the treatment of CEACAM-expressing tumors. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) also known as CD66e (Cluster of Differentiation 66e), and carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6, CD66c) are members of the CEACAM gene family (Thomas et al., 15 Genes Cancer 2023, 14, 12-29; Ma, et al, (2024) Mol Cancer Ther, 23:939-948). CEACAM5 and CEACAM6 are anchored to the cell membrane through a glycosylphophatidylinositol (GPI), are heavily glycosylated, and are members of the Ig supergene family. CEACAM5 and CEACAM6 are overexpressed in pancreatic, colorectal and other cancers and are hence good cell surfaces antigens for the development of degrader antibody drug conjugates. 20 Included in the scope of the embodiments of the invention are functional variants of the CEACAM antibody constructs or antigen binding domain described herein. The term “functional variant” as used herein refers to an antibody construct having an antigen binding domain with substantial or significant sequence identity or similarity to a parent antibody construct or antigen binding domain, which functional variant retains the biological activity of 25 the antibody construct or antigen binding domain of which it is a variant. Functional variants encompass, for example, those variants of the antibody constructs or antigen binding domain described herein (the parent antibody construct or antigen binding domain) that retain the ability to recognize target cells expressing CEACAM to a similar extent, the same extent, or to a higher extent, as the parent antibody construct or antigen binding domain. 30 Labetuzumab (CEA-CIDETM, Immunomedics, CAS Reg. No.219649-07-7), also known as MN-14 and hMN14, is a humanized IgG1 monoclonal antibody and has been studied for the treatment of colorectal cancer (Blumenthal, R. et al (2005) Cancer Immunology Immunotherapy 54(4):315-327). Tusamitamab (CAS Reg. No.2349294-95-5) is a humanized monoclonal antibody which binds to CEA (WO 2014 / 079886; WO 2020 / 216847). NEO-201 antibody binds 35 both CEACAM5 and CEACAM6 through a glycol-epitope (US11767367). 28 15077.006WO2 In an exemplary embodiment, the degrader antibody conjugate composition of the invention comprises an antibody construct that comprises an antigen binding domain that specifically recognizes and binds HER2. In certain embodiments, the degrader antibody conjugate composition comprises an anti-HER2 antibody. In one embodiment of the invention, 5 an anti-HER2 antibody of an antibody conjugate composition of the invention comprises a humanized anti-HER2 antibody, e.g., huMAb4D5-1, huMAb4D5-2, huMAb4D5-3, huMAb4D5- 4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7 and huMAb4D5-8, as described in Table 3 of US 5821337, which is specifically incorporated by reference herein. Those antibodies contain human framework regions with the complementarity-determining regions of a murine antibody 10 (4D5) that binds to HER2. The humanized antibody huMAb4D5-8 is also referred to as trastuzumab, commercially available under the tradename HERCEPTIN™ (Genentech, Inc.). Trastuzumab (CAS 180288-69-1, HERCEPTIN^, huMAb4D5-8, rhuMAb HER2, Genentech) is a recombinant DNA-derived, IgG1 kappa, monoclonal antibody. Trastuzumab is a humanized version of a murine anti-HER2 antibody (4D5) that selectively binds with high affinity in a cell- 15 based assay (Kd = 5 nM) to the extracellular domain of HER2 (US 5677171; US 5821337; US 6054297; US 6165464; US 6339142; US 6407213; US 6639055; US 6719971; US 6800738; US 7074404; Coussens et al (1985) Science 230:1132-9; Slamon et al (1989) Science 244:707-12; Slamon et al (2001) New Engl. J. Med.344:783-792). In an exemplary embodiment, the antibody construct or antigen binding domain 20 comprises the CDR regions of trastuzumab. In an embodiment of the invention, the anti-HER2 antibody further comprises the framework regions of the trastuzumab. In an exemplary embodiment, the anti-HER2 antibody further comprises one or both variable regions of trastuzumab. In an exemplary embodiment, the antibody is cysteine-engineered trastuzumab. 25 In another embodiment of the invention, an anti-HER2 antibody of an antibody conjugate composition of the invention comprises a humanized anti-HER2 antibody, e.g., humanized 2C4, as described in US 7862817. An exemplary humanized 2C4 antibody is pertuzumab (CAS Reg. No.380610-27-5), PERJETA™ (Genentech, Inc.). Pertuzumab is a HER dimerization inhibitor (HDI) and functions to inhibit the ability of HER2 to form active 30 heterodimers or homodimers with other HER receptors (such as EGFR / HER1, HER2, HER3 and HER4). See, for example, Harari and Yarden, Oncogene 19:6102-14 (2000); Yarden and Sliwkowski. Nat Rev Mol Cell Biol 2:127-37 (2001); Sliwkowski, M. et al (2003) Nat Struct Biol 10:158-9; Cho et al. (2003) Nature 421:756-60; and Malik et al. (2003) Pro Am Soc Cancer Res 44:176-7). PERJETA™ is approved for the treatment of breast cancer. 29 15077.006WO2 In an embodiment of the invention, the antibody construct or antigen binding domain comprises the CDR regions of pertuzumab. In an embodiment of the invention, the anti-HER2 antibody further comprises the framework regions of the pertuzumab. In an embodiment of the invention, the anti-HER2 antibody further comprises one or both variable regions of 5 pertuzumab. In an exemplary embodiment, the antibody is cysteine-engineered pertuzumab. In another embodiment of the invention, an anti-HER2 antibody of a DAC comprises 7C2, an anti-HER2 monoclonal antibody (Lewis, G. et al (2024) Nature Communications 15:466). Anti-HER2 murine (WO 1998 / 017797)and humanized (WO 2016 / 040723) 7C2 10 antibodies binds to an epitope in domain I of HER2. This epitope is distinct from the epitope bound by trastuzumab, which binds to domain IV of HER2, and the epitope bound by pertuzumab, which binds to domain II of HER2. By binding domain IV, trastuzumab disrupts ligand-independent HER2-HER3 complexes, thereby inhibiting downstream signaling (e.g. PI3K / AKT). In contrast, pertuzumab binding to domain II prevents ligand-driven HER2 15 interaction with other HER family members (e.g. HER3, HER1 or HER4), thus also preventing downstream signal transduction. Binding of MAb 7C2 to domain I does not result in interference of trastuzumab or pertuzumab binding to domains IV and II, respectively, thereby offering the potential of combining a 7C2 DAC with trastuzumab, trastuzumab emtansine (T-DM-1), and / or pertuzumab 20 In another embodiment of the invention, a DAC comprises a bispecific antibody that binds to HER2 and another tumor-associated antigen, including but not limited to: HER3, BCMA, PSMA (prostate-specific membrane antigen), EGFR, DLL1, ANG-2, CD1, CD3, CD16, and CD47 (Zong, H. et al (2024) Acta Pharmacologica Sinica 45:1727–1739). In another embodiment of the invention, an anti-HER2 antibody of a DAC comprises 25 margetuximab (also called MGAH22), another anti-HER2 monoclonal antibody. The Fc region of margetuximab is optimized for increased binding to the activating Fc gamma Rs but decreased binding to the inhibitory Fc.gamma.Rs on immune effector cells. Margetuximab is approved by the FDA for treatment of patients with relapsed or refractory advanced breast cancer whose tumors express HER2 at the 2+ level by immunohistochemistry and lack evidence 30 of HER2 gene amplification by FISH. In another embodiment of the invention, an anti-HER2 antibody of a DAC comprises anti-HER2 monoclonal antibody HT-19 which binds to an epitope in human HER2 distinct from the epitope of trastuzumab or pertuzumab. HT-19 was shown to inhibit HER2 signaling comparable to trastuzumab and enhance HER2 degradation in combination with trastuzumab 35 and pertuzumab (Bergstrom D. A. et al., (2015) Cancer Res.; 75:LB-231). 30 15077.006WO2 ANTIBODY TARGETS In some embodiments, the antibody of an antibody conjugate composition is capable of binding one or more targets selected from (e.g., specifically binds to a target selected from) 5T4, ABL, ABCF1, ACVR1, ACVR1B, ACVR2, ACVR2B, ACVRL1, ADORA2A, Aggrecan, 5 AGR2, AICDA, AIF1, AIGI, AKAP1, AKAP2, AMH, AMHR2, ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANPEP, APC, APOC1, AR, aromatase, ATX, AX1, Axl, AZGP1 (zinc- a-glycoprotein), B7.1, B7.2, B7-H1, B7-H3, B7-H4, BAD, BAFF, BAG1, BAI1, BCR, BCL2, BCL6, BDNF, BLNK, BLR1 (MDR15), BIyS, BMP1, BMP2, BMP3B (GDFIO), BMP4, BMP6, BMP8, BMPRTA, BMPR1B, BMPR2, BPAG1 (plectin), BRCA1, C19orflO (IL27w), 10 C3, C4A, C5, C5R1, CANT1, CAPRIN-1, CASP1, CASP4, CAV1, CCBP2 (D6 / JAB61), CCLI (1-309), CCLI1 (eotaxin), CCL13 (MCP-4), CCL15 (MIP-Id), CCL16 (HCC-4), CCL17 (TARC), CCL18 (PARC), CCL19 (MIP-3b), CCL2 (MCP-1), MCAF, CCL20 (MIP-3a), CCL21 (MEP-2), SLC, exodus-2, CCL22(MDC / STC-1), CCL23 (MPIF-I), CCL24 (MPIF-2 / eotaxin-2), CCL25 (TECK), CCL26 (eotaxin-3), CCL27 (CTACK / ILC), CCL28, CCL3 (MIP-Ia), CCL4 15 (MIPIb), CCL5 (RANTES), CCL7 (MCP-3), CCL8 (mcp-2), CCNA1, CCNA2, CCND1, CCNE1, CCNE2, CCR1 (CKR1 / HM145), CCR2 (mcp-IRB / RA), CCR3 (CKR3 / CMKBR3), CCR4, CCR5 (CMKBR5 / ChemR13), CCR6 (CMKBR6 / CKR-L3 / STRL22 / DRY6), CCR7 (CKR7 / EBI1), CCR8 (CMKBR8 / TERI / CKR-L1), CCR9 (GPR-9-6), CCRL1 (VSHK1), CCRL2 (L-CCR), CD164, CD19, CDIC, CD2, CD20, CD21, CD200, CD22, CD24, CD27, CD28, CD3, 20 CD30, CD33, CD35, CD37, CD38, CD3E, CD3G, CD3Z, CD4, CD38, CD40, CD40L, CD44, CD45RB, CD47, CD52, CD69, CD72, CD74, CD79A, CD79B, CD8, CD80, CD81, CD83, CD86, CD117 (cKit), CD123, CD137, CD152, CD274, CDH1 (Ecadherin), CDH3 (Pcadherin), CDH1O, CDH12, CDH13, CDH18, CDH19, CDH2O, CDH5, CDH7, CDH8, CDH9, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, CDKN1A (p21Wap1 / Cip1), CDKN1B (p27Kip1), 25 CDKN1C, CDKN2A (p16INK4a), CDKN2B, CDKN2C, CDKN3, CEACAM5, CEACAM6, CEBPB, CERI, CHGA, CHGB, Chitinase, CHST1O, CKLFSF2, CKLFSF3, CKLFSF4, CKLFSF5, CKLFSF6, CKLFSF7, CKLFSF8, CLDN3, CLDN7 (claudin-7), CLDN18.2 (claudin 18.2), CLL-1, CLN3, CLU (clusterin), cMet, CMKLR1, CMKOR1 (RDC1), CNR1, COL18A1, COLIA1, COL4A3, COL6A1, CR2, Cripto, CRP, CSF1 (M-CSF), CSF2 (GM-CSF), 30 CSF3 (GCSF), CTL8, CTNNB1 (b-catenin), CTSB (cathepsin B), CX3CL1 (SCYD1), CX3CR1 (V28), CXCL1 (GRO1), CXCL1O (IP-IO), CXCLI1 (1-TAC / IP-9), CXCL12 (SDF1), CXCL13, CXCL14, CXCL16, CXCL2 (GRO2), CXCL3 (GRO3), CXCL5 (ENA-78 / LIX), CXCL6 (GCP- 2), CXCL9 (MIG), CXCR3 (GPR9 / CKR-L2), CXCR4, CXCR6 (TYMSTR / STRL33 / Bonzo), CYB5, CYC1, CYSLTR1, DAB2IP, DES, DKFZp451J0118, DNCL1, DPP4, E2F1, Engel, 35 Edge, Fennel, EFNA3, EFNB2, EGF, EGFR, ELAC2, ENG, Enola, ENO2, ENO3, EPHA1, 31 15077.006WO2 EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPRA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6, EPHRIN-A1, EPHRIN-A2, EPHRINA3, EPHRIN- A4, EPHRIN-A5, EPHRIN-A6, EPHRIN-B1, EPHRIN-B2, EPHRIN-B3, EPHB4, EPG, ERBB2 (Her-2), EREG, ERK8, Estrogen receptor, Earl, ESR2, F3 (TF), FADD, 5 farnesyltransferase, FasL, FAP, FASNf, FCER1A, FCER2, FCGR3A, FGF, FGF1 (aFGF), FGF10, FGF11, FGF12, FGF12B, FGF13, FGF14, FGF16, FGF17, FGF18, FGF19, FGF2 (bFGF). FGF20, FGF21, FGF22, FGF23, FGF3 (int-2), FGF4 (HST), FGF5, FGF6 (HST-2), FGF7 (KGF), FGF8, FGF9, FGFR3, FIGF (VEGFD), FILI (EPSILON), FBL1 (ZETA), FLJ12584, FLJ25530, FLRT1 (fibronectin), FLT1, FLT-3, FOLR1 (folate receptor alpha), FOS, 10 FOSL1 (FRA-1), FY (DARC), GABRP (GABAa), GAGEB1, GAGEC1, GALNAC4S-6ST, GATA3, GD2, GDF5, GFI1, GGT1, GM-CSF, GNAS1, GNRH1, GPC-1, GPR2 (CCR10), GPR31, GPR44, GPR81 (FKSG80), GRCC1O (C1O), GRP, GSN (Gelsolin), GSTP1, HAVCR2, HDAC, HDAC4, HDAC5, HDAC7A, HDAC9, Hedgehog, HGF, HIF1A, HIP1, histamine and histamine receptors, HLA-A, HLA-DRA, HLA-E, HM74, HMOXI, HSP90, HUMCYT2A, 15 ICEBERG, ICOSL, ID2, IFN-a, IFNA1, IFNA2, IFNA4, IFNA5, EFNA6, BFNA7, IFNB1, IFNgamma, IFNW1, IGBP1, IGF1, IGFIR, IGF2, IGFBP2, IGFBP3, IGFBP6, DL-1, ILIO, ILIORA, ILIORB, IL-1, IL1R1 (CD121a), IL1R2 (CD121b), IL-IRA, IL-2, IL2RA (CD25), IL2RB (CD122), IL2RG (CD132), IL-4, IL-4R (CD123), IL-5, IL5RA (CD125), IL3RB (CD131), IL-6, IL6RA, (CD126), IR6RB (CD130), IL-7, IL7RA (CD127), IL-8, CXCR1 20 (IL8RA), CXCR2, (IL8RB / CD128), IL-9, IL9R (CD129), IL-10, IL10RA (CD210), IL10RB (CDW210B), IL-11, IL11RA, IL-12, IL-12A, IL-12B, IL-12RB1, IL-12RB2, IL-13, IL13RA1, IL13RA2, IL14, IL15, IL15RA, IL16, IL17, IL17A, IL17B, IL17C, IL17R, IL18, IL18BP, IL18R1, IL18RAP, IL19, ILIA, ILIB, ILIF10, ILIF5, IL1F6, ILIF7, IL1F8, DL1F9, ILIHYI, ILIR1, ILIR2, ILIRAP, ILIRAPLI, ILIRAPL2, ILIRL1, IL1RL2, ILIRN, IL2, IL20, IL20RA, 25 IL21R, IL22, IL22R, IL22RA2, IL23, DL24, IL25, IL26, IL27, IL28A, IL28B, IL29, IL2RA, IL2RB, IL2RG, IL3, IL30, IL3RA, IL4, IL4, IL6ST (glycoprotein 130), ILK, INHA, INHBA, INSL3, INSL4, IRAK1, IRAK2, ITGA1, ITGA2, ITGA3, ITGA6 (.alpha.6 integrin), ITGAV, ITGB3, ITGB4 (.beta.4 integrin), ITGB6 (beta.6 integrin), JAG1, JAK1, JAK3, JTB, JUN, K6HF, KAI1, KDR, KITLG, KLF5 (GC Box BP), KLF6, KLK10, KLK12, KLK13, KLK14, 30 KLK15, KLK3, KLK4, KLK5, KLK6, KLK9, KRT1, KRT19 (Keratin 19), KRT2A, KRTHB6 (hair-specific type II keratin), LAMA5, LEP (leptin), Lingo-p75, Lingo-Troy, LIV-1, LPS, LRRC15, LTA (TNF-b)), LTB, LTB4R (GPR16), LTB4R2, LTBR, MACMARCKS, MAG or OMgp, MAP2K7 (c-Jun), MCP-1, MDK, MIB1, midkine, MIF, MISRII, MJP-2, MK, MKI67 (Ki-67), MMP2, MMP9, MS4A1, MSMB, MT3 (metallothionectin-UI), mTOR, MTSS1, MUC1 35 (mucin), MUC16, MYC, MYD88, NCK2, neurocan, Nectin-4, NFKBI, NFKB2, NGFB (NGF), 32 15077.006WO2 NGFR, NgR-Lingo, NgRNogo66, (Nogo), NgR-p75, NgR-Troy, NMEI (NM23A), NOTCH, NOTCH1, NOX5, NPPB, NROB1, NROB2, NRID1, NR1D2, NR1H2, NR1H3, NR1H4, NR112, NR113, NR2C1, NR2C2, NR2E1, NR2E3, NR2F1, NR2F2, NR2F6, NR3C1, NR3C2, NR4A1, NR4A2, NR4A3, NR5A1, NR5A2, NR6A1, NRP1, NRP2, NT5E, NTN4, ODZI, 5 OPRDI, P2RX7, PAP, PART1, PATE, PAWR, PCA3, PCDGF, PCNA, PDGFA, PDGFB, PDGFRA, PDGFRB, PECAMI, peg-asparaginase, PF4 (CXCL4), PGF, PGR, phosphacan, PIAS2, PI3 Kinase, PIK3CG, PLAU (uPA), PLG, PLXDCI, PKC, PKC-beta, PPBP (CXCL7), PPID, PR1, PRKCQ, PRKD1, PRL, PROC, PROK2, PSAP, PSCA, PSMA, PTAFR, PTEN, PTGS2 (COX-2), PIN, RAC2 (P21Rac2), RANK, RANK ligand, RARB, RGS1, RGS13, RGS3, 10 RNFI1O (ZNF144), Ron, ROBO2, RXR, S100A2, SCGB 1D2 (lipophilin B), SCGB2A1 (mammaglobin 2), SCGB2A2 (mammaglobin 1), SCYE1 (endothelial Monocyte-activating cytokine), SDF2, SERPENA1, SERPINA3, SERPINB5 (maspin), SERPINEI (PAI-I), SERPINFI, SHIP-1, SHIP-2, SHB1, SHB2, SHBG, SfcAZ, SLC2A2, SLC33A1, SLC43A1, SLIT2, SPP1, SPRR1B (Spr1), ST6GAL1, STAB1, STATE, STEAP, STEAP2, TB4R2, TBX21, 15 TCP1O, TDGF1, TEK, TGFA, TGFB1, TGFB1I1, TGFB2, TGFB3, TGFBI, TGEBR1, TGFBR2, TGFBR3, THIL, THBS1 (thrombospondin-1), THBS2, THBS4, THPO, TIE (Tie-1), TIMP3, tissue factor, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TNF, TNF-a, TNFAIP2 (B94), TNFAIP3, TNFRSF11A, TNFRSF1A, TNFRSF1B, TNFRSF21, TNFRSF5, TNFRSF6 (Fas), TNFRSF7, TNFRSF8, TNFRSF9, TNFSF1O 20 (TRAIL), TNFSF11 (TRANCE), TNFSF12 (APO3L), TNFSF13 (April), TNFSF13B, TNSF14 (HVEM-L), TNFRSF14 (HVEM), TNFSF15 (VEGI), TNFSF18, TNFSF4 (OX40 ligand), TNFSF5 (CD40 ligand). TNFSF6 (FasL), TNFSF7 (CD27 ligand), TNFSF8 (CD30 ligand), TNFSF9 (4-1BB ligand), TOLLIP, Toll-like receptors, TOP2A (topoisomerase 1ia), TP53, TPM1, TPM2, TRADD, TRAF1, TRAF2, TRAF3, TRAF4, TRAF5, TRAF6, TRKA, TREM1, 25 TREM2, TROP2, TRPC6, TSLP, TWEAK, Tyrosinase, uPAR, VEGF, VEGFB, VEGFC, versican, VHL C5, VLA-4, Wnt-1, XCL1 (tymphotactin), XCL2 (SCM-Ib), XCRI (GPR5 / CCXCR1), YYI, ZFPM2, CLEC4C (BDCA-2, DLEC, CD303, CLECSF7), CLEC4D (MCL, CLECSF8), CLEC4E (Mincle), CLEC6A (Dectin-2). CLEC5A (MDL-1, CLECSF5), CLEC1B (CLEC-2), CLEC9A (DNGR-1), CLEC7A (Dectin-1), PDGFRa, SLAMF7, GP6 30 (GPVI), LILRA1 (CD85I), LILRA2 (CD85H, ILT1), LILRA4 (CD85G, ILT7), LILRA5 (CD85F, ILT11), LILRA6 (CD85b, ILT8), NCR1 (CD335, LY94, NKp46), NCR3 (CD335, LY94, NKp46), NCR3 (CD337, NKp30), OSCAR, TARM1, CD300C, CD300E, CD300LB (CD300B), CD300LD (CD300D), KIR2DL4 (CD158D), KIR2DS, KLRC2 (CD159C, NKG2C), KLRK1 (CD314, NKG2D), NCR2 (CD336, NKp44), PILRB, SIGLEC1 (CD169, SN), 33 15077.006WO2 SIGLEC14, SIGLEC15 (CD33L3), SIGLEC16, SIRPB1 (CD172B), TREM1 (CD354), Tissue Factor (CD142), TREM2, and KLRF1 (NKp80). In some embodiments, the antibody binds to an antigen selected from CDH1, CD19, CD20, CD29, CD30, CD38, CD40, CD47, EpCAM, MUC1, MUC16, EGFR, HER2, SLAMF7, 5 and gp75. In some embodiments, the antibody of an antibody conjugate composition of the invention is capable of binding to one or more tumor-associated antigens (TAA), cell-surface receptors, and immune-specific antigens to confer specificity to the targeting of the conjugate and enable safe and systemic delivery of an active drug moiety. 10 Certain tumor-associated antigens are known in the art, and can be prepared for use in generating antibodies using methods and information which are well known in the art. In attempts to discover effective cellular targets for cancer diagnosis and therapy, researchers have sought to identify transmembrane or otherwise tumor-associated polypeptides that are specifically expressed on the surface of one or more particular type(s) of cancer cell as 15 compared to on one or more normal non-cancerous cell(s). Often, such tumor-associated polypeptides are more abundantly expressed on the surface of the cancer cells as compared to on the surface of the non-cancerous cells. The identification of such tumor-associated cell surface antigen polypeptides allows more specificity in targeting cancer cells for destruction via antibody-based therapies. 20 Examples of TAAs include, but are not limited to, those listed below including (1)-(54). For convenience, information relating to these antigens, all of which are known in the art, is listed below and includes names, alternative names, Genbank accession numbers and primary reference(s), following nucleic acid and protein sequence identification conventions of the National Center for Biotechnology Information (NCBI). Nucleic acid and protein sequences 25 corresponding to TAAs listed below including (1)-(54) are available in public databases such as GenBank. TAAs targeted by antibodies include all amino acid sequence variants and isoforms possessing at least about 70%, 80%, 85%, 90%, or 95% sequence identity relative to the sequences identified in the cited references, and / or which exhibit substantially the same biological properties or characteristics as a TAA having a sequence found in the cited references. 30 For example, a TAA having a variant sequence generally is able to bind specifically to an antibody that binds specifically to the TAA with the corresponding sequence listed. The sequences and disclosure in the reference specifically recited herein are expressly incorporated by reference. The disclosure in the references specifically recited herein are expressly incorporated by 35 reference. 34 15077.006WO2 (1) BMPR1B (bone morphogenetic protein receptor-type IB, Genbank accession no. NM_001203) ten Dijke, P., et al. Science 264 (5155):101-104 (1994), Oncogene 14 (11):1377- 1382 (1997)); WO2004063362 (Claim 2); WO2003042661 (Claim 12); US2003134790-A1 (Page 38-39); WO2002102235 (Claim 13; Page 296); WO2003055443 (Page 91-92); 5 WO200299122 (Example 2; Page 528-530); WO2003029421 (Claim 6); WO2003024392 (Claim 2; Fig 112); WO200298358 (Claim 1; Page 183); WO200254940 (Page 100-101); WO200259377(Page 349-350); WO200230268 (Claim 27; Page 376); WO200148204 (Example; Fig 4) NP_001194 bone morphogenetic protein receptor, type IB / pid=NP_001194.1 – Cross-references: MIM:603248; NP_001194.1; AY065994. 10 (2) E16 (LAT1, SLC7A5, Genbank accession no. NM_003486) Biochem. Biophys. Res. Commun.255 (2), 283-288 (1999), Nature 395 (6699):288-291 (1998), Gaugitsch, H.W., et al. (1992) J. Biol. Chem.267 (16):11267-11273); WO2004048938 (Example 2); WO2004032842 (Example IV); WO2003042661 (Claim 12); WO2003016475 (Claim 1); WO200278524 (Example 2); WO200299074 (Claim 19; Page 127-129); WO200286443 (Claim 27; Pages 222, 15 393); WO2003003906 (Claim 10; Page 293); WO200264798 (Claim 33; Page 93-95); WO200014228 (Claim 5; Page 133-136); US2003224454 (Fig 3); WO2003025138 (Claim 12; Page 150); NP_003477 solute carrier family 7 (cationic amino acid transporter, y+ system), member 5 / pid=NP_003477.3 – Homo sapiens Cross-references: MIM:600182; NP_003477.3; NM_015923; NM_003486_1. 20 (3) STEAP1 (six transmembrane epithelial antigen of prostate, Genbank accession no. NM_012449) Cancer Res.61 (15), 5857-5860 (2001), Hubert, R.S., et al. (1999) Proc. Natl. Acad. Sci. U.S.A.96 (25):14523-14528); WO2004065577 (Claim 6); WO2004027049 (Fig 1L); EP1394274 (Example 11); WO2004016225 (Claim 2); WO2003042661 (Claim 12); US2003157089 (Example 5); US2003185830 (Example 5); US2003064397 (Fig 2); 25 WO200289747 (Example 5; Page 618-619); WO2003022995 (Example 9; Fig 13A, Example 53; Page 173, Example 2; Fig 2A); NP_036581 six transmembrane epithelial antigen of the prostate Cross-references: MIM:604415; NP_036581.1; NM_012449_1. (4) 0772P (CA125, MUC16, Genbank accession no. AF361486) J. Biol. Chem.276 (29):27371-27375 (2001)); WO2004045553 (Claim 14); WO200292836 (Claim 6; Fig 12);30 WO200283866 (Claim 15; Page 116-121); US2003124140 (Example 16); US 798959. Cross- references: GI:34501467; AAK74120.3; AF361486_1. (5) MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin, Genbank accession no. NM_005823) Yamaguchi, N., et al. Biol. Chem.269 (2), 805-808 (1994), Proc. Natl. Acad. Sci. U.S.A.96 (20):11531-11536 (1999), Proc. Natl. Acad. Sci. U.S.A.93 (1):136- 35 140 (1996), J. Biol. Chem.270 (37):21984-21990 (1995)); WO2003101283 (Claim 14); 35 15077.006WO2 (WO2002102235 (Claim 13; Page 287-288); WO2002101075 (Claim 4; Page 308-309); WO200271928 (Page 320-321); WO9410312 (Page 52-57); Cross-references: MIM:601051; NP_005814.2; NM_005823_1. (6) Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), 5 member 2, type II sodium-dependent phosphate transporter 3b,Genbank accession no. NM_006424) J. Biol. Chem.277 (22):19665-19672 (2002), Genomics 62 (2):281-284 (1999), Field, J.A., et al. (1999) Biochem. Biophys. Res. Commun.258 (3):578-582); WO2004022778 (Claim 2); EP1394274 (Example 11); WO2002102235 (Claim 13; Page 326); EP875569 (Claim 1; Page 17-19); WO200157188 (Claim 20; Page 329); WO2004032842 (Example IV); 10 WO200175177 (Claim 24; Page 139-140); Cross-references: MIM:604217; NP_006415.1; NM_006424_1. (7) Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5b Hlog, sema domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (36emaphoring) 5B, Genbank accession no. 15 AB040878) Nagase T., et al. (2000) DNA Res.7 (2):143-150); WO2004000997 (Claim 1); WO2003003984 (Claim 1); WO200206339 (Claim 1; Page 50); WO200188133 (Claim 1; Page 41-43, 48-58); WO2003054152 (Claim 20); WO2003101400 (Claim 11); Accession: Q9P283; EMBL; AB040878; BAA95969.1. Genew; HGNC:10737. (8) PSCA hlg (2700050C12Rik, C530008O16Rik, RIKEN cDNA 2700050C12, RIKEN 20 cDNA 2700050C12 gene, Genbank accession no. AY358628); Ross et al. (2002) Cancer Res. 62:2546-2553; US2003129192 (Claim 2); US2004044180 (Claim 12); US2004044179 (Claim 11); US2003096961 (Claim 11); US2003232056 (Example 5); WO2003105758 (Claim 12); US2003206918 (Example 5); EP1347046 (Claim 1); WO2003025148 (Claim 20); Cross- references: GI:37182378; AAQ88991.1; AY358628_1. 25 (9) ETBR (Endothelin type B receptor, Genbank accession no. AY275463); Nakamuta M., et al. Biochem. Biophys. Res. Commun.177, 34-39, 1991; Ogawa Y., et al. Biochem. Biophys. Res. Commun.178, 248-255, 1991; Arai H., et al. Jpn. Circ. J.56, 1303-1307, 1992; Arai H., et al. J. Biol. Chem.268, 3463-3470, 1993; Sakamoto A., Yanagisawa M., et al. Biochem. Biophys. Res. Commun.178, 656-663, 1991; Elshourbagy N.A., et al. J. Biol. Chem. 30 268, 3873-3879, 1993; Haendler B., et al. J. Cardiovasc. Pharmacol.20, s1-S4, 1992; Tsutsumi M., et al. Gene 228, 43-49, 1999; Strausberg R.L., et al. Proc. Natl. Acad. Sci. U.S.A.99, 16899- 16903, 2002; Bourgeois C., et al. J. Clin. Endocrinol. Metab.82, 3116-3123, 1997; Okamoto Y., et al. Biol. Chem.272, 21589-21596, 1997; Verheij J.B., et al. Am. J. Med. Genet.108, 223-225, 2002; Hofstra R.M.W., et al. Eur. J. Hum. Genet.5, 180-185, 1997; Puffenberger E.G., et al. 35 Cell 79, 1257-1266, 1994; Attie T., et al., Hum. Mol. Genet.4, 2407-2409, 1995; Auricchio A., 36 15077.006WO2 et al. Hum. Mol. Genet.5:351-354, 1996; Amiel J., et al. Hum. Mol. Genet.5, 355-357, 1996; Hofstra R.M.W., et al. Nat. Genet.12, 445-447, 1996; Svensson P.J., et al. Hum. Genet.103, 145-148, 1998; Fuchs S., et al. Mol. Med.7, 115-124, 2001; Pingault V., et al. (2002) Hum. Genet.111, 198-206; WO2004045516 (Claim 1); WO2004048938 (Example 2); 5 WO2004040000 (Claim 151); WO2003087768 (Claim 1); WO2003016475 (Claim 1); WO2003016475 (Claim 1); WO200261087 (Fig 1); WO2003016494 (Fig 6); WO2003025138 (Claim 12; Page 144); WO200198351 (Claim 1; Page 124-125); EP522868 (Claim 8; Fig 2); WO200177172 (Claim 1; Page 297-299); US2003109676; US6518404 (Fig 3); US5773223 (Claim 1a; Col 31-34); WO2004001004. 10 (10) MSG783 (RNF124, hypothetical protein FLJ20315, Genbank accession no. NM_017763); WO2003104275 (Claim 1); WO2004046342 (Example 2); WO2003042661 (Claim 12); WO2003083074 (Claim 14; Page 61); WO2003018621 (Claim 1); WO2003024392 (Claim 2; Fig 93); WO200166689 (Example 6); Cross-references: LocusID:54894; NP_060233.2; NM_017763_1. 15 (11) STEAP2 (HGNC_8639, IPCA-1, PCANAP1, STAMP1, STEAP2, STMP, prostate cancer associated gene 1, prostate cancer associated protein 1, six transmembrane epithelial antigen of prostate 2, six transmembrane prostate protein, Genbank accession no. AF455138) Lab. Invest.82 (11):1573-1582 (2002)); WO2003087306; US2003064397 (Claim 1; Fig 1); WO200272596 (Claim 13; Page 54-55); WO200172962 (Claim 1; Fig 4B); WO2003104270 20 (Claim 11); WO2003104270 (Claim 16); US2004005598 (Claim 22); WO2003042661 (Claim 12); US2003060612 (Claim 12; Fig 10); WO200226822 (Claim 23; Fig 2); WO200216429 (Claim 12; Fig 10); Cross-references: GI:22655488; AAN04080.1; AF455138_1. (12) TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel, subfamily M, member 4, Genbank accession no. NM_017636) Xu, X.Z., et al. Proc. 25 Natl. Acad. Sci. U.S.A.98 (19):10692-10697 (2001), Cell 109 (3):397-407 (2002), J. Biol. Chem.278 (33):30813-30820 (2003)); US2003143557 (Claim 4); WO200040614 (Claim 14; Page 100-103); WO200210382 (Claim 1; Fig 9A); WO2003042661 (Claim 12); WO200230268 (Claim 27; Page 391); US2003219806 (Claim 4); WO200162794 (Claim 14; Fig 1A-D); Cross- references: MIM:606936; NP_060106.2; NM_017636_1. 30 (13) CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor, Genbank accession no. NP_003203 or NM_003212) Ciccodicola, A., et al. EMBO J.8 (7):1987-1991 (1989), Am. J. Hum. Genet.49 (3):555-565 (1991)); US2003224411 (Claim 1); WO2003083041 (Example 1); WO2003034984 (Claim 12); WO200288170 (Claim 2; Page 52- 53); WO2003024392 (Claim 2; Fig 58); WO200216413 (Claim 1; Page 94-95, 105); 37 15077.006WO2 WO200222808 (Claim 2; Fig 1); US5854399 (Example 2; Col 17-18); US5792616 (Fig 2); Cross-references: MIM:187395; NP_003203.1; NM_003212_1. (14) CD21 (CR2 (Complement receptor 2) or C3DR (C3d / Epstein Barr virus receptor) or Hs.73792 Genbank accession no. M26004) Fujisaku et al. (1989) J. Biol. Chem.264 (4):2118- 5 2125); Weis J.J., et al. J. Exp. Med.167, 1047-1066, 1988; Moore M., et al. Proc. Natl. Acad. Sci. U.S.A.84, 9194-9198, 1987; Barel M., et al. Mol. Immunol.35, 1025-1031, 1998; Weis J.J., et al. Proc. Natl. Acad. Sci. U.S.A.83, 5639-5643, 1986; Sinha S.K., et al. (1993) J. Immunol.150, 5311-5320; WO2004045520 (Example 4); US2004005538 (Example 1); WO2003062401 (Claim 9); WO2004045520 (Example 4); WO9102536 (Fig 9.1-9.9); 10 WO2004020595 (Claim 1); Accession: P20023; Q13866; Q14212; EMBL; M26004; AAA35786.1. (15) CD79b (CD79B, CD79^, Igb (immunoglobulin-associated beta), B29, Genbank accession no. NM_000626 or 11038674) Proc. Natl. Acad. Sci. U.S.A. (2003) 100 (7):4126- 4131, Blood (2002) 100 (9):3068-3076, Muller et al. (1992) Eur. J. Immunol.22 (6):1621- 15 1625); WO2004016225 (claim 2, Fig 140); WO2003087768, US2004101874 (claim 1, page 102); WO2003062401 (claim 9); WO200278524 (Example 2); US2002150573 (claim 5, page 15); US5644033; WO2003048202 (claim 1, pages 306 and 309); WO 99 / 558658, US6534482 (claim 13, Fig 17A / B); WO200055351 (claim 11, pages 1145-1146); Cross-references: MIM:147245; NP_000617.1; NM_000626_1. 20 (16) FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain containing phosphatase anchor protein 1a), SPAP1B, SPAP1C, Genbank accession no. NM_030764, AY358130) Genome Res. 13 (10):2265-2270 (2003), Immunogenetics 54 (2):87-95 (2002), Blood 99 (8):2662-2669 (2002), Proc. Natl. Acad. Sci. U.S.A.98 (17):9772-9777 (2001), Xu, M.J., et al. (2001) Biochem. Biophys. Res. Commun.280 (3):768-775; WO2004016225 (Claim 2); 25 WO2003077836; WO200138490 (Claim 5; Fig 18D-1-18D-2); WO2003097803 (Claim 12); WO2003089624 (Claim 25); Cross-references: MIM:606509; NP_110391.2; NM_030764_1. (17) HER2 (ErbB2, Genbank accession no. M11730) Coussens L., et al. Science (1985) 230(4730):1132-1139); Yamamoto T., et al. Nature 319, 230-234, 1986; Semba K., et al. Proc. Natl. Acad. Sci. U.S.A.82, 6497-6501, 1985; Swiercz J.M., et al. J. Cell Biol.165, 869-880, 30 2004; Kuhns J.J., et al. J. Biol. Chem.274, 36422-36427, 1999; Cho H.-S., et al. Nature 421, 756-760, 2003; Ehsani A., et al. (1993) Genomics 15, 426-429; WO2004048938 (Example 2); WO2004027049 (Fig 1I); WO2004009622; WO2003081210; WO2003089904 (Claim 9); WO2003016475 (Claim 1); US2003118592; WO2003008537 (Claim 1); WO2003055439 (Claim 29; Fig 1A-B); WO2003025228 (Claim 37; Fig 5C); WO200222636 (Example 13; Page 35 95-107); WO200212341 (Claim 68; Fig 7); WO200213847 (Page 71-74); WO200214503 (Page 38 15077.006WO2 114-117); WO200153463 (Claim 2; Page 41-46); WO200141787 (Page 15); WO200044899 (Claim 52; Fig 7); WO200020579 (Claim 3; Fig 2); US5869445 (Claim 3; Col 31-38); WO9630514 (Claim 2; Page 56-61); EP1439393 (Claim 7); WO2004043361 (Claim 7); WO2004022709; WO200100244 (Example 3; Fig 4); Accession: P04626; EMBL; M11767; 5 AAA35808.1. EMBL; M11761; AAA35808.1. (18) NCA (CEACAM6, Genbank accession no. M18728); Barnett T., et al. Genomics 3, 59-66, 1988; Tawaragi Y., et al. Biochem. Biophys. Res. Commun.150, 89-96, 1988; Strausberg R.L., et al. Proc. Natl. Acad. Sci. U.S.A.99:16899-16903, 2002; WO2004063709; EP1439393 (Claim 7); WO2004044178 (Example 4); WO2004031238; WO2003042661 (Claim 12); 10 WO200278524 (Example 2); WO200286443 (Claim 27; Page 427); WO200260317 (Claim 2); Accession: P40199; Q14920; EMBL; M29541; AAA59915.1. EMBL; M18728. (19) MDP (DPEP1, Genbank accession no. BC017023) Proc. Natl. Acad. Sci. U.S.A.99 (26):16899-16903 (2002)); WO2003016475 (Claim 1); WO200264798 (Claim 33; Page 85-87); JP05003790 (Fig 6-8); WO9946284 (Fig 9); Cross-references: MIM:179780; AAH17023.1; 15 BC017023_1. (20) IL20R^ (IL20Ra, ZCYTOR7, Genbank accession no. AF184971); Clark H.F., et al. Genome Res.13, 2265-2270, 2003; Mungall A.J., et al. Nature 425, 805-811, 2003; Blumberg H., et al. Cell 104, 9-19, 2001; Dumoutier L., et al. J. Immunol.167, 3545-3549, 2001; Parrish- Novak J., et al. J. Biol. Chem.277, 47517-47523, 2002; Pletnev S., et al. (2003) Biochemistry 20 42:12617-12624; Sheikh F., et al. (2004) J. Immunol.172, 2006-2010; EP1394274 (Example 11); US2004005320 (Example 5); WO2003029262 (Page 74-75); WO2003002717 (Claim 2; Page 63); WO200222153 (Page 45-47); US2002042366 (Page 20-21); WO200146261 (Page 57- 59); WO200146232 (Page 63-65); WO9837193 (Claim 1; Page 55-59); Accession: Q9UHF4; Q6UWA9; Q96SH8; EMBL; AF184971; AAF01320.1. 25 (21) Brevican (BCAN, BEHAB, Genbank accession no. AF229053) Gary S.C., et al. Gene 256, 139-147, 2000; Clark H.F., et al. Genome Res.13, 2265-2270, 2003; Strausberg R.L., et al. Proc. Natl. Acad. Sci. U.S.A.99, 16899-16903, 2002; US2003186372 (Claim 11); US2003186373 (Claim 11); US2003119131 (Claim 1; Fig 52); US2003119122 (Claim 1; Fig 52); US2003119126 (Claim 1); US2003119121 (Claim 1; Fig 52); US2003119129 (Claim 1); 30 US2003119130 (Claim 1); US2003119128 (Claim 1; Fig 52); US2003119125 (Claim 1); WO2003016475 (Claim 1); WO200202634 (Claim 1). (22) EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5, Genbank accession no. NM_004442) Chan, J. and Watt, V.M., Oncogene 6 (6), 1057-1061 (1991) Oncogene 10 (5):897-905 (1995), Annu. Rev. Neurosci.21:309-345 (1998), Int. Rev. Cytol.196:177-244 (2000)); 35 WO2003042661 (Claim 12); WO200053216 (Claim 1; Page 41); WO2004065576 (Claim 1); 39 15077.006WO2 WO2004020583 (Claim 9); WO2003004529 (Page 128-132); WO200053216 (Claim 1; Page 42); Cross-references: MIM:600997; NP_004433.2; NM_004442_1. (23) ASLG659 (B7h, Genbank accession no. AX092328) US20040101899 (Claim 2); WO2003104399 (Claim 11); WO2004000221 (Fig 3); US2003165504 (Claim 1); 5 US2003124140 (Example 2); US2003065143 (Fig 60); WO2002102235 (Claim 13; Page 299); US2003091580 (Example 2); WO200210187 (Claim 6; Fig 10); WO200194641 (Claim 12; Fig 7b); WO200202624 (Claim 13; Fig 1A-1B); US2002034749 (Claim 54; Page 45-46); WO200206317 (Example 2; Page 320-321, Claim 34; Page 321-322); WO200271928 (Page 468-469); WO200202587 (Example 1; Fig 1); WO200140269 (Example 3; Pages 190-192); 10 WO200036107 (Example 2; Page 205-207); WO2004053079 (Claim 12); WO2003004989 (Claim 1); WO200271928 (Page 233-234, 452-453); WO 0116318. (24) PSCA (Prostate stem cell antigen precursor, Genbank accession no. AJ297436) Reiter R.E., et al. Proc. Natl. Acad. Sci. U.S.A.95, 1735-1740, 1998; Gu Z., et al. Oncogene 19, 1288-1296, 2000; Biochem. Biophys. Res. Commun. (2000) 275(3):783-788; WO2004022709; 15 EP1394274 (Example 11); US2004018553 (Claim 17); WO2003008537 (Claim 1); WO200281646 (Claim 1; Page 164); WO 2003003906 (Claim 10; Page 288); WO 200140309 (Example 1; Fig 17); US 2001055751 (Example 1; Fig 1b); WO 200032752 (Claim 18; Fig 1); WO 1998 / 51805 (Claim 17; Page 97); WO 1998 / 51824 (Claim 10; Page 94); WO 1998 / 40403 (Claim 2; Fig 1B); Accession: O43653; EMBL; AF043498; AAC39607.1. 20 (25) GEDA (Genbank accession No. AY260763); AAP14954 lipoma HMGIC fusion- partner-like protein / pid=AAP14954.1 – Homo sapiens Species: Homo sapiens (human) WO2003054152 (Claim 20); WO2003000842 (Claim 1); WO2003023013 (Example 3, Claim 20); US2003194704 (Claim 45); Cross-references: GI:30102449; AAP14954.1; AY260763_1. (26) BAFF-R (B cell -activating factor receptor, BlyS receptor 3, BR3, Genbank 25 accession No. AF116456); BAFF receptor / pid=NP_443177.1 – Homo sapiens Thompson, J.S., et al. Science 293 (5537), 2108-2111 (2001); WO2004058309; WO2004011611; WO2003045422 (Example; Page 32-33); WO2003014294 (Claim 35; Fig 6B); WO2003035846 (Claim 70; Page 615-616); WO200294852 (Col 136-137); WO200238766 (Claim 3; Page 133); WO200224909 (Example 3; Fig 3); Cross-references: MIM:606269; NP_443177.1; 30 NM_052945_1; AF132600. (27) CD22 (B-cell receptor CD22-B isoform, BL-CAM, Lyb-8, Lyb8, SIGLEC-2, FLJ22814, Genbank accession No. AK026467); Wilson et al. (1991) J. Exp. Med.173:137-146; WO2003072036 (Claim 1; Fig 1); Cross-references: MIM:107266; NP_001762.1; NM_001771_1. 40 15077.006WO2 (28) CD79a (CD79A, CD79^, immunoglobulin-associated alpha, a B cell-specific protein that covalently interacts with Ig beta (CD79B) and forms a complex on the surface with Ig M molecules, transduces a signal involved in B-cell differentiation), pI: 4.84, MW: 25028 TM: 2 [P] Gene Chromosome: 19q13.2, Genbank accession No. NP_001774.10) 5 WO2003088808, US20030228319; WO2003062401 (claim 9); US2002150573 (claim 4, pages 13-14); WO9958658 (claim 13, Fig 16); WO9207574 (Fig 1); US5644033; Ha et al. (1992) J. Immunol.148(5):1526-1531; Mueller et al. (1992) Eur. J. Biochem.22:1621-1625; Hashimoto et al. (1994) Immunogenetics 40(4):287-295; Preud’homme et al. (1992) Clin. Exp. Immunol. 90(1):141-146; Yu et al. (1992) J. Immunol.148(2) 633-637; Sakaguchi et al. (1988) EMBO J. 10 7(11):3457-3464. (29) CXCR5 (Burkitt’s lymphoma receptor 1, a G protein-coupled receptor that is activated by the CXCL13 chemokine, functions in lymphocyte migration and humoral defense, plays a role in HIV-2 infection and perhaps development of AIDS, lymphoma, myeloma, and leukemia); 372 aa, pI: 8.54 MW: 41959 TM: 7 [P] Gene Chromosome: 11q23.3, Genbank 15 accession No. NP_001707.1) WO 2004040000; WO2004 / 015426; US2003105292 (Example 2); US6555339 (Example 2); WO 2002 / 61087 (Fig 1); WO200157188 (Claim 20, page 269); WO200172830 (pages 12-13); WO 2000 / 22129 (Example 1, pages 152-153, Example 2, pages 254-256); WO 199928468 (claim 1, page 38); US 5440021 (Example 2, col 49-52); WO9428931 (pages 56-58); WO 1992 / 17497 (claim 7, Fig 5); Dobner et al. (1992) Eur. J. 20 Immunol.22:2795-2799; Barella et al. (1995) Biochem. J.309:773-779. (30) HLA-DOB (Beta subunit of MHC class II molecule (Ia antigen) that binds peptides and presents them to CD4+ T lymphocytes); 273 aa, pI: 6.56 MW: 30820 TM: 1 [P] Gene Chromosome: 6p21.3, Genbank accession No. NP_002111.1) Tonnelle et al. (1985) EMBO J. 4(11):2839-2847; Jonsson et al. (1989) Immunogenetics 29(6):411-413; Beck et al. (1992) J. 25 Mol. Biol.228:433-441; Strausberg et al. (2002) Proc. Natl. Acad. Sci USA 99:16899-16903; Servenius et al. (1987) J. Biol. Chem.262:8759-8766; Beck et al. (1996) J. Mol. Biol.255:1-13; Naruse et al. (2002) Tissue Antigens 59:512-519; WO9958658 (claim 13, Fig 15); US6153408 (Col 35-38); US5976551 (col 168-170); US6011146 (col 145-146); Kasahara et al. (1989) Immunogenetics 30(1):66-68; Larhammar et al. (1985) J. Biol. Chem.260(26):14111-14119. 30 (31) P2X5 (Purinergic receptor P2X ligand-gated ion channel 5, an ion channel gated by extracellular ATP, may be involved in synaptic transmission and neurogenesis, deficiency may contribute to the pathophysiology of idiopathic detrusor instability); 422 aa), pI: 7.63, MW: 47206 TM: 1 [P] Gene Chromosome: 17p13.3, Genbank accession No. NP_002552.2) Le et al. (1997) FEBS Lett.418(1-2):195-199; WO2004047749; WO2003072035 (claim 10); Touchman 41 15077.006WO2 et al. (2000) Genome Res.10:165-173; WO200222660 (claim 20); WO2003093444 (claim 1); WO2003087768 (claim 1); WO2003029277 (page 82). (32) CD72 (B-cell differentiation antigen CD72, Lyb-2), pI: 8.66, MW: 40225 TM: 1 [P] Gene Chromosome: 9p13.3, Genbank accession No. NP_001773.1) WO2004042346 (claim 5 65); WO 2003 / 026493 (pages 51-52, 57-58); WO 2000 / 75655 (pages 105-106); Von Hoegen et al. (1990) J. Immunol.144(12):4870-4877; Strausberg et al. (2002) Proc. Natl. Acad. Sci USA 99:16899-16903. (33) LY64 (Lymphocyte antigen 64 (RP105), type I membrane protein of the leucine rich repeat (LRR) family, regulates B-cell activation and apoptosis, loss of function is associated 10 with increased disease activity in patients with systemic lupus erythematosus); 661 aa, pI: 6.20, MW: 74147 TM: 1 [P] Gene Chromosome: 5q12, Genbank accession No. NP_005573.1) US2002193567; WO9707198 (claim 11, pages 39-42); Miura et al. (1996) Genomics 38(3):299- 304; Miura et al. (1998) Blood 92:2815-2822; WO2003083047; WO9744452 (claim 8, pages 57-61); WO200012130 (pages 24-26). 15 (34) FcRH1 (Fc receptor-like protein 1, a putative receptor for the immunoglobulin Fc domain that contains C2 type Ig-like and ITAM domains, may have a role in B-lymphocyte differentiation); 429 aa, pI: 5.28, MW: 46925 TM: 1 [P] Gene Chromosome: 1q21-1q22, Genbank accession No. NP_443170.1) WO2003077836; WO200138490 (claim 6, Fig 18E-1- 18-E-2); Davis et al. (2001) Proc. Natl. Acad. Sci USA 98(17):9772-9777; WO2003089624 20 (claim 8); EP1347046 (claim 1); WO2003089624 (claim 7). (35) IRTA2 (Immunoglobulin superfamily receptor translocation associated 2, a putative immunoreceptor with possible roles in B cell development and lymphomagenesis; deregulation of the gene by translocation occurs in some B cell malignancies); 977 aa, pI: 6.88 MW: 106468 TM: 1 [P] Gene Chromosome: 1q21, Genbank accession No. Human:AF343662, AF343663, 25 AF343664, AF343665, AF369794, AF397453, AK090423, AK090475, AL834187, AY358085; Mouse:AK089756, AY158090, AY506558; NP_112571.1. WO2003024392 (claim 2, Fig 97); Nakayama et al. (2000) Biochem. Biophys. Res. Commun.277(1):124-127; WO2003077836; WO200138490 (claim 3, Fig 18B-1-18B-2). (36) TENB2 (TMEFF2, tomoregulin, TPEF, HPP1, TR, putative transmembrane 30 proteoglycan, related to the EGF / heregulin family of growth factors and follistatin); 374 aa, NCBI Accession: AAD55776, AAF91397, AAG49451, NCBI RefSeq: NP_057276; NCBI Gene: 23671; OMIM: 605734; SwissProt Q9UIK5; Genbank accession No. AF179274; AY358907, CAF85723, CQ782436 WO 2004074320; JP 2004113151; WO 2003042661; WO2003009814; EP1295944 (pages 69-70); WO 200230268 (page 329); WO 200190304; 35 US2004249130; US 2004022727; WO 2004063355; US 2004197325; US2003232350; 42 15077.006WO2 US2004005563; US 2003124579; Horie et al. (2000) Genomics 67:146-152; Uchida et al. (1999) Biochem. Biophys. Res. Commun.266:593-602; Liang et al. (2000) Cancer Res.60:4907- 12; Glynne-Jones et al. (2001) Int J Cancer. Oct 15;94(2):178-84. (37) PMEL17 (silver homolog; SILV; D12S53E; PMEL17; SI; SIL); ME20; gp100) 5 BC001414; BT007202; M32295; M77348; NM_006928; McGlinchey, R.P. et al. (2009) Proc. Natl. Acad. Sci. U.S.A.106 (33), 13731-13736; Kummer, M.P. et al. (2009) J. Biol. Chem.284 (4), 2296-2306. (38) TMEFF1 (transmembrane protein with EGF-like and two follistatin-like domains 1; Tomoregulin-1); H7365; C9orf2; C9ORF2; U19878; X83961; NM_080655; NM_003692; 10 Harms, P.W. (2003) Genes Dev.17 (21), 2624-2629; Gery, S. et al. (2003) Oncogene 22 (18):2723-2727. (39) GDNF-Ra1 (GDNF family receptor alpha 1; GFRA1; GDNFR; GDNFRA; RETL1; TRNR1; RET1L; GDNFR-alpha1; GFR-ALPHA-1); U95847; BC014962; NM_145793 NM_005264; Kim, M.H. et al. (2009) Mol. Cell. Biol.29 (8), 2264-2277; Treanor, J.J. et al. 15 (1996) Nature 382 (6586):80-83. (40) Ly6E (lymphocyte antigen 6 complex, locus E; Ly67,RIG-E,SCA-2,TSA-1); NP_002337.1; NM_002346.2; de Nooij-van Dalen, A.G. et al. (2003) Int. J. Cancer 103 (6), 768-774; Zammit, D.J. et al. (2002) Mol. Cell. Biol.22 (3):946-952. (41) TMEM46 (shisa homolog 2 (Xenopus laevis); SHISA2); NP_001007539.1; 20 NM_001007538.1; Furushima, K. et al. (2007) Dev. Biol.306 (2), 480-492; Clark, H.F. et al. (2003) Genome Res.13 (10):2265-2270. (42) Ly6G6D (lymphocyte antigen 6 complex, locus G6D; Ly6-D, MEGT1); NP_067079.2; NM_021246.2; Mallya, M. et al. (2002) Genomics 80 (1):113-123; Ribas, G. et al. (1999) J. Immunol.163 (1):278-287. 25 (43) LGR5 (leucine-rich repeat-containing G protein-coupled receptor 5; GPR49, GPR67); NP_003658.1; NM_003667.2; Salanti, G. et al. (2009) Am. J. Epidemiol.170 (5):537- 545; Yamamoto, Y. et al. (2003) Hepatology 37 (3):528-533. (44) RET (ret proto-oncogene; MEN2A; HSCR1; MEN2B; MTC1; PTC; CDHF12; Hs.168114; RET51; RET-ELE1); NP_066124.1; NM_020975.4; Tsukamoto, H. et al. (2009) 30 Cancer Sci.100 (10):1895-1901; Narita, N. et al. (2009) Oncogene 28 (34):3058-3068. (45) LY6K (lymphocyte antigen 6 complex, locus K; LY6K; HSJ001348; FLJ35226); NP_059997.3; NM_017527.3; Ishikawa, N. et al. (2007) Cancer Res.67 (24):11601-11611; de Nooij-van Dalen, A.G. et al. (2003) Int. J. Cancer 103 (6):768-774. 43 15077.006WO2 (46) GPR19 (G protein-coupled receptor 19; Mm.4787); NP_006134.1; NM_006143.2; Montpetit, A. and Sinnett, D. (1999) Hum. Genet.105 (1-2):162-164; O’Dowd, B.F. et al. (1996) FEBS Lett.394 (3):325-329. (47) GPR54 (KISS1 receptor; KISS1R; GPR54; HOT7T175; AXOR12); NP_115940.2; 5 NM_032551.4; Navenot, J.M. et al. (2009) Mol. Pharmacol.75 (6):1300-1306; Hata, K. et al. (2009) Anticancer Res.29 (2):617-623. (48) ASPHD1 (aspartate beta-hydroxylase domain containing 1; LOC253982); NP_859069.2; NM_181718.3; Gerhard, D.S. et al. (2004) Genome Res.14 (10B):2121-2127. (49) Tyrosinase (TYR; OCAIA; OCA1A; tyrosinase; SHEP3); NP_000363.1; 10 NM_000372.4; Bishop, D.T. et al. (2009) Nat. Genet.41 (8):920-925; Nan, H. et al. (2009) Int. J. Cancer 125 (4):909-917. (50) TMEM118 (ring finger protein, transmembrane 2; RNFT2; FLJ14627); NP_001103373.1; NM_001109903.1; Clark, H.F. et al. (2003) Genome Res.13 (10):2265-2270; Scherer, S.E. et al. (2006) Nature 440 (7082):346-351. 15 (51) GPR172A (G protein-coupled receptor 172A; GPCR41; FLJ11856; D15Ertd747e); NP_078807.1; NM_024531.3; Ericsson, T.A. et al. (2003) Proc. Natl. Acad. Sci. U.S.A.100 (11):6759-6764; Takeda, S. et al. (2002) FEBS Lett.520 (1-3):97-101. (52) CD33, a member of the sialic acid binding, immunoglobulin-like lectin family, is a 67-kDa glycosylated transmembrane protein. CD33is expressed on most myeloid and 20 monocytic leukemia cells in addition to committed myelomonocytic and erythroid progenitor cells. It is not seen on the earliest pluripotent stem cells, mature granulocytes, lymphoid cells, or nonhematopoietic cells (Sabbath et al., (1985) J. Clin. Invest.75:756-56; Andrews et al., (1986) Blood 68:1030-5). CD33 contains two tyrosine residues on its cytoplasmic tail, each of which is followed by hydrophobic residues similar to the immunoreceptor tyrosine-based inhibitory motif 25 (ITIM) seen in many inhibitory receptors. (53) CLL-1 (CLEC12A, MICL, and DCAL2), encodes a member of the C-type lectin / C- type lectin-like domain (CTL / CTLD) superfamily. Members of this family share a common protein fold and have diverse functions, such as cell adhesion, cell-cell signaling, glycoprotein turnover, and roles in inflammation and immune response. The protein encoded by this gene is a 30 negative regulator of granulocyte and monocyte function. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. This gene is closely linked to other CTL / CTLD superfamily members in the natural killer gene complex region on chromosome 12p13 (Drickamer K (1999) Curr. Opin. Struct. Biol.9 (5):585–90; van Rhenen A, et al., (2007) Blood 110 (7):2659–66; Chen CH, et al. 35 (2006) Blood 107 (4):1459–67; Marshall AS, et al. (2006) Eur. J. Immunol.36 (8):2159–69; 44 15077.006WO2 Bakker AB, et al. (2005) Cancer Res.64 (22):8443–50; Marshall AS, , et al. (2004) J. Biol. Chem.279 (15):14792–802). CLL-1 has been shown to be a type II transmembrane receptor comprising a single C-type lectin-like domain (which is not predicted to bind either calcium or sugar), a stalk region, a transmembrane domain and a short cytoplasmic tail containing an ITIM 5 motif. (54) TROP2 (tumor-associated calcium signal transducer 2) is a transmembrane glycoprotein encoded by the TACSTD2 gene (Linnenbach AJ, et al (1993) Mol Cell Biol.13(3): 1507–15; Calabrese G, et al (2001) Cytogenet Cell Genet.92(1–2): 164–5). TROP2 is an intracellular calcium signal transducer that is differentially expressed in many cancers. It signals 10 cells for self-renewal, proliferation, invasion, and survival. It has stem cell-like qualities. TROP2 is expressed in many normal tissues, though in contrast, it is overexpressed in many cancers (Ohmachi T, et al., (2006) Clin. Cancer Res., 12(10):3057-3063; Muhlmann G, et al., (2009) J. Clin. Pathol., 62(2):152-158; Fong D, et al., (2008) Br. J. Cancer, 99(8):1290-1295; Fong D, et al., (2008) Mod. Pathol., 21(2):186-191; Ning S, et al., (2013) Neurol. Sci., 34(10):1745-1750). 15 Overexpression of TROP2 is of prognostic significance. Several ligands have been proposed that interact with TROP2. TROP2 signals the cells via different pathways and it is transcriptionally regulated by a complex network of several transcription factors. Human TROP2 (TACSTD2: tumor-associated calcium signal transducer 2, GA733-1, EGP-1, M1S1; hereinafter, referred to as hTROP2) is a single-pass transmembrane type 1 cell 20 membrane protein consisting of 323 amino acid residues. While the presence of a cell membrane protein involved in immune resistance, which is common to human trophoblasts and cancer cells (Faulk W P, et al. (1978), Proc. Natl. Acad. Sci.75(4):1947-1951), has previously been suggested, an antigen molecule recognized by a monoclonal antibody against a cell membrane protein in a human choriocarcinoma cell line was identified and designated as TROP2 as one of 25 the molecules expressed In human trophoblasts (Lipinski M, et al. (1981), Proc. Natl. Acad. Sci. 78(8):5147-5150). This molecule was also designated as tumor antigen GA733-1 recognized by a mouse monoclonal antibody GA733 (Linnenbach A J, et al., (1989) Proc. Natl. Acad. Sci. 86(1):27-31) obtained by immunization with a gastric cancer cell line or an epithelial glycoprotein (EGP-1; Basu A, et al., Int. J. Cancer, 62 (4), 472-479 (1995)) recognized by a 30 mouse monoclonal antibody RS7-3G11 obtained by immunization with non-small cell lung cancer cells. In 1995, however, the TROP2 gene was cloned, and all of these molecules were confirmed to be identical molecules (Fornaro M, et al., (1995) Int. J. Cancer, 62(5):610-618). The DNA sequence and amino acid sequence of hTROP2 are available on a public database and can be referred to, for example, under Accession Nos. NM_002353 and NP_002344 (NCBI). 45 15077.006WO2 BCL-XL TPI-SP-VHL COMPOUNDS The degrader antibody conjugate composition of the invention comprises a Bcl-xL target protein binder and VHL ligand moiety (TPI-Sp-VHL). The Bcl-xL target protein of interest (TPI) binder is covalently attached to the VHL ligand by a spacer unit (Sp). 5 The degrader antibody conjugate composition of the present disclosure may be prepared from a compound comprising a target protein binder (TPI) covalently attached to a VHL ligand by a spacer unit (Sp) having Formula II: TPI−Sp−VHL II or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, 10 or isotopic analog thereof, wherein: TPI binds to Bcl-xL; VHL ligand has Formula IIa: a wherein A is a cyclic structure selected from C3−C20 carbocyclyl, C6−C20 aryl, C1−C20 15 heteroaryl, and C2-C20 heterocyclyl, each of which are substituted with one or more groups independently selected from H, F, Cl, Br, I, −CN, −NO2, C1−C12 alkyl, C2−C12 alkenyl, C2−C12 alkynyl, C1−C12 heteroalkyl, −(C1−C12 heteroalkyldiyl)−(C6−C20 aryl), −(C1−C12 heteroalkyldiyl)−(C6−C20 aryldiyl)−(C1−C12 heteroalkyl), −(C1−C12 heteroalkyldiyl)−(C6−C20 aryldiyl)−(C2-C20 heterocyclyl), (C1−C6 alkyldiyl)−(C6−C20 aryl), −(C1−C6 alkyldiyl)−NRaRb, 20 −(C1−C6 alkyldiyl)−ORa, (C1−C6 alkyldiyl)−(C3−C20 carbocyclyl), (C1-C6 alkyldiyl)−(C2-C20 heterocyclyl), (C1−C6 alkyldiyl)−(C1−C20 heteroaryl), C6−C20 aryl, C3−C20 carbocyclyl, C2−C20 heterocyclyl, C1−C20 heteroaryl, −C(=NH)NH(OH), −C(=NH)NH2, −C(=O)NRaRb, −C(=O)NRa−NRaRb, −C(=O)NH(C1-C6alkyldiyl)−NRaRb, −C(=O)ORa, −NRaRb, −NRaS(O)2Ra, −NO2, −ORa, −OC(=O)Ra, −SRa, −S(O)Ra, −S(O)2Ra, −S(O)2NRa, and −S(O)3H; 46 15077.006WO2 Rais independently selected from H, C1−C6 alkyl, phenyl, and benzyl, wherein phenyl and benzyl are optionally substituted with one or more groups independently selected from the group consisting of F, Cl, −CN, C1−C12alkyl, C2−C12alkenyl, and C2−C12alkynyl; or where two Ragroups form a five-, six-, or seven-membered heteroaryl or heterocyclyl 5 ring; Rbis independently selected from H, OH, C1−C6 alkyl, phenyl, and benzyl, wherein phenyl and benzyl are optionally substituted with one or more groups independently selected from the group consisting of F, Cl, −CN, C1−C12 alkyl, C2−C12 alkenyl, and C2−C12 alkynyl; Rcis selected from OH and −SO2F; 10 Rdis selected from H and F; Cyc is a ring structure selected from the group consisting of C3−C20carbocyclyl, C6−C20aryl, C2-C20 heterocyclyl, and C1−C20 heteroaryl; n is 0 or 1; R1is selected from the group consisting of H, C1−C12alkyl, and C1−C12heteroalkyl; 15 R2is selected from the group consisting of H, C1−C12alkyl, and C1−C12heteroalkyl; or where R2forms a five-, six-, or seven-membered heteroaryl or heterocyclyl ring with A; X1is selected from the group consisting of H, −NHC(=O)−, (C3−C20carbocyclyl)− C(=O)NH−, C1−C12heteroalkyl, and C1−C20heteroaryl; or where X1forms a five-, six-, or seven-membered heteroaryl or heterocyclyl ring with R1; 20 Sp is selected from the group consisting of a bond, O, NH, C1−C12 alkyldiyl, C1−C60 heteroalkyldiyl, C3−C20 carbocyclyldiyl, C2-C20 heterocyclyldiyl, C6-C20 aryldiyl, C1−C40 heteroaryldiyl, −(C3−C20carbocyclyldiyl)−(C1−C60heteroalkyldiyl)−, −(C3−C20carbocyclyldiyl)−(C1−C12alkyldiyl)−, −(C2-C20heterocyclyldiyl)−(C1−C60heteroalkyldiyl)−, −(C2-C20heterocyclyldiyl)−(C1−C12alkyldiyl)−, −(C2-C20heterocyclyldiyl)−(C2-C2025 heterocyclyldiyl)−, −(C1−C20heteroaryldiyl)−(C3−C20carbocyclyldiyl)−(C1−C60heteroalkyldiyl)−, a solubilizing unit, and combinations thereof, where the solubilizing unit is selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), a glycoside, C1−C60heteroalkyldiyl, and combinations thereof; one of A, Ra, Rb, Cyc, R1, R2, and X1is attached to Sp; and 30 each alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, heteroalkyl, heteroalkyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl is independently and optionally substituted with one or more groups selected from F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C^CH, −C^CCH3, − CH2CH2CH3, −CH(CH3)2, −CH2CH(CH3)2, −CH(CH2CH2), −CH(CH2CH2CH2), −CH2OH, − 47 15077.006WO2 CH2OCH3, −CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, − CH2CH2SO2CH3, −CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, − CH(CH3)CN, −C(CH3)2CN, −CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, − CH2N(CH3)2, −CO2H, −COCH3, −CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, − 5 CONHCH3, −CON(CH3)2, −C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, − N(CH3)COCH3, −NHS(O)2CH3, −N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, − NHC(=NH)H, −NHC(=NH)CH3, −NHC(=NH)NH2, −NHC(=O)NH2, −NO2, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, −OCH2CH2OH, −OCH2CH2N(CH3)2, −OCH2F, −OCHF2, − OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H. 10 An exemplary embodiment of the VHL ligand of the Formula II compound has Formula IIb: IIb. An exemplary embodiment of the VHL ligand of the Formula II compound has Formula IIc: 15 IIc wherein: R3, R4, R5, and R6are independently selected from the group consisting of H, F, Cl, Br, I, −CN, C1−C12alkyl, C2−C12alkenyl, C2−C12alkynyl, C1−C12heteroalkyl, −(C1−C12heteroalkyldiyl)−(C6−C20aryl), −(C1−C12heteroalkyldiyl)−(C6−C20aryldiyl)−(C1−C1220 heteroalkyl), −(C1−C12heteroalkyldiyl)−(C6−C20aryldiyl)−(C2-C20heterocyclyl), (C1−C648 15077.006WO2 alkyldiyl)−(C6−C20 aryl), −(C1−C6 alkyldiyl)−NRaRb, −(C1−C6 alkyldiyl)−ORa, (C1−C6 alkyldiyl)−(C3−C20 carbocyclyl), (C1-C6 alkyldiyl)−(C2-C20 heterocyclyl), (C1−C6 alkyldiyl)−(C1−C20 heteroaryl), C6−C20 aryl, C3−C20 carbocyclyl, C2−C20 heterocyclyl, C1−C20 heteroaryl, −C(=NH)NH(OH), −C(=NH)NH2, −C(=O)NRaRb, −C(=O)NRa−NRaRb, 5 −C(=O)NH(C1-C6 alkyldiyl)−NRaRb, −C(=O)ORa, −NRaRb, −NO2, −ORa, −OC(=O)Ra, −SRa, −S(O)Ra, −S(O)2Ra, −S(O)2NRa, −S(O)3H, and Sp; Rais independently selected from H, C1−C6alkyl, phenyl, and benzyl, wherein phenyl and benzyl are optionally substituted with one or more groups independently selected from the group consisting of F, Cl, −CN, C1−C12 alkyl, C2−C12 alkenyl, C2−C12 alkynyl, and Sp; 10 or where two Ragroups form a five-, six-, or seven-membered heteroaryl or heterocyclyl group; Rbis independently selected from H, OH, C1−C6alkyl, phenyl, and benzyl, wherein phenyl and benzyl are optionally substituted with one or more groups independently selected from the group consisting of F, Cl, −CN, C1−C12alkyl, C2−C12alkenyl, C2−C12alkynyl, and Sp; 15 or where R3and R4together form a five-membered or six-membered heteroaryl or heterocyclyl group comprising one or more heteroatoms independently selected from N, O, P and S; X1is selected from the group consisting of H, and −NHCO−; or where X1forms a five-, six-, or seven-membered heteroaryl or heterocyclyl ring with R1; 20 one of X1, R1, R2, R3, R4, R5, R6, Ra, Rb, and Cyc is attached to Sp; and each alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, heteroalkyl, heteroalkyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl is independently and optionally substituted with one or more groups selected from F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C^CH, −C^CCH3, −25 CH2CH2CH3, −CH(CH3)2, −CH2CH(CH3)2, −CH(CH2CH2), −CH(CH2CH2CH2), −CH2OH, − CH2OCH3, −CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, − CH2CH2SO2CH3, −CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, − CH(CH3)CN, −C(CH3)2CN, −CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, − CH2N(CH3)2, −CO2H, −COCH3, −CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, −30 CONHCH3, −CON(CH3)2, −CONHS(O)2N(CH3)2, −C(CH3)2CONH2, −NH2, −NHCH3, − N(CH3)2, −NHCOCH3, −N(CH3)COCH3, −NHS(O)2CH3, −N(CH3)C(CH3)2CONH2, − N(CH3)CH2CH2S(O)2CH3, −NHC(=NH)H, −NHC(=NH)CH3, −NHC(=NH)NH2, − NHC(=O)NH2, −NO2, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, −OCH2CH2OH, − 49 15077.006WO2 OCH2CH2N(CH3)2, −OCH2F, −OCHF2, −OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, − S(O)2CH3, and −S(O)3H. An exemplary embodiment of the Formula II compound includes wherein one or more of R3, R4, R5, and R6are independently selected from F and OH. 5 An exemplary embodiment of the Formula II compound includes wherein X1forms a five-, six-, or seven-membered heteroaryl or heterocyclyl ring with R1. An exemplary embodiment of the Formula II compound includes wherein X1is attached to the spacer unit. An exemplary embodiment of the Formula II compound includes wherein Sp is C1−C60 10 heteroalkyldiyl having the formula: −(CH2CH2X2)n−(CH2)m− where X2is independently selected from NH and O, m is an integer from 1 to 5, and n is an integer from 1 to 50. An exemplary embodiment of the Formula II compound includes wherein Sp is C1−C60 heteroalkyldiyl having the formula: −(CH2CH2O)n−(CH2)m− where m is an integer from 1 to 5, and n is an integer from 1 to 50. 15 An exemplary embodiment of the Formula II compound includes wherein Sp is −(C3−C20carbocyclyldiyl)−(C1−C60heteroalkyldiyl)− . An exemplary embodiment of the Formula II compound includes wherein Sp is C1−C60heteroalkyldiyl. An exemplary embodiment of the Formula II compound includes wherein Sp is selected 20 from the group consisting of −S(O)2CH2CH2−, −S(O)2NHCH2CH2−, −S(O)2CH2CH2CH2−, and −S(O)2NHCH2CH2CH2−. An exemplary embodiment of the Formula II compound includes wherein Sp has a formula selected from the group consisting of: 50 15077.006WO2 51 15077.006WO2 where the wavy lines indicate the points of attachment to the target protein binder TPI and to the VHL ligand. An exemplary embodiment of the Formula II compound includes wherein the target 5 protein binder TPI has Formula IId: IId wherein: R7is a C1−C20 heteroaryl substituted with one or more groups independently selected from H, F, Cl, −CH3, −CN, −NO2, −OH, and −OCH3; 10 R8aand R8bare independently selected from the group consisting of H, F, Cl, −CN, −C(=NH)NH(OH), −C(=NH)NH2, −C(=O)NRaRb, −C(=O)NRa−NRaRb, −C(=O)NH−(C1-C6alkyldiyl)−NRaRb, −C(=O)ORa, −NRaRb, −NO2, −ORa, −OC(=O)Ra, −SRa, −S(O)Ra, −S(O)2Ra, −S(O)2NRa, and −S(O)3H, C1−C12alkyl, −C1−C12heteroalkyl, C3−C20carbocyclyl, C6−C20aryl, C2-C20heterocyclyl, and C1−C20heteroaryl; 52 15077.006WO2 Rais independently selected from H, C1−C6 alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, −NO2, −OH, C1−C12alkyl, C2−C12alkenyl, C2−C12alkynyl, and −C1−C12 heteroalkyl; 5 or where two Ragroups form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring; Rbis independently selected from H, OH, −C1−C6 alkyl, −O−(C1−C6 alkyl), phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, C1−C12 alkyl, C2−C12 alkenyl, C2−C12 10 alkynyl, and −C1−C12 heteroalkyl; Reis selected from H, C1−C6 alkyl, and −C1−C12 heteroalkyl; Rfis selected from H, C1−C6 alkyl, and −C1−C12 heteroalkyl; or Rfand Sp form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring; R9is selected from the group consisting of H, F, Cl, −CN, −NO2, −OH, and −OCH3; 15 Y1is selected from N and CR11c; Y2is selected from N and CR10b; R10aand R10bare independently selected from H, F, Cl, −CN, −NO2, −OH, C1−C12alkyl, C2−C12alkenyl, C2−C12alkynyl, and −C1−C12heteroalkyl; R11a, R11b, and R11care independently selected from the group consisting of H, F, Cl, 20 −CN, −NO2, −OH, −OCH3, C1-C12 alkyl, and −C1−C12 heteroalkyl; and R12is selected from the group consisting of −(C1−C6 alkyldiyl)−(C3−C20 carbocyclyl), −(C1−C6alkyldiyl)−(C3−C20carbocyclyl)−(C1−C12heteroalkyl), −(C1−C6alkyldiyl)−(C3−C20carbocyclyl)−*, and −(C1−C6alkyldiyl)−(C3−C20carbocyclyl)−(C1−C12heteroalkyl)−*; where the asterisk is the attachment site to the spacer unit Sp. 25 An exemplary embodiment of the target protein binder TPI of Formula IId includes wherein R7is selected from: 53 15077.006WO2 , substituted with one or more groups independently selected from H, F, Cl, −CH3, −CN, −NO2, −OH, and −OCH3. 5 An exemplary embodiment of the target protein binder TPI of Formula IId includes wherein R7is: . An exemplary embodiment of the target protein binder TPI of Formula IId includes wherein R8ais selected from H, −CH3 and cyclopropyl, and R8bis H. 10 An exemplary embodiment of the target protein binder TPI of Formula IId includes wherein R9, R10a, and R10bare each H. An exemplary embodiment of the target protein binder TPI of Formula IId includes wherein each Rais H. An exemplary embodiment of the target protein binder TPI of Formula IId includes 15 wherein each Rbis H. An exemplary embodiment of Formula IId includes wherein Reand Rfare each H. 54 15077.006WO2 An exemplary embodiment of the target protein binder TPI of Formula IId includes wherein R11ais H, and R11bis −CH3. An exemplary embodiment of the target protein binder TPI of Formula IId includes wherein R12is −(C1−C6alkyldiyl)−(C3−C20carbocyclyl). 5 An exemplary embodiment of the target protein binder TPI of Formula IId includes wherein −(C1−C6 alkyldiyl)− is −CH2−, and C3−C20 carbocyclyl is selected from cyclohexyl and adamantyl, substituted with one or more groups selected from H, F, Cl, −OH, −C1−C12 alkyl, and −C1−C12heteroalkyl. Exemplary Bcl-xL target protein binder and VHL ligand (TPI-Sp-VHL) compounds of 10 Table 1 were prepared and characterized according to the Examples herein. Each compound in Table 1 was characterized by mass spectrometry and demonstrated to have the correct parent ion and mass. Other analytic techniques such as NMR were used to confirm structure and purity. It is intended that the compounds of the invention include all stereoisomeric forms of, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such 15 as racemic mixtures Certain exemplary TPI-Sp-VHL compounds of Table 1 were tested for their effects in inhibiting cellular proliferation against certain cancer cell lines and degradation of Bcl-xL target protein (Table 1a).. Bcl-xL target protein binder and VHL ligand (TPI-Sp-VHL) compounds may be converted to target protein binder and VHL ligand linker ((TPI-Sp-VHL)-L) compounds 20 of Table 2 for conjugation with an antibody to form Degrader Antibody Conjugate (DAC) compositions of Tables 3. Assessment of biological activity and other properties may be conducted according to the methods of Examples 104-107. In some instances, the Cell proliferation dose response IC50 value or degradation dose response DC50 of Table 4 is an average of repetitive assays. Certain 25 exemplary Bcl-xL-VHL compounds were tested for their effects in inhibiting cellular proliferation and degradation of Bcl-xL protein. Table 1 Bcl-xL-VHL compounds (BXV) B N o. 55 15077.006WO2 BXV-1 1268.6 B B B 56 15077.006WO2 BXV-5 1295.6 B B B 57 15077.006WO2 BXV-9 1307.7 B B B 58 15077.006WO2 BXV-13 1240.5 B B B 59 15077.006WO2 BXV-17 1271.5 B B B 60 15077.006WO2 BXV-21 1282.5 B B 61 15077.006WO2 BXV-24 1242.4 B B 62 15077.006WO2 BXV-27 1290.5 B B B 63 15077.006WO2 BXV-31 1247.6 B B 64 15077.006WO2 BXV-34 1274.5 B B 65 15077.006WO2 BXV-37 1334.5 B B 66 15077.006WO2 BXV-40 1206.4 B B 67 15077.006WO2 BXV-43 1241.4 B B B 68 15077.006WO2 BXV-47 1268.5 B B 69 15077.006WO2 BXV-50 1362.6 B B 70 15077.006WO2 BXV-53 1312.6 B B 71 15077.006WO2 BXV-56 1288.5 B B B 72 15077.006WO2 BXV-60 1318.5 B B 73 15077.006WO2 BXV-63 1286.5 B B 74 15077.006WO2 BXV-66 1286.5 B B B 75 15077.006WO2 BXV-70 1294.6 B B B 76 15077.006WO2 BXV-74 1264.5 B B B 77 15077.006WO2 BXV-78 1250.5 B B B 78 15077.006WO2 BXV-82 1264.5 B ANTIBODY LINKER UNITS The antibody conjugate composition of the invention comprises an antibody linker covalently attaching the Bcl-xL target protein binder and VHL ligand (TPI-Sp-VHL) moiety to 5 an antibody. The TPI-Sp-VHL moiety is attached to a linker unit to prepare target protein binder and VHL ligand linker ((TPI-Sp-VHL)-L) compounds for conjugation with an antibody (Ab) to form Degrader Antibody Conjugate (DAC) compositions. In one aspect, the antibody linker of the antibody conjugates and target protein binder and VHL ligand linker compound comprises a branched phenyl maleimide group and other 10 linker units described in WO 2023 / 173121, which is incorporated by reference herein. In some embodiments, an immolative group (IM), and TPI-Sp-VHL moiety together is selected from the following structures: ; 79 15077.006WO2 ; 5 wherein the wavy line indicates an attachment site to the remainder of the molecule (i.e., a compound of Structure (I) or conjugate of Structure (II)) and a TPI-Sp-VHL moiety. Amino acids of embodiments above may be replaced or used in addition to other amino acids, in some embodiments, a peptide group (PEP) is Asn-Cit, Arg-Cit, Val-Glu, Ser-Cit, Lys- Cit, Asp-Cit, Phe-Lys, Glu-Val-Cit, Glu-Val-Cit, Glu-Glu-Val-Cit, or Glu-Glu-Glu-Val-Cit, and 10 an immolative group is PABC. In some embodiments, the phenyl portion of the PABC is substituted with one or more substituents. In some embodiments, the substituents have one of the following structures: , , , 80 15077.006WO2 In some embodiments, an immolative group comprises one of the following structures: . In some embodiments, a trigger element, an immolative unit (IM), and TPI-Sp-VHL 5 moiety together comprise one of the following structures: . In some embodiments, an immolative unit (IM) has a structure selected from the following: 10 , , , 81 15077.006WO2 an . The structures above show a substitution pattern of 1, 3, 4 on the phenyl ring of an immolative unit (IM). In some embodiments, a substitution pattern may be 1, 2, 4 (i.e., 1 being a linkage to a TPI-Sp-VHL, 2 being a linkage to the remainder of the molecule and 4 being a 5 linkage to the carbohydrate) or 1, 3, 5 (i.e., 1 being a linkage to a TPI-Sp-VHL, 3 being a linkage to the remainder of the molecule and 4 being a linkage to the carbohydrate). Although cleavable linkers (e.g., linkers with trigger elements or immolative unit) can provide certain advantages, linkers need not be cleavable. For non-cleavable linkers, a TPI-Sp- VHL release may not depend on the differential properties between the plasma and some 10 cytoplasmic compartments. The release of a TPI-Sp-VHL can occur after internalization of the conjugate of Structure (II) via antigen-mediated endocytosis and delivery to lysosomal compartment, where the targeting moiety (or binding fragment thereof) can be degraded to the level of amino acids through intracellular proteolytic degradation. This process can release a TPI-Sp-VHL moiety or TPI-Sp-VHL moiety derivative. A TPI-Sp-VHL moiety or TPI-Sp-VHL 15 moiety derivative can be more hydrophilic and less membrane permeable, which can lead to less bystander effects and less non-specific toxicities compared to conjugates with a cleavable linker. Conjugates with non-cleavable linkers can have greater stability in circulation than conjugates with cleavable linkers. Non-cleavable linkers can include alkylene chains, or can be polymeric, such as, for example, based upon polyalkylene glycol polymers, amide polymers, or can include 20 segments of alkylene chains, polyalkylene glycols and / or amide polymers. The linker can contain a polyethylene glycol segment having from 1 to 6 ethylene glycol units. In some embodiments, -L1-R1or L2-R2comprises a linker that is non-cleavable in vivo. In some embodiments, a trigger element and an immolative unit (IM) together comprise one of the following structures: 82 15077.006WO2 5 ; 83 15077.006WO2 . BCL-XL TPI-SP-VHL LINKER COMPOUNDS 5 The degrader antibody conjugate (DAC) compositions of the invention are prepared by conjugation of an antibody (Ab) with a Bcl-xL target protein binder and VHL ligand linker (BXVL) compound. A BXVL compound is selected from Formula III: (TPI−Sp−VHL)−L3−Z III 10 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopic analog thereof, wherein: 84 15077.006WO2 TPI is a target protein binder that binds to Bcl-xL; VHL ligand has Formula IIIa: IIIa or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, 5 or isotopic analog thereof, wherein: A is a cyclic structure selected from C3−C20carbocyclyl, C6−C20aryl, C1−C20heteroaryl, and C2-C20heterocyclyl, each of which are substituted with one or more groups independently selected from H, F, Cl, Br, I, −CN, −NO2, C1−C12 alkyl, C2−C12 alkenyl, C2−C12 alkynyl, C1−C12 heteroalkyl, −(C1−C12 heteroalkyldiyl)−(C6−C20 aryl), −(C1−C12 heteroalkyldiyl)−(C6−C20 10 aryldiyl)−(C1−C12 heteroalkyl), −(C1−C12 heteroalkyldiyl)−(C6−C20 aryldiyl)−(C2-C20 heterocyclyl), (C1−C6 alkyldiyl)−(C6−C20 aryl), −(C1−C6 alkyldiyl)−NRaRb, −(C1−C6 alkyldiyl)−ORa, (C1−C6alkyldiyl)−(C3−C20carbocyclyl), (C1-C6alkyldiyl)−(C2-C20heterocyclyl), (C1−C6alkyldiyl)−(C1−C20heteroaryl), C6−C20aryl, C3−C20carbocyclyl, C2−C20heterocyclyl, C1−C20heteroaryl, −C(=NH)NH(OH), −C(=NH)NH2, −C(=O)NRaRb, 15 −C(=O)NRa−NRaRb, −C(=O)NH(C1-C6alkyldiyl)−NRaRb, −C(=O)ORa, −NRaRb, −NRaS(O)2Ra, −NO2, −ORa, −OC(=O)Ra, −SRa, −S(O)Ra, −S(O)2Ra, −S(O)2NRa, and −S(O)3H; Rais independently selected from H, C1−C6alkyl, phenyl, and benzyl, wherein phenyl and benzyl are optionally substituted with one or more groups independently selected from the group consisting of F, Cl, −CN, C1−C12alkyl, C2−C12alkenyl, and C2−C12alkynyl; 20 or where two Ragroups form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring; Rbis independently selected from H, OH, C1−C6 alkyl, phenyl, and benzyl, wherein phenyl and benzyl are optionally substituted with one or more groups independently selected from the group consisting of F, Cl, −CN, C1−C12alkyl, C2−C12alkenyl, and C2−C12alkynyl; 25 Rcis selected from OH and −SO2F; Rdis selected from H and F; 85 15077.006WO2 Cyc is a ring structure selected from the group consisting of C3−C20 carbocyclyl, C6−C20 aryl, C2-C20 heterocyclyl, and C1−C20 heteroaryl; n is 0 or 1; R1is selected from the group consisting of H, C1−C12 alkyl, and C1−C12 heteroalkyl; 5 R2is selected from the group consisting of H, C1−C12 alkyl, and C1−C12 heteroalkyl; or where R2forms a five-, six-, or seven-membered heteroaryl or heterocyclyl ring with A; X1is selected from the group consisting of H, −NHC(=O)−, (C3−C20carbocyclyl)− C(=O)NH−, C1−C12heteroalkyl, and C1−C20heteroaryl; or where X1forms a five-, six-, or seven-membered heteroaryl or heterocyclyl ring with R1; 10 Sp is selected from the group consisting of a bond, O, NH, C1−C12alkyldiyl, C1−C60heteroalkyldiyl, C3−C20carbocyclyldiyl, C2-C20heterocyclyldiyl, C6-C20aryldiyl, C1−C40heteroaryldiyl, −(C3−C20carbocyclyldiyl)−(C1−C60heteroalkyldiyl)−, −(C3−C20carbocyclyldiyl)−(C1−C12alkyldiyl)−, −(C2-C20heterocyclyldiyl)−(C1−C60heteroalkyldiyl)−, −(C2-C20heterocyclyldiyl)−(C1−C12alkyldiyl)−, −(C2-C20heterocyclyldiyl)−(C2-C2015 heterocyclyldiyl)−, −(C1−C20heteroaryldiyl)−(C3−C20carbocyclyldiyl)−(C1−C60heteroalkyldiyl)−, a solubilizing unit, and combinations thereof, where the solubilizing unit is selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), a glycoside, C1−C60 heteroalkyldiyl, and combinations thereof; TPI−Sp−VHL moiety is covalently attached to an antibody linker L3; 20 Z is: where the wavy line is the attachment to L3; one of A, Ra, Rb, Cyc, R1, R2, and X1is attached to Sp; one of A, Ra, Rb, Cyc, R1, R2, X1, and Sp is attached to L3; and 25 each alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, heteroalkyl, heteroalkyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl is independently and optionally substituted with one or more groups selected from F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C^CH, −C^CCH3, − CH2CH2CH3, −CH(CH3)2, −CH2CH(CH3)2, −CH(CH2CH2), −CH(CH2CH2CH2), −CH2OH, −30 CH2OCH3, −CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, − CH2CH2SO2CH3, −CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, − 86 15077.006WO2 CH(CH3)CN, −C(CH3)2CN, −CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, − CH2N(CH3)2, −CO2H, −COCH3, −CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, − CONHCH3, −CON(CH3)2, −C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, − N(CH3)COCH3, −NHS(O)2CH3, −N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, − 5 NHC(=NH)H, −NHC(=NH)CH3, −NHC(=NH)NH2, −NHC(=O)NH2, −NO2, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, −OCH2CH2OH, −OCH2CH2N(CH3)2, −OCH2F, −OCHF2, − OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H. An exemplary embodiment of the VHL ligand of the Formula III compound has Formula IIIb: 10 IIIb . An exemplary embodiment of the VHL ligand of the Formula III compound has Formula IIIc: IIIc wherein: 15 R3, R4, R5, and R6are independently selected from the group consisting of H, F, Cl, Br, I, −CN, C1−C12alkyl, C2−C12alkenyl, C2−C12alkynyl, C1−C12heteroalkyl, −(C1−C12heteroalkyldiyl)−(C6−C20aryl), −(C1−C12heteroalkyldiyl)−(C6−C20aryldiyl)−(C1−C12heteroalkyl), −(C1−C12heteroalkyldiyl)−(C6−C20aryldiyl)−(C2-C20heterocyclyl), (C1−C6alkyldiyl)−(C6−C20aryl), −(C1−C6alkyldiyl)−NRaRb, −(C1−C6alkyldiyl)−ORa, (C1−C620 alkyldiyl)−(C3−C20carbocyclyl), (C1-C6alkyldiyl)−(C2-C20heterocyclyl), (C1−C6alkyldiyl)−(C1−C20heteroaryl), C6−C20aryl, C3−C20carbocyclyl, C2−C20heterocyclyl, C1−C2087 15077.006WO2 heteroaryl, −C(=NH)NH(OH), −C(=NH)NH2, −C(=O)NRaRb, −C(=O)NRa−NRaRb, −C(=O)NH(C1-C6 alkyldiyl)−NRaRb, −C(=O)ORa, −NRaRb, −NO2, −ORa, −OC(=O)Ra, −SRa, −S(O)Ra, −S(O)2Ra, −S(O)2NRa, and −S(O)3H; Rais independently selected from H, C1−C6 alkyl, phenyl, and benzyl, wherein phenyl 5 and benzyl are optionally substituted with one or more groups independently selected from the group consisting of F, Cl, −CN, C1−C12 alkyl, C2−C12 alkenyl, and C2−C12 alkynyl; or where two Ragroups form a five-, six-, or seven-membered heteroaryl or heterocyclyl group; Rbis independently selected from H, OH, C1−C6alkyl, phenyl, and benzyl, wherein 10 phenyl and benzyl are optionally substituted with one or more groups independently selected from the group consisting of F, Cl, −CN, C1−C12 alkyl, C2−C12 alkenyl, and C2−C12 alkynyl; or where R3and R4together form a five-membered or six-membered heteroaryl or heterocyclyl group comprising one or more heteroatoms independently selected from N, O, P and S; 15 one of X1, R1, R2, R3, R4, R5, R6, Ra, Rb, and Cyc is attached to Sp; one of X1, R1, R2, R3, R4, R5, R6, Ra, Rb, and Cyc is attached to L3; and each alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, heteroalkyl, heteroalkyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl is independently and optionally substituted with one or more20 groups selected from F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C^CH, −C^CCH3, − CH2CH2CH3, −CH(CH3)2, −CH2CH(CH3)2, −CH(CH2CH2), −CH(CH2CH2CH2), −CH2OH, − CH2OCH3, −CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, − CH2CH2SO2CH3, −CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, − CH(CH3)CN, −C(CH3)2CN, −CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, − 25 CH2N(CH3)2, −CO2H, −COCH3, −CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, − CONHCH3, −CON(CH3)2, −CONHS(O)2N(CH3)2, −C(CH3)2CONH2, −NH2, −NHCH3, − N(CH3)2, −NHCOCH3, −N(CH3)COCH3, −NHS(O)2CH3, −N(CH3)C(CH3)2CONH2, − N(CH3)CH2CH2S(O)2CH3, −NHC(=NH)H, −NHC(=NH)CH3, −NHC(=NH)NH2, − NHC(=O)NH2, −NO2, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, −OCH2CH2OH, −30 OCH2CH2N(CH3)2, −OCH2F, −OCHF2, −OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, − S(O)2CH3, and −S(O)3H. An exemplary embodiment of the Formula III compound includes wherein the target protein binder TPI has Formula IIId: 88 15077.006WO2 d wherein: R7is a C1−C20heteroaryl substituted with one or more groups independently selected from H, F, Cl, −CH3, −CN, −NO2, −OH, and −OCH3; 5 R8aand R8bare independently selected from the group consisting of H, F, Cl, −CN, −C(=NH)NH(OH), −C(=NH)NH2, −C(=O)NRaRb, −C(=O)NRa−NRaRb, −C(=O)NH−(C1-C6alkyldiyl)−NRaRb, −C(=O)ORa, −NRaRb, −NO2, −ORa, −OC(=O)Ra, −SRa, −S(O)Ra, −S(O)2Ra, −S(O)2NRa, and −S(O)3H, C1−C12alkyl, −C1−C12heteroalkyl, C3−C20carbocyclyl, C6−C20aryl, C2-C20heterocyclyl, and C1−C20heteroaryl; 10 Rais independently selected from H, C1−C6alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, −NO2, −OH, C1−C12alkyl, C2−C12alkenyl, C2−C12alkynyl, and −C1−C12heteroalkyl; or where two Ragroups form a five-, six-, or seven-membered heteroaryl or heterocyclyl 15 ring; Reis selected from H, C1−C6 alkyl, and −C1−C12 heteroalkyl; Rfis selected from H, C1−C6 alkyl, and −C1−C12 heteroalkyl; or Rfand Sp form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring; Rbis independently selected from H, OH, −C1−C6 alkyl, −O−(C1−C6 alkyl), phenyl, and 20 benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, C1−C12alkyl, C2−C12alkenyl, C2−C12alkynyl, and −C1−C12heteroalkyl; R9is selected from the group consisting of H, F, Cl, −CN, −NO2, −OH, and −OCH3; Y1is selected from N and CR11c; 25 Y2is selected from N and CR10b; R10aand R10bare independently selected from H, F, Cl, −CN, −NO2, −OH, C1−C12 alkyl, C2−C12 alkenyl, C2−C12 alkynyl, and −C1−C12 heteroalkyl; 89 15077.006WO2 R11a, R11b, and R11care independently selected from the group consisting of H, F, Cl, −CN, −NO2, −OH, −OCH3, C1-C12alkyl, and −C1−C12heteroalkyl; and R12is selected from the group consisting of −(C1−C6alkyldiyl)−(C3−C20carbocyclyl), −(C1−C6 alkyldiyl)−(C3−C20 carbocyclyl)−(C1−C12 heteroalkyl), −(C1−C6 alkyldiyl)−(C3−C20 5 carbocyclyl)−*, and −(C1−C6 alkyldiyl)−(C3−C20 carbocyclyl)−(C1−C12 heteroalkyl)−*; where the asterisk is the attachment site to the spacer unit Sp. An exemplary embodiment of the antibody linker L3of the Formula III compound has the formula: −1 − − − 10 wherein: Str1is a stretcher unit covalently attached to Z; PEP is a protease-cleavable, peptide or amino acid unit covalently attached to Str1and IM or the TPI-Sp-VHL moiety when y is 1; IM is an immolative unit covalently attached to the TPI-Sp-VHL moiety when z is 1; 15 y is 0 or 1; and z is 0 or 1. An exemplary embodiment of the Formula IIId compound includes wherein R7is selected from: 90 15077.006WO2 , substituted with one or more groups independently selected from H, F, Cl, −CH3, −CN, −NO2, −OH, and −OCH3. An exemplary embodiment of the Formula IIId compound includes wherein R7is: 5 An exemplary embodiment of the Formula IIId compound includes wherein R8ais selected from H, −CH3 and cyclopropyl, and R8bis H. An exemplary embodiment of the Formula IIId compound includes wherein R9, R10a, and R10bare each H. 10 An exemplary embodiment of the Formula IIId compound includes wherein each Rais H. An exemplary embodiment of the Formula IIId compound includes wherein each Rbis H. An exemplary embodiment of Formula IIId includes wherein Reand Rfare each H. 15 An exemplary embodiment of the Formula IIId compound includes wherein R11ais H, and R11bis −CH3. An exemplary embodiment of the Formula IIId compound includes wherein R12is −(C1−C6alkyldiyl)−(C3−C20carbocyclyl). An exemplary embodiment of the Formula IIId compound includes wherein −(C1−C620 alkyldiyl)− is −CH2−, and C3−C20carbocyclyl is selected from cyclohexyl and adamantyl, substituted with one or more groups selected from H, F, Cl, −OH, −C1−C12alkyl, and −C1−C12heteroalkyl. Exemplary Bcl-xL target protein binder and VHL ligand linker (BXVL) compounds of Table 2 were prepared and characterized according to the Examples herein. Each compound in 25 Table 2 were characterized by mass spectrometry and demonstrated to have the correct parent ion and mass. It is intended that the compounds of the invention include all stereoisomeric forms of, including but not limited to, diastereomers, enantiomers and atropisomers, as well as 91 15077.006WO2 mixtures thereof such as racemic mixtures. The BXVL compounds of Table 2 were conjugated to antibodies to prepare the Degrader Antibody Conjugates (DAC) compounds of Table 3. Table 2 Bcl-xL-VHL linker compounds (BXVL) BXVL- Structure MW N B B 92 15077.006WO2 BXVL-3 3230.6 B B 93 15077.006WO2 BXVL-6 3310.8 B B 94 15077.006WO2 BXVL-9 3284.7 B 95 15077.006WO2 BXVL-11 3205.6 B B 96 15077.006WO2 BXVL-14 3311.8 B B 97 15077.006WO2 BXVL-17 3272.7 B B 98 15077.006WO2 BXVL-20 3196.6 B 99 15077.006WO2 BXVL-22 3455.7 B 100 15077.006WO2 BXVL-24 3276.6 B B 101 15077.006WO2 BXVL-27 3298.5 B 102 15077.006WO2 BXVL-29 3256.6 B B 103 15077.006WO2 BXVL-32 3387.7 B B 104 15077.006WO2 BXVL-35 3386.6 B B 105 15077.006WO2 BXVL-38 3320.6 B B 106 15077.006WO2 BXVL-41 3370.6 B B 107 15077.006WO2 BXVL-44 3378.8 B B 108 15077.006WO2 BXVL-47 3408.7 B B 109 15077.006WO2 BXVL-50 2659.8 B 110 15077.006WO2 BXVL-52 3411.7 B 111 15077.006WO2 BXVL-54 3334.7 B B 112 15077.006WO2 BXVL-57 3419.8 B 113 15077.006WO2 BXVL-59 3535.7 B 114 15077.006WO2 BXVL-61 3482.8 B 115 15077.006WO2 BXVL-63 3611.9 B B 116 15077.006WO2 BXVL-66 3318.4 B B 117 15077.006WO2 BXVL-69 3370.6 B B 118 15077.006WO2 BXVL-72 3362.4 B B 119 15077.006WO2 BXVL-75 3344.4 B B 120 15077.006WO2 BXVL-78 B B 121 15077.006WO2 BXVL-81 BCL-XL DEGRADER ANTIBODY CONJUGATES The degrader antibody conjugates (DAC) of the invention induce target-specific protein degradation. Tumor targeting brings specificity to minimize off-target effects. The degrader antibody conjugates (DAC) comprise a Bcl-xL target protein binder and 5 VHL ligand moiety (TPI-Sp-VHL) covalently attached to an antibody by an antibody linker, wherein the antibody binds to a tumor-associated antigen or cell-surface receptor and the target protein binder of the TPI-Sp-VHL binds to Bcl-xL. An exemplary embodiment of the DAC includes wherein the antibody binds to HER2. An exemplary embodiment of the DAC includes wherein the antibody is selected from 10 trastuzumab and pertuzumab. An exemplary embodiment of the DAC includes wherein the antibody has a modified Fc region. An exemplary embodiment of the DAC includes wherein the antibody has Fc mutations selected from: 15 (i) LALAPA (L234A / L235A / P329A); (ii) LALAPG (L234A / L235A / P329G); (iii) LALASKPA (L234A, L235A, S267K, P329A); (iv) LALAPA-YTE (L234A / L235A / P329A-M252Y / S254T / T256E); (v) LALAPG-YTE (L234A / L235A / P329G-M252Y / S254T / T256E); and 20 (vi) LALASKPA-YTE (L234A, L235A, S267K, P329A- M252Y / S254T / T256E), according to EU numbering. An exemplary embodiment of the DAC includes wherein the antibody linker is covalently attached to a cysteine amino acid of the antibody. 122 15077.006WO2 An exemplary embodiment of the DAC includes wherein the antibody is a cysteine- engineered antibody. An exemplary embodiment of the DAC includes wherein the antibody has one engineered cysteine mutation site selected from heavy-chain E152C, S239C, K246C and S375C, 5 numbered according to the EU system. An exemplary embodiment of the DAC includes wherein the antibody has two or three engineered cysteine mutation sites selected from heavy-chain E152C, S239C, K246C and S375C, numbered according to the EU system. An exemplary embodiment of the DAC includes wherein the cysteine-mutant antibody 10 comprises a heavy chain cysteine mutation in a sequence selected from the group consisting of: S L F K . An exemplary embodiment of the DAC includes wherein the cysteine-mutant antibody comprising one, two, or three engineered cysteine mutation sites is selected from (i) to (xvi): (i) HC S239C; 15 (ii) HC K246C; (iii) HC S375C; (iv) HC E152C; (v) HC S239C and K246C; (vi) HC S239C and S375C; 20 (vii) HC S239C and E152C; (viii) HC K246C and S375C; (ix) HC K246C and E152C; (x) HC S375C and E152C; (xi) HC S239C, K246C, and S375C; 25 (xii) HC S239C, K246C, and E152C; (xiii) HC S239C, S375C, and E152C; (xiv) HC K246C, S375C, and E152C; (xv) HC S239C, S375C, and E152C; 123 15077.006WO2 (xvi) HC K246C, S375C, and E152C. Exemplary embodiments of DAC include Formula I: Ab−[L−(TPI−Sp−VHL)]pI or a pharmaceutically acceptable salt thereof, 5 wherein: Ab is the antibody; L is the antibody linker; TPI−Sp−VHL is a moiety comprising a Bcl-xL target protein binder TPI and a VHL ligand wherein the TPI is covalently attached to the VHL ligand by a spacer unit Sp; and 10 p is an integer from 1 to 12. An exemplary embodiment of the DAC of Formula I includes wherein the TPI, the VHL ligand, or the spacer unit Sp is attached to the antibody linker L. An exemplary embodiment of the DAC of Formula I includes wherein the VHL ligand has Formula Ia: 15 Ia wherein A is a cyclic structure selected from C3−C20carbocyclyl, C6−C20aryl, C1−C20heteroaryl, and C2-C20heterocyclyl, each of which are substituted with one or more groups independently selected from H, F, Cl, Br, I, −CN, −NO2, C1−C12 alkyl, C2−C12 alkenyl, C2−C12 alkynyl, C1−C12 heteroalkyl, −(C1−C12 heteroalkyldiyl)−(C6−C20 aryl), −(C1−C12 20 heteroalkyldiyl)−(C6−C20aryldiyl)−(C1−C12heteroalkyl), −(C1−C12heteroalkyldiyl)−(C6−C20aryldiyl)−(C2-C20 heterocyclyl), (C1−C6 alkyldiyl)−(C6−C20 aryl), −(C1−C6 alkyldiyl)−NRaRb, −(C1−C6alkyldiyl)−ORa, (C1−C6alkyldiyl)−(C3−C20carbocyclyl), (C1-C6alkyldiyl)−(C2-C20heterocyclyl), (C1−C6alkyldiyl)−(C1−C20heteroaryl), C6−C20aryl, C3−C20carbocyclyl, C2−C20heterocyclyl, C1−C20heteroaryl, −C(=NH)NH(OH), −C(=NH)NH2, −C(=O)NRaRb, 124 15077.006WO2 −C(=O)NRa−NRaRb, −C(=O)NH(C1-C6 alkyldiyl)−NRaRb, −C(=O)ORa, −NRaRb, −NRaS(O)2Ra, −NO2, −ORa, −OC(=O)Ra, −SRa, −S(O)Ra, −S(O)2Ra, −S(O)2NRa, and −S(O)3H; Rais independently selected from H, C1−C6 alkyl, phenyl, and benzyl, wherein phenyl and benzyl are optionally substituted with one or more groups independently selected from the 5 group consisting of F, Cl, −CN, C1−C12 alkyl, C2−C12 alkenyl, and C2−C12 alkynyl; or where two Ragroups form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring; Rbis independently selected from H, OH, C1−C6alkyl, phenyl, and benzyl, wherein phenyl and benzyl are optionally substituted with one or more groups independently selected 10 from the group consisting of F, Cl, −CN, C1−C12 alkyl, C2−C12 alkenyl, and C2−C12 alkynyl; Rcis selected from OH and −SO2F; Rdis selected from H and F; Cyc is a ring structure selected from the group consisting of C3−C20 carbocyclyl, C6−C20 aryl, C2-C20 heterocyclyl, and C1−C20 heteroaryl. 15 n is 0 or 1; R1is selected from the group consisting of H, C1−C12alkyl, and C1−C12heteroalkyl; R2is selected from the group consisting of H, C1−C12 alkyl, and C1−C12 heteroalkyl, or where R2forms a five-, six-, or seven-membered heteroaryl or heterocyclyl ring with A; X1is selected from the group consisting of H, −NHC(=O)−, (C3−C20carbocyclyl)− 20 C(=O)NH−, C1−C12heteroalkyl, and C1−C20heteroaryl; or where X1forms a five-, six-, or seven-membered heteroaryl or heterocyclyl ring with R1; Sp is selected from the group consisting of a bond, O, NH, C1−C12alkyldiyl, C1−C60heteroalkyldiyl, C3−C20carbocyclyldiyl, C2-C20heterocyclyldiyl, C6-C20aryldiyl, C1−C40heteroaryldiyl, −(C3−C20carbocyclyldiyl)−(C1−C60heteroalkyldiyl)−, −(C3−C2025 carbocyclyldiyl)−(C1−C12alkyldiyl)−, −(C2-C20heterocyclyldiyl)−(C1−C60heteroalkyldiyl)−, −(C2-C20heterocyclyldiyl)−(C1−C12alkyldiyl)−, −(C2-C20heterocyclyldiyl)−(C2-C20heterocyclyldiyl)−, −(C1−C20heteroaryldiyl)−(C3−C20carbocyclyldiyl)−(C1−C60heteroalkyldiyl)−, a solubilizing unit, and combinations thereof, where the solubilizing unit is selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), a glycoside, C1−C6030 heteroalkyldiyl, and combinations thereof; L is the antibody linker; one of A, Ra, Rb, Cyc, R1, R2, and X1is attached to Sp; and one of A, Ra, Rb, Cyc, R1, R2, X1and Sp is attached to L; 125 15077.006WO2 where each alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, heteroalkyl, heteroalkyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl is independently and optionally substituted with one or more groups selected from F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C^CH, −C^CCH3, − 5 CH2CH2CH3, −CH(CH3)2, −CH2CH(CH3)2, −CH(CH2CH2), −CH(CH2CH2CH2), −CH2OH, − CH2OCH3, −CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, − CH2CH2SO2CH3, −CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, − CH(CH3)CN, −C(CH3)2CN, −CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, − CH2N(CH3)2, −CO2H, −COCH3, −CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, −10 CONHCH3, −CON(CH3)2, −C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, − N(CH3)COCH3, −NHS(O)2CH3, −N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, − NHC(=NH)H, −NHC(=NH)CH3, −NHC(=NH)NH2, −NHC(=O)NH2, −NO2, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, −OCH2CH2OH, −OCH2CH2N(CH3)2, −OCH2F, −OCHF2, − OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H. 15 An exemplary embodiment of the DAC of Formula Ia includes wherein Cyc is a five-, six-, or seven-membered ring structure selected from the group consisting of thiazole, triazole, phenyl, pyridine, pyrazine, pyridazine, and pyrimidine, substituted with one or more groups independently selected from H, F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C^CH, − C^CCH3, −CH2CH2CH3, −CH(CH3)2, −CH2CH(CH3)2, −CH(CH2CH2), −CH(CH2CH2CH2), −20 CH2OH, −CH2OCH3, −CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, − CH2CH2SO2CH3, −CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, − CH(CH3)CN, −C(CH3)2CN, −CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, − CH2N(CH3)2, −CO2H, −COCH3, −CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, − CONHCH3, −CON(CH3)2, −C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, −25 N(CH3)COCH3, −NHS(O)2CH3, −N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, − NHC(=NH)H, −NHC(=NH)CH3, −NHC(=NH)NH2, −NHC(=O)NH2, −NO2, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, −OCH2CH2OH, −OCH2CH2N(CH3)2, −OCH2F, −OCHF2, − OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H. An exemplary embodiment of the DAC of Formula Ia includes wherein Cyc is a five-, 30 six-, or seven-membered ring structure selected from the group consisting of thiazole, triazole, phenyl, pyridine, pyrazine, pyridazine, and pyrimidine, substituted with one or more groups independently selected from H, F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C^CH, − C^CCH3, −CH2CH2CH3, −CH(CH3)2, −CH2CH(CH3)2, −CH(CH2CH2), −CH(CH2CH2CH2), − 126 15077.006WO2 CH2OH, −CH2OCH3, −CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, − CH2CH2SO2CH3, −CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, − CH(CH3)CN, −C(CH3)2CN, −CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, − CH2N(CH3)2, −CO2H, −COCH3, −CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, − 5 CONHCH3, −CON(CH3)2, −C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, − N(CH3)COCH3, −NHS(O)2CH3, −N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, − NHC(=NH)H, −NHC(=NH)CH3, −NHC(=NH)NH2, −NHC(=O)NH2, −NO2, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, −OCH2CH2OH, −OCH2CH2N(CH3)2, −OCH2F, −OCHF2, − OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H. 10 An exemplary embodiment of the DAC of Formula Ia includes wherein R1is C1−C12alkyl. An exemplary embodiment of the DAC of Formula Ia includes wherein R2is selected from the group consisting of H, C1−C12 alkyl, and C1−C12 heteroalkyl. An exemplary embodiment of the DAC of Formula Ia includes wherein R2is selected 15 from H, −CH3, −CH2OH, −CH2CH2OH, −CH2OPO2OH, −CH2CH2OPO2OH, −CH2COOH, −CH2CH2COOH, −CH2CH2CONHS(O)2CH3, and −CH2CH2CONHS(O)2CH2CH2N(CH3)2. An exemplary embodiment of the DAC of Formula Ia includes wherein X1is C1−C20 heteroaryldiyl selected from the group consisting of triazole, isoxazole, and oxadiazole. An exemplary embodiment of the DAC of Formula Ia includes wherein X1is − 20 C(=O)NH−. An exemplary embodiment of the VHL ligand of the DAC of Formula I has Formula Ib: Ib. An exemplary embodiment of the VHL ligand of the DAC of Formula I has Formula Ic: 127 15077.006WO2 wherein: R3, R4, R5, and R6are independently selected from the group consisting of H, F, Cl, Br, I, −CN, C1−C12alkyl, C2−C12alkenyl, C2−C12alkynyl, C1−C12heteroalkyl, −(C1−C125 heteroalkyldiyl)−(C6−C20aryl), −(C1−C12heteroalkyldiyl)−(C6−C20aryldiyl)−(C1−C12heteroalkyl), −(C1−C12heteroalkyldiyl)−(C6−C20aryldiyl)−(C2-C20heterocyclyl), (C1−C6alkyldiyl)−(C6−C20aryl), −(C1−C6alkyldiyl)−NRaRb, −(C1−C6alkyldiyl)−ORa, (C1−C6alkyldiyl)−(C3−C20carbocyclyl), (C1-C6alkyldiyl)−(C2-C20heterocyclyl), (C1−C6alkyldiyl)−(C1−C20heteroaryl), C6−C20aryl, C3−C20carbocyclyl, C2−C20heterocyclyl, C1−C2010 heteroaryl, −C(=NH)NH(OH), −C(=NH)NH2, −C(=O)NRaRb, −C(=O)NRa−NRaRb, −C(=O)NH(C1-C6 alkyldiyl)−NRaRb, −C(=O)ORa, −NRaRb, −NO2, −ORa, −OC(=O)Ra, −SRa, −S(O)Ra, −S(O)2Ra, −S(O)2NRa, and −S(O)3H; Rais independently selected from H, C1−C6 alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group 15 consisting of H, F, Cl, −CN, C1−C12alkyl, C2−C12alkenyl, and C2−C12alkynyl; or where two Ragroups form a five-, six-, or seven-membered heteroaryl or heterocyclyl group; Rbis independently selected from H, OH, C1−C6 alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the 20 group consisting of H, F, Cl, −CN, C1−C12 alkyl, C2−C12 alkenyl, and C2−C12 alkynyl; or where R3and R4together form a five-membered or six-membered heteroaryl or heterocyclyl group comprising one or more heteroatoms independently selected from N, O, P and S; one of X1, R1, R2, R3, R4, R5, R6, Ra, Rb, and Cyc is attached to the spacer unit; 25 one of X1, R1, R2, R3, R4, R5, R6, Ra, Rb, Cyc, and Sp is attached to L; and where each alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, heteroalkyl, heteroalkyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, 128 15077.006WO2 heteroaryl, and heteroaryldiyl is independently and substituted with one or more groups selected from H, F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C^CH, −C^CCH3, −CH2CH2CH3, − CH(CH3)2, −CH2CH(CH3)2, −CH(CH2CH2), −CH(CH2CH2CH2), −CH2OH, −CH2OCH3, − CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, −CH2CH2SO2CH3, − 5 CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, −CH(CH3)CN, −C(CH3)2CN, − CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, −CH2N(CH3)2, −CO2H, −COCH3, − CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, −CONHCH3, −CON(CH3)2, − CONHS(O)2N(CH3)2, −C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, − N(CH3)COCH3, −NHS(O)2CH3, −N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, − 10 NHC(=NH)H, −NHC(=NH)CH3, −NHC(=NH)NH2, −NHC(=O)NH2, −NO2, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, −OCH2CH2OH, −OCH2CH2N(CH3)2, −OCH2F, −OCHF2, − OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H. An exemplary embodiment of the DAC of Formula Ic includes wherein one or more of R3, R4, R5, and R6are independently selected from F and OH. 15 An exemplary embodiment of the DAC of Formula I includes wherein X1forms a five-, six-, or seven-membered heteroaryl or heterocyclyl ring with R1. An exemplary embodiment of the DAC of Formula I includes wherein X1is attached to the spacer unit. An exemplary embodiment of the DAC of Formula I includes wherein Sp is C1−C6020 heteroalkyldiyl having the formula: −(CH2CH2X2)n−(CH2)m− where X2is independently selected from NH and O, m is an integer from 1 to 5, and n is an integer from 1 to 50. An exemplary embodiment of the DAC of Formula I includes wherein Sp is −(C3−C20carbocyclyldiyl)−(C1−C60heteroalkyldiyl)− . An exemplary embodiment of the DAC of Formula I includes wherein Sp is C1−C6025 heteroalkyldiyl. An exemplary embodiment of the DAC of Formula I includes wherein Sp is selected from the group consisting of −S(O)2CH2CH2−, −S(O)2NHCH2CH2−, −S(O)2CH2CH2CH2−, − S(O)2NHCH2CH2CH2−, −S(O)2CH2CH2CH2O−, and −S(O)2NHCH2CH2CH2O−. An exemplary embodiment of the DAC of Formula I includes wherein Sp has a formula 30 selected from the group consisting of: 129 15077.006WO2 130 15077.006WO2 where the wavy lines indicate the points of attachment to the target protein binder TPI and to the VHL ligand. An exemplary embodiment of the DAC of Formula I includes wherein the Bcl-xL target 5 protein binder TPI has Formula Id: Id wherein: R7is a C1−C20 heteroaryl substituted with one or more groups independently selected from H, F, Cl, −CH3, −CN, −NO2, −OH, and −OCH3; 10 R8aand R8bare independently selected from the group consisting of H, F, Cl, −CN, −C(=NH)NH(OH), −C(=NH)NH2, −C(=O)NRaRb, −C(=O)NRa−NRaRb, −C(=O)NH−(C1-C6alkyldiyl)−NRaRb, −C(=O)ORa, −NRaRb, −NO2, −ORa, −OC(=O)Ra, −SRa, −S(O)Ra, −S(O)2Ra, −S(O)2NRa, and −S(O)3H, C1−C12alkyl, −C1−C12heteroalkyl, C3−C20carbocyclyl, C6−C20aryl, C2-C20heterocyclyl, and C1−C20heteroaryl; 131 15077.006WO2 Rais independently selected from H, C1−C6 alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, −NO2, −OH, C1−C12alkyl, C2−C12alkenyl, C2−C12alkynyl, and −C1−C12 heteroalkyl; 5 or where two Ragroups form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring; Rbis independently selected from H, OH, −C1−C6 alkyl, −O−(C1−C6 alkyl), phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, C1−C12 alkyl, C2−C12 alkenyl, C2−C12 10 alkynyl, and −C1−C12 heteroalkyl; Reis selected from H, C1−C6 alkyl, and −C1−C12 heteroalkyl; Rfis selected from H, C1−C6 alkyl, and −C1−C12 heteroalkyl; or Rfand Sp form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring; R9is selected from the group consisting of H, F, Cl, −CN, −NO2, −OH, and −OCH3; 15 Y1is selected from N and CR11c; Y2is selected from N and CR10b; R10aand R10bare independently selected from H, F, Cl, −CN, −NO2, −OH, C1−C12alkyl, C2−C12alkenyl, C2−C12alkynyl, and −C1−C12heteroalkyl; R11a, R11b, and R11care independently selected from the group consisting of H, F, Cl, 20 −CN, −NO2, −OH, −OCH3, C1-C12 alkyl, and −C1−C12 heteroalkyl; and R12is selected from the group consisting of −(C1−C6 alkyldiyl)−(C3−C20 carbocyclyl), −(C1−C6alkyldiyl)−(C3−C20carbocyclyl)−(C1−C12heteroalkyl), −(C1−C6alkyldiyl)−(C3−C20carbocyclyl)−*, and −(C1−C6alkyldiyl)−(C3−C20carbocyclyl)−(C1−C12heteroalkyl)−*; where the asterisk * is the attachment site to the spacer unit Sp. 25 An exemplary embodiment of Formula Id includes wherein R7is selected from: 132 15077.006WO2 , substituted with one or more groups independently selected from H, F, Cl, −CH3, −CN, −NO2, −OH, and −OCH3. 5 An exemplary embodiment of Formula Id includes wherein R7is: . An exemplary embodiment of Formula Id includes wherein R8ais selected from H, −CH3 and cyclopropyl, and R8bis H. An exemplary embodiment of Formula Id includes wherein R9, R10a, and R10bare each 10 H. An exemplary embodiment of Formula Id includes wherein each Rais H. An exemplary embodiment of Formula Id includes wherein each Rbis H. An exemplary embodiment of Formula Id includes wherein Reand Rfare each H. An exemplary embodiment of Formula Id includes wherein R11ais H, and R11bis −CH3. 15 An exemplary embodiment of Formula Id includes wherein R12is −(C1−C6 alkyldiyl)−(C3−C20 carbocyclyl). 133 15077.006WO2 An exemplary embodiment of Formula Id includes wherein −(C1−C6 alkyldiyl)− is −CH2−, and C3−C20 carbocyclyl is selected from cyclohexyl and adamantyl, substituted with one or more groups selected from H, F, Cl, −OH, −C1−C12 alkyl, and −C1−C12 heteroalkyl. An exemplary embodiment of Formula Id includes wherein Formula Id is selected from: 5 a . 134 15077.006WO2 An exemplary embodiment of Formula Id includes wherein Y1is N. An exemplary embodiment of Formula Id includes the formulas: 5 An exemplary embodiment of the DAC of Formula I includes wherein L has the formula: −Str−(PEP)y−(IM)z− wherein: Str is a stretcher unit covalently attached to the antibody; 135 15077.006WO2 PEP is a protease-cleavable, peptide or amino acid unit covalently attached to Str and IM or the TPI-Sp-VHL moiety; IM is an immolative unit covalently attached to the TPI-Sp-VHL moiety; y is 0 or 1; and z is 0 or 1. 5 An exemplary embodiment of the DAC of Formula I includes wherein L is a branched linker and Str is covalently attached to: (i) the antibody; and (ii) a solubilizing unit comprising a group selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), and a glycoside, or combinations thereof, wherein the terminus of the solubilizing unit is a group selected from an amino acid, amino, hydroxyl, hydrogen, carboxylic acid, glycerol, or a sugar such as 10 pentaerythritol, maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof. An exemplary embodiment of the DAC of Formula I includes wherein L is a branched linker and PEP is covalently attached to: (i) Str and IM or the TPI-Sp-VHL moiety; and (ii) a solubilizing unit comprises a group selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), and a glycoside, or combinations thereof, wherein the terminus of the solubilizing unit is 15 a group selected from an amino acid, amino, hydroxyl, hydrogen, carboxylic acid, glycerol, or a sugar such as pentaerythritol, maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof. An exemplary embodiment of the DAC of Formula I includes wherein L is a branched linker and IM is covalently attached to: (i) the TPI-Sp-VHL moiety; and (ii) a solubilizing unit 20 comprises a group selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), and a glycoside, or combinations thereof, wherein the terminus of the solubilizing unit is a group selected from an amino acid, amino, hydroxyl, hydrogen, carboxylic acid, glycerol, or a sugar such as pentaerythritol, maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof. An exemplary embodiment of the DAC of Formula I includes wherein Str has the 25 structure: or hydrolyzed succinimide forms thereof, wherein: * indicates the point of attachment to a cysteine thiol of Ab; ** indicates the point of attachment to PEP or to the TPI-Sp-VHL moiety; 30 Rgis selected from the group consisting of C1-C12alkyldiyl, C1-C12alkyldiyl-C(=O), C1- C12 alkyldiyl−NH, (CH2CH2O)r, (CH2CH2O)r−C(=O), (CH2CH2O)r-CH2, C1−C12 136 15077.006WO2 heteroalkyldiyl, C6−C20 aryldiyl, (C6−C20 aryldiyl)−(C1−C12 alkyldiyl), and (C6−C20 aryldiyl)− (C1−C12 heteroalkyldiyl); r is an integer ranging from 1 to 10; and alkyldiyl, heteroalkyldiyl, and aryldiyl are independently and substituted with one or 5 more groups selected from H, F, Cl, −CN, −NH2, −CH2NH2, −OH, −OCH3, −OCH2CH3, − OCH2CH2OCH3, −OCH2CH2OH, −OCH2CH2N(CH3)2, −OCH2F, −OCHF2, −OCF3, − OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, −S(O)3H, and a solubilizing unit selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), and a glycoside, or combinations thereof with a terminus selected from an amino acid, amino, hydroxyl, halide, hydrogen, 10 carboxylic acid, glycerol, or a sugar such as pentaerythritol, maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof. An exemplary embodiment of the DAC of Formula I includes wherein Rgis selected from −(CH2)5−, −CH2−, −CH2CH2−, −CH2CH2OCH2CH2C(=O)−, and −CH(CH2NH2)C(=O)−. An exemplary embodiment of the DAC of Formula I includes wherein Rgis selected 15 from C6−C20 aryldiyl, (C6−C20 aryldiyl)−(C1−C12 alkyldiyl), and (C6−C20 aryldiyl)−(C1−C12 heteroalkyldiyl). An exemplary embodiment of the DAC of Formula I includes wherein PEP-IM has the formula: 20 wherein * indicates the point of attachment to Str and ** indicates the point of attachment to the TPI-Sp-VHL moiety; AA is independently selected from a natural or unnatural amino acid side chain, or one or more of AA, and an adjacent nitrogen atom form a 5-membered ring proline amino acid; Cyc1is selected from C6-C20aryldiyl and C1-C20heteroaryldiyl, substituted with one or 25 more groups selected from H, F, Cl, NO2, −OH, −OCH3, a C-glycoside, and glucuronic acid having the structure: ; 137 15077.006WO2 R13is selected from the group consisting of −CH(R14)O−, −CH2−, −CH2N(R14)CH(R14)− , −CH(R14)OC(=O)−, −CH(R14)OC(=O)N(R14)CH(R13)−, −CH(R14)OP(=O)2OCH(R14)−, and − CH(R14)OC(=O)N(R14)−(C1-C6 alkyldiyl)−N(R14)C(=O)OCH(R14)−; R14is selected from H, C1-C6 alkyl, C(=O)−C1-C6 alkyl, and −C(=O)N(R15)2; 5 R15is independently selected from the group consisting of H, C1-C12 alkyl, and − (CH2CH2O)n−(CH2)m−OH, where m is an integer from 1 to 5, and n is an integer from 2 to 50, or two R15groups together form a 5- or 6-membered heterocyclyl ring; y1is an integer from 1 to 12; and z1is 0 or 1. 10 An exemplary embodiment of the DAC of Formula I includes wherein IM is selected from the formulae: 138 15077.006WO2 wherein: * indicates the point of attachment to PEP; and ** indicates the point of attachment to the TPI-Sp-VHL moiety. 5 An exemplary embodiment of the DAC of Formula I includes wherein L has the structure: wherein: L1is independently selected from a bond, C1−C12alkyldiyl, C1−C60heteroalkyldiyl, and 10 a solubilizing unit selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), and a glycoside, or combinations thereof; L1ais independently selected from an amino acid, amino, hydroxyl, halide, hydrogen, carboxylic acid, glycerol, or a sugar such as pentaerythritol, maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof; 15 o is 0, 1, or 2; L2is selected from a bond, C1−C12alkyldiyl, and C1−C60heteroalkyldiyl; 139 15077.006WO2 * indicates the point of attachment to a cysteine thiol of Ab; and ** indicates the point of attachment to the TPI-Sp-VHL moiety. An exemplary embodiment of the DAC of Formula I includes wherein one of (L1−L1a) is F. 5 An exemplary embodiment of the DAC of Formula I includes wherein L has the structure: . An exemplary embodiment of the DAC of Formula I includes wherein L1−L1ais a solubilizing unit selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), and a 10 glycoside, or combinations thereof with a terminus selected from an amino acid, amino, hydroxyl, halide, hydrogen, carboxylic acid, glycerol, or a sugar such as pentaerythritol, maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof. An exemplary embodiment of the DAC of Formula I includes wherein L1or L2is selected from (N(CH3)CH2C(=O))q, (N(CH3)CH2CH2C(=O))q, 15 N(CH3)CH2CH2OCH2CH2C(=O))q, (CH2CH2O)q, (CH2CH2O)q−C(=O), and (CH2CH2O)q-CH2, where q is an integer from 2 to 20. An exemplary embodiment of the DAC of Formula I includes wherein L comprises a solubilizing unit selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), and a glycoside, or combinations thereof. 20 An exemplary embodiment of the DAC of Formula I includes wherein the solubilizing unit is monovalent and the terminus of the solubilizing unit is a group selected from an amino acid, amino, hydroxyl, hydrogen, carboxylic acid, glycerol, or a sugar such as pentaerythritol, maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof. An exemplary embodiment of the DAC of Formula I includes wherein the solubilizing 25 unit and the terminus of the solubilizing unit covalently attached to Str are selected from the structures: 140 15077.006WO2 5 ; 141 15077.006WO2 ; 5 wherein * indicates the point of attachment to Str. An exemplary embodiment of the DAC of Formula I includes the formulas: 142 15077.006WO2 wherein indicates the point of attachment to a cysteine thiol of Ab and indicates the point of attachment to the TPI-Sp-VHL moiety. The invention includes all reasonable combinations, and permutations of the features, of 5 the Formula I embodiments. In certain embodiments, the degrader antibody conjugates (DAC) of the invention include those with anti-cancer activity. The DAC selectively deliver an effective dose of a TPI- Sp-VHL drug to tumor tissue or hematopoietic cell, whereby greater selectivity (i.e., a lower efficacious dose) may be achieved while increasing the therapeutic index (“therapeutic 10 window”) relative to unconjugated TPI-Sp-VHL drug. Drug loading in Table 3 is represented as DAR, the number of Bcl-xL TPI-Sp-VHL moieties per antibody in an DAC of Formula I. Drug TPI-Sp-VHLloading may range from 1 to about 8 drug moieties (D) per antibody. DAC of Formula I include mixtures or collections of antibodies conjugated with a range of TPI-Sp-VHL drug moieties, from 1 to about 8. In some 15 embodiments, the number of TPI-Sp-VHL drug moieties that can be conjugated to an antibody is limited by the number of reactive or available amino acid side chain residues such as lysine and cysteine. In some embodiments, free cysteine residues are introduced into the antibody amino acid sequence by the methods described herein. In such aspects, p may be 1, 2, 3, 4, 5, 6, 7, or 8, and ranges thereof, such as from 1 to 8 or from 2 to 5. Exemplary DAC of Formula I 20 include, but are not limited to, antibodies that have 1, 2, 3, or 4 engineered cysteine amino acids (Lyon, R. et al. (2012) Methods in Enzym.502:123-138). In some embodiments, one or more 143 15077.006WO2 free cysteine residues are already present in an antibody forming intra-chain and inter-chain disulfide bonds (native disulfide groups), without the use of engineering, in which case the existing free, reduced cysteine residues may be used to conjugate the antibody to a drug. In some embodiments, an antibody is exposed to reducing conditions prior to conjugation of the 5 antibody in order to generate one or more free cysteine residues. For some antibody conjugates, p may be limited by the number of attachment sites on the antibody. For example, where the attachment is a cysteine thiol, as in certain exemplary embodiments described herein, an antibody may have only one or a limited number of cysteine thiol groups, or may have only one or a limited number of sufficiently reactive thiol groups, to 10 which the drug may be attached. In other embodiments, one or more lysine amino groups in the antibody may be available and reactive for conjugation with a BXV-L compound of Formula III. In certain embodiments, higher drug loading, e.g. p >5, may cause aggregation, insolubility, toxicity, or loss of cellular permeability of certain antibody-drug conjugates. In certain embodiments, the average drug loading for an antibody conjugate ranges from 1 to about 8; 15 from about 2 to about 6; or from about 3 to about 5. In certain embodiments, an antibody is subjected to denaturing conditions to reveal reactive nucleophilic groups such as lysine or cysteine. The loading (drug / antibody ratio) of an antibody conjugate may be controlled in different ways, and for example, by: (i) limiting the molar excess of the BXV-L intermediate compound 20 relative to antibody, (ii) limiting the conjugation reaction time or temperature, and (iii) partial or limiting reductive denaturing conditions for optimized antibody reactivity. It is to be understood that where more than one nucleophilic group of the antibody reacts with a BXV-L, then the resulting product is a mixture of antibody conjugate compounds with a distribution of one or more TPI-Sp-VHL drug moieties attached to an antibody. The average 25 number of drugs per antibody may be calculated from the mixture by a dual ELISA antibody assay, which is specific for antibody and specific for the drug. Individual DAC molecules may be identified in the mixture by mass spectroscopy and separated by HPLC, for example hydrophobic interaction chromatography, HIC (McDonagh et al. (2006) Prot. Engr. Design & Selection 19(7):299-307; Hamblett et al. (2004) Clin. Cancer Res.10:7063-7070; Hamblett, 30 K.J., et al. “Effect of drug loading on the pharmacology, pharmacokinetics, and toxicity of an anti-CD30 antibody-drug conjugate,” Abstract No.624, American Association for Cancer Research, 2004 Annual Meeting, March 27-31, 2004, Proceedings of the AACR, Volume 45, March 2004; Alley, S.C., et al. “Controlling the location of drug attachment in antibody-drug conjugates,” Abstract No.627, American Association for Cancer Research, 2004 Annual 35 Meeting, March 27-31, 2004, Proceedings of the AACR, Volume 45, March 2004). In certain 144 15077.006WO2 embodiments, a homogeneous antibody conjugate with a single loading value may be isolated from the conjugation mixture by electrophoresis or chromatography. Exemplary embodiments of the degrader antibody conjugates (DAC) of Formula I are compiled in Table 3. DAC of Table 3 were prepared by the methods of Examples 101-103. 5 Assessment of DAC biological activity and other properties may be conducted according to the methods of Examples 104-107 and compiled in Table 5. In some instances, the Cell proliferation dose response IC50 value of Table 3 is an average of repetitive assays. Certain exemplary DAC were tested for their effects in inhibiting cellular proliferation and degradation of Bcl-xL protein. As shown in Table 5, certain Bcl-xL-VHL DAC exhibited very potent 10 degradation of Bcl-xL protein in cells (DC50, Dmax) and resulting in potent inhibition of cellular proliferation (IC50). The inhibition of cellular proliferation was increased with the addition of standard-of-care chemotherapy agent paclitaxel. The data demonstrates the potential use of Bcl-xL-VHL DAC, including combination therapy, in the treatment of cancer patients with tumors expressing the HER2 receptor and other tumor-associated antigens. 15 Table 3 Bcl-xL-VHL Degrader Antibody Conjugates (DAC-BXV) D 1 2 3 4 5 6 7 8 HER2 145 15077.006WO2 9 pertuzumab 8 BXVL-14 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 HER2 146 15077.006WO2 26 trastuzumab S375CE152C 4 BXVL-20 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 HER2 147 15077.006WO2 43 pertuzumab S375C V264C 4 BXVL-13 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 HER2 148 15077.006WO2 59 pertuzumab 6 BXVL-44 6 6 6 6 6 6 6 6 6 6 7 7 7 7 HER2 149 15077.006WO2 74 pertuzumab S239C S375C 4 BXVL-39 7 7 7 7 7 8 8 8 8 8 8 8 8 HER2 150 15077.006WO2 88 pertuzumab S239C S375C 4 BXV-L-40 8 9 9 9 PHARMACEUTICAL COMPOSITIONS OF DEGRADER ANTIBODY CONJUGATES The invention provides a composition, e.g., a pharmaceutically or pharmacologically acceptable composition or formulation, comprising a Bcl-xL TPI-Sp-VHL degrader antibody 5 conjugate (DAC) composition of the invention as described herein and a pharmaceutically acceptable diluent, vehicle, carrier or excipient. In an exemplary embodiment, a pharmaceutical composition comprises a mixture of the antibody conjugate DAC, wherein the average drug TPI-Sp-VHL loading per antibody in the mixture of antibody conjugate compounds is about 2 to about 8. A DAC of the invention can 10 have an average TPI-Sp-VHL to antibody ratio (DAR) of about 0.4 to about 10. A skilled artisan will recognize that the number of TPI-Sp-VHL moieties conjugated to the antibody may vary amongst DAC in a composition comprising multiple DAC of the invention and thus the DAR can be measured as an average which may be referred to as the drug to antibody ratio (DAR) which can be assessed by any suitable means, many of which are known in the art. The average 15 number of TPI-Sp-VHL moieties per antibody (DAR) in preparations of DAC from conjugation reactions may be characterized by conventional means such as mass spectrometry, ELISA assay, and HPLC. The quantitative distribution of DAC in a composition in terms of p may also be determined. In certain instances, separation, purification, and characterization of homogeneous DAC where p is a certain value from antibody drug conjugates (ADC) with other drug loadings 20 may be achieved by purification means such as reverse phase HPLC or electrophoresis. 151 15077.006WO2 A TPI-Sp-VHL degrader antibody conjugate (DAC) composition can be formulated for parenteral administration, such as intradermal, subcutaneous, intramuscular (IM), or intravenous (IV) injections, infusion, or administration into a body cavity or lumen of an organ. Alternatively, the DAC as a pharmaceutical composition can be injected into otherwise placed 5 into a specific site of the body, such as a tumor. Compositions for injection will commonly comprise a solution of the DAC dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and an isotonic solution of one or more salts such as sodium chloride, e.g., Ringer's solution. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose, any bland 10 fixed oil can be employed, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These pharmaceutical compositions desirably are sterile and generally free of undesirable matter. These pharmaceutical compositions can be made sterilized by conventional, well known sterilization techniques. The pharmaceutical compositions can contain pharmaceutically 15 acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The pharmaceutical composition may contain any suitable concentration of the DAC . The concentration of the DAC in the pharmaceutical composition can vary widely, and will be 20 selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. In certain embodiments, the concentration of DAC in a solution formulation for injection will range from about 0.1% (w / w) to about 10% (w / w). METHODS OF TREATING CANCER WITH DEGRADER ANTIBODY CONJUGATES 25 By inducing target-specific degradation of tumor-associated proteins and conferring specificity to minimize off-target toxicity effects, the TPI-Sp-VHL antibody conjugate (DAC) compositions of the invention may be useful in the treatment of diseases and disorders such as cancer. The DAC direct a tumor-associated antigen-binding antibody to a cell that expresses the antigen and deliver a protein-degrading moiety to the target cell. A target protein such as RIPK2, 30 KRAS, Bcl-xL, or WEE1 is ubiquitinated and subsequently degraded. The invention provides a method for treating cancer with a pharmaceutical composition of the DAC. The method includes administering a therapeutically effective amount of an antibody conjugate composition as described herein to a subject in need thereof, such as a 152 15077.006WO2 patient that has cancer and is in need of treatment for the cancer. The method includes administering a therapeutically effective amount of an DAC selected from Table 3. In certain embodiments, the DAC include those with anticancer activity (Figures 1-4). The DAC selectively delivers an effective dose of an active form of the TPI-Sp-VHL protein 5 target degrader moiety to tumor tissue, whereby greater selectivity (i.e., a lower efficacious dose) may be achieved while increasing the therapeutic index (“therapeutic window”) relative to an unconjugated protein target degrader compound. It is contemplated that the DAC may be used to treat various hyperproliferative diseases or disorders, e.g. characterized by the overexpression of a tumor antigen. Exemplary 10 hyperproliferative disorders include benign or malignant solid tumors and hematological disorders such as leukemia and lymphoid malignancies. Examples of cancer to be treated herein include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, leukemia or lymphoid malignancies including acute myeloid leukemia, squamous cell cancer, epithelial squamous cell cancer, lung cancer including small- 15 cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal 20 cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer. In some embodiments, the DAC may be useful in therapy to treat solid tumors such as lung cancer; non-small cell lung cancer, squamous cell lung cancer, small cell lung cancer, breast cancer, and neuroendocrine cancers such as neuroendocrine prostate cancer, castration-resistant neuroendocrine prostate cancer (NEPC) and lung 25 neuroendocrine tumors. In some embodiments, the DAC may be useful in therapy to treat blood-borne hematological cancers such as leukemias; acute myelogenous leukemia (AML) and myelomas; multiple myeloma (MM). In another aspect, an DAC for use as a medicament is provided. In certain embodiments, the invention provides an DAC for use in a method of treating an individual comprising 30 administering to the individual an effective amount of the antibody conjugate composition in a pharmaceutical composition. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, e.g., as described herein. In a further aspect, the invention provides for the use of an DAC in the manufacture or 35 preparation of a medicament. In one embodiment, the medicament is for treatment of cancer, the 153 15077.006WO2 method comprising administering to an individual having cancer an effective amount of the medicament. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, e.g., as described herein. 5 Dosing can be by any suitable route, e.g. by injections, such as intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic. Various dosing schedules including but not limited to single or multiple administrations over various time-points, bolus administration, and pulse infusion are contemplated herein. The DAC dose can range from about 5 mg / kg (body weight) to about 50 mg / kg, from about 10 µg / kg to 10 about 5 mg / kg, or from about 100 µg / kg to about 1 mg / kg. The DAC dose can be about 100, 200, 300, 400, or 500 µg / kg. The DAC dose can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / kg. The DAC dose can also be outside of these ranges, depending on the particular conjugate as well as the type and severity of the cancer or disorder being treated. Frequency of administration can range from a single dose to multiple doses per week, or more frequently. In some embodiments, 15 the DAC is administered from about once per month to about five times per week. In some embodiments, the DAC is administered once per week. The DAC can be used either alone or in combination with other therapeutic agents in a therapy regimen. DAC may be administered concurrently in a regimen with one or more other drugs during the same treatment cycle, on the same day of treatment as the one or more other 20 drugs, and, optionally, at the same time as the one or more other drugs. For instance, for cancer therapies given every 3 weeks, the concurrently administered drugs are each administered on day-1 of a 3-week cycle. For instance, an DAC may be co-administered with at least one additional therapeutic agent, such as a chemotherapeutic agent. Such combination therapies encompass combined administration (where two or more therapeutic agents are included in the 25 same or separate formulations), and separate administration, in which case, administration of the DAC can occur prior to, simultaneously, and / or following, administration of the additional therapeutic agent. DAC can also be used in combination with radiation therapy. EXAMPLES General Synthetic Schemes and Examples 30 The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by 154 15077.006WO2 using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art of prepared as described herein. Synthesis of Bcl-xL-VHL linker compound (BVL) intermediates 5 Example Int.1 Synthesis of 5,8,11,14,17,20,23,26,29-nonamethyl- 4,7,10,13,16,19,22,25,28-nonaoxo-2,5,8,11,14,17,20,23,26,29-decaazahentriacontan-31-oic acid (Int 1) Step A. Preparation of Int 1a 10 To a solution of tert-butyl methylglycinate (100 g, 550 mmol, 1.00 eq, hydrochloride) and N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methylglycine (171 g, 550 mmol, 1.00 eq) in dimethyl formamide (400 mL) was added diisopropylethylamine (142 g, 1.10 mol, 192 mL, 2.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (251 g, 661 mmol, 1.20 eq). Then the mixture was stirred at 25 °C for 1 h. The reaction mixture was 15 poured into water (3 L) and extracted with ethyl acetate (3 × 200 mL). The organic layer was washed with brine (3 × 200 mL) and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash ® Silica Flash Column, Eluent of 30~90% ethyl acetate / petroleum ether gradient @ 120 mL / min) to afford tert-butyl N-(N-(((9H- fluoren-9-yl)methoxy)carbonyl)-N-methylglycyl)-N-methylglycinate, Int 1a, (230 g, 524 mmol, 20 95% yield) as yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 7.89 (t, J = 8.4 Hz, 2H), 7.69 - 7.56 (m, 2H), 7.41 (q, J = 7.4 Hz, 2H), 7.37 - 7.25 (m, 2H), 4.33 - 4.08 (m, 4H), 4.04 - 3.93 (m, 3H), 2.97 - 2.79 (m, 6H), 1.45 - 1.35 (m, 9H). Step B. Preparation of Int 1b 25 A solution of Int 1a, (230 g, 524 mmol, 1.00 eq) in trifluoroacetic acid (500 mL) and dichloromethane (500 mL) was stirred at 25 °C for 3 h. The reaction mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 50~100% ethyl acetate / petroleum ether gradient at 120 mL / min) to afford N-(N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methylglycyl)-N- 155 15077.006WO2 methylglycine, Int 1b, (200 g, 523 mmol, 99% yield) as yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 7.89 (br t, J = 8.8 Hz, 2H), 7.72 - 7.56 (m, 2H), 7.41 (q, J = 7.2 Hz, 2H), 7.37 - 7.25 (m, 2H), 4.35 - 4.23 (m, 2H), 4.23 - 4.08 (m, 2H), 4.07 - 3.97 (m, 3H), 3.01 - 2.77 (m, 6H). Step C. Preparation of Int 1d 5 To a solution of Int 1b, (35.0 g, 91.5 mmol, 1.00 eq) in dichloromethane (600 mL) was added to 2-chlorotrityl chloride resin (175 g). Then diisopropylethylamine (29.6 g, 228 mmol, 39.9 mL, 2.50 eq) was added. The mixture was stirred at 25°C for 2 h. The mixture was filtered and washed with dimethyl formamide (600 mL) and 10 dichloromethane / methanol / diisopropylethylamine (600 mL, 80:15:5). The mixture was filtered and washed with dimethyl formamide (3 × 600 mL) and dichloromethane (3 × 600 mL). This reaction was in parallel twice. The resin, Int 1c, was stored at 0 °C for next step. Elongation of the polysarcosine oligomer was performed until the desired length was obtained, by alternating remove Fmoc and amide coupling steps. In the first step, the resin, Int 15 1c, was treated with piperidine (50%) in dimethyl formamide at 25°C for 1 min and washed with dimethyl formamide (4 times). For the amide coupling step, to the resin was added a solution of N-(N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methylglycyl)-N-methylglycine (1.30 eq), O-(7- azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (1.50 eq) and diisopropylethylamine (2 eq) in dimethylformamide. The reaction vessel was stirred at 25 °C 20 for 2 h and the resin was extensively washed with dimethyl formamide (4 times) and dichloromethane (3 times). The resin, Int 1d, was dried under vacuum and stored at 0 °C. Step D. Preparation of Int 1e 156 15077.006WO2 The resin, Int 1d, in piperidine (500 mL) and dimethyl formamide (500 mL) was agitated with nitrogen atmosphere at 15 °C for 1 min. The mixture was filtered and washed with dimethyl formamide (3 × 500 mL) and dichloromethane (500 mL), then the filter cake was 5 concentrated in vacuum. The resin, Int 1e, (the equivalent of 50 g of Int 1f loaded on resin) was dried under vacuum and stored at 0 °C. Step E. Preparation of Int 1f The resin, Int 1d, (42 g) in piperidine (40.0 mL) and dimethyl formamide (160 mL) was 10 agitated with nitrogen atmosphere for 1 h at 25°C. Then the solution was drained and the resin was washed with dimethyl formamide (3 × 120 mL) and dichloromethane (3 × 120 mL). Then it was agitated in 1,1,1,3,3,3-Hexafluro-2-propanol (40 mL) and DCM (160 mL) with nitrogen atmosphere for 1 h at 25 °C and filtered. The filtrate was concentrated to give a residue, which was purified by prep-HPLC (column: Waters Atlantis T3150*30mm*5um;mobile phase: 15 [water(FA)-ACN];gradient:1%-20% B over 10 min) to give 5,8,11,14,17,20,23,26,29- nonamethyl-4,7,10,13,16,19,22,25,28-nonaoxo-2,5,8,11,14,17,20,23,26,29- 157 15077.006WO2 decaazahentriacontan-31-oic acid, Int 1, (550 mg, 754 μmol) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 4.50 - 3.50 (m, 24H), 2.95 - 270 (m, 23H), 2.49 - 2.37 (m, 3H). Example Int.2 Synthesis of tert-butyl 4-(3-(2, 5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)-2-fluoro-6-(3-oxo-3-(2,3,5,6-tetrafluorophenoxy)propyl)phenoxy)butanoate (Int 2) 5 Step A. Preparation of Int 2a To a solution of 2-fluoro-3-methoxyaniline (11.0 g, 77.9 mmol, 1.00 equiv) in N,N- dimethyl formamide (40.0 mL) was added a solution of 1-bromopyrrolidine-2, 5-dione (13.9 g, 78.0 mmol, 1.00 equiv) dropwise. The mixture was stirred at 15 °C for 3 h. The mixture was 10 diluted with brine (300 mL) and extracted with ethyl acetate (3 × 300 mL). The organic layers were collected and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel (SiO2, petroleum ether / ethyl acetate=1 / 0 to 3 / 1) and concentrated to afford 4-bromo-2-fluoro-3-methoxyaniline, Int.2a, (26.0 g, 118 mmol, 75% yield) as yellow 15 oil.1H NMR (400 MHz, DMSO-d6) δ = 7.03 (dd, J = 8.8, 1.2 Hz, 1H), 6.47 (t, J = 8.8 Hz, 1H), 5.38 (s, 2H), 3.86 - 3.78 (m, 3H). Step B. Preparation of Int 2b To a solution of Int.2a, (10.0 g, 45.5 mmol, 1.00 equiv) in dichloromethane (100 mL) was added borontribromide (171 g, 682 mmol, 65.7 mL, 15.0 equiv) at 0 °C. The mixture was 20 stirred at 15 °C for 0.5 h. The reaction mixture was quenched by addition water (300 mL) at 0 °C. After filtration, the filtrate was extracted with ethyl acetate (3 × 200 mL). The organic layers were collected and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 3-amino-6-bromo-2-fluorophenol, Int.2b, (22.5 g, crude) as yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 9.95 - 9.35 (m, 1H), 6.90 (dd, J = 25 8.8, 1.6 Hz, 1H), 6.20 - 6.16 (m, 1H), 5.15 (br s, 2H). MS (ESI) m / z 205.9 [M+H]+Step C. Preparation of Int 2c To a solution of Int.2b, (16.0 g, 77.7 mmol, 1.00 equiv), cesium carbonate (50.6 g, 155 mmol, 2.00 equiv) and potassium iodide (1.29 g, 7.77 mmol, 0.100 equiv) in N, N-dimethyl formamide (50.0 mL) was added tert-butyl 4-bromobutanoate (19.1 g, 85.4 mmol, 1.10 equiv). 30 The mixture was stirred at 85 °C for 12 h. The mixture was diluted with brine (300 mL) and extracted with ethyl acetate (3 × 200 mL). The organic layers were collected and dried over 158 15077.006WO2 anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel (SiO2, petroleum ether / ethyl acetate=1 / 0 to 3 / 1) and concentrated to afford tert-butyl 4-(3-amino-6- bromo-2-fluorophenoxy)butanoate, Int.2c, (17.0 g, 48.8 mmol, 62% yield) as brown oil.1H 5 NMR (400 MHz, DMSO-d6) δ = 7.03 (dd, J = 8.8, 1.6 Hz, 1H), 6.46 (t, J = 8.8 Hz, 1H), 5.36 (s, 2H), 3.98 - 3.93 (m, 2H), 2.43 (t, J = 7.2 Hz, 2H), 1.91 (br t, J = 6.8 Hz, 2H), 1.40 (s, 9H). Step D. Preparation of Int 2d To a solution of Int.2c, (12.0 g, 34.5 mmol, 1.00 equiv) and ethyl (E)-3-(4,4,5,5- 10 tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (19.5 g, 86.2 mmol, 2.50 equiv) in dioxane (100 mL) and water (10.0 mL) was added 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (1.41 g, 3.45 mmol, 0.100 equitv), potassium phosphate (11.0 g, 51.7 mmol, 1.50 equiv) and bis(dibenzylideneacetone)-palladium(0) (1.58 g, 1.72 mmol, 0.050 equiv.). The mixture was stirred at 90 °C for 12 h under nitrogen atmosphere. The mixture was concentrated under 15 reduced pressure to give a crude product, which was purified by column chromatography on silica gel (SiO2, petroleum ether / ethyl acetate=1 / 0 to 3 / 1) and concentrated to afford tert-butyl (E)-4-(3-amino-6-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-fluorophenoxy)butanoate, Int.2d, (11.0 g, 30.0 mmol, 86% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 7.70 (d, J = 16.0 Hz, 1H), 7.30 (dd, J = 8.8, 1.2 Hz, 1H), 6.50 (t, J = 8.4 Hz, 1H), 6.32 (d, J = 16.0 Hz, 1H), 5.87 20 (s, 2H), 4.14 (q, J = 7.2 Hz, 2H), 4.01 (t, J = 6.4 Hz, 2H), 2.40 (t, J = 7.2 Hz, 2H), 1.92 (quin, J = 6.8 Hz, 2H), 1.38 (s, 9H), 1.25 - 1.22 (m, 3H). Step E. Preparation of Int 2e A mixture of Int.2d, (5.00 g, 13.6 mmol, 1.00 equiv) in methanol (100 mL) was added 25 palladium on activated carbon (5.00 g, 10% purity). The mixture was stirred at 25 °C for 12 h 159 15077.006WO2 under hydrogen (50 Psi) atmosphere. The reaction mixture was filtered concentrated under reduced pressure to afford tert-butyl 4-(3-amino-6-(3-ethoxy-3-oxopropyl)-2- fluorophenoxy)butanoate, Int.2e, (3.40 g, crude) as black oil.1H NMR (400 MHz, DMSO-d6) δ = 6.64 (dd, J = 8.4, 1.6 Hz, 1H), 6.39 (t, J = 8.4 Hz, 1H), 5.01 - 4.91 (m, 2H), 4.03 (q, J = 6.8 5 Hz, 2H), 3.93 (t, J = 6.8 Hz, 2H), 2.74 - 2.64 (m, 2H), 2.47 - 2.44 (m, 2H), 2.39 (t, J = 6.8 Hz, 2H), 1.90 (quin, J = 6.8 Hz, 2H), 1.40 (s, 9H), 1.15 (t, J = 6.8 Hz, 3H). Step F. Preparation of Int 2f To a solution of Int.2e, (5.00 g, 13.5 mmol, 1.00 equiv) in methanol (10.0 mL), 10 tetrahydrofuran (10.0 mL) and water (10.0 mL) was added lithium hydroxide monohydrate (852 mg, 20.3 mmol, 1.50 equiv). The mixture was stirred at 15 °C for 1 h. The mixture was quenched with hydrochloric acid (1M) until pH=7. The mixture was concentrated to remove tetrahydrofuran and methanol. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 × 150 mL). The organic layers were collected and dried over anhydrous sodium15 sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 3-(4- amino-2-(4-(tert-butoxy)-4-oxobutoxy)-3-fluorophenyl)propanoic acid, Int.2f, (4.00 g, crude) as yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 12.45 - 11.77 (m, 1H), 6.65 (dd, J = 8.4, 1.2 Hz, 1H), 6.39 (t, J = 8.4 Hz, 1H), 4.96 (s, 2H), 3.93 (t, J = 6.4 Hz, 2H), 2.66 (t, J = 7.2 Hz, 2H), 2.41 - 2.36 (m, 4H), 1.90 (quin, J = 6.8 Hz, 2H), 1.40 (s, 9H). 20 Step G. Preparation of Int 2g To a solution of Int.2f, (4.00 g, 11.7 mmol, 1.00 equiv) in dichloromethane (50.0 mL) was added triethylamine (3.56 g, 35.2 mmol, 4.89 mL, 3.00 equiv) and methyl 2,5-dioxo-2,5- dihydro-1H-pyrrole-1-carboxylate (2.00 g, 12.9 mmol, 2.00 mL, 1.10 equiv) at 0 °C. The 160 15077.006WO2 mixture was stirred at 15 °C for 2 h. The mixture was diluted with water (100 mL) and extracted with dichloromethane (3 × 80 mL). The organic layers were collected and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 3-(2-(4-(tert-butoxy)-4-oxobutoxy)-4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3- 5 fluorophenyl)propanoic acid, Int.2g, (4.50 g, crude) as brown oil.1H NMR (400 MHz, DMSO- d6) δ = 7.25 (s, 2H), 7.16 (d, J = 8.8 Hz, 1H), 7.08 - 7.03 (m, 1H), 4.01 (br t, J = 6.4 Hz, 2H), 2.87 (br t, J = 7.6 Hz, 2H), 2.52 - 2.51 (m, 2H), 2.42 - 2.36 (m, 4H), 1.39 (s, 9H). Step H. Preparation of Int 2h 10 To a solution of Int.2g, (4.50 g, 10.7 mmol, 1.00 equiv) and 2,3,5,6-tetrafluorophenol (3.55 g, 21.4 mmol, 2.00 equiv) in dichloromethane (50.0 mL) and N,N-dimethylacetamide (5.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.09 g, 21.4 mmol, 2.00 equiv) at 0 °C. The mixture was stirred at 15 °C for 1 h. The mixture was concentrated under reduced pressure to give a crude product, which was purified by reversed- 15 phase HPLC (column: spherical C18, 20-45 um, 100Å, SW 330, mobile phase: [0.1% formic acid - acetonitrile]; B%: 85%-100%, 60 min). The desired fraction collected and lyophilized to afford tert-butyl 4-(3-(2, 5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-2-fluoro-6-(3-oxo-3-(2,3,5,6- tetrafluorophenoxy)propyl)phenoxy)butanoate, Int.2h, (3.00 g, 5.27 mmol, 49 %yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ = 7.97 - 7.91 (m, 1H), 7.26 (s, 2H), 7.24 (s, 1H), 20 7.13 - 7.08 (m, 1H), 4.06 (t, J = 6.4 Hz, 2H), 3.18 - 3.12 (m, 2H), 3.10 - 3.04 (m, 2H), 2.43 - 2.39 (m, 2H), 1.97 - 1.92 (m, 2H), 1.37 (s, 9H). MS (ESI) m / z 587.1 [M+H2O]+Step I. Preparation of Int 2i 161 15077.006WO2 To a solution of Int.2h, (1.00 g, 1.76 mmol, 1.00 equiv) in dichloromethane (15.0 mL) was added trifluoroacetic acid (76.8 g, 673 mmol, 50.0 mL, 383 equiv). The mixture was stirred at 15 °C for 0.5 h. The reaction mixture was lyophilized to give a crude product, which was triturated with methyl tert-butyl ether (10 mL) at 25 °C. Then filtered, the filter cake was dried 5 in vacuum to afford 4-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-2-fluoro-6-(3-oxo-3-(2,3,5,6- tetrafluorophenoxy)propyl)phenoxy)butanoic acid, Int.2i, (300 mg, 584 μmol, 33% yield) as a pink solid.1H NMR (400 MHz, DMSO-d6) δ = 13.15 - 11.06 (m, 1H), 7.94 (tt, J = 7.6, 10.8 Hz, 1H), 7.26 (s, 2H), 7.24 (s, 1H), 7.15 - 7.06 (m, 1H), 4.08 (t, J = 6.0 Hz, 2H), 3.23 - 3.13 (m, 2H), 3.11 - 3.02 (m, 2H), 2.42 (t, J = 7.4 Hz, 2H), 1.96 (quin, J = 6.8 Hz, 2H). 10 Step J. Preparation of Int 2j To a solution of Int.2i, (100 mg, 195 μmol, 1.00 equiv) in dichloromethane (3.00 mL) was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine, Int.2j, (52.1 mg, 390 μmol, 51.5 μL, 2.00 eqiv). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was used in next 15 step directly. Step K. Preparation of Int 2 162 15077.006WO2 To a solution of 5,8,11,14,17,20,23,26,29-nonamethyl-4,7,10,13,16,19,22,25,28- nonaoxo-2,5,8,11,14,17,20,23,26,29-decaazahentriacontan-31-oic acid, Int 1f, (137 mg, 188 μmol, 1.00 equiv) in dichloromethane (2.00 mL) and N,N-diisopropylethylamine (72.9 mg, 564 5 μmol, 98.3 μL, 3.00 equiv). The mixture was stirred at 25 °C for 10 min. Then to the mixture was added 2,3,5,6-tetrafluorophenyl 3-(2-(4-chloro-4-oxobutoxy)-4-(2,5-dioxo-2,5-dihydro-1H- pyrrol-1-yl)-3-fluorophenyl)propanoate, Int.2j, (100 mg, 188 μmol, 1.00 equiv) at 0 °C. The mixture was stirred at 25 °C for 20 min. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by prep-HPLC (column: UniSil 3-100 C18 10 UItra (150*25mm*3um); mobile phase: [water (formic acid)-acetonitrile]; gradient: 20%-50% B over 40 min). The desired fraction collected and lyophilized to afford 34-(3-(2,5-dioxo-2,5- dihydro-1H-pyrrol-1-yl)-2-fluoro-6-(3-oxo-3-(2,3,5,6-tetrafluorophenoxy)propyl)phenoxy)- 3,6,9,12,15,18,21,24,27,30-decamethyl-4,7,10,13,16,19,22,25,28,31-decaoxo- 3,6,9,12,15,18,21,24,27,30-decaazatetratriacontanoic acid, Int.2, (30.0 mg, 24.3 μmol, 12 % 15 yield, 99% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 13.48 - 12.07 (m, 1H), 8.00 - 7.87 (m, 1H), 7.26 (s, 2H), 7.25 - 7.20 (m, 1H), 7.13 - 7.06 (m, 1H), 4.34 - 4.19 (m, 8H), 4.15 - 3.98 (m, 11H), 3.93 (br d, J = 4.4 Hz, 2H), 3.16 (br d, J = 6.0 Hz, 2H), 3.11 - 3.06 (m, 163 15077.006WO2 2H), 2.95 - 2.71 (m, 31H), 2.35 - 2.29 (m, 2H), 1.99 - 1.89 (m, 2H). MS (ESI) m / z 1246.4 [M+Na]+Intermediate compounds Int K and Int L were prepared in a manner similar to that described for Int 1 and Int 2 using the appropriate compound as starting material. 5 L Synthesis of VHL intermediates Example Int 4 Synthesis of benzyl (2S,4R)-1-[(2S)-2-azido-3-methyl-butanoyl]- 4-hydroxy-pyrrolidine-2-carboxylate (Int 4) Step A. Preparation of Int 4A 10 To a solution of benzyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate;hydrochloride (98.3 g, 381 mmol, 1.2 eq) in DCM (1000 mL) were added DIEA (123 g, 954 mmol, 166 mL, 3 eq) and (2,5-dioxopyrrolidin-1-yl) (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoate (100 g, 318 mmol, 1 eq) in one portion. The mixture was stirred at 25°C for 2 hrs. The reaction mixture 15 was diluted with H2O (1000 mL) and extracted with DCM (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (Commercial hexanes / ethyl acetate = 100 / 1 to 1 / 1). Compound benzyl (2S,4R)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2- 20 carboxylate Int 4A (200 g, 475 mmol, 74.7% yield) was obtained as a yellow oil.1H NMR: (400 MHz, CDCl3) δ7.40 - 7.28 (m, 5H), 5.26 (d, J = 8.8 Hz, 1H), 5.22 - 5.10 (m, 2H), 4.73 (t, J = 8.4 Hz, 1H), 4.50 (s, 1H), 4.00 (d, J = 11.2 Hz, 1H), 3.72 - 3.64 (m, 1H), 3.09 (d, J = 2.0 Hz, 1H), 164 15077.006WO2 2.42 - 2.29 (m, 1H), 2.03 - 1.93 (m, 2H), 1.41 (s, 9H), 1.03 - 0.84 (m, 6H). LCMS: MS (ESI) m / z 421.2 [M+H]+. Step B. Preparation of Int 4B 5 To a solution of benzyl (2S,4R)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl- butanoyl]-4-hydroxy-pyrrolidine-2-carboxylate Int 4A (117 g, 278 mmol, 1 eq) in EtOAc (400 mL) was added HCl / EtOAc (4 M, 1500 mL, 21.5 eq) in one portion. The mixture was stirred at 20°C for 2 hrs. The reaction mixture was concentrated under reduced pressure to dryness. The residue was slurry with MTBE (1000mL) for 30min, then filtered and the filter cake was washed10 with MTBE (1000mL), dried in vacuum to give benzyl (2S,4R)-1-[(2S)-2-amino-3-methyl- butanoyl]-4-hydroxy-pyrrolidine-2-carboxylate Int 4B (100 g, crude, HCl) as a white solid. LCMS: MS (ESI) m / z 321.2 [M+H]+. Step C. Preparation of Int 4 15 To a solution of benzyl (2S,4R)-1-[(2S)-2-amino-3-methyl-butanoyl]-4-hydroxy- pyrrolidine-2-carboxylate Int 4B (70 g, 196 mmol, 1 eq, HCl) in CH3CN (700 mL) were added DIEA (76.0 g, 588 mmol, 102 mL, 3 eq) and 2-azido-1,3-dimethyl-4,5-dihydroimidazol-1- ium;hexafluorophosphate (67.1 g, 235 mmol, 1.2 eq) in one portion. The mixture was stirred at 0°C for 1 hr. The reaction mixture was diluted with H2O (1000 mL) and extracted with EtOAc 20 (500 mL x 3). The combined organic layers was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (Commercial hexanes / ethyl acetate = 100 / 1 to 1 / 1). Compound benzyl (2S,4R)-1-[(2S)-2-azido-3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2- carboxylate Int 4 (30 g, 86.6 mmol, 44.1% yield) was obtained as a yellow oil.1H NMR (400 25 MHz, CDCl3) δ7.38 - 7.29 (m, 5H), 5.27 - 5.07 (m, 2H), 4.75 (t, J = 8.0 Hz, 1H), 4.58 (s, 1H), 3.79 - 3.57 (m, 2H), 3.38 (d, J = 8.8 Hz, 1H), 2.53 (d, J = 4.0 Hz, 1H), 2.37 - 2.18 (m, 2H), 2.11 165 15077.006WO2 - 2.01 (m, 1H), 1.08 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H). LCMS: MS (ESI) m / z 347.2[M+H]+Example Int.5 Synthesis of (2,3,5,6-tetrafluorophenyl) (2S,4R)-1-[(2S)-2-azido- 3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2-carboxylate (Int 5) 5 Step A. Preparation of Int 5A To a solution of benzyl (2S,4R)-1-[(2S)-2-azido-3-methyl-butanoyl]-4-hydroxy- pyrrolidine-2-carboxylate Int 4 (2 g, 5.77 mmol, 1 eq) in MeOH (5 mL) and THF (5 mL) was added dropwise a solution of LiOH•H2O (1.21 g, 28.8 mmol, 5 eq) in H2O (5 mL). The mixture 10 was stirred at 0°C for 0.5hr. The reaction mixture was adjusted to pH=2 by addition HCl (1M) at 0°C and diluted with ice water 20 mL. The mixture was extracted with (Dichloromethane : Isopropanol =3:1) 60 mL (10 mL × 6). The organic layers were dried over Na2SO4and filtered to collect filtrate. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash 15 Column, Eluent of 0~100% Ethyl acetate / Commercial hexanes gradient @ 80 mL / min) to obtain compound (2S,4R)-1-[(2S)-2-azido-3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2-carboxylic acid Int 5A (1.17 g, 4.57 mmol, 79.1% yield) as colorless oil.1H NMR (400 MHz, DMSO-d6) δ4.34 - 4.27 (m, 2H), 3.78 (d, J = 8.0 Hz, 1H), 3.60 - 3.51 (m, 2H), 2.19 - 2.10 (m, 1H), 2.10 - 2.00 (m, 1H), 1.92 - 1.84 (m, 1H), 1.00 - 0.92 (m, 6H). LCMS: MS (ESI) m / z 257.2 [M+H]+. 20 Step B. Preparation of Int 5 To a solution of (2S,4R)-1-[(2S)-2-azido-3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2- carboxylic acid Int 5A (2.5 g, 9.76 mmol, 1 eq) and 2,3,5,6-tetrafluorophenol (4.86 g, 29.2 mmol, 3 eq) in DCM (30 mL) was added EDCI, 1-Ethyl-3-(3′- 166 15077.006WO2 dimethylaminopropyl)carbodiimide, CAS Reg. No.1892-57-5 (7.48 g, 39.0 mmol, 4 eq). The mixture was stirred at 20°C for 1hr. The reaction mixture was quenched by addition H2O 10 mL and extracted with DCM (20 mL x3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by 5 prep-HPLC (column: Phenomenex luna C18 (250*70mm,15 um);mobile phase: [H2O(0.1% TFA)-ACN];gradient:30%-60% B over 25.0 min). Compound (2,3,5,6-tetrafluorophenyl) (2S,4R)-1-[(2S)-2-azido-3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2-carboxylate Int 5 (3 g, 7.42 mmol, 76.06% yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ8.11- 7.90 (m, 1H), 4.80 (t, J = 8.4 Hz, 1H), 4.45 (s, 1H), 3.93 (d, J = 8.0 Hz, 1H), 3.69 (s, 2H), 2.44- 10 2.34 (m, 1H), 2.18-2.00 (m, 2H), 1.05-0.89 (m, 6H). LCMS: MS (ESI) m / z 405.0 [M+H]+. Example Int.6 Synthesis of (2S,4R)-4-acetoxy-1-[(2S)-3-methyl-2-[4-(3- sulfamoylpropoxy)triazol-1-yl]butanoyl]pyrrolidine-2-carboxylate (VHL Int 6) 15 Step A. Preparation of Int 6a. 167 15077.006WO2 To a solution of benzyl (2S,4R)-1-[(2S)-2-azido-3-methyl-butanoyl]-4-hydroxy- pyrrolidine-2-carboxylate (1.00 g, 2.89 mmol, 1 eq) and tert-butyl-(3-ethynoxypropoxy)- dimethyl-silane (866 mg, 4.04 mmol, 1.4 eq) in THF (5 mL), t-BuOH (5 mL) and H2O (5 mL) was added sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate Int 4 5 (857 mg, 4.33 mmol, 1.5 eq) and copper sulfate (230 mg, 1.44 mmol, 221μL, 0.5 eq). The mixture was stirred at 30oC for 2 hr. The reaction mixture was quenched by addition H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound benzyl (2S,4R)-1-[(2S)-2-[4-[3-[tert-10 butyl(dimethyl)silyl]oxypropoxy]triazol-1-yl]-3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2- carboxylate Int 6a (1.6 g, crude) was obtained as yellow oil. LCMS: MS (ESI) m / z 561.3[M+H]+Step B. Preparation of Int 6b To a solution of Int 6a (1.60 g, 2.85 mmol, 1 eq) in DCM (20 mL) was added TEA (577 15 mg, 5.71 mmol, 794µL, 2 eq), Ac2O (349 mg, 3.42 mmol, 321µL, 1.2 eq) and DMAP (34.8 mg, 285µmol, 0.1 eq). The mixture was stirred at 20oC for 1 hr. The reaction mixture was quenched by addition H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound benzyl (2S,4R)-4-acetoxy-1-[(2S)-2-[4-[3-[tert- 20 butyl(dimethyl)silyl]oxypropoxy]triazol-1-yl]-3-methylbutanoyl]pyrrolidine-2-carboxylate Int 6b (1.7 g, crude) was obtained as yellow oil. LCMS: MS (ESI) m / z 603.3[M+H]+Step C. Preparation of Int 6c To a solution of Int 6b (1.70 g, 2.82 mmol, 1 eq) in MeOH (20 mL) was added acetyl chloride (664 mg, 8.46 mmol, 601µL, 3 eq) at 0oC. After the addition, the reaction was allowed 25 to warm to 20oC and stirred for 1 hr. The reaction mixture was quenched by addition H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @30 80 mL / min). The eluent was removed under reduced pressure to give benzyl (2S,4R)-4-acetoxy- 1-[(2S)-2-[4-(3-hydroxypropoxy)triazol-1-yl]-3-methyl-butanoyl]pyrrolidine-2-carboxylate Int 6c (660 mg, 1.35 mmol, 47.9% yield) as colorless oil.1H NMR (400 MHz, DMSO-d6) δ7.68 (s, 1H), 7.39 - 7.33 (m, 5H), 5.29 - 5.24 (m, 2H), 5.20 - 5.11 (m, 2H), 4.55 (t, J = 5.2 Hz, 1H), 4.44 (t, J = 8.4 Hz, 1H), 4.11 (t, J = 6.4 Hz, 2H), 3.96 (s, 2H), 3.52 (q, J = 6.0 Hz, 2H), 2.47 - 2.35 168 15077.006WO2 (m, 2H), 2.21 - 2.14 (m, 1H), 1.93 (m, 3H), 1.86 - 1.79 (m, 2H), 0.95 (d, J = 6.4 Hz, 3H), 0.69 (d, J = 6.4 Hz, 3H). LCMS: MS (ESI) m / z 489.2[M+H]+Step D. Preparation of Int 6d. To a solution of Int 6c (660 mg, 1.35 mmol, 1 eq) in DCM (15 mL) was added pyridine 5 (213 mg, 2.70 mmol, 218μL, 2 eq) and methylsulfonyl methanesulfonate (282 mg, 1.62 mmol, 1.2 eq) at 0oC. After the addition, the reaction was allowed to warm to 20oC and stirred for 2 hr. The reaction mixture was quenched by addition H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound benzyl (2S,4R)-4-10 acetoxy-1-[(2S)-3-methyl-2-[4-(3-methylsulfonyloxypropoxy)triazol-1-yl]butanoyl]pyrrolidine- 2-carboxylate Int 6d (790 mg, crude) was obtained as yellow oil. LCMS: MS (ESI) m / z 567.2[M+H]+Step E. Preparation of Int 6e. A mixture of Int 6d (790 mg, 1.39 mmol, 1 eq) and potassium;ethanethioate (318 mg, 15 2.79 mmol, 2 eq) in DMF (10 mL) was stirred at 40oC for 2 hr. The reaction mixture was quenched by addition H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl 20 acetate / Petroleum ether gradient @ 80 mL / min). The eluent was removed under reduced pressure. Compound benzyl (2S,4R)-4-acetoxy-1-[(2S)-2-[4-(3-acetylsulfanylpropoxy)triazol- 1-yl]-3-methylbutanoyl]pyrrolidine-2-carboxylate Int 6e (640 mg, 1.17 mmol, 84.0% yield) was obtained as a white solid. LCMS: MS (ESI) m / z 547.2[M+H]+ Step F. Preparation of Int 6f. 25 To a solution of Int 6e (600 mg, 1.10 mmol, 1 eq) in MeCN (6 mL) and HCl (3N, 0.6 mL) was added NCS (439 mg, 3.29 mmol, 3 eq). The mixture was stirred at 25oC for 0.5 hr. The reaction mixture was quenched by addition H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give benzyl (2S,4R)-4-acetoxy-1-[(2S)-2-[4-(3- 30 chlorosulfonylpropoxy)triazol-1-yl]-3-methylbutanoyl]pyrrolidine-2-carboxylate Int 6f (630 mg, crude) as colorless oil. LCMS: MS (ESI) m / z 571.1 [M+H]+ Step G. Preparation of VHL Int 6. To a solution of Int 6f (630 mg, 1.10 mmol, 1 eq) in THF (6 mL) was added NH3∙H2O (1.55 g, 11.0 mmol, 1.70 mL, 25% purity, 10 eq) at 0oC. The mixture was stirred at 0oC for 10 35 min. The reaction mixture was quenched by addition H2O (20 mL) and extracted with EtOAc 169 15077.006WO2 (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 80 mL / min). The eluent was removed under reduced 5 pressure to give benzyl (2S,4R)-4-acetoxy-1-[(2S)-3-methyl-2-[4-(3-sulfamoylpropoxy)triazol- 1-yl]butanoyl]pyrrolidine-2-carboxylate Int 6 (470 mg, 852μmol, 77.2% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ7.72 (s, 1H), 7.40 - 7.31 (m, 5H), 6.86 (s, 2H), 5.31 - 5.22 (m, 2H), 5.20 - 5.09 (m, 2H), 4.44 (t, J = 8.4 Hz, 1H), 4.23 - 4.13 (m, 2H), 3.96 (s, 2H), 3.14 - 3.07 (m, 2H), 2.45 - 2.35 (m, 2H), 2.24 - 2.06 (m, 3H), 1.93 (s, 3H), 0.95 (d, J = 6.4 Hz, 10 3H), 0.69 (d, J = 6.4 Hz, 3H). LCMS: MS (ESI) m / z 552.1[M+H]+ Example Int.7 Synthesis of (2S,4R)-1-[(2S)-2-azido-3-methyl-butanoyl]-4- hydroxy-N-[(1S)-1-[2-hydroxy-4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Int 7) 15 Step A. Preparation of Int 7A 1-(4-bromo-2-hydroxy-phenyl)ethanone (20 g, 93.0 mmol, 1 eq) in DCM (1000 mL) were added DIEA (36.0 g, 279 mmol, 48.6 mL, 3 eq) and bromo(methoxy)methane (17.4 g, 139 20 mmol, 11.3 mL, 1.5 eq) in one portion at 0 °C under N2. The mixture was warmed at 20°C and stirred for 2 hrs. The reaction mixture was diluted with H2O (500 mL) and extracted with DCM (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over 170 15077.006WO2 anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 3 / 1). Compound 1-[4-bromo-2-(methoxymethoxy) phenyl]ethanone Int 7A(24 g, 463 mmol, 99.6% yield) was obtained as yellow oil.1H NMR: (400 MHz, CDCl3) δ7.49 (d, J = 8.0 Hz, 1H), 7.27 5 (d, J = 1.6 Hz, 1H), 7.11 - 7.05 (m, 1H), 5.18 (s, 2H), 3.42 (s, 3H), 2.51 (s, 3H). Step B. Preparation of Int 7B To a solution of 1-[4-bromo-2-(methoxymethoxy)phenyl]ethanone Int 7A(20 g, 77.1 mmol, 1 eq) in THF (1200 mL) were added Ti(OEt)4 (52.8 g, 231 mmol, 48.0 mL, 3 eq) and (S)- 2-methylpropane-2-sulfinamide (11.2 g, 92.6 mmol, 1.2 eq) in one portion. The mixture was 10 heated to 80°C and stirred for 16 hrs. After cooling to room temperature, the mixture was adjusted to pH = 7 with saturated aqueous NaHCO3 and extracted with EtOAc (500 mL x 3). The combined organic phase was washed with brine (500 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 3 / 1). Compound (NE,S)- 15 N-[1-[4-bromo-2-(methoxymethoxy)phenyl]ethylidene]-2-methyl-propane-2-sulfinamide Int 7B (20 g, 331 mmol, 71.5% yield) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) δ7.27 (d, J = 1.6 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.11 - 7.06 (m, 1H), 5.14 (s, 2H), 3.41 (s, 3H), 2.63 (s, 3H), 1.22 (s, 9H). LCMS: MS (ESI) m / z 364.1 [M+H]+. Step C. Preparation of Int 7C 20 To a solution of (NE,S)-N-[1-[4-bromo-2-(methoxymethoxy)phenyl]ethylidene]-2- methyl-propane-2-sulfinamide Int 7B (50 g, 138 mmol, 1 eq) and CeCl3 (17.0 g, 69.0 mmol, 0.5 eq) in THF (500 mL) was added NaBH4(10.4 g, 276 mmol, 2 eq) in portions under N2at -65°C. The mixture was warmed to 20°C and stirred for 16 hrs. The reaction mixture was quenched by addition NH4Cl (500 mL) at 0°C, and then diluted with H2O (200 mL), extracted with EtOAc (500 25 mL). The combined organic layers were washed with brine 300 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). Compound (S)-N-[(1S)- 1-[4-bromo-2-(methoxymethoxy)phenyl]ethyl]-2-methyl-propane-2-sulfinamide Int 7C (25 g, 68.6 mmol, 49.7% yield) was obtained as a white solid.1H NMR: (400 MHz, DMSO) δ7.40 (d, J 30 = 8.4 Hz, 1H), 7.22 (d, J = 1.6 Hz, 1H), 7.21 - 7.17 (m, 1H), 5.70 (d, J = 8.0 Hz, 1H), 5.37 - 5.18 (m, 2H), 4.68 (t, J = 6.8 Hz, 1H), 3.40 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.08 (s, 9H). Step D. Preparation of Int 7D A mixture of (S)-N-[(1S)-1-[4-bromo-2-(methoxymethoxy)phenyl]ethyl]-2-methyl- propane-2-sulfinamide Int 7C (15 g, 41.1 mmol, 1 eq), 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2- 35 dioxaborolan-2-yl)thiazole (23.1 g, 102 mmol, 2.5 eq), K2CO3 (14.2 g, 102 mmol, 2.5 eq) in 171 15077.006WO2 dioxane (150 mL) and H2O (30 mL) was degassed and purged with N2 for 3 times, then added Pd(dppf)Cl2(3.01 g, 4.12 mmol, 0.1 eq) to the reaction mixture in one portion. The reaction mixture was heated to 90°C and stirred for 3 hrs under N2atmosphere. After cooling to room temperature, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 5 mL x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). Compound (S)-N-[(1S)-1-[2-(methoxymethoxy)-4-(4-methylthiazol-5-yl)phenyl]ethyl]-2-methyl-propane- 2-sulfinamide Int 7D (15 g, 39.2 mmol, 95.2% yield) was obtained as a yellow oil.1H NMR: 10 (400 MHz, DMSO-d6) δ8.99 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.23 - 7.00 (m, 2H), 5.68 (d, J = 7.8 Hz, 1H), 5.48 - 5.19 (m, 2H), 4.76 (t, J = 7.2 Hz, 1H), 3.42 (s, 3H), 2.47 (s, 3H), 1.37 (d, J = 6.8 Hz, 3H), 1.11 (s, 9H). LCMS: MS (ESI) m / z 383.1 [M+H]+Step E. Preparation of Int 7E To a solution of (S)-N-[(1S)-1-[2-(methoxymethoxy)-4-(4-methylthiazol-5- 15 yl)phenyl]ethyl]-2-methyl-propane-2-sulfinamide Int 7D (15 g, 39.2 mmol, 1 eq) in EtOAc (20 mL) was added HCl / EtOAc (4 M, 150 mL, 15.3 eq) in one portion. The mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to dryness. The residue was slurry with MTBE (50 mL) for 30 min, then filtered and the filter cake was washed with MTBE (50 mL), dried in vacuum to give 2-[(1S)-1-aminoethyl]-5-(4-methylthiazol-5-yl) 20 phenol Int 7E (12 g, crude, HCl) as a yellow solid. LCMS: MS (ESI) m / z 235.1 [M+H]+Step F. Preparation of Int 7 To a solution of 2-[(1S)-1-aminoethyl]-5-(4-methylthiazol-5-yl)phenol Int 7E (5 g, 18.4 mmol, 1 eq, HCl) and (2,3,5,6-tetrafluorophenyl) (2S,4R)-1-[(2S)-2-azido-3-methyl-butanoyl]- 4-hydroxy-pyrrolidine-2-carboxylate Int 5 (8.21 g, 20.3 mmol, 1.1 eq) in DCM (100 mL) was 25 added DIEA (9.55 g, 73.8 mmol, 12.8 mL, 4 eq) in one portion. The mixture was stirred at 25°C for 1 hr. The reaction mixture was adjusted to pH = 3 with TFA and extracted with DCM (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). Compound30 (2S, 4R)-1-[(2S)-2-azido-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[2-hydroxy-4-(4- methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide Int 7 (7.7 g, 16.2 mmol, 88.2% yield) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ10.17 - 9.65 (m, 1H), 9.00 - 8.90 (m, 1H), 8.41 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.96 - 6.85 (m, 2H), 5.10 (t, J = 7.2 Hz, 1H), 4.51 (t, J = 8.4 Hz, 1H), 4.28 (s, 1H), 3.72 (d, J = 8.4 Hz, 1H), 3.57 - 3.48 172 15077.006WO2 (m, 2H), 2.45 (s, 3H), 2.15 - 1.97 (m, 2H), 1.82 - 1.69 (m, 1H), 1.35 - 1.27 (m, 3H), 1.02-0.93 (m, 6H). LCMS: MS (ESI) m / z 473.1[M+H]+. Example Int.8 Synthesis of allyl N-[(1S)-2-[[(1S)-2-[4-[[2-[(1S)-1-aminoethyl]- 5-(4-methylthiazol-5-yl)phenoxy]methyl]anilino]-1-methyl-2-oxo-ethyl]amino]-1-methyl-2- 5 oxo-ethyl]carbamate, Int 8 Step A. Preparation of Int 8A To a solution of 2-[(1S)-1-aminoethyl]-5-(4-methylthiazol-5-yl)phenol Int 7E (1 g, 3.69 mmol, 1 eq, HCl) in THF (5 mL) and H2O (5 mL) were added NaHCO3(930 mg, 11.08 mmol, 10 431 μL, 3 eq) and Boc2O (1.21 g, 5.54 mmol, 1.27 mL, 1.5 eq) at 0°C. The mixture was warmed and stirred at 25 °C for 1hr. The reaction mixture was extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (20 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give tert-butyl N-[(1S)-1-[2- 15 hydroxy-4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamate Int 8A (1.05 g, 3.14 mmol, 85.01% yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ9.74 (s, 1H), 8.95 (s, 1H), 7.32-7.24 (m, 2H), 6.93 – 6.85 (m, 2H), 4.91(t, J = 7.2 Hz, 1H), 2.45 (s, 3H), 1.36 (s, 9H), 1.24 (d, J = 7.2 Hz, 3H). LCMS: MS (ESI) m / z 335.1 [M+H]+. Step B. Preparation of Int 8B 20 To a solution of Int 8A (400 mg, 1.20 mmol, 1 eq) in DMF (6 mL) were added K2CO3 (495 mg, 3.59 mmol, 3 eq) and allyl N-[(1S)-2-[[(1S)-2-[4-(chloromethyl)anilino]-1-methyl-2- oxo-ethyl]amino]-1-methyl-2-oxo-ethyl]carbamate (659 mg, 1.79 mmol, 1.5 eq). The mixture was stirred at 25°C for 1 hr. The reaction mixture was diluted with H2O 10 mL and extracted 25 with EtOAc (10 mL * 3). The combined organic layers were washed with brine 15 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue 173 15077.006WO2 was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ethergradient @ 75 mL / min) to give tert-butyl N- [(1S)-1-[2-[[4-[[(2S)-2-[[(2S)-2- (allyloxycarbonylamino)propanoyl]amino]propanoyl]amino]phenyl] methoxy]-4-(4- 5 methylthiazol-5-yl)phenyl]ethyl]carbamate Int 8B (382 mg, 573 μmol, 47.97% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.97 (s, 1H), 8.10 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.46 - 7.34 (m, 6H), 7.07-7.02 (m, 2H), 5.95 - 5.86 (m, 1H), 5.29 (d, J = 17.1 Hz, 1H), 5.19 - 5.14 (m, 3H), 5.01 (t, J = 14.8 Hz, 1H), 4.48 - 4.45 (m, 2H), 4.43 - 4.38 (m, 1H), 4.10-4.03 (m, 1H), 2.41 (s, 3H), 1.37 (s, 9H), 1.31 (d, J = 7.2 Hz, 3H), 1.26 (d, J = 7.2 Hz, 10 3H), 1.21 (d, J = 7.2 Hz, 3H). LCMS: MS (ESI) m / z 666.4 [M+H]+. Step C. Preparation of Int 8 A mixture of Int 8B (382 mg, 573 μmol, 1 eq) in HCOOH (4 mL) was stirred at 25°C for 2 hrs. The reaction mixture was concentrated under reduced pressure. The residue was purified 15 by prep-HPLC (column: Phenomenex luna C18250*50mm*15um;mobile phase: [H2O (0.1% TFA)-ACN];gradient:20%-50% B over 10.0 min) to give allyl N-[(1S)-2-[[(1S)-2-[4-[[2-[(1S)- 1-aminoethyl]-5-(4-methylthiazol-5-yl)phenoxy]methyl]anilino]-1-methyl-2-oxo-ethyl]amino]- 1-methyl-2-oxo-ethyl]carbamate Int 8 (260 mg, 459 μmol, 80.11% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ9.98 (s, 1H), 9.02 (s, 1H), 8.19 (d, J = 3.6 Hz, 2H), 8.11 (d, J = 20 7.2 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.47 - 7.40 (m, 3H), 7.21 (d, J = 1.2 Hz, 1H), 7.16 - 7.14 (m, 1H), 5.97 - 5.82 (m, 1H), 5.33 - 5.13 (m, 4H), 4.72 - 4.64 (m, 1H), 4.50 - 4.35 (m, 3H), 4.06 (t, J = 14.4 Hz, 1H), 2.41 (s, 3H), 1.49 (d, J = 6.8 Hz, 3H), 1.31 (d, J = 7.2 Hz, 3H), 1.21 (d, J = 7.2 Hz, 3H). LCMS: MS (ESI) m / z 566.2 [M+H]+. Example Int.11 Synthesis of (2S,4R)-1-[(2S)-2-azido-3-methyl-butanoyl]-N-[(1S)-25 1-[3-fluoro-2-hydroxy-4-(4-methylthiazol-5-yl)phenyl]ethyl]-4-hydroxy-pyrrolidine-2- carboxamide, Int 11 174 15077.006WO2 Following the similar experimental procedure as Int 7, compound Int 11 (1.45 g, 2.96 mmol, 76.28% yield) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ9.07 (s, 1H), 8.48 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.88-6.84 (m, 1H), 5.17-5.14 (m, 1H), 5 4.50 (t, J = 8.0 Hz, 1H), 4.26 (s, 1H), 3.71 (d, J = 8.4 Hz, 1H), 3.53-3.48 (m, 2H), 2.27 (s, 3H), 2.10-2.03 (m, 2H), 1.78-1.75 (m, 2H), 1.28-1.27 (m, 3H), 0.99-0.95 (m, 6H). LCMS: MS (ESI) m / z 491.2 [M+H]+. Example Int.12 Synthesis of allyl N-[(1S)-2-[[(1S)-2-[4-[[6-[(1S)-1-aminoethyl]- 2-fluoro-3-(4-methylthiazol-5-yl) phenoxy] methyl] anilino]-1-methyl-2-oxo-ethyl] amino]-1- 10 methyl-2-oxo-ethyl] carbamate, Int 12 Following the similar experimental procedure as Int 8, compound Int 12 (0.40 g, 685 μmol, 49.3% yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ10.01 (s, 1H), 9.12 (s, 1H), 8.28 (s, 1H), 8.14 (d, J = 7.3 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.45 - 7.37 (m, 15 4H), 7.23 (t, J = 7.6 Hz, 1H), 5.97 - 5.82 (m, 1H), 5.29 (d, J = 17.6 Hz, 1H), 5.17 (d, J = 10.4 Hz, 1H), 5.12 - 5.01 (m, 2H), 4.51 - 4.45 (m, 2H), 4.43 - 4.35 (m, 2H), 4.12 - 4.01 (m, 1H), 2.34 (s, 3H), 1.31 (d, J = 7.2 Hz, 3H), 1.27 - 1.18 (m, 6H). LCMS: MS (ESI) m / z 584.1 [M+H]+. Example Int.13 Synthesis of (2S,4R)-1-[(2S)-2-azido-3-methyl-butanoyl]-4- hydroxy-N-[(1R)-2-hydroxy-1-[2-hydroxy-4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2- 20 carboxamide Int 13 175 15077.006WO2 Step A. Preparation of Int 13A To a solution of 5-bromo-2-iodo-phenol (85.0 g, 284 mmol, 1 eq) in DCM (800 mL) were 5 added DIEA (91.9 g, 711 mmol, 124 mL, 2.5 eq) and bromo(methoxy)methane (53.3 g, 427 mmol, 34.8 mL, 1.5 eq) at 0°C. The mixture warmed up to 20°C and stirred for 2hrs. The reaction mixture was quenched by addition of H2O (1000 mL) at 0°C, and then extracted with DCM (500 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by10 column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 10 / 1). Compound 4-bromo- 1-iodo-2-(methoxymethoxy)benzene Int 13A (100 g, crude) was obtained as a light yellow oil. 1H NMR: (400 MHz, CDCl3) δ7.62 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 6.92 (dd, J = 2.0, 8.4 Hz, 1H), 5.24 (s, 2H), 3.52 (s, 3H). Step B. Preparation of Int 13B 15 To a solution of Int 13A (30.0 g, 87.5 mmol, 1 eq) in THF (250 mL) was added dropwise lithium;chloro(isopropyl)magnesium;chloride (1.3 M, 80.8 mL, 1.2 eq) at -78°C over 60 min. After addition, the mixture was stirred at this temperature for 30 min, and then 2-[tert- butyl(dimethyl)silyl]oxyacetaldehyde (18.3 g, 105 mmol, 20.0 mL, 1.2 eq) in THF (50 mL) was added dropwise at -78°C. The resulting mixture was stirred at -78°C for 1hr. The reaction 20 mixture was quenched by addition of NH4Cl (500 mL) mL at 0°C, and then diluted with H2O (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to 176 15077.006WO2 give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 10 / 1) to give 1-[4-bromo-2-(methoxymethoxy)phenyl]-2-[tert- butyl(dimethyl)silyl]oxy-ethanol Int 13B (31.0 g, 79.2 mmol, 90.6% yield) was obtained as colorless oil.1H NMR: (400 MHz, CDCl3) δ7.39 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 5 7.17 (dd, J = 1.6, 8.0 Hz, 1H), 5.19 (s, 2H), 5.09 - 5.00 (m, 1H), 3.87 (dd, J = 3.6, 10.0 Hz, 1H), 3.48 (s, 3H), 3.45 (dd, J = 8.0, 10.0 Hz, 1H), 2.97 (d, J = 3.2 Hz, 1H), 0.92 (s, 9H), 0.06 (d, J = 6.8 Hz, 6H). Step C. Preparation of Int 13C To a solution of Int 13B (31.0 g, 79.2 mmol, 1 eq) in DCM (450 mL) was added DMP 10 (40.3 g, 95.1 mmol, 29.5 mL, 1.2 eq) at 0°C. The mixture was warmed to 20°C and stirred for 1hr. The reaction mixture was quenched by addition of aq. Na2S2O3 (500 mL) at 0°C, and then diluted with H2O (1000 mL) and adjusted to pH=8-9 with aq. NaHCO3, and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue 15 was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 5 / 1). Compound 1-[4-bromo-2-(methoxymethoxy)phenyl]-2-[tert-butyl(dimethyl)silyl]oxy-ethanone Int 13C (28.2 g, 72.4 mmol, 91.3% yield) was obtained as a white solid.1H NMR: (400 MHz, CDCl3) δ7.68 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.23 (dd, J = 1.6, 8.4 Hz, 1H), 5.27 (s, 2H), 4.84 (s, 2H), 3.52 (s, 3H), 0.94 (s, 9H), 0.12 (s, 6H). 20 Step D. Preparation of Int 13D To a solution of Int 13C (28.0 g, 71.9 mmol, 1 eq) and (S)-2-methylpropane-2- sulfinamide (13.1 g, 108 mmol, 1.5 eq) in THF (300 mL) was added Ti(OEt)4(49.2 g, 216 mmol, 44.7 mL, 3 eq) at 20°C. The mixture was stirred at 80°C for 12hrs. The reaction mixture was cooled to 15°C and quenched by addition of aq. NaHCO3 (500 mL) at 0°C, and then diluted 25 with H2O (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 5 / 1). Compound (NE,S)-N-[1-[4-bromo-2- (methoxymethoxy)phenyl]-2-[tert-butyl(dimethyl)silyl]oxy-ethylidene]-2-methyl-propane-2- 30 sulfinamide Int 13D (23.0 g, 46.7 mmol, 64.9% yield) was obtained as a brown oil. LCMS: MS (ESI) m / z 492.1 [M+H]+. Step E. Preparation of Int 13E To a solution of Int 13D (11.5 g, 23.4 mmol, 1 eq) and CeCl3(2.88 g, 11.7 mmol, 734 μL, 0.5 eq) in THF (200 mL) was added NaBH4 (1.79 g, 47.3 mmol, 2.03 eq) at -60°C under N2. 35 The mixture was warmed to 25°C and stirred at 25°C for 6hrs. The reaction mixture was 177 15077.006WO2 quenched by addition of aq. NH4Cl (50 mL) at 0°C. Two batches were combined with work-up and then diluted with H2O (500 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography 5 (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 1 / 1). Compound (S)-N-[(1R)-1-[4-bromo-2- (methoxymethoxy)phenyl]-2-[tert-butyl(dimethyl)silyl]oxy-ethyl]-2-methyl-propane-2- sulfinamide Int 13E (9.50 g, 19.0 mmol, 40.6% yield, 98.8% purity) was obtained as a light yellow solid.1H NMR: (400 MHz, DMSO-d6) δ7.39 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 1.6 Hz, 1H), 7.19 (dd, J = 1.6, 8.0 Hz, 1H), 5.56 (d, J = 8.8 Hz, 1H), 5.31 - 5.21 (m, 2H), 4.64 (td, J = 10 6.0, 8.8 Hz, 1H), 3.66 (d, J = 6.0 Hz, 2H), 3.40 (s, 3H), 1.10 (s, 9H), 0.80 (s, 9H), -0.05 (s, 6H). LCMS: MS (ESI) m / z 494.1 [M+H]+. Step F. Preparation of Int 13F A mixture of Int 13E (5.80 g, 11.7 mmol, 1 eq), 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)thiazole (5.28 g, 23.5 mmol, 2 eq), Pd(dppf)Cl2 (858 mg, 1.17 mmol, 0.1 eq) 15 and K2CO3 (4.86 g, 35.2 mmol, 3 eq) in dioxane (120 mL) and H2O (12 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 90°C for 2hrs under N2atmosphere. The reaction mixture was cooled to 15°C, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1). Compound (S)-N-[(1R)-2-[tert-butyl(dimethyl) -20 silyl]oxy-1-[2-(methoxymethoxy)-4-(5-methylthiazol-4-yl)phenyl]ethyl]-2-methyl-propane-2- sulfinamide Int 13F (8 g, crude) was obtained as a brown oil.1H NMR: (400 MHz, DMSO-d6) δ8.99 (s, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.14 (s, 1H), 7.11 (d, J = 7.6 Hz, 1H), 5.57 (d, J = 9.2 Hz, 1H), 5.34 - 5.26 (m, 2H), 4.76 - 4.65 (m, 1H), 3.93 (s, 3H), 3.71 (d, J = 6.0 Hz, 2H), 2.45 (s, 3H), 1.13 (s, 9H), 0.80 (s, 9H), -0.04 (s, 6H). LCMS: MS (ESI) m / z 513.3 [M+H]+. 25 Step G. Preparation of Int 13G To a solution of Int 13F (4.00 g, 7.80 mmol, 1 eq) in EtOAc (10 mL) was added HCl / EtOAc (4 M, 50 mL) at 25°C. The mixture was stirred at 25°C for 1hr. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (20 mL) at 25oC for 10 min, the solid was filtered and the filter cake was30 dried under reduced pressure to give 2-[(1R)-1-amino-2-hydroxyethyl]-5-(5-methylthiazol-4- yl)phenol Int 13G (2.07 g, 6.40 mmol, 82.1% yield, 2HCl) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ10.52 (s, 1H), 9.04 (s, 1H), 8.39 (s, 3H), 7.46 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 1.2 Hz, 1H), 6.99 (dd, J = 1.6, 8.0 Hz, 1H), 4.54 - 4.42 (m, 1H), 3.75-3.73 (m, 2H), 2.46 (s, 3H). LCMS: MS (ESI) m / z 251.0 [M+H]+. 178 15077.006WO2 Step H. Preparation of 6-[(1R)-1-amino-2-hydroxy-ethyl]-2-fluoro-3-(4-methylthiazol-5- yl)phenol VHL Int 13H Following a similar procedure to preparation of Int 13G, VHL Int-13H was obtained (580 mg, 1.70 mmol, 75.18% yield, 2HCl) as a light yellow solid. 51H NMR: (400 MHz, DMSO-d6) δ10.53 (br d, J = 1.2 Hz, 1H), 9.13 (s, 1H), 8.45 (br d, J = 3.6 Hz, 2H), 7.30 (d, J = 7.6 Hz, 1H), 7.05 - 6.96 (m, 1H), 4.57 (br d, J = 3.2 Hz, 1H), 3.79 - 3.73 (m, 2H), 2.32 (s, 3H). LCMS: MS (ESI) m / z 269.0 [M+H]+Step I. Preparation of Int 13 To a solution of (2S,4R)-1-[(2S)-2-azido-3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2- 10 carboxylic acid Int 5A (872 mg, 3.40 mmol, 1.1 eq) in DMF (20 mL) were added HATU, hexafluorophosphate azabenzotriazole tetramethyl uranium, CAS Reg. No.148893-10-1 (1.18 g, 3.09 mmol, 1 eq) and DIEA (1.60 g, 12.4 mmol, 2.16 mL, 4 eq) at 0°C. After addition, the mixture was stirred at this temperature for 5 min, and then Int 13G (1.00 g, 3.09 mmol, 1 eq, 2HCl) was added at 0°C. The resulting mixture warmed to 25°C and stirred for 25 min. The 15 reaction mixture was quenched by addition of H2O (100 mL) at 0°C and adjusted to pH=5-6 with aq. citric acid at 0°C and extracted with DCM / i-PrOH=3 / 1 (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) and then (SiO2, EtOAc:MeOH=1:0 to 1:1). Compound (2S,4R)-1-[(2S)-2-20 azido-3-methyl-butanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-[2-hydroxy-4-(4-methylthiazol-5- yl)phenyl]ethyl]pyrrolidine-2-carboxamide Int 13 (1.50 g, 3.07 mmol, 99.2% yield) was obtained as a light yellow solid.1H NMR: (400 MHz, DMSO-d6) δ9.80 (s, 1H), 8.95 (s, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 4.8 Hz, 1H), 6.93-6.87 (m, 1H), 5.18-5.13 (m, 2H), 4.70 (t, J = 5.6 Hz, 1H), 4.57-4.56 (m, 1H), 4.29 (s, 1H), 3.73 (d, J = 8.0 Hz, 1H), 3.62-3.60 (m, 1H), 25 3.53-3.47 (m, 2H), 2.45 (s, 3H), 2.11-2.04 (m, 2H), 1.82-1.79 (m, 1H), 1.00-0.93 (m, 6H). LCMS: MS (ESI) m / z 489.1 [M+H]+. Example Int.14 Synthesis of allyl N-[(1S)-2-[[(1S)-2-[4-[[2-[(1R)-1-amino-2- phosphonooxy-ethyl]-5-(4-methylthiazol-5-yl)phenoxy]methyl]anilino]-1-methyl-2-oxo- ethyl]amino]-1-methyl-2-oxo-ethyl]carbamate, Int 14 30 Step A. Preparation of Int 14A 179 15077.006WO2 To a mixture of Int 13G (0.5 g, 2.00 mmol, 1eq) in THF (5 mL)and H2O (5 mL) was added NaHCO3 (455 mg, 5.41 mmol, 211 μL, 3.5 eq) and Boc2O (371mg, 1.70 mmol, 391 μL, 1.1 eq), and then stirred at 20°C for 18 hrs. The reaction mixture was adjusted to pH= 6 with 2N 5 HCl. The reaction mixture was partitioned between EtOAc 20 mL and water 20 mL. The organic phase was separated, washed with brine 5mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude was purified by column chromatography (SiO2, petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give tert-butyl N-[(1R)-2- hydroxy-1-[2-hydroxy-4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamate Int 14A (0.35 g, 999 10 μmol, 64.6% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ9.78 (s, 1H), 8.96 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.06 (br d, J = 8.4 Hz, 1H), 6.98 - 6.80 (m, 2H), 4.92-4.89 (m, 1H), 4.75 (t, J = 5.2 Hz, 1H), 3.66 - 3.44 (m, 2H), 2.46 (s, 3H), 1.38 (s, 9H). LCMS: MS (ESI) m / z 351.2 [M+H]+. Step B. Preparation of Int 14B 15 To a solution of Int 14A (0.33 g, 942μmol, 1 eq) in DMF (10 mL) was added K2CO3 (390 mg, 2.83 mmol, 3 eq) and allyl N-[(1S)-2-[[(1S)-2-[4-(chloromethyl)anilino]-1-methyl-2- oxo-ethyl]amino]-1-methyl-2-oxo-ethyl]carbamate (520 mg, 1.41 mmol, 1.5 eq), and then stirred at 20°C for 2 hrs. The reaction mixture was partitioned between EtOAc 20 mL and water 20 20 mL. The organic phase was separated, washed with brine 10 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give tert-butyl N-[(1R)-1- [2-[[4-[[(2S)-2-[[(2S)-2- (allyloxycarbonylamino)propanoyl]amino]propanoyl]amino]phenyl]meth-oxy]-4-(4- 25 methylthiazol-5-yl)phenyl]-2-hydroxy-ethyl]carbamate Int 14B (0.4 g, 587 μmol, 62.3% yield) 180 15077.006WO2 as white solid.1H NMR (400 MHz, DMSO-d6) δ9.98 (s, 1H), 8.98 (s, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.48 - 7.32 (m, 4H), 7.16 - 6.99 (m, 3H), 5.99 - 5.81 (m, 1H), 5.30 (d, J = 17.2 Hz, 1H), 5.20-5.16 (m, 3H), 5.08 - 5.00 (m, 1H), 4.79 (t, J = 5.6 Hz, 1H), 4.64 - 4.34 (m, 3H), 4.11 - 4.04 (m, 1H), 3.61 - 3.54 (m, 1H), 2.41 (s, 3H), 1.38 (s, 9H), 1.31 (d, J = 13.2 5 Hz, 3H), 1.22 (d, J = 7.2 Hz, 3H). LCMS: MS (ESI) m / z 682.3 [M+H]+. Step C. Preparation of Int 14C To a solution of Int 14B (0.200 g, 293 μmol, 1 eq) and 2H-tetrazole (205 mg, 2.93 mmol, 260 μL, 10 eq) in DMF (2 mL) was added N-ditert-butoxyphosphanyl-N-ethyl- 10 ethanamine (731 mg, 2.93 mmol, 10 eq) at 25°C. The mixture was stirred at 25°C for 0.5hr, then H2O2 (330 mg, 2.91 mmol, 280 μL, 30% purity, 10 eq) was added at 0°C. The mixture was warmed to 25°C and stirred at 25°C for 0.5hr. The reaction mixture was quenched by addition of aq. Na2S2O3(5 mL) at 0°C, and then diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, 15 filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1). Compound tert-butyl N-[(1R)-1-[2-[[4-[[(2S)-2-[[(2S)-2- (allyloxycarbonylamino)propanoyl]amino]propanoyl]amino]phenyl]methoxy]-4-(4-methylthi- azol-5-yl)phenyl]-2-ditert-butoxyphosphoryloxy-ethyl]carbamate Int 14C (0.220 g, 252 μmol, 20 86.4% yield) was obtained as a light yellow oil. LCMS: MS (ESI) m / z 896.3 [M+Na]+. Step C. Preparation of Int 14 A mixture of Int 14C (0.200 g, 229 μmol, 1 eq) in HCOOH (2 mL) was stirred at 25°C for 4hrs under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to 25 give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:5%-40% B over 8.0 min ) to 181 15077.006WO2 give Int 14 (122 mg, 154 μmol, 67.3% yield, 97.92% purity, TFA) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ9.98 (s, 1H), 9.03 (s, 1H), 8.56 (br s, 2H), 8.11 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 7.2 Hz, 1H), 7.22 (d, J = 1.2 Hz, 1H), 7.15 (dd, J = 1.2, 8.0 Hz, 1H), 5.98 - 5.81 (m, 1H), 5.38 - 5.09 5 (m, 4H), 4.82 (t, J = 5.6 Hz, 1H), 4.47 (td, J = 1.6, 3.6 Hz, 2H), 4.43 - 4.34 (m, 1H), 4.14 (t, J = 6.0 Hz, 2H), 4.06 (quin, J = 7.2 Hz, 1H), 2.40 (s, 3H), 1.31 (d, J = 7.2 Hz, 3H), 1.21 (d, J = 7.2 Hz, 3H). LCMS: MS (ESI) m / z 662.1 [M+H]+. Example Int.17 Synthesis of (2S,4R)-1-[(2S)-2-azido-3-methyl-butanoyl]-N- [(1R)-1-[3-fluoro-2-hydroxy-4-(4-methylthiazol-5-yl)phenyl]-2-hydroxy-ethyl]-4-hydroxy- 10 pyrrolidine-2-carboxamide, Int 17 Following the similar experimental procedure as Int 13, compound Int 17 (0.8 g, 1.58 mmol, 58.81% yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.41 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.90 - 6.81 (m, 1H), 5.19 (d, J = 5.2 Hz, 15 1H), 4.60 - 4.52 (m, 1H), 4.28 (s, 1H), 3.73 (d, J = 8.4 Hz, 1H), 3.62 (s, 1H), 3.57-3.50 (m, 3H), 2.34 (s, 3H), 2.15 - 2.01 (m, 2H), 1.81-1.73 (m, 1H), 1.00-0.92 (m, 6H). LCMS: MS (ESI) m / z 507.2 [M+H]+. Example Int.18 Synthesis of allyl N-[(1S)-2-[[(1S)-2-[4-[[6-[(1R)-1-amino-2- phosphonooxy-ethyl]-2-fluoro-3-(4-methylthiazol-5-yl)phenoxy]methyl]anilino]-1-methyl-2- 20 oxo-ethyl]amino]-1-methyl-2-oxo-ethyl]carbamate VHL Int 18. 182 15077.006WO2 Step A. Preparation of Int 18a. To a solution of Int 19b (450 mg, 643 μmol, 1 eq) in DMF (5.00 mL) was added 2H- tetrazole (450 mg, 6.43 mmol, 570 μL, 10 eq) and N-ditert-butoxyphosphanyl-N-ethyl- 5 ethanamine (1.60 g, 6.43 mmol, 10 eq). The suspension was degassed and purged with N2for 3 times. The mixture was stirred at 20°C for 0.5 h. The reaction mixture was diluted with H2O 10 mL and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert- butyl N-[(1R)-1-[2-[[4-[[(2S)-2-[[(2S)-2-10 (allyloxycarbonylamino)propanoyl]amino]propanoyl]amino]phenyl]methoxy]-3-fluoro-4-(4- methylthiazol-5-yl)phenyl]-2-ditert-butoxyphosphanyloxy-ethyl]carbamate Int 18a (560 mg, crude) as a light yellow oil. LCMS: MS (ESI) m / z 820.3 [M-55]+Step B. Preparation of Int 18b. To a solution of Int 18a (560 mg, 639 μmol, 1 eq) in DMF (5.00 mL) was added H2O2 15 (724 mg, 6.39 mmol, 614 μL, 30% purity, 10 eq) dropwise at 0°C. The reaction mixture was warmed 20°C and stirred for 0.5 h. The reactions were quenched with aqueous H2O (20 mL) at 10°C, and then stirred for 2 min. The precipitate was filtered, and the filtrate was extracted with EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum20 ether / ethyl acetate = 100 / 1 to 0 / 1) to give tert-butyl N-[(1R)-1-[2-[[4-[[(2S)-2-[[(2S)-2- (allyloxycarbonylamino)propanoyl]amino]propanoyl]amino]phenyl]methoxy]-3-fluoro-4-(4- methylthiazol-5-yl)phenyl]-2-ditert-butoxyphosphoryloxy-ethyl]carbamate Int 18b (450 mg, 504.50 μmol, 78.92% yield) as a colorless oil. LCMS: MS (ESI) m / z 892.4 [M+H]+183 15077.006WO2 Step C. Preparation of VHL Int 18. A solution of Int 18b (440 mg, 493 μmol, 1 eq) in HCOOH (10.0 mL) was stirred at 20°C for 6 h. The mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18250*50mm*15um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:10%- 5 40% B over 10.0 min ) to give VHL Int 18 (190 mg, 239.39 μmol, 48.53% yield, TFA) as a white solid.1H NMR (400 MHz, DMSO-d6) δ10.00 (s, 1H), 9.17 (s, 1H), 8.16 - 8.05 (m, 1H), 7.65 (br d, J = 8.0 Hz, 2H), 7.51 - 7.34 (m, 4H), 5.99 - 5.83 (m, 1H), 5.34 - 5.25 (m, 1H), 5.21 - 5.10 (m, 3H), 4.85 - 4.77 (m, 1H), 4.47 (br dd, J = 2.4, 3.6 Hz, 2H), 4.44 - 4.37 (m, 1H), 4.15 - 4.10 (m, 2H), 4.06 - 4.00 (m, 1H), 2.35 (s, 3H), 1.32 (br d, J = 6.8 Hz, 3H), 1.21 (br d, J = 7.0 10 Hz, 3H). LCMS: MS (ESI) m / z 680.1 [M+H]+Example Int.19 Synthesis of allyl N-[(1S)-2-[[(1S)-2-[4-[[6-[(1R)-1-amino-2- hydroxy-ethyl]-2-fluoro-3-(4-methylthiazol-5-yl)phenoxy]methyl]anilino]-1-methyl-2-oxo- ethyl]amino]-1-methyl-2-oxo-ethyl]carbamate VHL Int 19. Step A. Preparation of Int 18a. 15 To a solution of 6-[(1R)-1-amino-2-hydroxy-ethyl]-2-fluoro-3-(4-methylthiazol-5- yl)phenol Int 13H (580 mg, 2.16 mmol, 1 eq) in THF (10.0 mL) and H2O (2.00 mL) was added Boc2O (940 mg, 4.32 mmol, 993 μL, 2 eq) and NaHCO3(545 mg, 6.49 mmol, 252 μL, 3 eq). The mixture was stirred at 20°C for 2 h. The reaction mixture was diluted with H2O 10 mL and 20 extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ethergradient @ 35 mL / min) to give tert- butyl N-[(1R)-1-[3-fluoro-2-hydroxy-4-(4-methylthiazol-5-yl)phenyl]-2-hydroxy- 25 ethyl]carbamate Int 19a (600 mg, 1.63 mmol, 75.34% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ8.78 (s, 1H), 7.10 (dd, J = 1.2, 8.0 Hz, 1H), 6.89 (dd, J = 6.8, 8.0 Hz, 1H), 5.59 - 5.49 (m, 1H), 5.08 - 5.00 (m, 1H), 4.03 (br d, J = 2.8 Hz, 2H), 2.45 (d, J = 1.3 Hz, 3H), 1.46 (s, 9H). LCMS: MS (ESI) m / z 369.1 [M+H]+Step B. Preparation of Int 19b. 184 15077.006WO2 To a solution of Int 19a (550 mg, 1.49 mmol, 1 eq) in DMF (10.0 mL) was added K2CO3 (620 mg, 4.48 mmol, 3 eq) and allyl N-[(1S)-2-[[(1S)-2-[4-(chloromethyl)anilino]-1-methyl-2- oxo-ethyl]amino]-1-methyl-2-oxo-ethyl]carbamate (1.10 g, 2.99 mmol, 2 eq). The suspension 5 was degassed and purged with N2 for 3 times. The mixture was stirred at 20°C for 1 h. The reaction mixture was diluted with H2O 20 mL and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl10 acetate / Petroleum ethergradient @ 45 mL / min) to give tert-butyl N-[(1R)-1-[2-[[4-[[(2S)-2- [[(2S)-2-(allyloxycarbonylamino)propanoyl]amino]propanoyl]amino]phenyl]methoxy]-3-fluoro- 4-(4-methylthiazol-5-yl)phenyl]-2-hydroxy-ethyl]carbamate Int 19b (790 mg, 1.13 mmol, 75.62% yield) as a light yellow solid.. LCMS: MS (ESI) m / z 700.3 [M+H]+Step C. Preparation of VHL Int 19. 15 A solution of Int 19b (300 mg, 428 μmol, 1 eq) in HCOOH (8.00 mL) was stirred at 20°C for 6 h. The mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:5%- 35% B over 8.0 min ) to give Int 19 (140 mg, 196.16 μmol, 45.76% yield, TFA) as a white solid. 20 1H NMR (400 MHz, DMSO-d6) δ10.00 (s, 1H), 9.16 (s, 1H), 8.43 - 8.27 (m, 3H), 8.11 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.47 - 7.39 (m, 3H), 7.37 (s, 1H), 7.36 (d, J = 6.4 Hz, 1H), 6.01 - 5.81 (m, 1H), 5.72 - 5.49 (m, 1H), 5.29 (br d, J = 16.4 Hz, 1H), 5.17 (br d, J = 10.8 Hz, 1H), 5.13 (s, 2H), 4.61 - 4.32 (m, 4H), 4.14 - 4.01 (m, 1H), 3.71 - 3.57 (m, 2H), 2.35 (s, 3H), 1.32 (d, J = 7.2 Hz, 3H), 1.21 (d, J = 7.2 Hz, 3H). LCMS: MS (ESI) m / z 600.2 [M+H]+25 Example Int.20 Synthesis of allyl N-[(1S)-2-[[(1S)-2-[4-[[6-[(1S)-1-[[(2S,4R)-1- [(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-pyrrolidine-2-carbonyl] amino] ethyl]-2- 185 15077.006WO2 fluoro-3-(4-methylthiazol-5-yl) phenoxy] methyl] anilino]-1-methyl-2-oxo-ethyl] amino]-1- methyl-2-oxo-ethyl] carbamate, Int 20 To a solution of tert-butyl N-[(1S)-1-[(2S,4R)-2-[[(1S)-1-[3-fluoro-2-hydroxy-4-(4- 5 methylthiazol-5-yl)phenyl]ethyl]carbamoyl]-4-hydroxy-pyrrolidine-1-carbonyl]-2,2-dimethyl- propyl]carbamate Int 20a (0.2 g, 346 μmol, 1 eq) and allyl N-[(1S)-2-[[(1S)-2-[4- (chloromethyl)anilino]-1-methyl-2-oxo-ethyl]amino]-1-methyl-2-oxo-ethyl]carbamate (318 mg, 864 μmol, 2.5 eq) in DMF (3 mL) was added K2CO3 (143 mg, 1.04 mmol, 3 eq). The reaction mixture was stirred at 20°C for 2 hr. The residue was diluted with water 20 mL and extracted 10 with EtOAc 6 ml x3. The combined organic layers were washed with brine 20 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1). Compound tert-butyl N-[(1S)-1-[(2S,4R)-2-[[(1S)-1-[2-[[4-[[(2S)-2-[[(2S)-2- (allyloxycarbonylamino) propanoyl] amino] propanoyl] amino] phenyl] methoxy]-3-fluoro-4-(4-15 methylthiazol-5-yl) phenyl] ethyl] carbamoyl]-4-hydroxy-pyrrolidine-1-carbonyl]-2,2-dimethyl- propyl] carbamate Int 20b (180 mg, 198 μmol, 57.23% yield) was obtained as a brown solid. LCMS: MS (ESI) m / z 910.4 [M+H]+ Step B. Preparation of Int 20 A solution of Int 20b (0.16 g, 176 μ mol, 1 eq) in HCOOH (8.45 mg, 176 μ mol, 1 eq) 20 was stirred at 20°C for 2 hr. The reaction mixture was concentrated under reduced pressure to remove HCOOH. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 186 15077.006WO2 75*30mm*3 um; mobile phase: [H2O (0.1%TFA)-ACN]; gradient:20%-50% B over 8.0 min) to give Int 20 (0.08 g, 98.8 μ mol, 28.09% yield) as a white solid. LCMS: MS (ESI) m / z 810.5 [M+H]+ Example Int.21 Synthesis of [(3R,5S)-5-[[(1S)-1-[2-[[4-[[(2S)-2-[[(2S)-2-5 (allyloxycarbonylamino)propanoyl]amino]propanoyl]amino]phenyl]methoxy]-4-(4- methylthiazol-5-yl)phenyl]ethyl]carbamoyl]-1-[(2S)-3-methyl-2-[4-(6-oxohexoxy)triazol-1- yl]butanoyl]pyrrolidin-3-yl] acetate, Int 21 187 15077.006WO2 Step A. Preparation of Int 21b To a solution of (2S,4R)-1-[(2S)-2-azido-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[2- hydroxy-4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide Int 21a (400 mg, 846.45 μmol, 1 eq) in DMF (4 mL) were added allyl N-[(1S)-2-[[(1S)-2-[4- 5 (chloromethyl)anilino]-1-methyl-2-oxo-ethyl]amino]-1-methyl-2-oxo-ethyl]carbamate (467 mg, 1.27 mmol, 1.5 eq) and K2CO3(350 mg, 2.54 mmol, 3 eq). The reaction mixture was stirred at 25°C for 1 hr. The reaction mixture was added H2O 30 mL and extracted with ethyl acetate (30 mL x 3), the organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column10 chromatography (SiO2, Ethyl acetate / MeOH =100 / 0 to 50 / 50) to give allyl N-[(1S)-2-[[(1S)-2- [4-[[2-[(1S)-1-[[(2S,4R)-1-[(2S)-2-azido-3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2- carbonyl]amino]ethyl]-5-(4-methylthiazol-5-yl)phenoxy]methyl]anilino]-1-methyl-2-oxo- ethyl]amino]-1-methyl-2-oxo-ethyl]carbamate Int 21b (0.38 g, 472 μmol, 55.8% yield) as a brown solid. LCMS: MS (ESI) m / z 804.2[M+H]+15 Step B. Preparation of Int 21c To a solution of Int 21b (0.36 g, 447 μmol, 1 eq) in THF:t-BuOH:H2O=1:1:1 (4 mL) were added tert-butyl-(6-ethynoxyhexoxy)-dimethyl-silane (172 mg, 671 μmol, 1.5 eq), sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (133 mg, 671 μmol, 1.5 eq) and CuSO4(35.7 mg, 223 μmol, 34.3 μL, 0.5 eq). The reaction mixture was 20 heated to 30oC and stirred for 2 hr. After cooling to room temperature, the mixture was water (10 mL) was added and then extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by column chromatography (SiO2, Ethyl acetate / MeOH=100 / 0 to 50 / 50) to give allyl N-[(1S)-2-[[(1S)-2-[4-25 [[2-[(1S)-1-[[(2S,4R)-1-[(2S)-2-[4-[6-[tert-butyl(dimethyl)silyl]oxyhexoxy]triazol-1-yl]-3- methyl-butanoyl]-4-hydroxy-pyrrolidine-2-carbonyl]amino]ethyl]-5-(4-methylthiazol-5- yl)phenoxy]methyl]anilino]-1-methyl-2-oxo-ethyl]amino]-1-methyl-2-oxo-ethyl]carbamate Int 21c (0.26 g, 245.20 μmol, 54.76% yield) as a brown solid. LCMS: MS (ESI) m / z 1060.4[M+H]+Step C. Preparation of Int 21d 30 To a solution of Int 21c (240 mg, 226 μmol, 1 eq) in DCM (3 mL) were added Ac2O (57.7 mg, 565 μmol, 53.1 μL, 2.5 eq), TEA (91.6 mg, 905 μmol, 126 μL, 4 eq) and DMAP (2.7 mg, 22.6 μmol, 0.1 eq). The reaction mixture was stirred at 25°C for 30 min. The reaction mixture was added H2O 20 mL and extracted with DCM (20 mL x 3), the organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure35 to give [(3R,5S)-5-[[(1S)-1-[2-[[4-[[(2S)-2-[[(2S)-2- 188 15077.006WO2 (allyloxycarbonylamino)propanoyl]amino]propanoyl]amino]phenyl]methoxy]-4-(4- methylthiazol-5-yl)phenyl]ethyl]carbamoyl]-1-[(2S)-2-[4-[6-[tert- butyl(dimethyl)silyl]oxyhexoxy]triazol-1-yl]-3-methyl-butanoyl]pyrrolidin-3-yl] acetate Int 21d (310 mg, crude) as a brown solid. LCMS: MS (ESI) m / z 1102.4[M+H]+5 Step D. Preparation of Int 21e To a solution of Int 21d (310 mg, 281 μmol, 1 eq) in MeOH (3 mL) was added dropwise acetyl chloride (33.1 mg, 421 μmol, 29.9 μL, 1.5 eq). The reaction mixture was stirred at 25°C for 30 min. The reaction mixture was added H2O 20 mL and extracted with ethyl acetate (20 mL x 3), the organic layer was washed with brine (10 mL), dried over Na2SO4,10 filtered and concentrated under reduced pressure to give [(3R,5S)-5-[[(1S)-1-[2-[[4-[[(2S)-2- [[(2S)-2-(allyloxycarbonylamino)propanoyl]amino]propanoyl]amino]phenyl]methoxy]-4-(4- methylthiazol-5-yl)phenyl]ethyl]carbamoyl]-1-[(2S)-2-[4-(6-hydroxyhexoxy)triazol-1-yl]-3- methyl-butanoyl]pyrrolidin-3-yl] acetate Int 21e (0.27 g, crude) as a brown solid. LCMS: MS (ESI) m / z 988.3[M+H]+15 Step E. Preparation of Int 21 To a solution of Int 21e (250 mg, 253 μmol, 1 eq) in DCM (3 mL) was added Dess- Martin (322 mg, 759 μmol, 235 μL, 3 eq). The mixture was stirred at 25°C for 1 hr. The reaction mixture was added NaHCO320 mL and extracted with DCM (20 mL x 3), the organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under 20 reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 0:1) to give Int 21 (0.115 g, 116 μmol, 46.1% yield) as a yellow solid. LCMS: MS (ESI) m / z 986.3[M+H]+Synthesis of Bcl-xL-VHL compounds (BXV) Example BXV-2 Synthesis of 3-(6-(benzo[d]thiazol-2-ylamino)-5-methylpyridazin-25 3-yl)-7-(1-(cyclohexylmethyl)-5-methyl-1H-pyrazol-4-yl)-N-((3-((1-((S)-1-((2S,4R)-2-(((S)-1- (3-fluoro-2-hydroxy-4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidin-1- yl)-3-methyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)oxy)propyl)sulfonyl)imidazo[1,2- a]pyridine-8-carboxamide, BXV-2 189 15077.006WO2 Step A. Preparation of Int 22a. To a solution of methyl 7-chloroimidazo[1,2-a]pyridine-8-carboxylate (2.1 g, 9.97 mmol,5 1 eq) and 1-(cyclohexylmethyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazole (3.03 g, 9.97 mmol, 1 eq) in dioxane (40 mL) and H2O (4 mL) was added K3PO4190 15077.006WO2 (7.41 g, 34.9 mmol, 3.5 eq) and Pd(PPh3)4 (1.15 g, 997μmol, 0.1 eq) under N2 atmosphere. The mixture was degassed and purged with N2for 3 times, the reaction was allowed to heat to 100oC and stirred for 12 h. The reaction mixture was quenched by addition H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 120 mL / min). The eluent was removed under reduced pressure to give methyl 7-[1-(cyclohexylmethyl)-5-methyl-pyrazol-4- yl]imidazo[1,2-a]pyridine-8-carboxylate (2.30 g, 6.53 mmol, 65.5% yield), Int 22a as a brown 10 solid.1H NMR (400 MHz, DMSO-d6) δ8.63 (d, J = 7.2 Hz, 1H), 8.01 (d, J = 1.2 Hz, 1H), 7.58 (d, J = 1.2 Hz, 1H), 7.37 (s, 1H), 6.89 (d, J = 7.2 Hz, 1H), 3.91 (d, J = 7.2 Hz, 2H), 3.74 (s, 3H), 2.25 (s, 3H), 1.87 - 1.79 (m, 1H), 1.73 - 1.58 (m, 3H), 1.54 - 1.50 (m, 2H), 1.25 - 1.09 (m, 3H), 1.06 - 0.91 (m, 2H) LCMS: MS (ESI) m / z 479.1[M+H]+Step B. Preparation of Int 22b 15 To a solution of Int 22a (2.30 g, 6.53 mmol, 1 eq) in MeCN (25 mL) was added N- iodosuccinimide, NIS (1.54 g, 6.85 mmol, 1.05 eq) at 0oC. After the addition, the reaction was allowed to warm to 25oC and stirred for 2 h. The reaction mixture was quenched by addition H2O (100 mL) at 0oC, and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under 20 reduced pressure. The residue was purified by flash silica gel chromatography (Biotage®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~50% Petroleum ether : Ethyl acetate gradient @ 100 mL / min). The eluent was removed under reduced pressure. Compound methyl 7-[1- (cyclohexylmethyl)-5-methyl-pyrazol-4-yl]-3-iodo-imidazo[1,2-a]pyridine-8-carboxylate Int 22b (2.90 g, 6.06 mmol, 92.9% yield) was obtained as a yellow solid.1H NMR (400 MHz, 25 DMSO-d6) δ8.41 (d, J = 7.2 Hz, 1H), 7.75 (s, 1H), 7.40 (s, 1H), 7.05 (d, J = 7.2 Hz, 1H), 3.92 (d, J = 7.2 Hz, 2H), 3.75 (s, 3H), 2.26 (s, 3H), 1.88 - 1.80 (m, 1H), 1.72 - 1.58 (m, 3H), 1.54 - 1.51 (m, 2H), 1.27 - 1.11 (m, 3H), 1.08 - 0.92 (m, 2H). LCMS: MS (ESI) m / z 479.1[M+H]+Step C. Preparation of Int 22c To a solution of Int 22b (2.20 g, 4.60 mmol, 1 eq) in dioxane (40 mL) and H2O (4 mL) 30 was added Na2CO3 (1.22 g, 11.5 mmol, 2.5 eq) and Pd(dppf)Cl2 (336 mg, 459μmol, 0.1 eq) under N2atmosphere. The mixture was degassed and purged with N2for 3 times, the reaction was allowed to heat to 85oC and stirred for 2 h under N2 atmosphere. The reaction mixture was diluted with H2O (100 mL) at 0oC, and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated 35 under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage®; 191 15077.006WO2 40 g SepaFlash® Silica Flash Column, Eluent of 0~100% Petroleum ether : Ethyl acetate gradient @ 100 mL / min). The eluent was removed under reduced pressure to give methyl 7-[1- (cyclohexylmethyl)-5-methyl-pyrazol-4-yl]-3-[5-methyl-6-oxo-1-(2- trimethylsilylethoxymethyl)pyridazin-3-yl]imidazo[1,2-a]pyridine-8-carboxylate (2.40 g, 4.06 5 mmol, 88.3% yield), Int 22c as a yellow solid. LCMS: MS (ESI) m / z 591.3[M+H]+Step D. Preparation of Int 22d. A mixture of Int 22c (2.40 g, 4.06 mmol, 1 eq) in EtOH (10 mL) and HCl (10 mL, 6N) was stirred at 80oC for 4 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (100 mL) and the pH of the mixture as 10 adjusted to ~8 with sat. NaHCO3and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give methyl 7-[1-(cyclohexylmethyl)-5-methyl-pyrazol-4-yl]-3-(5- methyl-6-oxo-1H-pyridazin-3-yl)imidazo[1,2-a]pyridine-8-carboxylate, Int 22d (1.90 g, crude) as a brown solid. LCMS: MS (ESI) m / z 461.2[M+H]+15 Step E. Preparation of Int 22e. A mixture of Int 22d (1.90 g, 4.13 mmol, 1 eq) in POCl3(20 mL) was s stirred at 90oC for 1 h. The mixture was cooled to room temperature and concentrated almost to dryness. The residue was poured into ice / water (100 mL) and the pH of the mixture as adjusted to ~7 with sat. NaHCO3and then extracted with EtOAc (100 mL x 3). The combined organic layers were 20 washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~100% Petroleum ether : Ethyl acetate gradient @ 100 mL / min). The eluent was removed under reduced pressure to give methyl 3-(6-chloro-5- methyl-pyridazin-3-yl)-7-[1-(cyclohexylmethyl)-5-methyl-pyrazol-4-yl]imidazo[1,2-a]pyridine- 25 8-carboxylate Int 22e (1.90 g, 3.97 mmol, 96.2% yield) as a brown solid. LCMS: MS (ESI) m / z 479.2[M+H]+ Step F. Preparation of Int 22f. To a solution of Int 22e (1.90 g, 3.97 mmol, 1 eq) and 1,3-benzothiazol-2-amine (893 mg, 5.95 mmol, 1.5 eq) in dioxane (20 mL) was added Xantphos (459 mg, 793 μmol, 30 0.2 eq), DIEA (1.54 g, 11.9 mmol, 2.07 mL, 3 eq) and chloroform;(1E,4E)-1,5-diphenylpenta- 1,4-dien-3-one;palladium (410 mg, 396 μmol, 0.1 eq) under N2 atmosphere. The mixture was degassed and purged with N2 for 3 times, the reaction was allowed to heat to 120°C and stirred for 12 h under N2atmosphere. The reaction mixture was quenched by addition H2O (100 mL) at 0°C, and then extracted with EtOAc (100 mL x 3). The combined organic layers 35 were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced 192 15077.006WO2 pressure. The residue was purified by flash silica gel chromatography (Biotage®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate : Methanol gradient @ 120 mL / min). The eluent was removed under reduced pressure to give methyl 3-[6-(1,3- benzothiazol-2-ylamino)-5-methyl-pyridazin-3-yl]-7-[1-(cyclohexylmethyl)-5-methyl-pyrazol- 5 4-yl]imidazo[1,2-a]pyridine-8-carboxylate Int 22f (2.00 g, 3.37 mmol, 85.1% yield) as a yellow solid. LCMS: MS (ESI) m / z 593.2 [M+H]+ Step G. Preparation of Int 22g. A mixture of Int 22f (2.00 g, 3.37 mmol, 1 eq) and LiOH.H2O (849 mg, 20.2 mmol, 6 eq) in MeOH (10 mL), THF (10 mL) and H2O (10 mL) was stirred at 25°C for 12 h. The pH of 10 the reaction mixture was adjusted to ~6 with aq. HCl (3N). The solid precipitate was collected by filtration, washed with MeCN (20 mL x 2), and dried under reduced pressure to give 3-[6- (1,3-benzothiazol-2-ylamino)-5-methyl-pyridazin-3-yl]-7-[1-(cyclohexylmethyl)-5-methyl- pyrazol-4-yl]imidazo[1,2-a]pyridine-8-carboxylic acid Int 22g (1.90 g, 3.28 mmol, 97.3% yield) as a yellow solid.1H NMR (400 MHz, MeOD) δ10.31 (d, J = 7.2 Hz, 1H), 8.64 (s, 1H), 8.08 (s, 15 1H), 7.83 - 7.71 (m, 2H), 7.66 - 7.54 (m, 2H), 7.41 (t, J = 7.2 Hz, 1H), 7.31 - 7.19 (m, 1H), 4.02 (d, J = 7.2 Hz, 2H), 2.54 (s, 3H), 2.36 (s, 3H), 2.00 - 1.94 (m, 1H), 1.86 - 1.62 (m, 5H), 1.38 - 1.20 (m, 3H), 1.17 - 1.01 (m, 2H). LCMS: MS (ESI) m / z 579.2[M+H]+ Step H. Preparation of Int 22h. To a solution of Int 22g (140 mg, 241 μmol, 1 eq) and benzyl (2S,4R)-4-acetoxy-1- 20 [(2S)-3-methyl-2-[4-(3-sulfamoylpropoxy)triazol-1-yl]butanoyl]pyrrolidine-2-carboxylate (200 mg, 362 μmol, 1.5 eq) in DCM (3 mL) was added 2-chloro-1-methyl-pyridin-1-ium;iodide (148 mg, 580 μmol, 2.4 eq)， DMAP (29.5 mg, 241 μmol, 1 eq) and TEA (146 mg, 1.45 mmol, 202 μL, 6 eq). The mixture was stirred at 25°C for 12 h. The reaction mixture was quenched by addition H2O (10 mL) at 0°C, and then extracted with DCM (10 mL x 3). The combined organic 25 layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate: Methanol gradient @ 40 mL / min). The eluent was removed under reduced pressure to give benzyl (2S,4R)-4-acetoxy-1-[(2S)-2-[4-[3-[[3-[6-(1,3- benzothiazol-2-ylamino)-5-methyl-pyridazin-3-yl]-7-[1-(cyclohexylmethyl)-5-methyl-pyrazol-30 4-yl]imidazo[1,2-a]pyridine-8-carbonyl]sulfamoyl]propoxy]triazol-1-yl]-3-methyl- butanoyl]pyrrolidine-2-carboxylate Int 22h (250 mg, 224 μmol, 92.9% yield) as a yellow solid. LCMS: MS (ESI) m / z 1112.4 [M+H]+ Step I. Preparation of Int 22i. A mixture of Int 22h (250 mg, 224 μmol, 1 eq) and LiOH.H2O (47.1 mg, 1.12 mmol, 35 5 eq) in MeOH (1 mL), THF (1 mL) and H2O (1 mL) was stirred at 25°C for 1 h. The pH of 193 15077.006WO2 the reaction mixture was adjusted to ~6 with aq. HCl (3N). The reaction mixture was extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give (2S,4R)-1-[(2S)-2-[4-[3-[[3-[6-(1,3-benzothiazol-2- ylamino)-5-methyl-pyridazin-3-yl]-7-[1-(cyclohexylmethyl)-5-methyl-pyrazol-4-yl]imidazo[1,2- 5 a]pyridine-8-carbonyl]sulfamoyl]propoxy]triazol-1-yl]-3-methyl-butanoyl]-4-hydroxy- pyrrolidine-2-carboxylic acid Int 22i (200 mg, 204 μmol, 90.8% yield) as a yellow solid. LCMS: MS (ESI) m / z 980.3 [M+H]+ Step J. Preparation of Compound BXV-2 To a solution of Int 22i (30.0 mg, 30.6 μmol, 1 eq), 6-[(1S)-1-aminoethyl]-2-fluoro-3-(4- 10 methylthiazol-5-yl)phenol (7.72 mg, 30.6 μmol, 1 eq) and DIEA (11.8 mg, 91.8 μmol, 15.9 μL, 3 eq) in DMF (0.5 mL) was added PYAOP (23.9 mg, 45.9 μmol, 1.5 eq) at 0°C. After addition, the reaction was allowed to warm to 25°C and stirred for 1 h. The pH of the mixture was adjusted to 5~6 with TFA and filtered. The filtrate was purified by prep-HPLC (column: Waters Xbridge BEH C18100*25mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 15 35%-65% B over 8.0 min). The eluent was removed under freeze drying to give BXV-2 (6.50 mg, 5.35 μmol, 17.5% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ9.84 (d, J = 7.2 Hz, 1H), 9.02 (s, 1H), 8.39 (s, 1H), 8.21 (d, J = 7.6 Hz, 1H), 8.13 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.70 - 7.55 (m, 3H), 7.40 (t, J = 7.6 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.13 - 7.08 (m, 2H), 6.85 (t, J = 7.6 Hz, 1H), 5.27 - 5.18 (m, 1H), 5.11 (d, J = 10.0 Hz, 1H), 4.93 - 4.92 (m, 1H), 4.49 20 (t, J = 7.2 Hz, 1H), 4.41 - 4.30 (m, 1H), 4.23 (t, J = 6.4 Hz, 2H), 3.93 (d, J = 7.2 Hz, 2H), 3.80 (dd, J = 4.4, 10.8 Hz, 1H), 3.58-3.55 (m, 1H), 3.43 - 3.34 (m, 2H), 3.34 - 3.25 (m, 2H), 2.40 - 2.30 (m, 6H), 2.25 - 2.13 (m, 2H), 2.10 - 2.00 (m, 1H), 1.97 - 1.84 (m, 4H), 1.76 - 1.59 (m, 5H), 1.38 (d, J = 6.8 Hz, 3H), 1.30 - 1.16 (m, 3H), 1.14 - 0.98 (m, 5H), 0.73 (d, J = 6.8 Hz, 3H). LCMS: MS (ESI) m / z 1214.4 [M+H]+ 25 The following compounds were prepared in a manner similar to that described for BXV- 2 using the appropriate compound as starting material. B N 194 15077.006WO2 BXV-4 1H NMR (400 MHz, DMSO-d6) δ9.91 - , ), , , , , 4 - - - B 2 , .6 - = , J Example BXV-9 Synthesis of 3-[6-(1,3-benzothiazol-2-ylamino)-5-methyl- pyridazin-3-yl]-7-[1-[[3,5-dimethyl-7-[2-(methylamino)ethoxy]-1-adamantyl]methyl]-5-methyl- pyrazol-4-yl]-N-[4-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-5 yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-4-oxo- butyl]sulfonyl-imidazo[1,2-a]pyridine-8-carboxamide, BXV-9 195 15077.006WO2 Step A. Preparation of Int 23a. A mixture of tert-butyl N-[2-[[3-[(4-iodo-5-methyl-pyrazol-1-yl)methyl]-5,7-dimethyl-1- adamantyl]oxy]ethyl]-N-methyl-carbamate (1.5 g, 2.69 mmol, 1 eq), 4,4,5,5-tetramethyl-1,3,2- 5 dioxaborolane (2.75 g, 21.5 mmol, 3.12 mL, 8 eq), TEA (2.18 g, 21.5 mmol, 3.00 mL, 8 eq), Sphos (220 mg, 538 μmol, 0.2 eq) and benzonitrile;dichloropalladium (206 mg, 538 μmol, 0.2 eq) in dioxane (30 mL) was degassed and purged with N2for 3 times, and then the reaction mixture was heated to 100°C and stirred for 2 hr under N2atmosphere. After cooling to room temperature, the mixture was filtered and concentrated to give a residue. The residue was 10 purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate / Petroleum ether gradient @ 75 mL / min) to afford tert-butyl N-[2- [[3,5-dimethyl-7-[[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1- yl]methyl]-1-adamantyl]oxy]ethyl]-N-methyl-carbamate Int 23a (2.6 g, crude) as yellow oil which was used into the next step without further purification. LCMS: MS (ESI) m / z 558.3 15 [M+H]+Step B. Preparation of Int 23b. A mixture of Int 23a (2.38 g, 4.27 mmol, 2 eq), K3PO4(1.59 g, 7.48 mmol, 3.5 eq), Pd(PPh3)4 (493 mg, 427 μmol, 0.2 eq) in dioxane (40 mL) and H2O (4 mL) was degassed and 20 purged with N2 for 3 times, and then the mixture was heated to 100°C and stirred for 2 hr under N2atmosphere. After cooling to room temperature, the reaction mixture was quenched by addition H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 25 40 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ethergradient @ 75 mL / min) to obtain methyl 7-[1-[[3-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-5,7- 196 15077.006WO2 dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]imidazo[1,2-a]pyridine-8-carboxylate Int 23b (700 mg, 1.16 mmol, 54.08% yield) as yellow oil which was used into the next step without further purification. LCMS: MS (ESI) m / z 606.4 [M+H]+Step C. Preparation of Int 23c. 5 To a solution of Int 23b (700 mg, 1.16 mmol, 1 eq) in CH3CN (7 mL) was added NIS (311 mg, 1.39 mmol, 1.2 eq) in portions at 0°C. The reaction mixture was warmed to 25°C and stirred for 1 hr. The reaction mixture was added ice H2O 10 mL and extracted with ethyl acetate (10 mL x 3), the organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and 10 concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 0 to 65 / 45) to give methyl 7-[1-[[3- [2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl- pyrazol-4-yl]-3-iodo-imidazo[1,2-a]pyridine-8-carboxylate Int 23c (730 mg, 997.73 μmol, 86.34% yield) as yellow gum.1H NMR (400 MHz, DMSO-d6) δ8.40 (d, J = 7.2 Hz, 1H), 7.73 15 (s, 1H), 7.41 (s, 1H), 7.04 (d, J = 7.2 Hz, 1H), 3.89 (s, 2H), 3.74 (s, 3H), 3.43 - 3.41 (m, 2H), 3.20 (t, J = 5.6 Hz, 2H), 2.56 (s, 3H), 2.22 (s, 3H), 1.37 (s, 9H), 1.27 - 0.96 (m, 12H), 0.86 (s, 6H) LCMS: MS (ESI) m / z 732.1[M+H]+Step D. Preparation of Int 23d. 20 A mixture of Int 23c (700 mg, 956 μmol, 1 eq), 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one (525 mg, 1.44 mmol, 1.5 eq), Na2CO3 (253 mg, 2.39 mmol, 2.5 eq), Pd(dppf)Cl2 (70.0 mg, 95.6 μmol, 0.1 eq) in dioxane:H2O=10:1 (7 mL) was degassed and purged with N2 for 3 times, and then the mixture was heated to 85°C and stirred for 2 hr under N2atmosphere. After cooling to room 25 temperature, water (10 mL) was added and then extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with water (10 mL), brine (10 mL), dried over anhydrous 197 15077.006WO2 Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / to 0 / 100) to give methyl 7-[1-[[3-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5- methyl-pyrazol-4-yl]-3-[5-methyl-6-oxo-1-(2-trimethylsilylethoxymethyl)pyridazin-3- 5 yl]imidazo[1,2-a]pyridine-8-carboxylate Int 23d (610 mg, 722 μmol, 75.5% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ9.54 (d, J = 7.6 Hz, 1H), 8.42 (s, 1H), 8.13 (s, 1H), 7.44 (s, 1H), 7.14 (d, J = 7.6 Hz, 1H), 5.52 (s, 2H) 3.91 (s, 2H), 3.78 (s, 3H), 3.74 (t, J = 8.0 Hz, 2H), 3.43 (t, J = 5.6 Hz, 2H), 3.20 (t, J = 5.6 Hz, 2H), 2.54 (s, 3H), 2.27 (s, 3H), 2.20 (s, 3H), 1.37 (s, 9H), 1.28 - 0.99 (m, 14H), 0.86 (s, 6H), 0.08 (s, 9H) LCMS: MS (ESI) m / z 844.4 10 [M+H]+Step E. Preparation of Int 23e. To a solution of Int 23d (560 mg, 663 μmol, 1 eq) in EtOH (3 mL) was added HCl (6 M, 3 mL). The reaction mixture was heated to 80°C and stirred for 1 hr. After cooling to room15 temperature, the mixture was concentrated under reduced pressure to give methyl 7-[1-[[3,5- dimethyl-7-[2-(methylamino)ethoxy]-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]-3-(5-methyl- 6-oxo-1H-pyridazin-3-yl)imidazo[1,2-a]pyridine-8-carboxylate Int 23e (410 mg, crude) as a brown solid. LCMS: MS (ESI) m / z 614.3 [M+H]+Step F. Preparation of Int 23f. 20 To a solution of Int 23e (410 mg, 668 μmol, 1 eq) in THF (4 mL), H2O (4 mL) were added NaHCO3(561 mg, 6.68 mmol, 259 μL, 10 eq) and Boc2O (218 mg, 1.00 mmol, 230 μL, 1.5 eq). The reaction mixture was stirred at 25°C for 1 hr. The reaction mixture was added 198 15077.006WO2 H2O 10 mL and extracted with ethyl acetate (10 mL x 3), the organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Ethyl acetate / MeOH=100 / 0 to 90 / 10) to give methyl 7-[1-[[3-[2-[tert- 5 butoxycarbonyl(methyl)amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4- yl]-3-(5-methyl-6-oxo-1H-pyridazin-3-yl)imidazo[1,2-a]pyridine-8-carboxylate Int 23f (410 mg, 574 μmol, 85.9% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ13.08 (s, 1H), 9.39 (d, J = 7.2 Hz, 1H), 8.35 (s, 1H), 8.06 (s, 1H), 7.44 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 3.90 (s, 2H), 3.77 (s, 3H), 3.43 - 3.41 (m, 2 H), 3.20 - 3.18 (m, 2 H), 2.54 (s, 3H), 2.26 (s, 3H), 2.16 10 (s, 3H), 1.37 (s, 9 H), 1.29 - 0.99 (m, 12H), 0.86 (s, 6H). LCMS: MS (ESI) m / z 714.3 [M+H]+Step G. Preparation of Int 23g. To a solution of Int 23f (330 mg, 462. μmol, 1 eq) in DCM (4 mL) were added TEA (233 mg, 2.31 mmol, 321 μL, 5 eq) and Tf2O (391 mg, 1.39 mmol, 228 μL, 3 eq) at 0°C. The 15 reaction mixture was warmed to 25°C and stirred for 1 hr. The reaction mixture was quenched with H2O 10 mL and extracted with ethyl acetate (10 mL x 3), the organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 0 to 100 / 0) to give methyl 7-[1-[[3-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-20 5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]-3-[5-methyl-6- (trifluoromethylsulfonyloxy)pyridazin-3-yl]imidazo[1,2-a]pyridine-8-carboxylate Int 23g (310 mg, 366.46 μmol, 79.2% yield) as a yellow solid. LCMS: MS (ESI) m / z 846.3[M+H]+Step H Preparation of Int 23h 199 15077.006WO2 A mixture of Int 23g (310 mg, 366 μmol, 1 eq), 1,3-benzothiazol-2-amine (82.5 mg, 549 μmol, 1.5 eq), Xantphos (42.4 mg, 73.29 μmol, 0.2 eq), DIEA (142 mg, 1.10 mmol, 191 μL, 3 eq) and chloroform;(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one;palladium (37.9 mg, 36.6 μmol, 0.1 eq) in dioxane (4 mL) was degassed and purged with N2 for 3 times, and then the mixture 5 was heated to 120°C and stirred for 12 hr under N2 atmosphere. After cooling to room temperature, water (10 mL) was added and then extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by column chromatography (SiO2, Ethyl acetate / MeOH=100 / 0 to 70 / 30) to give methyl 3-[6-10 (1,3-benzothiazol-2-ylamino)-5-methyl-pyridazin-3-yl]-7-[1-[[3-[2-[tert- butoxycarbonyl(methyl)amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-met hyl-pyrazol- 4-yl]imidazo[1,2-a]pyridine-8-carboxylate Int 23h (300 mg, 354 μmol, 96.7% yield) as a yellow solid. LCMS: MS (ESI) m / z 846.4 [M+H]+ 15 To a solution of Int 23h (290 mg, 342 μmol, 1 eq) in THF (1 mL), MeOH (1 mL), H2O (1 mL) was added LiOH.H2O (71.9 mg, 1.71 mmol, 5 eq). The reaction mixture was stirred at 25°C for 12 hr. The mixture was acidified with 1N HCl (pH=5~6), more precipitate was formed, the solid was filtered and concentrated under reduced pressure to give 3-[6-(1,3-20 benzothiazol-2-ylamino)-5-methyl-pyridazin-3-yl]-7-[1-[[3-[2-[tert- butoxycarbonyl(methyl)amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4- yl]imidazo[1,2-a]pyridine-8-carboxylic acid Int 23i (200 mg, crude) as a yellow solid. LCMS: MS (ESI) m / z 832.4 [M+H]+Step J. Preparation of Int 23j. 200 15077.006WO2 To a solution of Int 23i (180 mg, 216 μmol, 1 eq) in DMF (2 mL) was added CDI (70.1 mg, 432 μmol, 2 eq), the mixture was heated to 100°C and stirred for 16 hr. Then tert-butyl 4- sulfamoylbutanoate (192 mg, 861 μmol, 4 eq) and DBU (98.3 mg, 646 μmol, 97.4 μL, 3 eq) was 5 added to the mixture at 25oC. The reaction mixture was heated to 100°C and stirred for 2 hr. After cooling to room temperature, water (10 mL) was added and then extracted with ethyl acetate (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by column chromatography (SiO2, Ethyl acetate / MeOH=100 / 0 to 70 / 30) to give tert-butyl 4-[[3-[6-(1,3-benzothiazol-2-ylamino)-5-10 methyl-pyridazin-3-yl]-7-[1-[[3-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-5,7-dimethyl-1- adamantyl]methyl]-5-methyl-pyrazol-4-yl]imidazo[1,2-a]pyridine-8- carbonyl]sulfamoyl]butanoate Int 23j (100 mg, 96.4 μmol, 44.7% yield) as yellow oil. LCMS: MS (ESI) m / z 1037.5 [M+H]+Step K. Preparation of Int 23k. 15 To a solution of Int 23j (100 mg, 96.4 μmol, 1 eq) in DCM (1 mL) was added TFA (1.54 g, 13.4 mmol, 1.00 mL, 139 eq). The reaction mixture was stirred at 25°C for 1 hr. The mixture was concentrated under reduced pressure to give 4-[[3-[6-(1,3-benzothiazol-2-ylamino)-5- methyl-pyridazin-3-yl]-7-[1-[[3,5-dimethyl-7-[2-(methylamino)ethoxy]-1-adamantyl]methyl]-5- 20 methyl-pyrazol-4-yl]imidazo[1,2-a]pyridine-8-carbonyl]sulfamoyl]butanoic acid Int 23k (80 mg, crude) as yellow oil. LCMS: MS (ESI) m / z 881.4 [M+H]+Step L. Preparation of Int 23l. 201 15077.006WO2 To a solution of Int 23k (15 mg, 15.2 μmol, 1 eq) in DMF (0.5 mL) were added (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4- methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (8.82 mg, 18.3 μmol, 1.2 eq, 5 HCl), DIEA (5.93 mg, 45.8 μmol, 7.99 μL, 3 eq) and PYAOP (11.9 mg, 22.9 μmol, 1.5 eq) at 0°C. The reaction mixture was warmed to 25°C and stirred for 1 hr. The reaction mixture was added H2O 5 mL and extracted with ethyl acetate (5 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl N-[2-[[3-[[4-[3-[6-(1,3-benzothiazol-2- ylamino)-5-methyl-pyridazin-3-yl]-8-[[4-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-10 methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl- propyl]amino]-4-oxo-butyl]sulfonylcarbamoyl]imidazo[1,2-a]pyridin-7-yl]-5-methyl-pyrazol-1- yl]methyl]-5,7-dimethyl-1-adamantyl]oxy]ethyl]-N-methyl-carbamate Int 23l (20 mg, crude) as yellow oil. LCMS: MS (ESI) m / z 1047.5 [M+H]+Step M. Preparation of Compound BXV-9 15 To a solution of Int 23l (20 mg, 14.2 μmol, 1 eq) in DCM (0.2 mL) was added TFA (153 mg, 1.35 mmol, 0.1 mL, 94.7 eq). The reaction mixture was stirred at 25°C and for 1 hr. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep- HPLC (TFA condition; column: Welch Ultimate C18120*30mm*5um;mobile phase: 20 [H2O(0.1% TFA)-ACN];gradient:35%-65% B over 8.0 min ) to give BXV-9 (4.4 mg, 3.21 μmol, 22.57% yield, 95.28% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6 +D2O) δ9.97 (d, J = 7.2 Hz 1H), 8.96 (s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 8.0 202 15077.006WO2 Hz, 1H), 7.54 (s, 1H), 7.44 - 7.33 (m, 5H), 7.30 - 7.23 (m, 2H), 4.93 - 4.85 (m, 1H), 4.51 (s, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.29 - 4.26 (m, 1H), 3.92 (s, 2H), 3.61 - 3.59 (m, 4H), 3.46 - 3.44 (m, 2H), 3.01 - 2.99(m, 2H), 2.55 (s, 3H), 2.43 (s, 3H), 2.39 - 2.33 (m, 2H), 2.31 (s, 3H), 2.06 - 1.93 (m, 4H), 1.88 - 1.69 (m, 4H), 1.47 (s, 3H), 1.37 - 1.31 (m, 6H), 1.18 - 1.06(m, 6H), 0.94 (s, 9H), 5 0.88 (s, 6H) LCMS: MS (ESI) m / z 1307.6[M+H]+The following compounds were prepared in a manner similar to that described for BXV- 9 using the appropriate compound as starting material. B N B s, , t, 9 3 Example BXV-18 Synthesis of 3-[6-(1,3-benzothiazol-2-ylamino)-5-methyl-10 pyridazin-3-yl]-7-[1-(cyclohexylmethyl)-5-methyl-pyrazol-4-yl]-N-[4-[1-[(1S)-1-[(2S,4R)-2- [[(1R)-1-[3-fluoro-2-hydroxy-4-(4-methylthiazol-5-yl) phenyl]-2-hydroxy-ethyl]carbamoyl]-4- hydroxy-pyrrolidine-1-carbonyl]-2-methyl-propyl]triazol-4-yl]oxybutyl]imidazo[1,2- a]pyridine-8-carboxamide, BXV-18 203 15077.006WO2 Step A. Preparation of Int 24a. To a solution of tert-butyl N-(4-hydroxybutyl) carbamate (5.00 g, 26.4 mmol, 1 eq) in 5 THF (50 mL) was added NaH (1.59 g, 39.6 mmol, 660 μL, 60% purity, 1.5 eq) at 0°C, and the reaction mixture was allowed to stir at 0°C for 15 min before addition of 1,1,2-trichloroethylene (6.94 g, 52.8 mmol, 6.94 mL, 2 eq) under N2. Then the reaction mixture was slowly warmed to 25°C and stirred for 12 hr under N2atmosphere. The mixture was cooled to 0 °C and the residue 204 15077.006WO2 was poured into ice-water 100 mL and stirred for 5 min. The aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (100 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Commercial hexanes: Ethyl acetate=1 / 0 to 10 / 1) to give tert- 5 butyl N-[4-[(E)-1,2-dichlorovinyloxy] butyl] carbamate Int 24a (4.50 g, 15.8 mmol, 60.0% yield) as colorless oil.1H NMR (400 MHz, DMSO-d6) δ6.89 - 6.77 (m, 1H), 6.07 (s, 1H), 4.01 (t, J = 6.4 Hz, 2H), 3.00 - 2.89 (m, 2H), 1.66 - 1.44 (m, 4H), 1.37 (s, 9H) Step B. Preparation of Int 24b To a solution of Int 24a (4.50 g, 15.8 mmol, 1 eq) in THF (45 mL) was added n-BuLi 10 (2.5 M, 15.8 mL, 2.5 eq) at -70°C. Then the mixture was slowly warmed to -40°C and stirred for 1 hr. The reaction mixture was quenched by addition NH4Cl (50 mL) mL at 0°C, and then diluted with H2O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 15 Commercial hexanes: Ethyl acetate=1 / 0 to 10 / 1). Compound tert-butyl N-(4-ethynoxybutyl) carbamate Int 24b (1.32 g, 6.19 mmol, 39.1 % yield) was obtained as colorless oil. 1H NMR (400 MHz, DMSO-d6) δ6.83 (s, 1H), 4.14-4.05 (m, 2H), 2.98 - 2.85 (m, 2H), 1.72 - 1.59 (m, 2H), 1.43-1.42 (m, 2H), 1.37 (s, 9H) Step C. Preparation of Int 24c 20 To a solution of Int 24b (1.32 g, 6.18 mmol, 5 eq) and benzyl (2S,4R)-4-acetoxy-1- [(2S)-2-azido-3-methyl-butanoyl]pyrrolidine-2-carboxylate (0.48 g, 1.24 mmol, 1 eq) in t-BuOH (5 mL), H2O (5 mL), THF (5 mL) were added CuSO4(98.6 mg, 618 μmol, 94.8 μL, 0.5 eq) and sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (367 mg, 1.85 mmol, 1.5 eq). The mixture was stirred at 20°C for 1 hr. The reaction mixture was quenched by 25 addition of H2O (30 mL), and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Commercial hexanes: Ethyl acetate=1 / 0 to 0 / 1) to give benzyl (2S,4R)-4-acetoxy-1-[(2S)-2-[4- [4-(tert-butoxycarbonylamino) butoxy] triazol-1-yl]-3-methyl-butanoyl] pyrrolidine-2- 30 carboxylate Int 24c (0.90 g, crude) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ7.68 (s, 1H), 7.40 - 7.33 (m, 5H), 6.84-6.81 (m, 1H), 5.27-5.26 (m, 1H), 5.25-5.22 (m, 1H), 5.16-5.14 (m, 2H), 4.44 (t, J = 8.4 Hz, 1H), 3.96-3.95 (m, 2H), 2.92 - 2.88 (m, 2H), 2.46 - 2.35 (m, 2H), 2.22 - 2.13 (m, 1H), 1.93 (s, 3H), 1.67-1.62 (m, 1H), 1.51-1.44 (m, 2H), 1.37 (s, 9H), 0.95 (d, J = 6.4 Hz, 3H), 0.68 (d, J = 6.4 Hz, 3H). LCMS: MS (ESI) m / z 602.4 [M+H]+ 35 Step D. Preparation of Int 24d 205 15077.006WO2 To a solution of Int 24c (0.80 g, 1.33 mmol, 1 eq) in EtOAc (8 mL) was added EtOAc / HCl (4 M, 6.65 mL, 20 eq). The mixture was stirred at 20°C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove EtOAc. Compound benzyl (2S,4R)-4-acetoxy-1-[(2S)-2-[4-(4-aminobutoxy) triazol-1-yl]-3-methyl-butanoyl] pyrrolidine-2- 5 carboxylate Int 24d (0.70 g, crude) was obtained as a brown solid. LCMS: MS (ESI) m / z...

Claims

15077.006WO2 CLAIMS 1. A degrader antibody conjugate composition comprising a target protein binder and VHL ligand moiety (TPI-Sp-VHL) covalently attached to an antibody by an antibody linker, wherein the antibody binds to a tumor-associated antigen or cell-surface receptor and the target protein binder of the TPI-Sp-VHL binds to Bcl-xL.

2. The degrader antibody conjugate composition of claim 1 wherein the antibody binds to HER2.

3. The degrader antibody conjugate composition of claim 2 wherein the antibody is selected from trastuzumab and pertuzumab.

4. The degrader antibody conjugate composition of claim 1 wherein the antibody has a modified Fc region.

5. The degrader antibody conjugate composition of claim 4 wherein the antibody has Fc mutations selected from: (i) LALAPA (L234A / L235A / P329A); (ii) LALAPG (L234A / L235A / P329G); (iii) LALASKPA (L234A, L235A, S267K, P329A); (iv) LALAPA-YTE (L234A / L235A / P329A-M252Y / S254T / T256E); (v) LALAPG-YTE (L234A / L235A / P329G-M252Y / S254T / T256E); and (vi) LALASKPA-YTE (L234A, L235A, S267K, P329A- M252Y / S254T / T256E), according to EU numbering.

6. The degrader antibody conjugate composition of claim 1, wherein the antibody linker is covalently attached to a cysteine amino acid of the antibody.

7. The degrader antibody conjugate composition of claim 1, wherein the antibody is a cysteine-engineered antibody.

8. The degrader antibody conjugate composition of claim 7 wherein the antibody has one engineered cysteine mutation site selected from heavy-chain E152C, S239C, K246C and S375C, numbered according to the EU system.

9. The degrader antibody conjugate composition of claim 7 wherein the antibody has two or three engineered cysteine mutation sites selected from heavy-chain E152C, S239C, K246C and S375C, numbered according to the EU system. 28415077.006WO2 10. The degrader antibody conjugate composition of claim 7 wherein the cysteine- mutant antibody comprises one or more sequences with a heavy chain cysteine mutation from the group consisting of: Se uence: mutant site SEQ ID NO: K L F Kaccording to the EU system.

11. The degrader antibody conjugate composition of claim 7 wherein the cysteine- mutant antibody comprising one, two, or three engineered cysteine mutation sites is selected from (i) to (xvi): (i) HC S239C; (ii) HC K246C; (iii) HC S375C; (iv) HC E152C; (v) HC S239C and K246C; (vi) HC S239C and S375C; (vii) HC S239C and E152C; (viii) HC K246C and S375C; (ix) HC K246C and E152C; (x) HC S375C and E152C; (xi) HC S239C, K246C, and S375C; (xii) HC S239C, K246C, and E152C; (xiii) HC S239C, S375C, and E152C; (xiv) HC K246C, S375C, and E152C; (xv) HC S239C, S375C, and E152C; and (xvi) HC K246C, S375C, and E152C.

12. The degrader antibody conjugate composition of claim 11 wherein the cysteine- mutant antibody binds to HER2. 28515077.006WO2 13. The degrader antibody conjugate composition of claim 11 wherein the cysteine- mutant antibody is cysteine mutant trastuzumab or pertuzumab.

14. The degrader antibody conjugate composition of any one of claims 1 to 13 having Formula I: Ab−[L−(TPI−Sp−VHL)]pI or a pharmaceutically acceptable salt thereof, wherein: Ab is the antibody; L is the antibody linker; TPI−Sp−VHL is a moiety comprising a Bcl-xL target protein binder TPI and a VHL ligand wherein the TPI is covalently attached to the VHL ligand by a spacer unit Sp; and p is an integer from 1 to 12; the TPI, the VHL ligand, or the spacer unit Sp is attached to the antibody linker L; and the VHL ligand has Formula Ia:Ia wherein A is a cyclic structure selected from C3−C20 carbocyclyl, C6−C20 aryl, C1−C20 heteroaryl, and C2-C20 heterocyclyl, each of which are substituted with one or more groups independently selected from H, F, Cl, Br, I, −CN, −NO2, −OH, C1−C12alkyl, C2−C12alkenyl, C2−C12alkynyl, C1−C12heteroalkyl, −(C1−C12heteroalkyldiyl)−(C6−C20aryl), −(C1−C12heteroalkyldiyl)−(C6−C20 aryldiyl)−(C1−C12 heteroalkyl), −(C1−C12 heteroalkyldiyl)−(C6−C20 aryldiyl)−(C2-C20 heterocyclyl), (C1−C6 alkyldiyl)−(C6−C20 aryl), −(C1−C6 alkyldiyl)−NRaRb, −(C1−C6 alkyldiyl)−ORa, (C1−C6 alkyldiyl)−(C3−C20 carbocyclyl), (C1-C6 alkyldiyl)−(C2-C20 heterocyclyl), (C1−C6 alkyldiyl)−(C1−C20 heteroaryl), C6−C20 aryl, C3−C20 carbocyclyl, C2−C20 heterocyclyl, C1−C20 heteroaryl, −C(=NH)NH(OH), −C(=NH)NH2, −C(=O)NRaRb, 28615077.006WO2 −C(=O)NRa−NRaRb, −C(=O)NH(C1-C6 alkyldiyl)−NRaRb, −C(=O)ORa, −NRaRb, −NRaS(O)2Ra, −NO2, −ORa, −OC(=O)Ra, −SRa, −S(O)Ra, −S(O)2Ra, −S(O)2NRa, and −S(O)3H; Rais independently selected from H, C1−C6 alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, −NO2, −OH, C1−C12 alkyl, C2−C12 alkenyl, and C2−C12 alkynyl; or where two Ragroups form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring; Rbis independently selected from H, OH, C1−C6alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, C1−C12 alkyl, C2−C12 alkenyl, and C2−C12 alkynyl; Rcis selected from OH and −SO2F; Rdis selected from H and F; Cyc is a ring structure selected from the group consisting of C3−C20 carbocyclyl, C6−C20 aryl, C2-C20 heterocyclyl, and C1−C20 heteroaryl. n is 0 or 1; R1is selected from the group consisting of H, C1−C12alkyl, and C1−C12heteroalkyl; R2is selected from the group consisting of H, C1−C12 alkyl, and C1−C12 heteroalkyl; or where R2forms a five- to ten-membered aryl, carbocyclyl, heteroaryl or heterocyclyl ring with A; X1is selected from the group consisting of H, −NHC(=O)−, (C3−C20 carbocyclyl)− C(=O)NH−, C1−C12 heteroalkyl, and C1−C20 heteroaryl; or where X1forms a five-, six-, or seven-membered heteroaryl or heterocyclyl ring with R1; Sp is selected from the group consisting of a bond, O, NH, C1−C12 alkyldiyl, C1−C60 heteroalkyldiyl, C3−C20 carbocyclyldiyl, C2-C20 heterocyclyldiyl, C6-C20 aryldiyl, C1−C40 heteroaryldiyl, −(C3−C20 carbocyclyldiyl)−(C1−C60 heteroalkyldiyl)−, −(C3−C20 carbocyclyldiyl)−(C1−C12 alkyldiyl)−, −(C2-C20 heterocyclyldiyl)−(C1−C60 heteroalkyldiyl)−, −(C2-C20 heterocyclyldiyl)−(C1−C12 alkyldiyl)−, −(C2-C20 heterocyclyldiyl)−(C2-C20 heterocyclyldiyl)−, −(C1−C20 heteroaryldiyl)−(C3−C20 carbocyclyldiyl)−(C1−C60 heteroalkyldiyl)−, a solubilizing unit, and combinations thereof, where the solubilizing unit is selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), a glycoside, C1−C60heteroalkyldiyl, and combinations thereof; L is the antibody linker; one of A, Ra, Rb, Cyc, R1, R2, and X1is attached to Sp; and one of A, Ra, Rb, Cyc, R1, R2, X1and Sp is attached to L; 28715077.006WO2 where each alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, heteroalkyl, heteroalkyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl is independently substituted with one or more groups selected from H, F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C^CH, −C^CCH3, −CH2CH2CH3, − CH(CH3)2, −CH2CH(CH3)2, −CH(CH2CH2), −CH(CH2CH2CH2), −CH2OH, −CH2OCH3, − CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, −CH2CH2SO2CH3, − CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, −CH(CH3)CN, −C(CH3)2CN, − CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, −CH2N(CH3)2, −CO2H, −COCH3, − CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, −CONHCH3, −CON(CH3)2, − C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, −N(CH3)COCH3, −NHS(O)2CH3, − N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, −NHC(=NH)H, −NHC(=NH)CH3, − NHC(=NH)NH2, −NHC(=O)NH2, −NO2, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, − OCH2CH2OH, −OCH2CH2N(CH3)2, −OCH2F, −OCHF2, −OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H.

15. The degrader antibody conjugate composition of claim 14 wherein Cyc is a five-, six-, or seven-membered ring structure selected from the group consisting of thiazole, triazole, phenyl, pyridine, pyrazine, pyridazine, and pyrimidine, substituted with one or more groups independently selected from H, F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C^CH, − C^CCH3, −CH2CH2CH3, −CH(CH3)2, −CH2CH(CH3)2, −CH(CH2CH2), −CH(CH2CH2CH2), − CH2OH, −CH2OCH3, −CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, − CH2CH2SO2CH3, −CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, − CH(CH3)CN, −C(CH3)2CN, −CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, − CH2N(CH3)2, −CO2H, −COCH3, −CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, − CONHCH3, −CON(CH3)2, −C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, − N(CH3)COCH3, −NHS(O)2CH3, −N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, − NHC(=NH)H, −NHC(=NH)CH3, −NHC(=NH)NH2, −NHC(=O)NH2, −NO2, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, −OCH2CH2OH, −OCH2CH2N(CH3)2, −OCH2F, −OCHF2, − OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H.

16. The degrader antibody conjugate composition of claim 14 wherein R1is C1−C12alkyl.

17. The degrader antibody conjugate composition of claim 14 wherein R2is selected from the group consisting of H, C1−C12 alkyl, and C1−C12 heteroalkyl. 28815077.006WO2 18. The degrader antibody conjugate composition of claim 14 wherein R2is selected from H, −CH3, −CH2OH, −CH2CH2OH, −CH2OPO2OH, −CH2CH2OPO2OH, −CH2COOH, −CH2CH2COOH, −CH2CH2CONHS(O)2CH3, and −CH2CH2CONHS(O)2CH2CH2N(CH3)2.

19. The degrader antibody conjugate composition of claim 14 wherein X1is − C(=O)NH−, or C1−C20 heteroaryldiyl selected from the group consisting of triazole, isoxazole, and oxadiazole.

20. The degrader antibody conjugate composition of claim 14 wherein the VHL ligand has Formula Ib:.

21. The degrader antibody conjugate composition of claim 20 wherein the VHL ligand has Formula Ic:Ic wherein: R3, R4, R5, and R6are independently selected from the group consisting of H, F, Cl, Br, I, −CN, C1−C12alkyl, C2−C12alkenyl, C2−C12alkynyl, C1−C12heteroalkyl, −(C1−C12heteroalkyldiyl)−(C6−C20aryl), −(C1−C12heteroalkyldiyl)−(C6−C20aryldiyl)−(C1−C12heteroalkyl), −(C1−C12heteroalkyldiyl)−(C6−C20aryldiyl)−(C2-C20heterocyclyl), (C1−C6alkyldiyl)−(C6−C20 aryl), −(C1−C6 alkyldiyl)−NRaRb, −(C1−C6 alkyldiyl)−ORa, (C1−C6 alkyldiyl)−(C3−C20 carbocyclyl), (C1-C6 alkyldiyl)−(C2-C20 heterocyclyl), (C1−C6 alkyldiyl)−(C1−C20 heteroaryl), C6−C20 aryl, C3−C20 carbocyclyl, C2−C20 heterocyclyl, C1−C20 28915077.006WO2 heteroaryl, −C(=NH)NH(OH), −C(=NH)NH2, −C(=O)NRaRb, −C(=O)NRa−NRaRb, −C(=O)NH(C1-C6 alkyldiyl)−NRaRb, −C(=O)ORa, −NRaRb, −NO2, −ORa, −OC(=O)Ra, −SRa, −S(O)Ra, −S(O)2Ra, −S(O)2NRa, and −S(O)3H; Rais independently selected from H, C1−C6 alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, C1−C12 alkyl, C2−C12 alkenyl, and C2−C12 alkynyl; or where two Ragroups form a five-, six-, or seven-membered heteroaryl or heterocyclyl group; Rbis independently selected from H, OH, C1−C6alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, C1−C12 alkyl, C2−C12 alkenyl, and C2−C12 alkynyl; or where R3and R4together form a five-membered or six-membered heteroaryl or heterocyclyl group comprising one or more heteroatoms independently selected from N, O, P and S; one of X1, R1, R2, R3, R4, R5, R6, Ra, Rb, and Cyc is attached to the spacer unit; one of X1, R1, R2, R3, R4, R5, R6, Ra, Rb, Cyc, and Sp is attached to L; and where each alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, heteroalkyl, heteroalkyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl is independently and substituted with one or more groups selected from H, F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C^CH, −C^CCH3, −CH2CH2CH3, − CH(CH3)2, −CH2CH(CH3)2, −CH(CH2CH2), −CH(CH2CH2CH2), −CH2OH, −CH2OCH3, − CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, −CH2CH2SO2CH3, − CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, −CH(CH3)CN, −C(CH3)2CN, − CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, −CH2N(CH3)2, −CO2H, −COCH3, − CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, −CONHCH3, −CON(CH3)2, − CONHS(O)2N(CH3)2, −C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, − N(CH3)COCH3, −NHS(O)2CH3, −N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, − NHC(=NH)H, −NHC(=NH)CH3, −NHC(=NH)NH2, −NHC(=O)NH2, −NO2, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, −OCH2CH2OH, −OCH2CH2N(CH3)2, −OCH2F, −OCHF2, − OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H.

22. The degrader antibody conjugate composition of claim 21 wherein one or more of R3, R4, R5, and R6are independently selected from F and OH. 29015077.006WO2 23. The degrader antibody conjugate composition of claim 14 wherein X1forms a five-, six-, or seven-membered heteroaryl or heterocyclyl ring with R1.

24. The degrader antibody conjugate composition of claim 14 wherein X1is attached to the spacer unit.

25. The degrader antibody conjugate composition of claim 14 wherein Sp is C1−C60 heteroalkyldiyl having the formula: −(CH2CH2X2)n−(CH2)m− where X2is independently selected from NH and O, m is an integer from 1 to 5, and n is an integer from 1 to 50.

26. The degrader antibody conjugate composition of claim 14 wherein Sp is −(C3−C20 carbocyclyldiyl)−(C1−C60 heteroalkyldiyl)− or C1−C60 heteroalkyldiyl.

27. The degrader antibody conjugate composition of claim 26 wherein Sp is selected from the group consisting of −S(O)2CH2CH2−, −S(O)2NHCH2CH2−, −S(O)2CH2CH2CH2−, − S(O)2NHCH2CH2CH2−, −S(O)2CH2CH2CH2O−, and −S(O)2NHCH2CH2CH2O−.

28. The degrader antibody conjugate composition of claim 14 wherein Sp has a formula selected from the group consisting of:29115077.006WO2where the wavy lines indicate the points of attachment to the target protein binder TPI and to the VHL ligand.

29. The degrader antibody conjugate composition of claim 14 wherein the Bcl-xL target protein binder TPI has Formula Id: 29215077.006WO2 dwherein: R7is a C1−C20heteroaryl substituted with one or more groups independently selected from H, F, Cl, −CH3, −CN, −NO2, −OH, and −OCH3; R8aand R8bare independently selected from the group consisting of H, F, Cl, −CN, −C(=NH)NH(OH), −C(=NH)NH2, −C(=O)NRaRb, −C(=O)NRa−NRaRb, −C(=O)NH−(C1-C6alkyldiyl)−NRaRb, −C(=O)ORa, −NRaRb, −NO2, −ORa, −OC(=O)Ra, −SRa, −S(O)Ra, −S(O)2Ra, −S(O)2NRa, and −S(O)3H, C1−C12alkyl, −C1−C12heteroalkyl, C3−C20carbocyclyl, C6−C20aryl, C2-C20heterocyclyl, and C1−C20heteroaryl; Rais independently selected from H, C1−C6alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, −NO2, −OH, C1−C12alkyl, C2−C12alkenyl, C2−C12alkynyl, and −C1−C12heteroalkyl; or where two Ragroups form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring; Rbis independently selected from H, OH, −C1−C6 alkyl, −O−(C1−C6 alkyl), phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, C1−C12 alkyl, C2−C12 alkenyl, C2−C12 alkynyl, and −C1−C12 heteroalkyl; Reis selected from H, C1−C6 alkyl, and −C1−C12 heteroalkyl; Rfis selected from H, C1−C6 alkyl, and −C1−C12 heteroalkyl; or Rfand Sp form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring; R9is selected from the group consisting of H, F, Cl, −CN, −NO2, −OH, and −OCH3; Y1is selected from N and CR11c; Y2is selected from N and CR10b; R10aand R10bare independently selected from H, F, Cl, −CN, −NO2, −OH, C1−C12 alkyl, C2−C12 alkenyl, C2−C12 alkynyl, and −C1−C12 heteroalkyl; 29315077.006WO2 R11a, R11b, and R11care independently selected from the group consisting of H, F, Cl, −CN, −NO2, −OH, −OCH3, C1-C12alkyl, and −C1−C12heteroalkyl; and R12is selected from the group consisting of −(C1−C6alkyldiyl)−(C3−C20carbocyclyl), −(C1−C6 alkyldiyl)−(C3−C20 carbocyclyl)−(C1−C12 heteroalkyl), −(C1−C6 alkyldiyl)−(C3−C20 carbocyclyl)−*, −(C1−C6 alkyldiyl)−(C3−C20 carbocyclyl)−O−*, and −(C1−C6 alkyldiyl)−(C3−C20 carbocyclyl)−(C1−C12 heteroalkyl)−*; where the asterisk * is the attachment site to the spacer unit Sp.

30. The degrader antibody conjugate composition of claim 29 wherein R7is selected from:, substituted with one or more groups independently selected from H, F, Cl, −CH3, −CN, −NO2, −OH, and −OCH3.

31. The degrader antibody conjugate composition of claim 30 wherein R7is:. 29415077.006WO2 32. The degrader antibody conjugate composition of claim 29 wherein R8ais selected from H, −CH3and cyclopropyl; R8bis H; and R9, R10a, and R10bare each H.

33. The degrader antibody conjugate composition of claim 29 wherein Reand Rfare each H.

34. The degrader antibody conjugate composition of claim 29 wherein R11ais H, and R11bis −CH3.

35. The degrader antibody conjugate composition of claim 29 wherein R12is −(C1−C6alkyldiyl)−(C3−C20carbocyclyl).

36. The degrader antibody conjugate composition of claim 35 wherein −(C1−C6alkyldiyl)− is −CH2−, and C3−C20carbocyclyl is selected from cyclohexyl and adamantyl, substituted with one or more groups selected from H, F, Cl, −OH, C1−C12alkyl, C1−C12heteroalkyl, and spiro cycloalkyl.

37. The degrader antibody conjugate composition of claim 29 wherein the Bcl-xL target protein binder TPI is selected from: a29515077.006WO2.

38. The degrader antibody conjugate composition of claim 29 wherein Y1is N.

39. The degrader antibody conjugate composition of claim 29 wherein Y2is CH.

40. The degrader antibody conjugate composition of claim 29 wherein the target protein binder TPI is selected from the formulas: 29615077.006WO2.

41. The degrader antibody conjugate composition of claim 14 wherein L has the formula: −Str−(PEP)y−(IM)z− wherein: Str is a stretcher unit covalently attached to the antibody; PEP is a protease-cleavable, peptide or amino acid unit covalently attached to Str and IM or the TPI-Sp-VHL moiety; 29715077.006WO2 IM is an immolative unit covalently attached to the TPI-Sp-VHL moiety; y is 0 or 1; and z is 0 or 1.

42. The degrader antibody conjugate composition of claim 41 wherein L is a branched linker and Str is covalently attached to: (i) the antibody; and (ii) a solubilizing unit comprising a group selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), and a glycoside, or combinations thereof, wherein the terminus of the solubilizing unit is a group selected from an amino acid, amino, hydroxyl, hydrogen, carboxylic acid, glycerol, or a sugar such as pentaerythritol, maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof.

43. The degrader antibody conjugate composition of claim 41 wherein L is a branched linker and PEP is covalently attached to: (i) Str and IM or the TPI-Sp-VHL moiety; and (ii) a solubilizing unit comprises a group selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), and a glycoside, or combinations thereof, wherein the terminus of the solubilizing unit is a group selected from an amino acid, amino, hydroxyl, hydrogen, carboxylic acid, glycerol, or a sugar such as pentaerythritol, maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof.

44. The degrader antibody conjugate composition of claim 41 wherein L is a branched linker and IM is covalently attached to: (i) the TPI-Sp-VHL moiety; and (ii) a solubilizing unit comprises a group selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), and a glycoside, or combinations thereof, wherein the terminus of the solubilizing unit is a group selected from an amino acid, amino, hydroxyl, hydrogen, carboxylic acid, glycerol, or a sugar such as pentaerythritol, maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof.

45. The degrader antibody conjugate composition of claim 41 wherein Str has the structure:or hydrolyzed succinimide forms thereof, wherein: * indicates the point of attachment to a cysteine thiol of Ab; ** indicates the point of attachment to PEP or to the TPI-Sp-VHL moiety; Rgis selected from the group consisting of C1-C12 alkyldiyl, C1-C12 alkyldiyl-C(=O), C1- C12alkyldiyl−NH, (CH2CH2O)r, (CH2CH2O)r−C(=O), (CH2CH2O)r-CH2, C1−C1229815077.006WO2 heteroalkyldiyl, C6−C20 aryldiyl, (C6−C20 aryldiyl)−(C1−C12 alkyldiyl), and (C6−C20 aryldiyl)− (C1−C12 heteroalkyldiyl); r is an integer ranging from 1 to 10; and alkyldiyl, heteroalkyldiyl, and aryldiyl are independently and substituted with one or more groups selected from H, F, Cl, −CN, −NH2, −CH2NH2, −OH, −OCH3, −OCH2CH3, − OCH2CH2OCH3, −OCH2CH2OH, −OCH2CH2N(CH3)2, −OCH2F, −OCHF2, −OCF3, − OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, −S(O)3H, and a solubilizing unit selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), and a glycoside, or combinations thereof with a terminus selected from an amino acid, amino, hydroxyl, halide, hydrogen, carboxylic acid, glycerol, or a sugar such as pentaerythritol, maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof.

46. The degrader antibody conjugate composition of claim 45 wherein Rgis selected from −(CH2)5−, −CH2−, −CH2CH2−, −CH2CH2OCH2CH2C(=O)−, and −CH(CH2NH2)C(=O)−.

47. The degrader antibody conjugate composition of claim 45 wherein Rgis selected from C6−C20 aryldiyl, (C6−C20 aryldiyl)−(C1−C12 alkyldiyl), and (C6−C20 aryldiyl)−(C1−C12 heteroalkyldiyl).

48. The degrader antibody conjugate composition of claim 41 wherein PEP-IM has the formula:wherein * indicates the point of attachment to Str and ** indicates the point of attachment to the TPI-Sp-VHL moiety; AA is independently selected from a natural or unnatural amino acid side chain, or one or more of AA, and an adjacent nitrogen atom form a 5-membered ring proline amino acid; Cyc1is selected from C6-C20aryldiyl and C1-C20heteroaryldiyl, substituted with one or more groups selected from H, F, Cl, NO2, −OH, −OCH3, a C-glycoside, and glucuronic acid having the tr t r; 29915077.006WO2 R13is selected from the group consisting of −CH(R14)O−, −CH2−, −CH2N(R14)CH(R14)− , −CH(R14)OC(=O)−, −CH(R14)OC(=O)N(R14)CH(R13)−, −CH(R14)OP(=O)2OCH(R14)−, and − CH(R14)OC(=O)N(R14)−(C1-C6 alkyldiyl)−N(R14)C(=O)OCH(R14)−; R14is selected from H, C1-C6 alkyl, C(=O)−C1-C6 alkyl, and −C(=O)N(R15)2; R15is independently selected from the group consisting of H, C1-C12 alkyl, and − (CH2CH2O)n−(CH2)m−OH, where m is an integer from 1 to 5, and n is an integer from 2 to 50, or two R15groups together form a 5- or 6-membered heterocyclyl ring; y1is an integer from 1 to 12; and z1is 0 or 1.

49. The degrader antibody conjugate composition of claim 41 wherein IM is selected from the formulae:30015077.006WO2wherein: * indicates the point of attachment to PEP; and ** indicates the point of attachment to the TPI-Sp-VHL moiety.

50. The degrader antibody conjugate composition of claim 14 wherein L has the structure:wherein: L1is independently selected from a bond, C1−C12alkyldiyl, C1−C60heteroalkyldiyl, and a solubilizing unit selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), and a glycoside, or combinations thereof; L1ais independently selected from an amino acid, amino, hydroxyl, halide, hydrogen, carboxylic acid, glycerol, or a sugar such as pentaerythritol, maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof; o is 0, 1, or 2; L2is selected from a bond, C1−C12alkyldiyl, and C1−C60heteroalkyldiyl; 30115077.006WO2 * indicates the point of attachment to a cysteine thiol of Ab; and ** indicates the point of attachment to the TPI-Sp-VHL moiety.

51. The degrader antibody conjugate composition of claim 50 wherein one of (L1− L1a) is F.

52. The degrader antibody conjugate composition of claim 50 wherein L has the structure:.

53. The degrader antibody conjugate composition of claim 50 wherein L1−L1ais a solubilizing unit selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), and a glycoside, or combinations thereof with a terminus selected from an amino acid, amino, hydroxyl, halide, hydrogen, carboxylic acid, glycerol, or a sugar such as pentaerythritol, maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof.

54. The degrader antibody conjugate composition of claim 50 wherein L1or L2is selected from (N(CH3)CH2C(=O))q, (N(CH3)CH2CH2C(=O))q, N(CH3)CH2CH2OCH2CH2C(=O))q, (CH2CH2O)q, (CH2CH2O)q−C(=O), and (CH2CH2O)q-CH2, where q is an integer from 2 to 20.

55. The degrader antibody conjugate composition of claim 14 wherein L comprises a solubilizing unit selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), and a glycoside, or combinations thereof.

56. The degrader antibody conjugate composition of claim 55 wherein the solubilizing unit is monovalent and the terminus of the solubilizing unit is a group selected from an amino acid, amino, hydroxyl, hydrogen, carboxylic acid, glycerol, or a sugar such as pentaerythritol, maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof.

57. The degrader antibody conjugate composition of claim 56 wherein the solubilizing unit and the terminus of the solubilizing unit covalently attached to Str are selected from the structures: 30215077.006WO2; 30315077.006WO2 ;wherein indicates the point of attachment to the remainder of L.

58. A degrader antibody conjugate selected from Table 3.

59. A BXV compound comprising a target protein binder (TPI) covalently attached to a VHL ligand by a spacer unit (Sp) having Formula II: TPI−Sp−VHL II or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopic analog thereof, wherein: the target protein binder TPI binds to Bcl-xL and has Formula IId: 30415077.006WO2 dwherein: R7is a C1−C20heteroaryl substituted with one or more groups independently selected from H, F, Cl, −CH3, −CN, −NO2, −OH, and −OCH3; R8aand R8bare independently selected from the group consisting of H, F, Cl, −CN, −C(=NH)NH(OH), −C(=NH)NH2, −C(=O)NRaRb, −C(=O)NRa−NRaRb, −C(=O)NH−(C1-C6alkyldiyl)−NRaRb, −C(=O)ORa, −NRaRb, −NO2, −ORa, −OC(=O)Ra, −SRa, −S(O)Ra, −S(O)2Ra, −S(O)2NRa, and −S(O)3H, C1−C12alkyl, −C1−C12heteroalkyl, C3−C20carbocyclyl, C6−C20aryl, C2-C20heterocyclyl, and C1−C20heteroaryl; Rais independently selected from H, C1−C6alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, −NO2, −OH, C1−C12alkyl, C2−C12alkenyl, C2−C12alkynyl, and −C1−C12heteroalkyl; or where two Ragroups form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring; Rbis independently selected from H, OH, −C1−C6 alkyl, −O−(C1−C6 alkyl), phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, C1−C12 alkyl, C2−C12 alkenyl, C2−C12 alkynyl, and −C1−C12 heteroalkyl; Reis selected from H, C1−C6 alkyl, and −C1−C12 heteroalkyl; Rfis selected from H, C1−C6 alkyl, and −C1−C12 heteroalkyl; or Rfand Sp form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring; R9is selected from the group consisting of H, F, Cl, −CN, −NO2, −OH, and −OCH3; Y1is selected from N and CR11c; Y2is selected from N and CR10b; R10aand R10bare independently selected from H, F, Cl, −CN, −NO2, −OH, C1−C12 alkyl, C2−C12 alkenyl, C2−C12 alkynyl, and −C1−C12 heteroalkyl; 30515077.006WO2 R11a, R11b, and R11care independently selected from the group consisting of H, F, Cl, −CN, −NO2, −OH, −OCH3, C1-C12alkyl, and −C1−C12heteroalkyl; and R12is selected from the group consisting of −(C1−C6alkyldiyl)−(C3−C20carbocyclyl), −(C1−C6 alkyldiyl)−(C3−C20 carbocyclyl)−(C1−C12 heteroalkyl), −(C1−C6 alkyldiyl)−(C3−C20 carbocyclyl)−*, and −(C1−C6 alkyldiyl)−(C3−C20 carbocyclyl)−(C1−C12 heteroalkyl)−*; where the asterisk is the attachment site to the spacer unit Sp. VHL ligand has Formula IIa:a wherein A is a cyclic structure selected from C3−C20carbocyclyl, C6−C20aryl, C1−C20heteroaryl, and C2-C20heterocyclyl, each of which are substituted with one or more groups independently selected from H, F, Cl, Br, I, −CN, −NO2, C1−C12 alkyl, C2−C12 alkenyl, C2−C12 alkynyl, C1−C12 heteroalkyl, −(C1−C12 heteroalkyldiyl)−(C6−C20 aryl), −(C1−C12 heteroalkyldiyl)−(C6−C20aryldiyl)−(C1−C12heteroalkyl), −(C1−C12heteroalkyldiyl)−(C6−C20aryldiyl)−(C2-C20 heterocyclyl), (C1−C6 alkyldiyl)−(C6−C20 aryl), −(C1−C6 alkyldiyl)−NRaRb, −(C1−C6alkyldiyl)−ORa, (C1−C6alkyldiyl)−(C3−C20carbocyclyl), (C1-C6alkyldiyl)−(C2-C20heterocyclyl), (C1−C6alkyldiyl)−(C1−C20heteroaryl), C6−C20aryl, C3−C20carbocyclyl, C2−C20heterocyclyl, C1−C20heteroaryl, −C(=NH)NH(OH), −C(=NH)NH2, −C(=O)NRaRb, −C(=O)NRa−NRaRb, −C(=O)NH(C1-C6alkyldiyl)−NRaRb, −C(=O)ORa, −NRaRb, −NRaS(O)2Ra, −NO2, −ORa, −OC(=O)Ra, −SRa, −S(O)Ra, −S(O)2Ra, −S(O)2NRa, and −S(O)3H; Rais independently selected from H, C1−C6alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, C1−C12alkyl, C2−C12alkenyl, and C2−C12alkynyl; or where two Ragroups form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring; 30615077.006WO2 Rbis independently selected from H, OH, C1−C6 alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, C1−C12alkyl, C2−C12alkenyl, and C2−C12alkynyl; Rcis selected from OH and −SO2F; Rdis selected from H and F; Cyc is a ring structure selected from the group consisting of C3−C20carbocyclyl, C6−C20aryl, C2-C20heterocyclyl, and C1−C20heteroaryl; n is 0 or 1; R1is selected from the group consisting of H, C1−C12alkyl, and C1−C12heteroalkyl; R2is selected from the group consisting of H, C1−C12alkyl, and C1−C12heteroalkyl; or where R2forms a five- to ten-membered aryl, carbocyclyl, heteroaryl or heterocyclyl ring with A; X1is selected from the group consisting of H, −NHC(=O)−, (C3−C20 carbocyclyl)− C(=O)NH−, C1−C12 heteroalkyl, and C1−C20 heteroaryl; or where X1forms a five-, six-, or seven-membered heteroaryl or heterocyclyl ring with R1; Sp is selected from the group consisting of a bond, O, NH, C1−C12alkyldiyl, C1−C60heteroalkyldiyl, C3−C20 carbocyclyldiyl, C2-C20 heterocyclyldiyl, C6-C20 aryldiyl, C1−C40 heteroaryldiyl, −(C3−C20 carbocyclyldiyl)−(C1−C60 heteroalkyldiyl)−, −(C3−C20 carbocyclyldiyl)−(C1−C12 alkyldiyl)−, −(C2-C20 heterocyclyldiyl)−(C1−C60 heteroalkyldiyl)−, −(C2-C20 heterocyclyldiyl)−(C1−C12 alkyldiyl)−, −(C2-C20 heterocyclyldiyl)−(C2-C20 heterocyclyldiyl)−, −(C1−C20 heteroaryldiyl)−(C3−C20 carbocyclyldiyl)−(C1−C60 heteroalkyldiyl)−, a solubilizing unit, and combinations thereof, where the solubilizing unit is selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), a glycoside, C1−C60 heteroalkyldiyl, and combinations thereof; one of A, Ra, Rb, Cyc, R1, R2, and X1is attached to Sp; and each alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, heteroalkyl, heteroalkyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl is independently and substituted with one or more groups selected from H, F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C^CH, −C^CCH3, −CH2CH2CH3, − CH(CH3)2, −CH2CH(CH3)2, −CH(CH2CH2), −CH(CH2CH2CH2), −CH2OH, −CH2OCH3, − CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, −CH2CH2SO2CH3, − CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, −CH(CH3)CN, −C(CH3)2CN, − CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, −CH2N(CH3)2, −CO2H, −COCH3, − 30715077.006WO2 CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, −CONHCH3, −CON(CH3)2, − C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, −N(CH3)COCH3, −NHS(O)2CH3, − N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, −NHC(=NH)H, −NHC(=NH)CH3, − NHC(=NH)NH2, −NHC(=O)NH2, −NO2, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, − OCH2CH2OH, −OCH2CH2N(CH3)2, −OCH2F, −OCHF2, −OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H.

60. The BXV compound of claim 59 wherein the VHL ligand has Formula IIb:IIb.

61. The BXV compound of claim 60 wherein the VHL ligand has Formula IIc:IIc wherein: R3, R4, R5, and R6are independently selected from the group consisting of H, F, Cl, Br, I, −CN, C1−C12alkyl, C2−C12alkenyl, C2−C12alkynyl, C1−C12heteroalkyl, −(C1−C12heteroalkyldiyl)−(C6−C20aryl), −(C1−C12heteroalkyldiyl)−(C6−C20aryldiyl)−(C1−C12heteroalkyl), −(C1−C12heteroalkyldiyl)−(C6−C20aryldiyl)−(C2-C20heterocyclyl), (C1−C6alkyldiyl)−(C6−C20aryl), −(C1−C6alkyldiyl)−NRaRb, −(C1−C6alkyldiyl)−ORa, (C1−C6alkyldiyl)−(C3−C20carbocyclyl), (C1-C6alkyldiyl)−(C2-C20heterocyclyl), (C1−C6alkyldiyl)−(C1−C20heteroaryl), C6−C20aryl, C3−C20carbocyclyl, C2−C20heterocyclyl, C1−C20heteroaryl, −C(=NH)NH(OH), −C(=NH)NH2, −C(=O)NRaRb, −C(=O)NRa−NRaRb, 30815077.006WO2 −C(=O)NH(C1-C6 alkyldiyl)−NRaRb, −C(=O)ORa, −NRaRb, −NO2, −ORa, −OC(=O)Ra, −SRa, −S(O)Ra, −S(O)2Ra, −S(O)2NRa, −S(O)3H, and Sp; Rais independently selected from H, C1−C6 alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, C1−C12 alkyl, C2−C12 alkenyl, C2−C12 alkynyl, and Sp; or where two Ragroups form a five-, six-, or seven-membered heteroaryl or heterocyclyl group; Rbis independently selected from H, OH, C1−C6alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, C1−C12 alkyl, C2−C12 alkenyl, C2−C12 alkynyl, and Sp; or where R3and R4together form a five-membered or six-membered heteroaryl or heterocyclyl group comprising one or more heteroatoms independently selected from N, O, P and S; X1is selected from the group consisting of H, and −NHCO−; or where X1forms a five-, six-, or seven-membered heteroaryl or heterocyclyl ring with R1; one of X1, R1, R2, R3, R4, R5, R6, Ra, Rb, and Cyc is attached to Sp; and each alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, heteroalkyl, heteroalkyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl is independently substituted with one or more groups selected from H, F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C^CH, −C^CCH3, −CH2CH2CH3, − CH(CH3)2, −CH2CH(CH3)2, −CH(CH2CH2), −CH(CH2CH2CH2), −CH2OH, −CH2OCH3, − CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, −CH2CH2SO2CH3, − CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, −CH(CH3)CN, −C(CH3)2CN, − CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, −CH2N(CH3)2, −CO2H, −COCH3, − CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, −CONHCH3, −CON(CH3)2, − CONHS(O)2N(CH3)2, −C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, − N(CH3)COCH3, −NHS(O)2CH3, −N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, − NHC(=NH)H, −NHC(=NH)CH3, −NHC(=NH)NH2, −NHC(=O)NH2, −NO2, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, −OCH2CH2OH, −OCH2CH2N(CH3)2, −OCH2F, −OCHF2, − OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H.

62. The BXV compound of claim 59 wherein R7of Formula IId is selected from: 30915077.006WO2, substituted with one or more groups independently selected from H, F, Cl, −CH3, −CN, −NO2, −OH, and −OCH3.

63. The BXV compound of claim 62 wherein R7of Formula IId is:.

64. The BXV compound of claim 59 wherein R8aof Formula IId is selected from H, −CH3and cyclopropyl; R8bis H; and R9, R10a, and R10bare each H.

65. The BXV compound of claim 59 wherein each Raof Formula IId is H; and each Rbof Formula IId is H.

66. The BXV compound of claim 59 wherein R11aof Formula IId is H, and R11bof Formula IId is −CH3.

67. The BXV compound of claim 59 wherein R12of Formula IId is −(C1−C6alkyldiyl)−(C3−C20carbocyclyl). 31015077.006WO2 68. The BXV compound of claim 67 wherein −(C1−C6 alkyldiyl)− is −CH2−, and C3−C20 carbocyclyl is selected from cyclohexyl and adamantyl, substituted with one or more groups selected from H, F, Cl, −OH, −C1−C12 alkyl, and −C1−C12 heteroalkyl.

69. A BXV compound selected from Table 1.

70. A Bcl-xL target protein binder and VHL ligand linker compound (BXV-L) having Formula III (TPI−Sp−VHL)−L3−Z III or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopic analog thereof, wherein: TPI is the target protein binder that binds to Bcl-xL and has Formula IIId:d wherein: R7is a C1−C20 heteroaryl substituted with one or more groups independently selected from H, F, Cl, −CH3, −CN, −NO2, −OH, and −OCH3; R8aand R8bare independently selected from the group consisting of H, F, Cl, −CN, −C(=NH)NH(OH), −C(=NH)NH2, −C(=O)NRaRb, −C(=O)NRa−NRaRb, −C(=O)NH−(C1-C6 alkyldiyl)−NRaRb, −C(=O)ORa, −NRaRb, −NO2, −ORa, −OC(=O)Ra, −SRa, −S(O)Ra, −S(O)2Ra, −S(O)2NRa, and −S(O)3H, C1−C12 alkyl, −C1−C12 heteroalkyl, C3−C20 carbocyclyl, C6−C20 aryl, C2-C20 heterocyclyl, and C1−C20 heteroaryl; Rais independently selected from H, C1−C6 alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, −NO2, −OH, C1−C12 alkyl, C2−C12 alkenyl, C2−C12 alkynyl, and −C1−C12 heteroalkyl; or where two Ragroups form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring; 31115077.006WO2 Rbis independently selected from H, OH, −C1−C6 alkyl, −O−(C1−C6 alkyl), phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, C1−C12alkyl, C2−C12alkenyl, C2−C12alkynyl, and −C1−C12 heteroalkyl; Reis selected from H, C1−C6 alkyl, and −C1−C12 heteroalkyl; Rfis selected from H, C1−C6 alkyl, and −C1−C12 heteroalkyl; or Rfand Sp form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring; R9is selected from the group consisting of H, F, Cl, −CN, −NO2, −OH, and −OCH3; Y1is selected from N and CR11c; Y2is selected from N and CR10b; R10aand R10bare independently selected from H, F, Cl, −CN, −NO2, −OH, C1−C12 alkyl, C2−C12 alkenyl, C2−C12 alkynyl, and −C1−C12 heteroalkyl; R11a, R11b, and R11care independently selected from the group consisting of H, F, Cl, −CN, −NO2, −OH, −OCH3, C1-C12 alkyl, and −C1−C12 heteroalkyl; and R12is selected from the group consisting of −(C1−C6 alkyldiyl)−(C3−C20 carbocyclyl), −(C1−C6 alkyldiyl)−(C3−C20 carbocyclyl)−(C1−C12 heteroalkyl), −(C1−C6 alkyldiyl)−(C3−C20 carbocyclyl)−*, and −(C1−C6 alkyldiyl)−(C3−C20 carbocyclyl)−(C1−C12 heteroalkyl)−*; where the asterisk is the attachment site to the spacer unit Sp; VHL ligand has Formula IIIa:IIIa or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or isotopic analog thereof, wherein: A is a cyclic structure selected from C3−C20 carbocyclyl, C6−C20 aryl, C1−C20 heteroaryl, and C2-C20 heterocyclyl, each of which are substituted with one or more groups independently selected from H, F, Cl, Br, I, −CN, −NO2, C1−C12 alkyl, C2−C12 alkenyl, C2−C12 alkynyl, C1−C12 heteroalkyl, −(C1−C12 heteroalkyldiyl)−(C6−C20 aryl), −(C1−C12 heteroalkyldiyl)−(C6−C20 31215077.006WO2 aryldiyl)−(C1−C12 heteroalkyl), −(C1−C12 heteroalkyldiyl)−(C6−C20 aryldiyl)−(C2-C20 heterocyclyl), (C1−C6 alkyldiyl)−(C6−C20 aryl), −(C1−C6 alkyldiyl)−NRaRb, −(C1−C6 alkyldiyl)−ORa, (C1−C6 alkyldiyl)−(C3−C20 carbocyclyl), (C1-C6 alkyldiyl)−(C2-C20 heterocyclyl), (C1−C6 alkyldiyl)−(C1−C20 heteroaryl), C6−C20 aryl, C3−C20 carbocyclyl, C2−C20 heterocyclyl, C1−C20 heteroaryl, −C(=NH)NH(OH), −C(=NH)NH2, −C(=O)NRaRb, −C(=O)NRa−NRaRb, −C(=O)NH(C1-C6 alkyldiyl)−NRaRb, −C(=O)ORa, −NRaRb, −NRaS(O)2Ra, −NO2, −ORa, −OC(=O)Ra, −SRa, −S(O)Ra, −S(O)2Ra, −S(O)2NRa, and −S(O)3H; Rais independently selected from H, C1−C6alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, C1−C12 alkyl, C2−C12 alkenyl, and C2−C12 alkynyl; or where two Ragroups form a five-, six-, or seven-membered heteroaryl or heterocyclyl ring; Rbis independently selected from H, OH, C1−C6alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, C1−C12alkyl, C2−C12alkenyl, and C2−C12alkynyl; Rcis selected from OH and −SO2F; Rdis selected from H and F; Cyc is a ring structure selected from the group consisting of C3−C20 carbocyclyl, C6−C20 aryl, C2-C20 heterocyclyl, and C1−C20 heteroaryl; n is 0 or 1; R1is selected from the group consisting of H, C1−C12 alkyl, and C1−C12 heteroalkyl; R2is selected from the group consisting of H, C1−C12 alkyl, and C1−C12 heteroalkyl; or where R2forms a five- to ten-membered aryl, carbocyclyl, heteroaryl or heterocyclyl ring with A; X1is selected from the group consisting of H, −NHC(=O)−, (C3−C20carbocyclyl)− C(=O)NH−, C1−C12heteroalkyl, and C1−C20heteroaryl; or where X1forms a five-, six-, or seven-membered heteroaryl or heterocyclyl ring with R1; Sp is selected from the group consisting of a bond, O, NH, C1−C12 alkyldiyl, C1−C60 heteroalkyldiyl, C3−C20carbocyclyldiyl, C2-C20heterocyclyldiyl, C6-C20aryldiyl, C1−C40heteroaryldiyl, −(C3−C20carbocyclyldiyl)−(C1−C60heteroalkyldiyl)−, −(C3−C20carbocyclyldiyl)−(C1−C12alkyldiyl)−, −(C2-C20heterocyclyldiyl)−(C1−C60heteroalkyldiyl)−, −(C2-C20heterocyclyldiyl)−(C1−C12alkyldiyl)−, −(C2-C20heterocyclyldiyl)−(C2-C20heterocyclyldiyl)−, −(C1−C20heteroaryldiyl)−(C3−C20carbocyclyldiyl)−(C1−C6031315077.006WO2 heteroalkyldiyl)−, a solubilizing unit, and combinations thereof, where the solubilizing unit is selected from polyglycine, polysarcosine, polyethyleneoxy (PEG), a glycoside, C1−C60 heteroalkyldiyl, and combinations thereof; TPI−Sp−VHL moiety is covalently attached to an antibody linker L3; Z is:where the wavy line is the attachment to L3; one of A, Ra, Rb, Cyc, R1, R2, and X1is attached to Sp; one of A, Ra, Rb, Cyc, R1, R2, X1, and Sp is attached to L3; and each alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, heteroalkyl, heteroalkyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl is independently substituted with one or more groups selected from H, F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C^CH, −C^CCH3, −CH2CH2CH3, − CH(CH3)2, −CH2CH(CH3)2, −CH(CH2CH2), −CH(CH2CH2CH2), −CH2OH, −CH2OCH3, − CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, −CH2CH2SO2CH3, − CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, −CH(CH3)CN, −C(CH3)2CN, − CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, −CH2N(CH3)2, −CO2H, −COCH3, − CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, −CONHCH3, −CON(CH3)2, − C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, −N(CH3)COCH3, −NHS(O)2CH3, − N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, −NHC(=NH)H, −NHC(=NH)CH3, − NHC(=NH)NH2, −NHC(=O)NH2, −NO2, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, − OCH2CH2OH, −OCH2CH2N(CH3)2, −OCH2F, −OCHF2, −OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H.

71. The BXV-L compound of claim 70 wherein the VHL ligand has Formula IIIb: 31415077.006WO2 .

72. The BXV-L compound of claim 71 wherein the VHL ligand has Formula IIIc:c wherein: R3, R4, R5, and R6are independently selected from the group consisting of H, F, Cl, Br, I, −CN, C1−C12alkyl, C2−C12alkenyl, C2−C12alkynyl, C1−C12heteroalkyl, −(C1−C12heteroalkyldiyl)−(C6−C20aryl), −(C1−C12heteroalkyldiyl)−(C6−C20aryldiyl)−(C1−C12heteroalkyl), −(C1−C12heteroalkyldiyl)−(C6−C20aryldiyl)−(C2-C20heterocyclyl), (C1−C6alkyldiyl)−(C6−C20aryl), −(C1−C6alkyldiyl)−NRaRb, −(C1−C6alkyldiyl)−ORa, (C1−C6alkyldiyl)−(C3−C20carbocyclyl), (C1-C6alkyldiyl)−(C2-C20heterocyclyl), (C1−C6alkyldiyl)−(C1−C20heteroaryl), C6−C20aryl, C3−C20carbocyclyl, C2−C20heterocyclyl, C1−C20heteroaryl, −C(=NH)NH(OH), −C(=NH)NH2, −C(=O)NRaRb, −C(=O)NRa−NRaRb, −C(=O)NH(C1-C6alkyldiyl)−NRaRb, −C(=O)ORa, −NRaRb, −NO2, −ORa, −OC(=O)Ra, −SRa, −S(O)Ra, −S(O)2Ra, −S(O)2NRa, and −S(O)3H; Rais independently selected from H, C1−C6 alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, C1−C12alkyl, C2−C12alkenyl, and C2−C12alkynyl; or where two Ragroups form a five-, six-, or seven-membered heteroaryl or heterocyclyl group; 31515077.006WO2 Rbis independently selected from H, OH, C1−C6 alkyl, phenyl, and benzyl, wherein phenyl and benzyl are substituted with one or more groups independently selected from the group consisting of H, F, Cl, −CN, C1−C12alkyl, C2−C12alkenyl, and C2−C12alkynyl; or where R3and R4together form a five-membered or six-membered heteroaryl or heterocyclyl group comprising one or more heteroatoms independently selected from N, O, P and S; one of X1, R1, R2, R3, R4, R5, R6, Ra, Rb, and Cyc is attached to Sp; one of X1, R1, R2, R3, R4, R5, R6, Ra, Rb, and Cyc is attached to L3; and each alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, heteroalkyl, heteroalkyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl is independently and substituted with one or more groups selected from H, F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C^CH, −C^CCH3, −CH2CH2CH3, − CH(CH3)2, −CH2CH(CH3)2, −CH(CH2CH2), −CH(CH2CH2CH2), −CH2OH, −CH2OCH3, − CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, −CH2CH2SO2CH3, − CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, −CH(CH3)CN, −C(CH3)2CN, − CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, −CH2N(CH3)2, −CO2H, −COCH3, − CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, −CONHCH3, −CON(CH3)2, − CONHS(O)2N(CH3)2, −C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, − N(CH3)COCH3, −NHS(O)2CH3, −N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, − NHC(=NH)H, −NHC(=NH)CH3, −NHC(=NH)NH2, −NHC(=O)NH2, −NO2, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, −OCH2CH2OH, −OCH2CH2N(CH3)2, −OCH2F, −OCHF2, − OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H.

73. The BXV-L compound of claim 70 wherein the antibody linker L3has the formula: −Str1−(PEP)y−(IM)z− wherein: Str1is a stretcher unit covalently attached to Z; PEP is a protease-cleavable, peptide or amino acid unit covalently attached to Str1and IM or the TPI-Sp-VHL moiety when y is 1; IM is an immolative unit covalently attached the TPI-Sp-VHL moiety when z is 1; y is 0 or 1; and z is 0 or 1.

74. The BXV-L compound of claim 70 wherein R7of Formula IIId is selected from: 31615077.006WO2, substituted with one or more groups independently selected from H, F, Cl, −CH3, −CN, −NO2, −OH, and −OCH3.

75. The BXV-L compound of claim 74 wherein R7is:.

76. The BXV-L compound of claim 70 wherein R8aof Formula IIId is selected from H, −CH3and cyclopropyl; R8bis H; and R9, R10a, and R10bof Formula IIId are each H.

77. The BXV-L compound of claim 70 wherein each Raof Formula IIId is H; and each Rbof Formula IIId is H.

78. The BXV-L compound of claim 70 wherein R11ais H, and R11bis −CH3 of Formula IIId.

79. The BXV-L compound of claim 70 wherein R12of Formula IIId is −(C1−C6alkyldiyl)−(C3−C20carbocyclyl). 31715077.006WO2 80. The BXV-L compound of claim 79 wherein −(C1−C6 alkyldiyl)− is −CH2−, and C3−C20 carbocyclyl of Formula IIId is selected from cyclohexyl and adamantyl, substituted with one or more groups selected from H, F, Cl, −OH, −C1−C12 alkyl, and −C1−C12 heteroalkyl.

81. A Bcl-xL target protein binder and VHL ligand linker compound (BXV-L) compound selected from Table 2.

82. A degrader antibody conjugate composition prepared by conjugation of a cysteine amino acid of an antibody with a BXV-L compound of claim 70.

83. A degrader antibody conjugate composition prepared by conjugation of a cysteine amino acid of an antibody with a BXV-L compound selected from Table 2.

84. A process for preparing a degrader antibody conjugate composition comprising reacting a cysteine amino acid of an antibody with a BXV-L compound of claim 70 whereby a degrader antibody conjugate composition is formed.

85. A pharmaceutical composition comprising a therapeutically effective amount of the degrader antibody conjugate composition of any one of claims 1 to 58, and one or more pharmaceutically acceptable diluent, vehicle, carrier or excipient.

86. A method for treating cancer comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 85, to a patient in need thereof, wherein the cancer is selected from hematological and solid tumors, wherein the cancer is selected from breast cancer, triple negative breast cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, colorectal cancer, and lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular cancer, leukemia, and acute myelogenous leukemia (AML).

87. The method of claim 86 wherein the degrader antibody conjugate of the pharmaceutical composition modulates the level of Bcl-xL target protein in the patient.

88. The method of claim 86 wherein a chemotherapeutic agent is administered in combination with the pharmaceutical composition of the degrader antibody conjugate.

89. Use of a degrader antibody conjugate composition of any one of claims 1 to 58 in the manufacture of a medicament for the treatment of cancer in a mammal.

90. A degrader antibody conjugate composition of any one of claims 1 to 58 for use in a method for treating cancer. 318