Universal ABT compounds and their uses

Abstract

Among other things, the present disclosure provides compounds comprising a universal antibody-binding moiety and a targeting moiety. In some embodiments, the provided compounds recruit various types of antibodies to diseased cells, such as cancer cells, and induce immune activity to kill such cells. The provided technology is useful for treating a variety of diseases, including cancer.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 537,034, filed July 26, 2017, which is incorporated herein by reference in its entirety.

[0002] The present invention relates to compounds and methods useful for recruiting antibodies to cancer cells. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention and methods of using the compositions in the treatment of various disorders. [Background technology]

[0003] Immune system activity can be utilized to prevent or treat a variety of conditions, disorders and diseases. Summary of the Invention [Means for solving the problem]

[0004] In some embodiments, the present disclosure provides technologies, e.g., compounds, compositions, methods, etc., that are particularly useful for recruiting antibodies against damaged or defective tissue (e.g., tumors, certain wounds, etc.), foreign objects or entities (e.g., pathogens), etc. In some embodiments, the provided technologies may induce, generate, promote, and / or enhance immune system activity, e.g., antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), etc., against target cells, tissues, objects, and / or entities. In some embodiments, the present disclosure is directed to the design and synthesis of new small molecules that can selectively redirect endogenous antibodies to diseased cells, e.g., cancer cells, and induce immune system activity, e.g., antibody-induced cell-mediated immune responses, e.g., cytotoxicity, ADCP, etc.

[0005] Although still in its infancy, the concept of using small molecules to template the human immune response shows real potential. Recent reports have demonstrated the use of small molecules to target antibodies to cancerous cells, such as breast cancer cells, melanoma cells, and nasopharyngeal epidermal carcinoma cells. Animal studies have demonstrated that these molecules can promote tumor rejection and antitumor immunity in mice. In some embodiments, such molecules can promote tumor regression and / or inhibit tumor growth. This process allows for selective targeting of endogenous antibodies to targeted cells, potentially harnessing the power of many immunotherapies, such as monoclonal antibody (mAb)-based therapeutics, while limiting the costs and side effects associated with administering exogenous antibodies. By developing similar methods to recruit antibodies to diseased cells, such as cancer cells, the proposed research will help expand this field, potentially creating new therapies for a variety of diseases.

[0006] In some embodiments, the present disclosure provides antibody recruiting molecules comprising an antibody-binding portion and a target-binding portion, optionally via a linker portion. In some embodiments, antibody recruiting molecules (ARMs) are a class of compounds comprised of two functional segments, i.e., a target-binding end (TBT) and an antibody-binding end (ABT), connected by a linker. The target-binding portion, e.g., the target-binding end, can confer specificity of the ARM for its target, e.g., a diseased cell of interest, by, for example, binding to a receptor that distinguishes the target from a non-target (e.g., diseased cells from other cell types). In particular, the ARM can enable target-specific recruitment of antibodies, e.g., endogenous antibodies, administered antibodies, etc., via the ABT, and / or can induce, generate, promote, and / or enhance immune activity, e.g., immune-mediated killing of target cells. Without intending to be bound by any particular theory, previous work in the Spiegel laboratory has reported that ARM-induced killing is mediated primarily through natural killer (NK) cells and macrophages, and that the primary receptor involved in this process is CD16a (or Fc gamma RIIIa).

[0007] Previously reported ABTs, such as those investigated by the Spiegel laboratory, have focused on molecules (antigens) that bind to the variable region of the Fab of an antibody. Among other things, the present disclosure embraces the recognition that the therapeutic success of this approach depends on the presence of sufficient levels of specific antibody populations, which can vary dramatically between individuals. In some embodiments, the present disclosure provides techniques that can circumvent the dependency on specific antibody populations and the undesirable effects that can result from individual variability in specific antibody populations. In particular, in some embodiments, the present disclosure provides ARMs that include ABTs ("universal ABTs" or "uABTs") that can bind to the Fc region of an antibody, thereby, among other things, recruiting antibodies of various antigen specificities. In some embodiments, Applicant describes the use of a class of ABTs that bind to conserved sites present in the Fc region of IgG. In some embodiments, uABTs enable the recruitment of all IgG subclasses (IgG1, IgG2, IgG3, IgG4). In some embodiments, uABTs enable the preferential recruitment of IgG1, IgG2, and / or IgG4. In some embodiments, the recruitment of antibodies, eg, IgG subclasses, is limited only by the administered dose of the ARM and / or is not limited by the level of antibodies with a particular Fab region in an individual.

[0008] To provide an ARM containing uABT, Applicant evaluated a number of peptides reported to bind to the Fc of human IgG for their applicability for use in the ARM platform. In some embodiments, an essential component of evaluating the therapeutic utility of this strategy is demonstrating that antibodies recruited in this orientation are capable of binding and activating CD16a.

[0009] Biochemical and cell-based assays demonstrate that a series of Fc-binding cyclic peptides can induce CD16a activation and indeed bind antibodies in a manner applicable to the ARM platform. In some embodiments, the present disclosure demonstrates that uABT can bind to a variety of antibodies. In some embodiments, in addition to affinity for all human IgG subclasses, these peptides are highly species cross-reactive, binding to secondary antibodies from goat, rabbit, and mouse, as explored by various evaluation methods. In some embodiments, uABT binds to IgG molecules but does not bind to human IgA or IgM.

[0010] Various TBTs can be utilized in accordance with the present disclosure. In an attempt to discover effective cellular targets for cancer therapy, researchers have sought to identify transmembrane or other tumor-associated polypeptides that are differentially expressed on the surface of one or more specific types of cancer cells compared to one or more normal, non-cancerous cell(s). Often, such tumor-associated polypeptides are more abundantly expressed on the surface of cancer cells compared to the surface of non-cancerous cells. The identification of such tumor-associated cell surface antigen polypeptides, i.e., tumor-associated antigens (TAAs), has created the ability to specifically target cancer cells for destruction. TBTs that selectively bind to TAAs can target targeted cancer cells, enabling cell-specific recruitment of antibodies, e.g., endogenous antibodies, via the TBT. Additional suitable TBTs are provided in the present disclosure.

[0011] In some embodiments, the present disclosure provides compounds, and pharmaceutically acceptable compositions thereof, that are effective in recruiting antibodies to diseased cells, e.g., cancer cells. In some embodiments, provided compounds induce antibody-dependent effector function. In some embodiments, provided compounds induce complement-dependent cytotoxicity (CDC). In some embodiments, provided compounds induce direct cytotoxicity. In some embodiments, provided compounds inhibit biological functions associated with steric blockage. In some embodiments, provided compounds induce antibody-dependent cell-mediated viral inhibition (ADCVI). In some embodiments, provided compounds induce ADCC and kill cancer cells. In some embodiments, provided compounds induce ADCP and kill cancer cells. In some embodiments, provided compounds induce both ADCC and ADCP.

[0012] In some embodiments, the present disclosure provides a medicament comprising: antibody binding moiety, a target binding moiety, and optionally a linker moiety, Including, The antibody binding moiety provides the agent capable of binding to two or more antibodies with different Fab regions.

[0013] In some embodiments, the antibody binding moiety, e.g., a universal antibody binding moiety, binds to the Fc region of an antibody. In some embodiments, the antibody binding moiety, e.g., a universal antibody binding moiety, binds to the conserved Fc region of an antibody. In some embodiments, the antibody binding moiety binds to the Fc region of an IgG antibody.

[0014] In some embodiments, the present disclosure provides compounds having the general formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. In some embodiments, the agent provided is a compound of Formula I or a salt thereof:

[0015] In some embodiments, the provided agent is a compound of formula Ia or a salt thereof. In some embodiments, the present disclosure provides a compound of formula Ia: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described in this disclosure. In some embodiments, the compound of formula I provided is a compound of formula Ia:

[0016] In some embodiments, the provided agent is a compound of formula Ib or a salt thereof. In some embodiments, the present disclosure provides a compound of formula Ib: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described in this disclosure. In some embodiments, the compound of formula I provided is a compound of formula Ib:

[0017] In some embodiments, the agents and compounds of the present disclosure, and pharmaceutically acceptable compositions thereof, are provided that are effective in recruiting antibodies to diseased cells, e.g., cancer cells. In some embodiments, the present disclosure provides compounds having the general formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. In some embodiments, the agent provided is a compound of Formula II or a salt thereof. In some embodiments, the compound of Formula I is provided is a compound of Formula II or a salt thereof. In some embodiments, the compound having the structure of Formula Ia is a compound of Formula II.

[0018] In some embodiments, the present disclosure provides a compound having the general formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. In some embodiments, the agent provided is a compound of formula III or a salt thereof. In some embodiments, the compound of formula I is provided is a compound of formula III or a salt thereof. In some embodiments, the compound having the structure of formula Ib is a compound of formula III.

[0019] The compounds of the present disclosure, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders, or conditions, including those described herein. In some embodiments, the condition, disorder, or disease is cancer. DETAILED DESCRIPTION OF THE INVENTION

[0020] 1. General Description of Certain Embodiments of the Invention: In some embodiments, the present disclosure provides ARM agents comprising an antibody binding moiety ("uABT") capable of binding to antibodies with different Fab structures. In particular, in some embodiments, the present disclosure provides agents comprising an antibody binding moiety that binds to the Fc region of an antibody, wherein such binding to the Fc region of the antibody does not interfere with one or more immune activities of the antibody, such as interaction with an Fc receptor (e.g., CD16a), recruitment of effector cells such as NK cells for ADCC, macrophages for ADCP, etc. As will be appreciated by those skilled in the art, the technologies (agents, compounds, compositions, methods, etc.) of the present disclosure, including uABTs, offer various advantages, such as the ability to utilize antibodies with different Fab regions in the immune system to avoid or minimize the undesirable effects of antibody variability among patient populations, and to induce and / or enhance immune activity against a target, e.g., killing of target diseased cells such as cancer cells.

[0021] In some embodiments, the disclosed technology is useful for recruiting antibodies to cancer cells. In some embodiments, the provided technology is useful for modulating immune activity, such as ADCC, ADCP, and combinations thereof, against a target (e.g., diseased cells, foreign objects or entities). In some embodiments, the provided technology is useful for modulating ADCC against target cells, e.g., diseased cells such as cancer cells. In some embodiments, the provided technology is useful for modulating ADCP against target cells, e.g., diseased cells such as cancer cells. In some embodiments, the provided agents can inhibit protein activity. In some embodiments, the target binding moiety is an inhibitor moiety. In some embodiments, the target binding moiety is an enzyme inhibitor moiety.

[0022] In some embodiments, the present disclosure provides a medicament comprising: antibody binding moiety, a target binding moiety, and optionally a linker moiety, Including, The antibody binding moiety provides the agent capable of binding to two or more antibodies with different Fab regions.

[0023] In some embodiments, provided agents comprise two or more antibody binding moieties. In some embodiments, provided agents comprise two or more target binding moieties.

[0024] The antibody binding moiety can interact with any part of an antibody. In some embodiments, the antibody binding moiety binds to the Fc region of an antibody. In some embodiments, the antibody binding moiety binds to the conserved Fc region of an antibody. In some embodiments, the antibody binding moiety binds to the Fc region of an IgG antibody. As will be appreciated by those of skill in the art, a variety of antibody binding moieties, linkers, and target binding moieties can be utilized in accordance with the present disclosure. Among other things, as demonstrated in the Examples, in some embodiments, the present disclosure provides antibody binding moieties, linkers, and target binding moieties, and combinations thereof, that are particularly useful and effective in constructing ARM molecules to recruit antibodies to target cells and / or to induce, generate, promote, and / or enhance immune system activity against target cells, e.g., diseased cells such as cancer cells.

[0025] In some embodiments, the present disclosure provides antibody binding moieties and / or agents (e.g., compounds of various formulas described in this disclosure, ARM molecules of this disclosure, etc.) that comprise an antibody binding moiety that can bind to an Fc region that binds to an Fc receptor, e.g., FcγRIIIA, CD16a, etc. In some embodiments, the provided moieties and / or agents comprise an antibody binding moiety that binds to a complex comprising an Fc region and an Fc receptor. In some embodiments, the present disclosure provides a complex comprising: A drug comprising: antibody binding moiety, a target binding moiety, and optionally a linker moiety, The drug comprising Fc region, and Fc receptors Including, The antibody binding portion of the agent provides the conjugate capable of binding to two or more antibodies with different Fab regions.

[0026] In some embodiments, the Fc region is the Fc region of an endogenous antibody of the subject. In some embodiments, the Fc region is the Fc region of an exogenous antibody. In some embodiments, the Fc region is the Fc region of an administered agent. In some embodiments, the Fc receptor is on diseased cells in the subject. In some embodiments, the Fc receptor is on cancer-affected cells in the subject.

[0027] In certain embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: ABT is the antibody binding moiety; L is a bivalent linker moiety connecting ABT with TBT; TBT is the target binding moiety to provide.

[0028] In some embodiments, the ABT is a universal antibody binding moiety.

[0029] In some embodiments, an antibody binding moiety comprises one or more amino acid residues. In some embodiments, an antibody binding moiety is or comprises a peptide moiety. In some embodiments, an antibody binding moiety is or comprises a cyclic peptide moiety. In some embodiments, such an antibody binding moiety comprises one or more naturally occurring amino acid residues. In some embodiments, such an antibody binding moiety comprises one or more non-naturally occurring amino acid residues.

[0030] In some embodiments, the amino acid has the structure of formula AI: NH(R a1 )-L a1 -C(R a2 )(R a3 )-L a2 -COOH, AI or a salt thereof, wherein: R a1 , R a2 , Ra3 each independently represents -L a -R'; L a1 and L a2 Each of the a and; Each L a are independently a covalent bond or C1 to C 20 Aliphatic or C1-C with 1-5 heteroatoms 20 an optionally substituted divalent radical selected from heteroaliphatic, wherein one or more methylene units of the radical are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-; Each -Cy- is independently C 3-20 Alicyclic ring, C 6-20 an optionally substituted divalent group selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; each R' is independently -R, -C(O)R, -CO2R, or -SO2R; Each R is independently -H, or C 1-30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6-30an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or Two R groups optionally and independently together form a covalent bond, or: two or more R groups on the same atom optionally and independently combine with that atom to form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to that atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or Two or more R groups on two or more atoms may optionally and independently be combined with their intervening atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. It has.

[0031] In some embodiments, the antibody binding moiety is a cyclic peptide moiety. In some embodiments, the present disclosure provides compounds of formula Ia: [ka] or a salt thereof, wherein: each Xaa is independently an amino acid residue; t is 0 to 50; z is 1 to 50; L is a linker moiety; TBT is the target binding moiety; Each R c independently, -L a -R'; each of a and b is independently 1 to 200; Each L a are independently a covalent bond or C1 to C 20 Aliphatic or C1-C with 1-5 heteroatoms 20an optionally substituted divalent radical selected from heteroaliphatic, wherein one or more methylene units of the radical are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-; Each -Cy- is independently C 3-20 Alicyclic ring, C 6-20 an optionally substituted divalent group selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; each R' is independently -R, -C(O)R, -CO2R, or -SO2R; Each R is independently -H, or C 1-30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6-30 an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or Two R groups optionally and independently together form a covalent bond, or: two or more R groups on the same atom optionally and independently combine with that atom to form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to that atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or Two or more R groups on two or more atoms may optionally and independently be combined with their intervening atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. to provide.

[0032] In some embodiments, a is 1. In some embodiments, b is 1. In some embodiments, a is 1 and b is 1, and the compound of Formula Ia is [ka] It has the following structure.

[0033] In some embodiments, each amino acid residue, e.g., each Xaa in Formula Ia, is independently a residue of an amino acid having the structure of Formula AI. In some embodiments, each Xaa is independently -N(R a1 )-L a1 -C(R a2 )(R a3 )-L a2 In some embodiments, for example, two or more side chains of an amino acid residue in a compound of Formula Ia (e.g., R a2 or R a3 and another amino acid residue R a2 or R a3 ) optionally form a bridge together (e.g., compounds I-10, I-12, I-14, I-18, I-19, I-22, I-23, I-25, etc.), e.g., in some embodiments, two cysteine ​​residues form a -SS- bridge typically observed in natural proteins. In some embodiments, the bridge formed is b The structure of (L bis the L described in this disclosure a In some embodiments, L b is independently connected to a backbone atom of the cyclic peptide (e.g., -(Xaa) in Formula Ia). z -) to a ring atom of the ring formed by L b contains an R group (e.g., L b where the methylene unit of is replaced by -C(R)2- or -N(R)-, the R group is an R group attached to a skeletal atom (e.g., R a1 , R a2 , R a3 etc.) together with their intervening atoms to form a ring. In some embodiments, L b is connected to the ring via an amino acid residue (e.g., Xaa in Formula Ia), e.g., -(Xaa) in Formula Ia z - is connected to a ring formed by In some embodiments, such side chains comprise an amino group or a carboxylic acid group.

[0034] In some embodiments, [ka] is the antibody binding moiety ( [ka] binds to the antibody). In some embodiments, [ka] is a universal antibody binding moiety. In some embodiments, [ka] is a universal antibody binding moiety that can bind to antibodies with different Fab regions. In some embodiments, [ka] is a universal antibody binding moiety that can bind to the Fc region. In some embodiments, the antibody binding moiety, e.g., [ka] can bind to an Fc region bound to an Fc receptor. In some embodiments, the antibody binding moiety, e.g., [ka] The antibody binding moiety has the structure [ka] In some embodiments, [ka] teeth, [ka] It has the following structure.

[0035] In certain embodiments, the present invention provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 3 and R 5 each independently represents hydrogen or C 1-6 an optionally substituted group selected from an aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R1 and R 1’ optionally, together with their intervening carbon atoms, form a 3- to 8-membered optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 3 and R 3’ optionally, together with their intervening carbon atoms, form a 3- to 8-membered optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R attached to the same carbon atom 5 Groups and R 5’ groups optionally taken together with their intervening carbon atoms form a 3- to 8-membered optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or The Two R's 5 The groups, optionally together with their intervening atoms, are C 1-10 wherein one to three methylene units of the chain are independently and optionally -S-, -SS-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, or -Cy 1 - and each -Cy 1 - is independently a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 1’ , R 3’ and R 5’ each independently represents hydrogen or an optionally substituted C 1-3 It is aliphatic; R 2 , R 4 and R 6each independently represents hydrogen or an optionally substituted C 1-4 is aliphatic or: R 2 and R 1 optionally, together with their intervening atoms, form a 4-8 membered, optionally substituted, saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 4 and R 3 optionally, together with their intervening atoms, form a 4- to 8-membered, optionally substituted, saturated or partially unsaturated, monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R 6 group and its adjacent R 5 groups optionally taken together with their intervening atoms form a 4-8 membered, optionally substituted, saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; L 1 teeth, [ka] is a trivalent linker moiety connecting L 2 is a covalent bond or C 1-30 wherein 1 to 10 methylene units of the chain are independently and optionally selected from the group consisting of -S-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, [ka] or -Cy 1 - and each -Cy 1 - is independently a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; TBT is the target binding moiety; Each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. to provide.

[0036] In some embodiments, the antibody binding moiety is or comprises a peptide moiety. In some embodiments, the present disclosure provides compounds having the structure of Formula Ib: [ka] or a salt thereof, wherein: each Xaa is independently an amino acid residue; each z is independently 1 to 50; each L is independently a linker moiety; TBT is the target binding moiety, Each R c independently, -L a -R'; each of a1 and a2 is independently 0 or 1, and at least one of a1 and a2 is not 0; each of a and b is independently 1 to 200; Each L a are independently a covalent bond or C1 to C 20 Aliphatic or C1-C with 1-5 heteroatoms 20 an optionally substituted divalent radical selected from heteroaliphatic, wherein one or more methylene units of the radical are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-; Each -Cy- is independently C 3-20 Alicyclic ring, C 6-20an optionally substituted divalent group selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; each R' is independently -R, -C(O)R, -CO2R, or -SO2R; Each R is independently -H, or C 1-30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6-30 an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or Two R groups optionally and independently together form a covalent bond, or: two or more R groups on the same atom optionally and independently combine with that atom to form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to that atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or Two or more R groups on two or more atoms may optionally and independently be combined with their intervening atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. to provide.

[0037] In some embodiments, a1 is 1. In some embodiments, a2 is 1. In some embodiments, b is 1. In some embodiments, the compound of formula Ib is [ka] In some embodiments, the compound of formula Ib has the structure: [ka] In some embodiments, the compound of formula Ib has the structure: [ka] In some embodiments, the compound of formula Ib has the structure: [ka] It has the following structure.

[0038] In some embodiments, each amino acid residue, e.g., each Xaa in Formula Ib, is independently a residue of an amino acid having the structure of Formula AI. In some embodiments, each Xaa is independently -N(R a1 )-L a1 -C(R a2 )(R a3 )-L a2 In some embodiments, for example, two or more side chains of an amino acid residue in a compound of Formula Ia (e.g., R a2 or R a3 and another amino acid residue R a2 or R a3 ) optionally form a bridge together (e.g., compounds I-10, I-12, I-14, I-18, I-19, I-22, I-23, I-25, etc.), e.g., in some embodiments, two cysteine ​​residues form a -SS- bridge typically observed in natural proteins. In some embodiments, the bridge formed is b The structure of (L b is the L described in this disclosurea In some embodiments, L b is independently connected to a backbone atom of the cyclic peptide (e.g., -(Xaa) in Formula Ia). z -) to a ring atom of the ring formed by L b contains an R group (e.g., L b where the methylene unit of is replaced by -C(R)2- or -N(R)-, the R group is an R group attached to a skeletal atom (e.g., R a1 , R a2 , R a3 etc.) together with their intervening atoms to form a ring. In some embodiments, L b is connected to the ring via the side chain of an amino acid residue (e.g., Xaa in Formula Ia), e.g., -(Xaa) in Formula Ib z - is connected to a ring formed by In some embodiments, such side chains comprise an amino group or a carboxylic acid group.

[0039] In some embodiments, R c -(Xaa)z- is an antibody binding moiety (R c -(Xaa)zH binds to an antibody). In some embodiments, R c -(Xaa)z- is a universal antibody binding moiety. In some embodiments, R c -(Xaa)z- is a universal antibody binding moiety that can bind to antibodies with different Fab regions. In some embodiments, R c -(Xaa)z- is a universal antibody binding moiety capable of binding to an Fc region. In some embodiments, the antibody binding moiety, e.g., R c A universal antibody binding moiety having the structure -(Xaa)z- can bind to an Fc region that binds to an Fc receptor. In some embodiments, R c -(Xaa)z- is [ka] In some embodiments, R c -(Xaa)zL- is [ka] It has the following structure.

[0040] In certain embodiments, the present invention provides a compound of formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 7 each independently represents hydrogen or C 1-6 an optionally substituted group selected from an aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R attached to the same carbon atom 7 Groups and R 7’ groups optionally taken together with their intervening carbon atoms form a 3- to 8-membered optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3- to 8-membered optionally substituted saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 7’ each independently represents hydrogen or an optionally substituted C 1-3 It is aliphatic; R 8 each independently represents hydrogen or an optionally substituted C 1-4 is aliphatic or: R 8 group and its adjacent R 7 groups optionally taken together with their intervening atoms form a 4-8 membered, optionally substituted, saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 9 is hydrogen, optionally substituted C 1-3 Aliphatic, or -C(O)-(optionally substituted C 1-3 aliphatic); L 3 teeth, [ka] is a bivalent linker moiety connecting the TBT is the target binding moiety; o is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) to provide.

[0041] 2. Compounds and Definitions: Compounds of the present invention include those generally described herein and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th The general principles of organic chemistry are identified according to Ed. Also, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5 th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0042] The terms "aliphatic" or "aliphatic group," as used herein, mean a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation but is not aromatic (also referred to herein as "carbocycle," "alicyclic," or "cycloalkyl"), and has a single point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") means a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0043] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or an atom or valence bond connecting two bridgeheads, and a "bridgehead" is any skeletal atom of a ring system that is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups shown below, in which each group is attached to the remainder of the molecule at an optionally substitutable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more of the substituents set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic groups include: [ka] Includes:

[0044] The term "lower alkyl" refers to a C 1-4 It refers to a straight-chain or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0045] The term "lower haloalkyl" refers to a C alkyl group substituted with one or more halogen atoms. 1-4 It refers to a straight-chain or branched alkyl group.

[0046] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (including as in N-substituted pyrrolidinyl) means one or more of:

[0047] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0048] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched hydrocarbon chain" refers to straight or branched divalent alkylene, alkenylene, and alkynylene chains as defined herein.

[0049] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH-) n - (where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3). A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0050] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0051] As used herein, the term "cyclopropylenyl" refers to the following structure: [ka] refers to a divalent cyclopropyl group of the formula:

[0052] The term "halogen" means F, Cl, Br, or I.

[0053] The term "aryl," used alone or as part of a larger moiety, such as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, wherein at least one ring of the system is aromatic and each ring of the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Also included within the scope of the term "aryl," as it is used herein, are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl.

[0054] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, e.g., "heteroaralkyl" or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic arrangement; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-," as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which terms include optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0055] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and that, in addition to carbon atoms, has one or more, preferably 1 to 4, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + It can be NR (as in N-substituted pyrrolidinyl).

[0056] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions are independently optionally substituted.

[0057] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0058] As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and if multiple positions in any given structure may be substituted with multiple substituents selected from a specified group, the substituents may be the same or different at all positions. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically viable compounds. The term "stable," as used herein, refers to compounds that are substantially unchanged when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0059] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH) 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0-4 SR°;-(CH2) 0-4 Ph (optionally substituted with R°); -(CH2) 0-4 O(CH2) 0-1 Ph (optionally substituted with R°); -CH=CHPh (optionally substituted with R°); -(CH2) 0-4 O(CH2) 0-1-pyridyl (optionally substituted by R°); -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-N(R°)C(NR°)N(R°)2;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR-, -SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-(CH2) 0-4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;-SiR°3;-(C 1-4 Linear or branched alkylene)ON(R°)2; or -(C 1-4 linear or branched alkylene)C(O)ON(R°), where each R° is optionally substituted as defined below and independently represents hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2)0-1 Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definitions, two independent occurrences of R° together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be optionally substituted as defined below.

[0060] Suitable monovalent substituents on R° (or the ring formed by two independent occurrences of R° together with their intervening atoms) are independently halogen, —(CH) 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1-4 Linear or branched alkylene)C(O)OR ● , or -SSR ● and each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0061] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S-(R * Each independent occurrence of is hydrogen, which may be substituted as defined below. 1-6 (Selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.) Preferred divalent substituents attached to adjacent substitutable carbon atoms of an "optionally substituted" group include: -O(CR * 2) 2-3 O-(R * Each independent occurrence of is hydrogen, which may be substituted as defined below. 1-6 aliphatic, or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0062] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ●, -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0063] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † Each R † are independently hydrogen, optionally substituted as defined below, C 1-6 aliphatic, non-replacement -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R † two independent occurrences of together with their intervening atom(s) form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0064] R † Suitable substituents on the aliphatic group are independently halogen, —R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0065] As used herein, the term "pharmaceutically acceptable salts" refers to those salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and 2-hydroxy-ethanesulfonate. Examples of salts that may be used include phosphate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0066] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts also include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0067] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure containing the replacement of a carbon with a C-enriched carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the present invention. In certain embodiments, the R of the provided compounds x contains one or more deuterium atoms.

[0068] The compounds of the present invention can be linked to a detectable moiety. It is understood that such compounds are useful as imaging agents. Those skilled in the art will recognize that the detectable moiety can be attached to the provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety capable of covalently binding to a detectable moiety. Such moieties are well known to those skilled in the art and include, for example, groups containing a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name a few. It is understood that such moieties can be attached to the provided compound directly or via a linking group such as a divalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties can be attached via click chemistry. In some embodiments, such moieties can be attached via 1,3-cycloaddition of an alkyne and an azide, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57.

[0069] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety that can be detected, such as primary and secondary labels. Radioisotopes (e.g., tritium, 32 P, 33 P, 35 S, or 14 C), primary labels, such as mass tags and fluorescent labels, are signal-generating reporter groups that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0070] The term "secondary label," as used herein, refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate for the generation of a detectable signal. In the case of biotin, the secondary intermediate may include a streptavidin-enzyme conjugate. For antigen labels, the secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups function as secondary labels because they transfer energy to another group in the process of non-radioactive fluorescence resonance energy transfer (FRET), which then generates the signal that is detected.

[0071] The terms "fluorescent label," "fluorescent dye," and "fluorophore," as used herein, refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), cascade blue, cascade yellow, coumarin 343, cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), dansyl, dapoxyl, dialkylaminocoumarin, 4',5'-dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, eosin, erythrosine, fluorescein, FAM, hydroxycoumarin, IRDye (IRD40, IRD700, IRD800), JOE, Lissamine rhodamine B, These include, but are not limited to, Marina Blue, methoxycoumarin, naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, pyrene, rhodamine B, rhodamine 6G, rhodamine green, rhodamine red, rhodol green, 2',4',5',7'-tetra-bromosulfone-fluorescein, tetramethylrhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, and Texas Red-X.

[0072] The term "mass tag," as used herein, refers to any moiety that can be uniquely detected by its mass using mass spectrometry (MS) detection techniques. Examples of mass tags include electrophoretic release tags such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone, and derivatives thereof. The synthesis and use of these mass tags are described in U.S. Patents 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of various lengths and base compositions, oligopeptides, oligosaccharides, and other synthetic polymers of various lengths and monomer compositions. A wide variety of organic molecules (biomolecules or synthetic compounds), both neutral and charged, in the appropriate mass range (100-2000 daltons) can also be used as mass tags.

[0073] Listed below are tumor-associated cell surface antigen polypeptides, or tumor-associated antigens (TAA), that enable the ability to specifically target cancer cells for destruction.

[0074] TAA includes 5T4, AOC3, ALK, AXL, C242, CA-125, CCL11, CCR5, CD2, CD3, CD4, CD5, CD15, CA15-3, CD18, CD19, CA19-9, CD20, CD22, CD23, CD25, CD28, CD30, CD31, CD33, CD37, CD38, C D40, CD41, CD44, CD44v6, CD51, CD52, CD54, CD56, CD62E, CD62P, CD62L, CD70, CD74, CD79-B, CD80, CD125, CD138, CD141, CD147, CD152, CD154, CD326, CEA, CTLA-4, CXCR2, EG FR, ErbB2, ErbB3, EpCAM, EphA2, EphB2, EphB4, FGFR (i.e., FGFR1, FGFR2, FGFR3, FGFR4), FLT3, folate receptor, FAP, GD2, GD3, GPNMB, HGF, HER2, ICAM, IGF-1 receptor, VEGFR1, TRPV1, CFTR, gpNMB, CA9, Crypto, c-KIT, c-MET, ACE, APP, adrenergic receptor-beta 2, claudin 3, mesothelin, MUC1, RON, ROR1, PD-L1, PD-L2, B7-H3, B7-B4, IL-2 receptor, IL-4 receptor, IL-13 receptor, integrin (α4, α v β3, α v β5, α v β6, α1β4, α4β1, α4β7, α5β1, α6β4, α IIb These include β3 integrin, IFN-α, IFN-γ, IgE, IGF-1 receptor, IL-1, IL-12, IL-23, IL-13, IL-22, IL-4, IL-5, IL-6, interferon receptor, ITGB2 (CD18), LFA-1 (CD11a), L-selectin (CD62L), mucin, MUC1, myostatin, NCA-90, NGF, PDGFRα, phosphatidylserine, prostate cancer cells, prostate-specific membrane antigen (PSMA), RANKL, rhesus factor, SLAMF7, sphingosine-1-phosphate, TAG-72, T cell receptor, tenascin-C, TGF-1, TGF-β2, TGF-β, TNF-α, TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, VEGFA, VEGFR2, and vimentin.

[0075] In some embodiments, the tumor-associated antigen is or includes a carbohydrate. In some embodiments, the provided TBT targets such a TAAA. In some embodiments, the carbohydrate is part of a glycoprotein. In some embodiments, the carbohydrate is part of a glycolipid. Many conditions, disorders, and diseases, for example, various types of cancer, are associated with aberrant glycosylation. Tumor-associated carbohydrate antigens (TACAs) include and / or are associated with altered sialic acid expression, altered Lewis carbohydrate antigen expression, altered ganglioside expression, etc. The TBTs of the present disclosure can target various types of TACAs, including those described in the art, for example, Chua and Durrant, Monoclonal Antibodies Against Tumor-Associated Carbohydrate Antigens, Carbohydrate Mahmut Caliskan, IntechOpen, DOI:10.5772 / 66996.

[0076] Alternatively, TBT may be a high-affinity binding moiety for one or more tumor-associated antigens or cell surface receptors selected from (1) to (36):

[0077] (1) BMPR1B (bone morphogenetic protein receptor-type IB, Genbank accession number NM.sub.--001203);

[0078] (2) E16 (LAT1, SLC7A5, Genbank accession number NM.sub.--003486);

[0079] (3) STEAP1 (six-transmembrane epithelial antigen of the prostate, Genbank accession number NM.sub.--012449);

[0080] (4) 0772P (CA125, MUC16, Genbank accession number AF361486);

[0081] (5) MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin, Genbank accession number NM.sub.-005823);

[0082] (6) Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute transporter family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b, Genbank accession number NM.sub.--006424);

[0083] (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, (semaphorin) 5B, Genbank accession number AB040878);

[0084] (8) PSCA hlg (2700050C12Rik, C530008016Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene, Genbank accession number AY358628);

[0085] (9) ETBR (endothelin type B receptor, Genbank accession number AY275463);

[0086] (10) MSG783 (RNF124, hypothetical protein FLJ20315, Genbank accession number NM.sub.--017763);

[0087] (11) STEAP2 (HGNC.sub.--8639, IPCA-1, PCANAP1, STAMPI, STEAP2, STMP, prostate cancer-associated gene 1, prostate cancer-associated protein 1, prostate six-transmembrane epithelial antigen 2, six-transmembrane prostate protein, Genbank accession number AF455138);

[0088] (12) TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel, subfamily M, member 4, Genbank accession number NM.sub.--017636);

[0089] (13) CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor, Genbank accession number NP.sub.--003203 or NM.sub.--003212);

[0090] (14) CD21 (CR2 (complement receptor 2) or C3DR (C3d / Epstein-Barr virus receptor) or Hs.73792, Genbank accession number M26004);

[0091] (15) CD79b (CD79B, CD79.beta, IGb (immunoglobulin-related beta), B29, Genbank accession number NM.sub.--000626);

[0092] (16) FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain-containing phosphatase anchor protein 1a), SPAP1B, SPAP1C, Genbank accession number NM.sub.--030764);

[0093] (17) HER2 (Genbank accession number M1730);

[0094] (18) NCA (Genbank accession number M18728);

[0095] (19) MDP (Genbank accession number BC017023);

[0096] (20) IL20Rα (Genbank accession number AF184971);

[0097] (21) brevican (Genbank accession number AF229053);

[0098] (22) EphB2R (Genbank accession number NM.sub.--004442);

[0099] (23) ASLG659 (Genbank accession number AX092328);

[0100] (24) PSCA (Genbank accession number AJ297436);

[0101] (25) GEDA (Genbank accession number AY260763);

[0102] (26)BAFF-R (B cell-activating factor receptor, BLyS receptor 3, BR3, NP.sub.--443177.1);

[0103] (27) CD22 (B cell receptor CD22-B isoform, NP.sub.--001762.1);

[0104] (28) CD79a (CD79A, CD79.alpha, immunoglobulin-associated alpha; a B cell-specific protein that covalently interacts with Ig beta (CD79B), forms a complex with IgM molecules on the surface, and transmits signals involved in B cell differentiation; Genbank accession number NP.sub.--001774.1);

[0105] (29) CXCR5 (Burkitt's lymphoma receptor 1, a G protein-coupled receptor activated by the CXCL13 chemokine, functions in lymphocyte migration and humoral defense, and plays a role in HIV-2 infection and possibly the development of AIDS, lymphoma, myeloma, and leukemia), Genbank accession number NP.sub.--001707.1);

[0106] (30) HLA-DOB (beta subunit of MHC class II molecule (Ia antigen), which binds peptides and presents them to CD4+ T lymphocytes, Genbank accession number NP.sub.--002111.1);

[0107] (31) P2X5 (purinergic receptor P2X ligand-gated ion channel 5, an ion channel gated by extracellular ATP, which may be involved in synaptic transmission and neurogenesis, and its deficiency may contribute to the pathophysiology of idiopathic detrusor instability, Genbank accession number NP.sub.--002552.2);

[0108] (32)CD72 (B cell differentiation antigen CD72, Lyb-2, Genbank accession number NP.sub.--001773.1);

[0109] (33) LY64 (lymphocyte antigen 64 (RP105), a type I membrane protein of the leucine-rich repeat (LRR) family, regulates B cell activation and apoptosis, and loss of function is associated with increased disease activity in patients with systemic lupus erythematosus, Genbank accession number NP.sub.--005573.1);

[0110] (34) FcRH1 (Fc receptor-like protein 1, a putative receptor for immunoglobulin Fc domains containing a C2-type Ig-like domain and an ITAM domain, which may play a role in B-lymphocyte differentiation, Genbank accession number NP.sub.--443170.1);

[0111] (35) IRTA2 (immunoglobulin superfamily receptor translocation-associated 2, a putative immune receptor with a possible role in B-cell development and lymphomagenesis; deregulation of the gene by translocation occurs in several B-cell malignancies; Genbank accession number NP.sub.--112571.1); and

[0112] (36) TENB2 (putative transmembrane proteoglycan, related to the EGF / heregulin family of growth factors and follistatin, Genbank accession number AF179274).

[0113] 3. Description of Exemplary Embodiments: In certain embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: ABT is the antibody binding moiety; L is a bivalent linker moiety connecting ABT with TBT; TBT is the target binding moiety to provide.

[0114] In some embodiments, the disclosure provides a compound of formula Ia or a salt thereof: In some embodiments, the disclosure provides a compound of formula Ib or a salt thereof:

[0115] In certain embodiments, the present invention provides a compound of formula II: or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 3 and R 5 each independently represents hydrogen or C 1-6 an optionally substituted group selected from an aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R 1 and R 1’ optionally, together with their intervening carbon atoms, form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 3 and R 3’optionally, together with their intervening carbon atoms, form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R attached to the same carbon atom 5 Groups and R 5’ groups optionally taken together with their intervening carbon atoms form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or The Two R's 5 The groups, optionally together with their intervening atoms, are C 1-10 forming a divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of the chain are independently and optionally -S-, -SS-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, or -Cy 1 - and each -Cy 1 - is independently a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 1’ , R 3’ and R 5’ each independently represents hydrogen or C 1-3 It is aliphatic; R 2 , R 4 and R 6 each independently represents hydrogen or C 1-4 is aliphatic or: R 2 and R 1 optionally, together with their intervening atoms, form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 4 and R 3optionally, together with their intervening atoms, form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R 6 group and its adjacent R 5 groups optionally taken together with their intervening atoms form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; L 1 teeth, [ka] is a trivalent linker moiety connecting L 2 is a covalent bond or C 1-10 A divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of the chain are independently and optionally selected from the group consisting of -S-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, [ka] or -Cy 1 - and each -Cy 1 - is independently a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; TBT is the target binding moiety; Each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. to provide.

[0116] In certain embodiments, the present invention provides a compound of formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 7 each independently represents hydrogen or C1-6 an optionally substituted group selected from an aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R attached to the same carbon atom 7 Groups and R 7’ groups optionally taken together with their intervening carbon atoms to form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 7’ each independently represents hydrogen or C 1-3 It is aliphatic; R 8 each independently represents hydrogen or C 1-4 is aliphatic or: R 8 group and its adjacent R 7 groups optionally taken together with their intervening atoms form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 9 is hydrogen, C 1-3 Aliphatic, or -C(O)C 1-3 It is aliphatic; L 3 teeth, [ka] is a bivalent linker moiety connecting the TBT is the target binding moiety; o is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) to provide.

[0117] antibody binding part Among other things, the present disclosure provides agents comprising universal antibody binding moieties that can bind to antibodies with different Fab regions and different specificities. In some embodiments, the antibody binding moieties of the present disclosure are universal antibody binding moieties that bind to the Fc region. In some embodiments, binding of the universal antibody binding moiety to the Fc region can occur simultaneously with binding of an Fc receptor, e.g., CD16a, to the same Fc region (e.g., at a different position / amino acid residue in the same Fc region). In some embodiments, upon binding of the universal antibody binding moiety, e.g., in a provided agent, compound, method, etc., the Fc region can still interact with the Fc receptor and carry out one or more or all of its immune activities, including recruitment of immune cells (e.g., effector cells such as NK cells) and / or immune system activity against a target cell, tissue, object, and / or entity, e.g., elicitation, generation, promotion, and / or enhancement of antibody-dependent cell-mediated cytotoxicity (ADCC) and / or ADCP.

[0118] A variety of universal antibody binding moieties may be utilized in accordance with the present disclosure. Among other things, the present disclosure provides techniques for identifying and / or evaluating universal antibody binding moieties and their use in ARMs, such as those described in the Examples. Those skilled in the art will appreciate that additional techniques in the art may be suitable for identifying and / or evaluating universal antibody binding moieties suitable for ARMs in accordance with the present disclosure. In some embodiments, a universal antibody binding moiety comprises one or more amino acid residues, each independently natural or non-natural. In some embodiments, a universal antibody binding moiety comprises: [ka] or a salt form thereof. In some embodiments, the universal antibody binding moiety has the structure: [ka] or a salt form thereof. In some embodiments, the universal antibody binding moiety is a peptide moiety, e.g., R c In some embodiments, the universal antibody binding moiety is or comprises a moiety having the structure -(Xaa)z-. In some embodiments, the universal antibody binding moiety is a cyclic peptide moiety, e.g., [ka] In some embodiments, the universal antibody binding moiety is or comprises a moiety having the structure R c -(Xaa)z- or [ka] In some embodiments, -(Xaa)z- is or comprises a peptide unit. In some embodiments, the peptide unit is an amino acid residue, e.g., a "positively charged amino acid residue," Xaa P In some embodiments, the peptide unit comprises an amino acid residue of formula AI having a side chain containing an aromatic group (an "aromatic amino acid residue", Xaa A In some embodiments, the peptide unit comprises a positively charged amino acid residue and an aromatic amino acid residue. In some embodiments, the peptide unit comprises a W. In some embodiments, the peptide unit comprises a positively charged amino acid residue and an aromatic amino acid residue. In some embodiments, the peptide unit comprises a Xaa A XaaXaa P Xaa P In some embodiments, the peptide unit is or comprises Xaa P Xaa P XaaXaa AIn some embodiments, the peptide unit is or comprises Xaa P Xaa A Xaa P In some embodiments, the peptide unit is or comprises two or more Xaa P Xaa A Xaa P In some embodiments, the peptide unit is or comprises Xaa P Xaa A Xaa P XaaXaa P Xaa A Xaa P In some embodiments, the peptide unit is or comprises Xaa P Xaa P Xaa A Xaa A Xaa P In some embodiments, the peptide unit is or comprises Xaa P Xaa P Xaa P Xaa A In some embodiments, the peptide unit is or comprises two or more Xaa A Xaa A Xaa P In some embodiments, the peptide unit is or comprises HWRGWA. In some embodiments, the peptide unit is or comprises WGRR. In some embodiments, the peptide unit is or comprises RRGW. In some embodiments, the peptide unit is or comprises NRFRGKYK. In some embodiments, the peptide unit is or comprises NARKFYK. In some embodiments, the peptide unit is or comprises positively charged amino acid residues, aromatic amino acid residues, and amino acid residues, e.g., with negatively charged side chains (e.g., at physiological pH of about 7.4, "negatively charged amino acid residues," Xaa N) comprises residues of an amino acid of formula AI. In some embodiments, the peptide residues are RHRFNKD. In some embodiments, the peptide unit is TY. In some embodiments, the peptide unit is TYK. In some embodiments, the peptide unit is RTY. In some embodiments, the peptide unit is RTYK. In some embodiments, the peptide unit is or comprises a sequence selected from PAM. In some embodiments, the peptide unit is WHL. In some embodiments, the peptide unit is ELVW. In some embodiments, the peptide unit is or comprises a sequence selected from AWHLGELVW. In some embodiments, the peptide unit is or comprises a sequence selected from DCAWHLGELVWCT, the two cysteine ​​residues of which are capable of forming a disulfide bond found in naturally occurring proteins. In some embodiments, the peptide unit is or comprises a sequence selected from Fc-III. In some embodiments, the peptide unit is or comprises a sequence selected from DpLpAWHLGELVW. In some embodiments, the peptide unit is or comprises a sequence selected from FcBP-1. In some embodiments, the peptide unit is or comprises a sequence selected from DpLpDCAWHLGELVWCT. In some embodiments, the peptide unit is or comprises a sequence selected from FcBP-2. In some embodiments, the peptide unit is or comprises a sequence selected from CDCAWHLGELVWCTC, the first and last cysteines of which, and two other cysteines within the sequence, can each independently form a disulfide bond as in a native protein. In some embodiments, the peptide unit is or comprises a sequence selected from Fc-III-4c. In some embodiments, the peptide unit is or comprises a sequence selected from FcRM. In some embodiments, the peptide unit is or comprises a cyclic peptide unit. In some embodiments, the cyclic peptide unit comprises an amide group formed by a side chain amino group and a C-terminal -COOH.

[0119] In some embodiments, -(Xaa)z- is [X 1 ] p1 [X 2 ] p2 -X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 -[X 13 ] p13 -[X 14 ] p14 [X 15 ] p15 [X 16 ] p16 (In the formula, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , and X 13 and each of p1, p2, p13, p14, p15, and p16 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , and X 13 Each of X is independently an amino acid residue of an amino acid of formula AI. 1 , X 2 , X 3 , X 4 , X 5 , X6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , and X 13 Each of X is independently a naturally occurring amino acid residue. 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , and X 13 is independently an unnatural amino acid residue described in this disclosure.

[0120] In some embodiments, a peptide unit comprises a functional group in an amino acid residue that can react with a functional group of another amino acid residue. In some embodiments, a peptide unit comprises an amino acid residue having a side chain that comprises a functional group that can react with another functional group on the side chain of another amino acid residue to form a linkage (see, e.g., the compounds in Table 1). In some embodiments, a functional group on one amino acid residue connects to a functional group on another amino acid residue to form a linkage (or bridge). The linkage is attached to a backbone atom of the peptide unit, but does not include a backbone atom. In some embodiments, a peptide unit comprises a linkage formed by two side chains of non-adjacent amino acid residues. In some embodiments, the linkage is attached to two backbone atoms of two non-adjacent amino acid residues. In some embodiments, both backbone atoms attached to the linkage are carbon atoms. In some embodiments, the linkage is attached to a backbone atom of the peptide unit, but does not include a backbone atom. b (L b is the L described in this disclosure a (L a is not a covalent bond). In some embodiments, L a In some embodiments, L aIn some embodiments, -Cy- includes -Cy-, where -Cy- is an optionally substituted heteroaryl. [ka] In some embodiments, L a teeth, [ka] In some embodiments, such L a can be formed by the -N3 group of the side chain of one amino acid residue and the -≡- of the side chain of another amino acid residue. In some embodiments, the linkage is formed through the connection of two thiol groups, e.g., two cysteine ​​residues. In some embodiments, L a In some embodiments, L a is -CH2-SS-CH2-. In some embodiments, the linkage is formed through the connection of an amino group (e.g., -NH2 in the side chain of a lysine residue) and a carboxylic acid group (e.g., -COOH in the side chain of an aspartic acid or glutamic acid residue). In some embodiments, L a In some embodiments, L a In some embodiments, L a is -CHCONH-(CH)-. In some embodiments, L a contains -C(O)-N(R')-, where R' is R, which together with the R groups on the peptide backbone form a ring (e.g., in I-27). a is —(CH)—N(R′)—CO—(CH). In some embodiments, —Cy- is optionally substituted phenylene. In some embodiments, —Cy- is optionally substituted 1,2-phenylene. In some embodiments, L a teeth, [ka] In some embodiments, L a teeth, [ka] In some embodiments, L a is an optionally substituted divalent C 2-20 In some embodiments, L a is optionally substituted -(CH2)9-CH=CH-(CH2)9-. In some embodiments, L a is -(CH2)3-CH=CH-(CH2)3-.

[0121] In some embodiments, the two amino acid residues attached to the linkage are separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more than 15 amino acid residues between them (excluding the two amino acid residues attached to the linkage). In some embodiments, that number is 1. In some embodiments, that number is 2. In some embodiments, that number is 3. In some embodiments, that number is 4. In some embodiments, that number is 5. In some embodiments, that number is 6. In some embodiments, that number is 7. In some embodiments, that number is 8. In some embodiments, that number is 9. In some embodiments, that number is 10. In some embodiments, that number is 11. In some embodiments, that number is 12. In some embodiments, that number is 13. In some embodiments, that number is 14. In some embodiments, that number is 15.

[0122] In some embodiments, each of p1, p2, p13, p14, p15, and p16 is 0. In some embodiments, -(Xaa)z- is -X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X11 X 12 -(In formula: X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , and X 12 each is independently an amino acid residue; X 6 is Xaa A or Xaa P and; X 9 is Xaa N and; X 12 is Xaa A or Xaa P is) is or contains

[0123] In some embodiments, X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , and X 12 Each of X is independently an amino acid residue of an amino acid of formula AI described in the present disclosure. 5 is Xaa A or Xaa P In some embodiments, X 5 is Xaa A In some embodiments, X 5 is Xaa P In some embodiments, X 5 is an amino acid residue whose side chain contains an optionally substituted saturated, partially saturated, or aromatic ring. In some embodiments, X 5 teeth, [ka] In some embodiments, X 5 teeth, [ka] In some embodiments, X 6 is Xaa A In some embodiments, X 6 is Xaa P In some embodiments, X 6 is His. In some embodiments, X 12 is Xaa A In some embodiments, X 12 is Xaa P In some embodiments, X 9 is Asp. In some embodiments, X 9 is Glu. In some embodiments, X 12 teeth, [ka] In some embodiments, X 12 teeth, [ka] In some embodiments, X 7 , X 10 , and X 11 each independently being an amino acid residue having a hydrophobic side chain (a "hydrophobic amino acid residue", Xaa H In some embodiments, X 7 is Xaa H In some embodiments, X 7 teeth, [ka] In some embodiments, X 7 In some embodiments, X is Val. 10 is Xaa H In some embodiments, X 10 is Met. In some embodiments, X10 teeth, [ka] In some embodiments, X 11 is Xaa H In some embodiments, X 11 teeth, [ka] In some embodiments, X 8 is Gly. In some embodiments, X 4 is Pro. In some embodiments, X 3 is Lys. In some embodiments, X 12 -COOH of Lys(X 3 ) and forms an amide bond with the side chain amino group of Lys(X 3 The other amino group of ) is connected to a linker moiety and then to a target binding moiety.

[0124] In some embodiments, -(Xaa)z- is -X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 -(In formula: X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , and X 12 each is independently an amino acid residue; At least two amino acid residues are linked by one or more L b are connected via; L b is C1~C 20 Aliphatic or C1-C with 1-5 heteroatoms 20an optionally substituted divalent radical selected from heteroaliphatic, wherein one or more methylene units of the radical are optionally and independently replaced by —C(R′)2—, —Cy-, —O—, —S—, —SS-, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—; L b is attached to a backbone atom of one amino acid residue and a backbone atom of another amino acid residue, but does not include the backbone atom; X 6 is Xaa A or Xaa P and; X 9 is Xaa N and; X 12 is Xaa A or Xaa P is) is or contains

[0125] In some embodiments, X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , and X 12 are independently an amino acid residue of the amino acid formula AI described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are b In some embodiments, X 5 and X 10 L b In some embodiments, one link L b In some embodiments, X 6 is Xaa A In some embodiments, X 6 is Xaa P In some embodiments, X6 is His. In some embodiments, X 9 is Asp. In some embodiments, X 9 In some embodiments, X is Glu. 12 is Xaa A In some embodiments, X 12 teeth, [ka] In some embodiments, X 12 teeth, [ka] In some embodiments, X 12 teeth, [ka] In some embodiments, X 4 , X 7 , and X 11 Each of Xaa H In some embodiments, X 4 is Xaa H In some embodiments, X 4 is Ala. In some embodiments, X 7 is Xaa H In some embodiments, X 7 teeth, [ka] In some embodiments, X 11 is Xaa H In some embodiments, X 11 teeth, [ka] In some embodiments, X 8 is Gly. In some embodiments, X 3 is Lys. In some embodiments, X 12-COOH of Lys(X 3 ) and forms an amide bond with the side chain amino group of Lys(X 3 The other amino group of L is connected to a linker moiety and then to a target binding moiety. b teeth, [ka] In some embodiments, L b teeth, [ka] In some embodiments, L b connects two alpha-carbon atoms of two different amino acid residues. In some embodiments, X 5 and X 10 Both of the amino acids are Cys, and the two -SH groups in their side chains form -SS- (L b is -CH2-SS-CH2-).

[0126] In some embodiments, -(Xaa)z- is -X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 -(In formula: X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , and X 12 each is independently an amino acid residue; At least two amino acid residues are linked by one or more L b are connected via; L b is C1~C 20Aliphatic or C1-C with 1-5 heteroatoms 20 an optionally substituted divalent radical selected from heteroaliphatic, wherein one or more methylene units of the radical are optionally and independently replaced by —C(R′)2—, —Cy-, —O—, —S—, —SS-, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—; L b is attached to a backbone atom of one amino acid residue and a backbone atom of another amino acid residue, but does not include the backbone atom; X 4 is Xaa A and; X 5 is Xaa A or Xaa P and; X 8 is Xaa N and; X 11 is Xaa A is) is or contains In some embodiments, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , and X 12 are independently an amino acid residue of the amino acid formula AI described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are b In some embodiments, one link L b In some embodiments, X 2 and X 12 L b In some embodiments, L bis -CH-SS-CH-. In some embodiments, L b is -CH-CH-S-CH-. In some embodiments, L b teeth, [ka] In some embodiments, L b teeth, [ka] In some embodiments, L b is -CH2CH2CO-N(R')-CH2CH2-. In some embodiments, R' together with the R group on the backbone atom to which -N(R')-CH2CH2- is attached forms a ring, e.g., I-27. In some embodiments, the ring formed is 3, 4, 5, 6, 7, or 8-membered. In some embodiments, the ring formed is monocyclic. In some embodiments, the ring formed is saturated. In some embodiments, L b teeth, [ka] is. In some embodiments, L b connects two alpha-carbon atoms of two different amino acid residues. In some embodiments, X 4 is Xaa A In some embodiments, X 4 is Tyr. In some embodiments, X 5 is Xaa A In some embodiments, X 5 is Xaa P In some embodiments, X 5 is His. In some embodiments, X 8 is Asp. In some embodiments, X 8 is Glu. X 11 is Tyr. In some embodiments, X 2 and X12 Both of the amino acids are Cys, and the two -SH groups in their side chains form -SS- (L b is -CH-SS-CH-). In some embodiments, X 3 , X 6 , X 9 , and X 10 Each of Xaa H In some embodiments, X 3 is Xaa H In some embodiments, X 3 is Ala. In some embodiments, X 6 is Xaa H In some embodiments, X 6 is Leu. In some embodiments, X 9 is Xaa H In some embodiments, X 9 is Leu. In some embodiments, X 9 teeth, [ka] In some embodiments, X 10 is Xaa H In some embodiments, X 10 In some embodiments, X is Val. 10 teeth, [ka] In some embodiments, X 7 In some embodiments, p1 is 1. In some embodiments, X 1 is Asp. In some embodiments, p13 is 1. In some embodiments, p14, p15, and p16 are 0. In some embodiments, X 13 is an amino acid residue containing a polar uncharged side chain (e.g., a "polar uncharged amino acid residue," Xaa L In some embodiments, X 13In some embodiments, p13 is 0. In some embodiments, R c is —NHCHCH(OH)CH. In some embodiments, R c is (R)-NHCHCH(OH)CH. In some embodiments, R c is (S)-NHCH2CH(OH)CH3.

[0127] In some embodiments, -(Xaa)z- is -X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 -(In formula: X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , and X 12 each is independently an amino acid residue; At least two amino acid residues are linked by one or more L b are connected via; L b is C1~C 20 Aliphatic or C1-C with 1-5 heteroatoms 20 an optionally substituted divalent radical selected from heteroaliphatic, wherein one or more methylene units of the radical are optionally and independently replaced by —C(R′)2—, —Cy—, —O—, —S—, —SS—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—; L bis attached to a backbone atom of one amino acid residue and a backbone atom of another amino acid residue, but does not include the backbone atom; X 5 is Xaa A or Xaa P and; X 8 is Xaa N and; X 11 is Xaa A is) is or contains In some embodiments, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , and X 12 are independently an amino acid residue of the amino acid formula AI described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are b In some embodiments, one link L b In some embodiments, there are two or more linked L b In some embodiments, there are two linked L b In some embodiments, X 2 and X 12 L b In some embodiments, X 4 and X 9 L b In some embodiments, X 4 and X 10 L b In some embodiments, L b is -CH-SS-CH-. In some embodiments, L b teeth, [ka] In some embodiments, L b teeth, [ka] In some embodiments, X 2 and X 12 Both of the amino acids are Cys, and the two -SH groups in their side chains form -SS- (L b is -CH-SS-CH-). In some embodiments, X 4 and X 10 Both of the amino acids are Cys, and the two -SH groups in their side chains form -SS- (L b is -CH-SS-CH-). In some embodiments, X 4 and X 9 L b are connected by L b teeth, [ka] In some embodiments, X 4 and X 9 L b are connected by L b teeth, [ka] is. In some embodiments, X 5 is Xaa A In some embodiments, X 5 is Xaa P In some embodiments, X 5 is His. In some embodiments, X 8 is Asp. In some embodiments, X 8 is Glu. In some embodiments, X 11 is Tyr. In some embodiments, X 11 teeth, [ka] In some embodiments, X 2 and X 12 L b are connected by L b is -CH-S-CHCH-. In some embodiments, L b connects two alpha-carbon atoms of two different amino acid residues. In some embodiments, X 3 , X 6 , and X 9 Each of Xaa H In some embodiments, X 3 is Xaa H In some embodiments, X 3 is Ala. In some embodiments, X 6 is Xaa H In some embodiments, X 6 is Leu. In some embodiments, X 6 teeth, [ka] In some embodiments, X 9 is Xaa H In some embodiments, X 9 is Leu. In some embodiments, X 9 teeth, [ka] In some embodiments, X 10 is Xaa H In some embodiments, X 10 In some embodiments, X is Val. 7 In some embodiments, p1 is 1. In some embodiments, X 1 is Xaa N In some embodiments, X 1 is Asp. In some embodiments, X 1In some embodiments, p13 is 1. In some embodiments, p14, p15, and p16 are 0. In some embodiments, X 13 is Xaa L In some embodiments, X 13 is Val.

[0128] In some embodiments, -(Xaa)z- is -X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15 X 16 -(In formula: X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , and X 16 each is independently an amino acid residue; At least two amino acid residues are linked together by a linking L b are connected via; L b is C1~C 20 Aliphatic or C1-C with 1-5 heteroatoms 20an optionally substituted divalent radical selected from heteroaliphatic, wherein one or more methylene units of the radical are optionally and independently replaced by —C(R′)2—, —Cy—, —O—, —S—, —SS—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—; L b is attached to a backbone atom of one amino acid residue and a backbone atom of another amino acid residue, but does not include the backbone atom; X 3 is Xaa N and; X 6 is Xaa A and; X 7 is Xaa A or Xaa P and; X 9 is Xaa N and; X 13 is Xaa A is) is or contains In some embodiments, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , and X 12 are independently an amino acid residue of the amino acid formula AI described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are b In some embodiments, one link L b In some embodiments, there are two or more linked L b In some embodiments, there are two linked L b In some embodiments, X 2 Lb By X 16 In some embodiments, X 4 L b By X 14 In some embodiments, X 2 and X 16 Both of the amino acids are Cys, and the two -SH groups in their side chains form -SS- (L b is -CH-SS-CH-). In some embodiments, X 4 and X 14 Both of the amino acids are Cys, and the two -SH groups in their side chains form -SS- (L b is -CH-SS-CH-). In some embodiments, L b connects two alpha-carbon atoms of two different amino acid residues. In some embodiments, X 3 is Asp. In some embodiments, X 3 is Glu. In some embodiments, X 5 is Xaa H In some embodiments, X 5 is Ala. In some embodiments, X 6 is Xaa A In some embodiments, X 6 is Tyr. In some embodiments, X 7 is Xaa A In some embodiments, X 7 is Xaa P In some embodiments, X 7 is His. In some embodiments, X 8 is Xaa H In some embodiments, X 8 is Ala. In some embodiments, X 9 is Gly. In some embodiments, X 10 is Asp. In some embodiments, X 10 is Glu. In some embodiments, X 11 is Xaa HIn some embodiments, X 11 is Leu. In some embodiments, X 12 is Xaa H In some embodiments, X 12 In some embodiments, X is Val. 13 is Xaa A In some embodiments, X 13 is Tyr. In some embodiments, X 15 is an amino acid residue containing a polar uncharged side chain (e.g., a "polar uncharged amino acid residue," Xaa L In some embodiments, X 15 In some embodiments, p1 is 1. In some embodiments, X 1 is Xaa N In some embodiments, X 1 is Asp. In some embodiments, X 1 is Glu.

[0129] As will be appreciated by one of skill in the art, an amino acid residue may be replaced by another amino acid residue having similar properties, for example, a Xaa H (e.g., Val, Leu, etc.) can be replaced by another Xaa H (e.g., Leu, Ile, Ala, etc.), and certain Xaa A is another Xaa A Xaa can be replaced by P is another Xaa P Xaa can be replaced by N is another Xaa N Xaa can be replaced by L is another Xaa L It can be replaced by, etc.

[0130] In some embodiments, the antibody binding moiety, e.g., universal antibody binding moiety, is a universal antibody binding moiety of a compound in Table 1. In some embodiments, the antibody binding moiety, e.g., universal antibody binding moiety, is or includes the following, optionally substituted: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0131] In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-1. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-2. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-3. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-4. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-5. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-6. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-7. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-8. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-9. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-10. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-11. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-12. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-13. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-14. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-15. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-16. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-17. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-18. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-19. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-20.In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-21. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-22. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-23. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-24. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-25. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-26. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-27. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-28. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-29. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-30. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-31. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-32. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-33. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-34. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-35. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-36. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-37. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-38. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-39. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-40.In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-41. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-42. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-43. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-44. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-45. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-46. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-47. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-48. In some embodiments, the universal antibody binding moiety is or comprises an optionally substituted A-49. In some embodiments, it is unsubstituted. In some embodiments, it is substituted.

[0132] In some embodiments, the universal antibody binding moiety comprises a peptide unit and is connected to a linker moiety through the C-terminus of the peptide unit. In some embodiments, it is connected to a linker moiety through the N-terminus of the peptide unit. In some embodiments, it is connected to a side group of the peptide unit.

[0133] In some embodiments, the antibody binding moiety, e.g., a universal antibody binding moiety, is or comprises a small molecule entity, e.g., having a molecular weight of less than 10,000, 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1,500, 1,000, etc. Suitable such antibody binding moieties include small molecule Fc binder moieties, e.g., those described in US9,745,339, US20130131321, etc.

[0134] As will be appreciated by those skilled in the art, antibodies of various properties and activities (e.g., antibodies recognizing different antigens with any modifications) can be recruited by the antibody binding moieties described herein. In some embodiments, such antibodies include antibodies administered to a subject, for example, for therapeutic purposes. In some embodiments, antibodies recruited by antibody binding moieties include antibodies against different antigens. In some embodiments, antibodies recruited by antibody binding moieties include antibodies whose antigen is not present on the surface or cell membrane of a target cell (e.g., a target cell such as a cancer cell). In some embodiments, antibodies recruited by antibody binding moieties include antibodies that do not target an antigen present on the surface or cell membrane of a target (e.g., a target cell such as a cancer cell). In some embodiments, an antigen on the surface of a target cell may interfere with the structure, morphology, and / or one or more properties and / or activities of the recruited antibody that binds to such antigen. In some embodiments, as will be appreciated by those skilled in the art, the provided technology comprises universal antibody binding moieties that recruit antibodies of diverse specificities, where no more than 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% percent of the recruited antibodies are directed against the same antigen, protein, lipid, carbohydrate, etc. Notably, one advantage of the present disclosure is that the provided technology comprising universal antibody binding moieties can utilize a diverse pool of antibodies, such as those present in serum. In some embodiments, a universal antibody binding moiety of the present disclosure (e.g., in an ARM) is contacted with a plurality of antibodies, wherein no more than 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% percent of the antibodies in the plurality are directed against the same antigen, protein, lipid, carbohydrate, etc.

[0135] amino acid In some embodiments, provided compounds and agents can include one or more amino acid residues, for example, in a universal antibody binding moiety, a linker moiety, etc. The amino acid moiety can be either a natural amino acid or an unnatural amino acid. In some embodiments, the amino acid has the structure of formula AI: NH(R a1 )-L a1 -C(R a2 )(R a3 )-L a2 -COOH, AI or a salt thereof, wherein each variable is independent as described in this disclosure. In some embodiments, the amino acid residue has -N(R a1 )-L a1 -C(R a2 )(R a3 )-L a2 It has the structure -CO-.

[0136] In some embodiments, L a1 is a covalent bond. In some embodiments, the compound of formula AI has the structure NH(R a1 )-C(R a2 )(R a3 )-L a2 -COOH.

[0137] In some embodiments, L a2 is a covalent bond. In some embodiments, the compound of formula AI has the structure NH(R a1 )-C(R a2 )(R a3 )-L a2 -COOH.

[0138] In some embodiments, L a1 is a covalent bond, and L a2 is a covalent bond. In some embodiments, the compound of formula AI has the structure NH(R a1 )-C(R a2 )(R a3 )-COOH.

[0139] In some embodiments, L a is a covalent bond. In some embodiments, L a is an arbitrarily substituted C 1-6 In some embodiments, L a is an arbitrarily substituted C 1-6 In some embodiments, L is alkylene. a is -CH-. In some embodiments, L a is -CHCH-. In some embodiments, L a is -CH2CH2CH2-.

[0140] In some embodiments, R' is R. In some embodiments, R a1 is R, where R is as described in this disclosure. In some embodiments, R a2 is R, where R is as described in this disclosure. In some embodiments, R a3 is R, where R is as described in this disclosure. In some embodiments, R a1 , R a2 , and R a3 Each of is independently R, where R is as described in this disclosure.

[0141] In some embodiments, R a1 is hydrogen. In some embodiments, R a2 is hydrogen. In some embodiments, R a3 is hydrogen. In some embodiments, R a1 is hydrogen and R a2 and R a3 At least one of R is hydrogen. a1 is hydrogen and R a2 and R a3 One of them is hydrogen and the other is not hydrogen.

[0142] In some embodiments, R a2 -L a-R, where R is as described in this disclosure. In some embodiments, R a2 -L a -R (wherein R is C 3-30 Alicyclic, C 5-30 In some embodiments, R is an optionally substituted group selected from aryl, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. a2 -L a -R (wherein R is C 6-30 aryl and 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon). In some embodiments, R a2 is the side chain of an amino acid. In some embodiments, R a2 is the side chain of a standard amino acid.

[0143] In some embodiments, R a3 -L a -R, where R is as described in this disclosure. In some embodiments, R a3 -L a -R (wherein R is C 3-30 Alicyclic, C 5-30 In some embodiments, R is an optionally substituted group selected from aryl, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. a3 -L a -R (wherein R is C 6-30 aryl and 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon). In some embodiments, R a3is the side chain of an amino acid. In some embodiments, R a3 is the side chain of a standard amino acid.

[0144] In some embodiments, R is a cyclic group. In some embodiments, R is an optionally substituted C 3-30 In some embodiments, R is cycloaliphatic.

[0145] In some embodiments, R is an aromatic group and the amino acid residue of the amino acid of formula AI is Xaa A In some embodiments, R is optionally substituted phenyl. In some embodiments, R is phenyl. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is 4-trifluoromethylphenyl. In some embodiments, R is 4-phenylphenyl. In some embodiments, R is an optionally substituted 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted 5-14 membered heteroaryl having 1-5 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is [ka] In some embodiments, R is an optionally substituted pyridinyl. In some embodiments, R is 1-pyridinyl. In some embodiments, R is 2-pyridinyl. In some embodiments, R is 3-pyridinyl. In some embodiments, R is [ka] is.

[0146] In some embodiments, R' is -COOH. In some embodiments, the compound of the amino acid residue of the amino acid of formula AI is Xaa H is.

[0147] In some embodiments, R' is -NH2. In some embodiments, the compound of the amino acid residue of the amino acid of formula AI is Xaa P is.

[0148] In some embodiments, R a2 or R a3 is R (R is a C 1-20 In some embodiments, the compound of amino acid residues of the amino acid of formula AI is Xaa H In some embodiments, R is -CH3. In some embodiments, R is ethyl. In some embodiments, R is propyl. In some embodiments, R is cyclopropyl.

[0149] In some embodiments, R a1 , R a2 , and R a3 two or more of are R and taken together form an optionally substituted ring as described herein.

[0150] In some embodiments, R a1 and R a2 and R a3 One of them is R, and together they form R a1 forms an optionally substituted 3- to 6-membered ring with no additional ring heteroatoms other than the nitrogen atom to which it is attached. In some embodiments, the ring formed is a 5-membered ring, such as that in proline.

[0151] In some embodiments, R a2 and R a3 is R and together form an optionally substituted 3-6 membered ring as described in this disclosure. In some embodiments, R a2 and R a3 is R and taken together form an optionally substituted 3-6 membered ring having one or more nitrogen ring atoms. In some embodiments, R a2 and R a3is R and together form an optionally substituted 3-6 membered ring having up to one ring heteroatom that is a nitrogen atom. In some embodiments, the ring is a saturated ring.

[0152] In some embodiments, the amino acid is a natural amino acid. In some embodiments, the amino acid is a non-natural amino acid. In some embodiments, the amino acid is an alpha-amino acid. In some embodiments, the amino acid is a beta-amino acid.

[0153] target In some forms, the present disclosure provides techniques for selectively directing agents (e.g., ARM compounds), antibodies, and immune cells, e.g., NK cells, that comprise target-binding moieties to a desired target site, including one or more targets. As one of skill in the art will appreciate, the provided techniques are useful for a variety of target types.

[0154] In some embodiments, the target is damaged or defective tissue. In some embodiments, the target is damaged tissue. In some embodiments, the target is defective tissue. In some embodiments, the target is associated with a disease, disorder, or condition, e.g., cancer, wound, etc. In some embodiments, the target is a tumor. In some embodiments, the target is or comprises a diseased cell. In some embodiments, the target is or comprises a cancer cell. In some embodiments, the target is a foreign body. In some embodiments, the target is or comprises an infectious agent. In some embodiments, the target is a microorganism. In some embodiments, the target is or comprises a bacterium. In some embodiments, the target is or comprises a virus.

[0155] In many embodiments, the target is a tissue and / or cell associated with a disease, disorder, or condition, particularly various types of cancer. In some embodiments, the target is or comprises a cancer cell. Among other things, the present disclosure provides techniques that are particularly useful for selectively targeting cancer cells by the immune system, for example, via recruiting antibodies (e.g., endogenous antibodies) and immune cells by using ARMs.

[0156] The targeting moiety typically comprises one or more physical, chemical and / or biological markers that can be utilized, for example, by the target binding portion of a provided compound (e.g., an ARM) to selectively recruit antibodies and / or fragments thereof, and / or immune cells to the target.

[0157] In some embodiments, cells at the target site contain one or more characteristic substances useful for targeting. In some embodiments, such substances are proteins and / or fragments thereof. In some embodiments, such substances are antigens specifically associated with a disease, disorder, or condition.

[0158] For example, in some embodiments, cancer cells may contain one or more tumor-specific or tumor-associated antigens. The target-binding moieties described in the present disclosure may selectively bind to such markers. In some embodiments, the target-binding moieties of the present disclosure are small molecules useful for binding to cell surface proteins and / or intracellular proteins.

[0159] In some embodiments, for example, the characteristic substance of a cell at a target site is or includes a carbohydrate on a glycosylated protein, e.g., on the cell surface. In some embodiments, the characteristic substance is or includes a lipid.

[0160] In some embodiments, for example, the characteristic substance of a cell at a target site is extracellular. In some embodiments, the characteristic substance is an extracellular protein. In some embodiments, the characteristic substance is on the cell surface. In some embodiments, the characteristic substance is a protein present on the cell surface. For example, in many tumor tissues, cell surface and / or extracellular mucins exhibit different levels and / or patterns of glycosylation, which can be utilized for targeting.

[0161] In some embodiments, a target site, such as a diseased tissue, has one or more physical, biological, and / or chemical properties that can be exploited by a target binding moiety. In some embodiments, such a property is pH. In some embodiments, such a property is the concentration of one or more chemical substances. For example, the tumor microenvironment is often hypoxic and / or acidic (e.g., pH 6.5-6.9 vs. 7.2-7.4).

[0162] In some embodiments, the target is or comprises a peptide or a fragment thereof. In some embodiments, the target is or comprises a protein or a fragment thereof. In some embodiments, the target is avidin. In some embodiments, the target is streptavidin. In some embodiments, the target is or comprises an antigen. In some embodiments, the target is or comprises a tumor-specific antigen. In some embodiments, the target is or comprises a tumor-associated antigen.

[0163] In some embodiments, the target is or comprises a nucleic acid.

[0164] In some embodiments, the target is or comprises a lipid.

[0165] In some embodiments, the target is or comprises a carbohydrate. In some embodiments, the target is or comprises a carbohydrate associated with a disease, disorder, or condition. In some embodiments, the target is or comprises a carbohydrate associated with cancer, for example, a carbohydrate on the surface of a cancer cell or as a glycan modification of an extracellular protein.

[0166] target binding moiety Various types and chemical classes of target-binding moieties can be utilized in accordance with the present disclosure, and numerous techniques (e.g., assays, reagents, kits, etc.) for identifying and / or evaluating the properties of target-binding moieties can be utilized in accordance with the present disclosure. Generally, target-binding moieties interact with target sites through one or more physical, biological, and / or chemical properties. In some embodiments, the target-binding moiety binds to a characteristic substance described in this disclosure. In some embodiments, the target-binding moiety binds to a surface, extracellular, and / or intracellular protein, carbohydrate, and / or nucleic acid. In some embodiments, the target-binding moiety binds to a surface protein of a target cell. In some embodiments, the target-binding moiety is a small molecule moiety. In some embodiments, the target-binding moiety is an antibody drug. In some embodiments, the target-binding moiety is a nucleic acid drug, such as an aptamer. In some embodiments, the target-binding moiety is a lipid moiety. Certain types of target-binding moieties are described below; one of skill in the art will understand that other types of target-binding moieties, including many known in the art, can also be utilized in accordance with the present disclosure.

[0167] In some embodiments, the target-binding moiety binds to the target via one or more proteins, lipids, nucleic acids, carbohydrates, small molecules, etc. of the target. For example, in some embodiments, the target-binding moiety binds to a tumor-specific antigen of the target cancer cell. In some embodiments, the tumor-specific antigen is or comprises a carbohydrate or a fragment thereof. In some embodiments, the tumor-specific antigen is or comprises a protein or a fragment thereof.

[0168] a. Small molecules In some embodiments, the target binding moiety is a small molecule moiety. In some embodiments, the small molecule moiety has a molecular weight of 8000, 7000, 6000, 5000, 4000, 3000, 2000, 1500, 1000, 900, 800, 700, or 600 or less. In some embodiments, the small molecule moiety has a molecular weight of 8000 or less. In some embodiments, the small molecule moiety has a molecular weight of 7000 or less. In some embodiments, the small molecule moiety has a molecular weight of 6000 or less. In some embodiments, the small molecule moiety has a molecular weight of 5000 or less. In some embodiments, the small molecule moiety has a molecular weight of 4000 or less. In some embodiments, the small molecule moiety has a molecular weight of 3000 or less. In some embodiments, the small molecule moiety has a molecular weight of 2000 or less. In some embodiments, the small molecule moiety has a molecular weight of 1500 or less. In some embodiments, the small molecule moiety has a molecular weight of 1000 or less. In some embodiments, the small molecule moiety has a molecular weight of 900 or less. In particular, the present disclosure encompasses the recognition that small molecule target binding moieties may be capable of binding to targets, for example, markers on the exterior, surface and / or interior of cancer cells.

[0169] In some embodiments, the small molecule target binding moiety is or comprises a protein or fragment thereof, e.g., a moiety that selectively binds to a cancer antigen. For example, in some embodiments, the target binding moiety is or comprises a moiety that selectively binds to prostate-specific membrane antigen (PSMA). In some embodiments, the target binding moiety is [ka] is or contains

[0170] In some embodiments, the small molecule target binding moiety is or comprises a biotin moiety. In some embodiments, the small molecule target binding moiety is [ka] In some embodiments, the small molecule target binding moiety is or comprises: [ka] is or contains

[0171] b. Peptide drugs In some embodiments, the target-binding moiety is or comprises a peptide agent. In some embodiments, the target-binding moiety is a peptide moiety. In some embodiments, the peptide moiety can be either linear or cyclic. In some embodiments, the target-binding moiety is or comprises a cyclic peptide moiety. A variety of peptide target-binding moieties are known in the art and can be utilized in accordance with the present disclosure.

[0172] In some embodiments, the target binding moiety is or comprises a peptide aptamer agent.

[0173] c. aptamer agent In some embodiments, the target-binding moiety is or comprises a nucleic acid agent. In some embodiments, the target-binding moiety is or comprises an oligonucleotide moiety. In some embodiments, the target-binding moiety is or comprises an aptamer agent. A variety of aptamer agents are known in the art or can be readily developed using common techniques and can be utilized in the techniques provided in accordance with the present disclosure.

[0174] Linker part In some embodiments, the antibody-binding moiety is optionally connected to the target-binding moiety via a linker moiety. Linker moieties of various types and / or for various purposes, such as those utilized in antibody-drug conjugates, can be utilized in accordance with the present disclosure.

[0175] A linker moiety can be either bivalent or multivalent. In some embodiments, the linker moiety is bivalent. In some embodiments, the linker is multivalent, connecting more than two moieties.

[0176] In some embodiments, the linker moiety is L. In some embodiments, L is , a covalent bond, or one or more aliphatic, aryl, or heteroatoms having 1 to 20 heteroatoms Aliphatic, heteroaromatic having 1 to 20 heteroatoms, or any combination thereof Divalent or polyvalent optionally substituted linear or branched C 1-100 It is the basis, One or more methylene units of the group may optionally and independently be C 1-6 alkylene, C 1-6 Alkenylene , divalent C with 1 to 5 heteroatoms 1-6 heteroaliphatic groups, [ka] , -Cy-, -C(R')2-, -O-, -S-, -SS-, -N(R')-, -C( O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -C(O)C(R')2N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, -C(O )O-, -P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, - P(O)(NR')-, -P(S)(OR')-, -P(S)(SR')-, -P(S) (R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')-, -P(NR')-, or -[(-OC(R')2-C(R')2-)n]- (n is 1 to 20).

[0177] In some embodiments, L is divalent. In some embodiments, L is C 1- 00Aliphatic and C with 1-50 heteroatoms 1-100 Selected from heteroaliphatic a divalent or optionally substituted linear or branched group in which one or more methyl groups The units may optionally and independently be C 1-6 alkylene, C 1-6 Alkenylene , 1~5 pieces Divalent C with heteroatoms 1-6 heteroaliphatic groups, [ka] , -Cy-, -C(R')2-, -O-, -S-, -SS-, -N(R')-, -C( O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -C(O)C(R')2N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, -C(O )O-, -P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, - P(O)(NR')-, -P(S)(OR')-, -P(S)(SR')-, -P(S) (R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')-, -P(NR')-, or -[(-OC(R')2-C(R')2-)n]- has been replaced with

[0178] In some embodiments, L is a covalent bond. In some embodiments, L is a divalent optionally substituted linear or branched C 1-100 In some embodiments, L is a divalent optionally substituted linear or branched C 6-100In some embodiments, L is a divalent optionally substituted linear or branched C alkyl group having 1 to 20 heteroatoms. 5-100 In some embodiments, L is a divalent, optionally substituted, linear or branched C alkyl group having 1 to 20 heteroatoms. 1-100 Heteroaliphatic groups are groups in which one or more methylene units are optionally and independently replaced.

[0179] In some embodiments, the linker moiety (e.g., L) is or comprises one or more polyethylene glycol units. In some embodiments, the linker moiety is -(CH2CH2O) n In some embodiments, one or more methylene units of L is or includes -(CH2CH2O) n -. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some embodiments, n is 16. In some embodiments, n is 17. In some embodiments, n is 18. In some embodiments, n is 19. In some embodiments, n is 20.

[0180] In some embodiments, a linker moiety comprises one or more moieties that can be utilized for attachment to other moieties, such as amino, carbonyl, etc. In some embodiments, a linker moiety comprises one or more -NR'- (where R' is as described in this disclosure). In some embodiments, -NR'- improves solubility. In some embodiments, -NR'- serves as a point of attachment to another moiety. In some embodiments, R' is -H. In some embodiments, one or more methylene units of L are independently replaced with -NR'- (where R' is as described in this disclosure).

[0181] In some embodiments, a linker moiety, e.g., L, comprises a -C(O)- group that can be used to connect moieties. In some embodiments, one or more methylene units of L are independently replaced with -C(O)-.

[0182] In some embodiments, the linker moiety is or includes one or more ring moieties, e.g., one or more methylene units of L are replaced with -Cy-. In some embodiments, the linker moiety, e.g., L, includes an aryl ring. In some embodiments, the linker moiety, e.g., L, includes a heteroaryl ring. In some embodiments, the linker moiety, e.g., L, includes an aliphatic ring. In some embodiments, the linker moiety, e.g., L, includes a heterocyclyl ring. In some embodiments, the linker moiety, e.g., L, includes a polycyclic ring. In some embodiments, the ring in the linker moiety, e.g., L, has 3 to 20 members. In some embodiments, the ring is 5-membered. In some embodiments, the ring is 6-membered. In some embodiments, the ring in the linker is the product of a cycloaddition reaction (e.g., click chemistry, and the like) utilized to link different moieties together.

[0183] In some embodiments, the linker moiety (e.g., L) is [ka] In some embodiments, the methylene units of L are or include: [ka] In some embodiments, -Cy- is replaced by [ka] is.

[0184] In some embodiments, the linker moiety is as described in Table 1. Additional linker moieties include, for example, L 2 In some embodiments, L is any of the L groups described in this disclosure. 1 In some embodiments, L is any of the L groups described in this disclosure. 2 In some embodiments, L is any of the L groups described in this disclosure. 3 In some embodiments, L is any of the L groups described in this disclosure. b is.

[0185] In some embodiments, L is [ka] is.

[0186] Certain embodiments of variables By way of example, exemplary embodiments of variables are described throughout this disclosure. As will be understood by one of ordinary skill in the art, embodiments of different variables may be combined in any manner.

[0187] As defined above and described herein, ABT is an antibody binding moiety.

[0188] In some embodiments, the ABT is an antibody binding moiety.

[0189] In some embodiments, the ABT is selected from those depicted in Table 1 below.

[0190] As defined above and described herein, L is a bivalent linker moiety that connects ABT with TBT.

[0191] In some embodiments, L is a bivalent linker moiety that connects ABT with TBT.

[0192] In some embodiments, L is selected from those depicted in Table 1 below.

[0193] As defined above and described herein, TBT is a target binding moiety.

[0194] In some embodiments, TBT is the target binding moiety.

[0195] In some embodiments, the TBT is selected from those depicted in Table 1 below.

[0196] R, as defined above and described herein 1 , R 3 and R 5 each independently represents hydrogen or C 1-6 an optionally substituted group selected from aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring, 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or: R 1 and R 1’optionally, together with their intervening carbon atoms, form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 3 and R 3’ optionally, together with their intervening carbon atoms, form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R bonded to the same carbon atom 5 Groups and R 5’ groups optionally taken together with their intervening carbon atoms form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R 5 The groups, optionally together with their intervening atoms, are C 1-10 forming a divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of the chain are independently and optionally -S-, -SS-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, or -Cy 1 - and each -Cy 1 - is independently a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0197] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is C 1-6is an optionally substituted group selected from aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring, 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 1 is an arbitrarily substituted C 1-6 In some embodiments, R 1 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 1 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 1 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 1 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0198] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0199] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0200] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0201] In some embodiments, R 1 and R 1’ optionally, taken together with their intervening carbon atoms, form a 3-8 membered saturated or partially unsaturated spirocyclic carbocyclic ring. In some embodiments, R 1 and R 1’ optionally, taken together with their intervening carbon atoms, form a 4-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0202] In some embodiments, R 1 is selected from those illustrated in Table 1 below.

[0203] In some embodiments, R is an R group described in this disclosure. 1 In some embodiments, R a2 is the R described in this disclosure 1 In some embodiments, R a3 is the R described in this disclosure 1 is.

[0204] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is C 1-6is an optionally substituted group selected from aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring, 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 3 is an arbitrarily substituted C 1-6 In some embodiments, R 3 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 3 is optionally substituted phenyl. In some embodiments, R 3 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 3 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 3 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 3 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0205] In some embodiments, R 3 is methyl. In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] is.

[0206] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] wherein the attachment site has the (S) stereochemistry. In some embodiments, R 3 teeth, [ka] wherein the attachment site has the (R) stereochemistry. In some embodiments, R 3 teeth, [ka] wherein the attachment site has the (S) stereochemistry. In some embodiments, R 3 teeth, [ka] where the attachment site has the (R) stereochemistry.

[0207] In some embodiments, R 3 teeth, [ka] wherein the attachment site has the (S) stereochemistry. In some embodiments, R 3 teeth, [ka] where the attachment site has the (R) stereochemistry.

[0208] In some embodiments, R 3 and R 3’ optionally, taken together with their intervening carbon atoms, form a 3-8 membered saturated or partially unsaturated spirocyclic carbocyclic ring. In some embodiments, R 3 and R 3’ optionally, taken together with their intervening carbon atoms, form a 4-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0209] In some embodiments, R 3 is selected from those illustrated in Table 1 below.

[0210] In some embodiments, R is an R group described in this disclosure. 2 In some embodiments, R a2 is the R described in this disclosure 2 In some embodiments, R a3 is the R described in this disclosure 2 is.

[0211] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is C 1-6is an optionally substituted group selected from aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring, 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 5 is an arbitrarily substituted C 1-6 In some embodiments, R 5 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 5 is optionally substituted phenyl. In some embodiments, R 5 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 5 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 5 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 5 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0212] In some embodiments, R 5 is methyl. In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] wherein the attachment site has the (S) stereochemistry. In some embodiments, R 5 teeth, [ka] wherein the attachment site has the (R) stereochemistry. In some embodiments, R 5 teeth, [ka] wherein the attachment site has the (S) stereochemistry. In some embodiments, R 5 teeth, [ka] wherein the attachment site has the (R) stereochemistry. In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] is.

[0213] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] is.

[0214] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] is.

[0215] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] is.

[0216] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 4 teeth, [ka] wherein the attachment site has the (S) stereochemistry. In some embodiments, R 4 teeth, [ka] where the attachment site has the (R) stereochemistry.

[0217] In some embodiments, R 5 and R 5’ Groups are optionally joined together with their intervening carbon atoms to form a 3-8 membered saturated or partially unsaturated spirocyclic carbocyclic ring. In some embodiments, R 5 and R 5’ The groups optionally, together with their intervening carbon atoms, form a 4-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0218] In some embodiments, two R 5 The groups, together with their intervening atoms, form C 1-10 forming a divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of the chain are independently and optionally -S-, -SS-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, or -Cy 1 - and each -Cy 1 - is independently a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0219] In some embodiments, two R 5 The groups, together with their intervening atoms, [ka] In some embodiments, two R 5 The groups, together with their intervening atoms, [ka] In some embodiments, two R 5 The groups, together with their intervening atoms, [ka] In some embodiments, two R 5 The groups, together with their intervening atoms, [ka] Form.

[0220] In some embodiments, R 5 is selected from those illustrated in Table 1 below.

[0221] In some embodiments, R is an R group described in this disclosure. 5 In some embodiments, R a2 is the R described in this disclosure 5 In some embodiments, R a3 is the R described in this disclosure 5 is.

[0222] R, as defined above and described herein 1’ , R 3’ and R 5’ each independently represents hydrogen or C 1-3 It is aliphatic.

[0223] In some embodiments, R 1’ is hydrogen. In some embodiments, R 1’ is C 1-3 It is aliphatic.

[0224] In some embodiments, R 1’ is methyl. In some embodiments, R 1’ is ethyl. In some embodiments, R 1’ is n-propyl. In some embodiments, R 1’ is isopropyl. In some embodiments, R 1’ is cyclopropyl.

[0225] In some embodiments, R 1’ is selected from those illustrated in Table 1 below.

[0226] In some embodiments, R 3’ is hydrogen. In some embodiments, R 3’ is C 1-3 It is aliphatic.

[0227] In some embodiments, R 3’ is methyl. In some embodiments, R 3’ is ethyl. In some embodiments, R 3’is n-propyl. In some embodiments, R 3’ is isopropyl. In some embodiments, R 3’ is cyclopropyl.

[0228] In some embodiments, R 3’ is selected from those illustrated in Table 1 below.

[0229] In some embodiments, R 5’ is hydrogen. In some embodiments, R 5’ is C 1-3 It is aliphatic.

[0230] In some embodiments, R 5’ is methyl. In some embodiments, R 5’ is ethyl. In some embodiments, R 5’ is n-propyl. In some embodiments, R 5’ is isopropyl. In some embodiments, R 5’ is cyclopropyl.

[0231] In some embodiments, R 5’ is selected from those illustrated in Table 1 below.

[0232] R, as defined above and described herein 2 , R 4 and R 6 each independently represents hydrogen or C 1-4 Aliphatic or: R 2 and R 1 optionally, together with their intervening atoms, form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 4 and R 3 optionally, together with their intervening atoms, form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R6 group and its adjacent R 5 The groups optionally combine with their intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0233] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is C 1-4 In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is n-propyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is n-butyl. In some embodiments, R 2 is isobutyl. In some embodiments, R 2 is tert-butyl.

[0234] In some embodiments, R 2 and R 1 together with their intervening atoms form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0235] In some embodiments, R 2 and R 1 together with their intervening atoms [ka] In some embodiments, R 2 and R 1 together with their intervening atoms [ka] Form.

[0236] In some embodiments, R 2 is selected from those illustrated in Table 1 below.

[0237] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C 1-4 In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is n-propyl. In some embodiments, R 4 is isopropyl. In some embodiments, R 4 is n-butyl. In some embodiments, R 4 is isobutyl. In some embodiments, R 4 is tert-butyl.

[0238] In some embodiments, R 4 and R 3 together with their intervening atoms form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0239] In some embodiments, R 4 and R 3 together with their intervening atoms [ka] In some embodiments, R 4 and R 3 together with their intervening atoms [ka] Form.

[0240] In some embodiments, R 4 is selected from those illustrated in Table 1 below.

[0241] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is C 1-4 In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl. In some embodiments, R 6 is n-propyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is n-butyl. In some embodiments, R 6 is isobutyl. In some embodiments, R 6 is tert-butyl.

[0242] In some embodiments, R 6 group and its adjacent R 5 The groups, taken together with their intervening atoms, form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0243] In some embodiments, R 6 group and its adjacent R 5 The groups, together with their intervening atoms, [ka] In some embodiments, R 6 group and its adjacent R 5 The groups, together with their intervening atoms, [ka] Form.

[0244] In some embodiments, R6 is selected from those illustrated in Table 1 below.

[0245] In some embodiments, R is an R group described in this disclosure. 1’ In some embodiments, R a2 is the R described in this disclosure 1’ In some embodiments, R a3 is the R described in this disclosure 1’ In some embodiments, R is an R group described in this disclosure. 3’ In some embodiments, R a2 is the R described in this disclosure 3’ In some embodiments, R a3 is the R described in this disclosure 3’ In some embodiments, R is an R group described in this disclosure. 2 In some embodiments, R a2 is the R described in this disclosure 2 In some embodiments, R a3 is the R described in this disclosure 2 In some embodiments, R is an R group described in this disclosure. 4 In some embodiments, R a2 is the R described in this disclosure 4 In some embodiments, R a3 is the R described in this disclosure 4 In some embodiments, R is an R group described in this disclosure. 6 In some embodiments, R a2 is the R described in this disclosure 6 In some embodiments, R a3 is the R described in this disclosure 6 is.

[0246] As defined above and described herein, L 1 teeth, [ka] is a trivalent linker moiety that connects

[0247] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] is.

[0248] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] is.

[0249] In some embodiments, L 1 is selected from those illustrated in Table 1 below.

[0250] As defined above and described herein, L 2 is a covalent bond or C 1-10 A divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of the chain are independently and optionally selected from the group consisting of -S-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, [ka] or -Cy 1 - and each -Cy 1- is independently a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0251] In some embodiments, L 2 is a covalent bond. In some embodiments, L 2 is C 1-10 A divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of the chain are independently and optionally selected from the group consisting of -S-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, [ka] or -Cy 1 - and each -Cy 1 - is independently a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0252] In some embodiments, L 2 teeth, [ka] In some embodiments, L 2 teeth, [ka] In some embodiments, L 2 teeth, [ka] In some embodiments, L 2 teeth, [ka] In some embodiments, L 2teeth, [ka] In some embodiments, L 2 teeth, [ka] is.

[0253] In some embodiments, L 2 is selected from those illustrated in Table 1 below.

[0254] In some embodiments, L is any of the L groups described in this disclosure. 2 is.

[0255] As defined above and described herein, TBT is a target binding moiety.

[0256] In some embodiments, TBT is the target binding moiety.

[0257] In some embodiments, TBT is [ka] In some embodiments, TBT is [ka] is.

[0258] In some embodiments, the TBT is selected from those depicted in Table 1 below.

[0259] As defined above and described herein, each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0260] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

[0261] In some embodiments, m is selected from those depicted in Table 1 below.

[0262] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10.

[0263] In some embodiments, n is selected from those depicted in Table 1 below.

[0264] R, as defined above and described herein 7 each independently represents hydrogen or C 1-6 an optionally substituted group selected from aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring, 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or: R bonded to the same carbon atom 7 Groups and R 7’Groups optionally combine with their intervening carbon atoms to form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0265] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is C 1-6 is an optionally substituted group selected from aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring, 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 7 is an arbitrarily substituted C 1-6 In some embodiments, R 7 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 7 is optionally substituted phenyl. In some embodiments, R 7 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 7 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 7 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 7 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0266] In some embodiments, R 7 is methyl. In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0267] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0268] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0269] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0270] In some embodiments, R 7 Groups and R 7’ The R groups, taken together with their intervening carbon atoms, form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring. In some embodiments, R groups attached to the same carbon atom 7 Groups and R 7’ The groups together with their intervening carbon atoms form a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0271] In some embodiments, R 7 is selected from those illustrated in Table 1 below.

[0272] R, as defined above and described herein 7’ each independently represents hydrogen or C 1-3 It is aliphatic.

[0273] In some embodiments, R 7’is hydrogen. In some embodiments, R 7’ is methyl. In some embodiments, R 7’ is ethyl. In some embodiments, R 7’ is n-propyl. In some embodiments, R 7’ is isopropyl.

[0274] In some embodiments, R 7’ is selected from those illustrated in Table 1 below.

[0275] R, as defined above and described herein 8 each independently represents hydrogen or C 1-4 Aliphatic or: R 8 group and its adjacent R 7 The groups optionally combine with their intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0276] In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is C 1-4 In some embodiments, R 8 is methyl. In some embodiments, R 8 is ethyl. In some embodiments, R 8 is n-propyl. In some embodiments, R 8 is isopropyl. In some embodiments, R 8 is n-butyl. In some embodiments, R 8 is isobutyl. In some embodiments, R 8 is tert-butyl.

[0277] In some embodiments, R 8 group and its adjacent R 7The groups, taken together with their intervening atoms, form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0278] In some embodiments, R 8 group and its adjacent R 7 The groups, together with their intervening atoms, [ka] In some embodiments, R 8 group and its adjacent R 7 The groups, together with their intervening atoms, [ka] Form.

[0279] In some embodiments, R 8 is selected from those illustrated in Table 1 below.

[0280] R, as defined above and described herein 9 is hydrogen, C 1-3 Aliphatic, or -C(O)C 1-3 It is aliphatic.

[0281] In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is C 1-3 In some embodiments, R 9 is -C(O)C 1-3 It is aliphatic.

[0282] In some embodiments, R 9 is methyl. In some embodiments, R 9 is ethyl. In some embodiments, R 9 is n-propyl. In some embodiments, R 9is isopropyl. In some embodiments, R 9 is cyclopropyl.

[0283] In some embodiments, R 9 is —C(O)Me. In some embodiments, R 9 is —C(O)Et. In some embodiments, R 9 is —C(O)CH CH CH. In some embodiments, R 9 is —C(O)CH(CH). In some embodiments, R 9 is —C(O)cyclopropyl.

[0284] In some embodiments, R 9 is selected from those illustrated in Table 1 below.

[0285] In some embodiments, R is an R group described in this disclosure. 7 In some embodiments, R a2 is the R described in this disclosure 7 In some embodiments, R a3 is the R described in this disclosure 7 In some embodiments, R is an R group described in this disclosure. 7’ In some embodiments, R a2 is the R described in this disclosure 7 In some embodiments, R a3 is the R described in this disclosure 7 In some embodiments, R is an R group described in this disclosure. 8 In some embodiments, R a2 is the R described in this disclosure 8 In some embodiments, R a3 is the R described in this disclosure 8 In some embodiments, R is an R group described in this disclosure. 8’ In some embodiments, R a2 is the R described in this disclosure 8 In some embodiments, Ra3 is the R described in this disclosure 8 In some embodiments, R is an R group described in this disclosure. 9 In some embodiments, R a2 is the R described in this disclosure 9 In some embodiments, R a3 is the R described in this disclosure 9 is.

[0286] As defined above and described herein, L 3 teeth, [ka] is a bivalent linker moiety that connects the to TBT.

[0287] In some embodiments, L 3 teeth, [ka] is a bivalent linker moiety that connects the to TBT.

[0288] In some embodiments, L 3 teeth, [ka] In some embodiments, L 3 teeth, [ka] In some embodiments, L 3 teeth, [ka] In some embodiments, L 3 teeth, [ka] In some embodiments, L 3 teeth, [ka] In some embodiments, L 3 teeth, [ka] is.

[0289] In some embodiments, L 3 is selected from those illustrated in Table 1 below.

[0290] In some embodiments, L is any of the L groups described in this disclosure. 3 is.

[0291] As defined above and described herein, o is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0292] In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4. In some embodiments, o is 5. In some embodiments, o is 6. In some embodiments, o is 7. In some embodiments, o is 8. In some embodiments, o is 9. In some embodiments, o is 10.

[0293] In some embodiments, o is selected from those depicted in Table 1 below.

[0294] In certain embodiments, the present invention provides a compound of formula II, wherein L 2 teeth, [ka] and TBT is [ka] which gives a compound of formula II-a: [ka] or a pharmaceutically acceptable salt thereof, 1 , R 1 , R 1’ , R 2 , R 3 , R 3’ , R 4 , R 5 , R 5’ , R 6 and m, both alone or in combination, are as defined above and as described in the embodiments herein.

[0295] In certain embodiments, the present invention provides a compound of formula II, wherein L 2 teeth, [ka] and TBT is [ka] which gives a compound of formula II-b: [ka] or a pharmaceutically acceptable salt thereof, 1 , R 1 , R 1’ , R 2 , R 3 , R 3’ , R 4 , R 5 , R 5’ , R 6and m, both alone or in combination, are as defined above and as described in the embodiments herein.

[0296] In certain embodiments, the present invention provides a compound of formula II, wherein L 2 teeth, [ka] and TBT is [ka] which gives a compound of formula II-c: [ka] or a pharmaceutically acceptable salt thereof, 1 , R 1 , R 1’ , R 2 , R 3 , R 3’ , R 4 , R 5 , R 5’ , R 6 and m, both alone or in combination, are as defined above and as described in the embodiments herein.

[0297] In certain embodiments, the present invention provides a compound of formula II, wherein L 2 teeth, [ka] and TBT is [ka] which results in a compound of formula II-d: [ka] or a pharmaceutically acceptable salt thereof, 1, R 1 , R 1’ , R 2 , R 3 , R 3’ , R 4 , R 5 , R 5’ , R 6 and m, both alone or in combination, are as defined above and as described in the embodiments herein.

[0298] In certain embodiments, the present invention provides a compound of formula II, wherein L 2 teeth, [ka] and TBT is [ka] which results in a compound of formula II-e: [ka] or a pharmaceutically acceptable salt thereof, 1 , R 1 , R 1’ , R 2 , R 3 , R 3’ , R 4 , R 5 , R 5’ , R 6 and m, both alone or in combination, are as defined above and as described in the embodiments herein.

[0299] In certain embodiments, the present invention provides a compound of formula II, wherein L 2 teeth, [ka] and TBT is [ka] which results in a compound of formula II-f: [ka] or a pharmaceutically acceptable salt thereof, 1 , R 1 , R 1’ , R 2 , R 3 , R 3’ , R 4 , R 5 , R 5’ , R 6 and m, both alone or in combination, are as defined above and as described in the embodiments herein.

[0300] In some embodiments, R a1 is R as described in this disclosure. In some embodiments, R a1 is an arbitrarily substituted C 1-4 It is aliphatic.

[0301] In some embodiments, L a1 is the L described in this disclosure a In some embodiments, L a1 is a covalent bond.

[0302] In some embodiments, L a2 is the L described in this disclosure a In some embodiments, L a2 is a covalent bond.

[0303] In some embodiments, L a is a covalent bond. In some embodiments, L a is C1~C 10 Aliphatic or C1-C with 1-5 heteroatoms 10heteroaliphatic, wherein one or more methylene units of the group are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-. In some embodiments, L a is an optionally substituted divalent group selected from C1-C5 aliphatic or C1-C5 heteroaliphatic having 1-5 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-. In some embodiments, L a is an optionally substituted divalent C1-C5 aliphatic group in which one or more methylene units are optionally and independently replaced with -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-. In some embodiments, L a is an optionally substituted divalent C1-C5 aliphatic. In some embodiments, L a is an optionally substituted divalent C1-C5 heteroaliphatic having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0304] In some embodiments, R a2 is R as described in this disclosure. In some embodiments, R a2 is the side chain of a natural amino acid. In some embodiments, Ra3 is R as described in this disclosure. In some embodiments, R a3 is the side chain of a natural amino acid. In some embodiments, R 2a and R 3a One of them is hydrogen.

[0305] In some embodiments, each -Cy- is independently C 3-20 Alicyclic ring, C 6-20 An optionally substituted divalent group selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, -Cy- is, for example, a substituted or unsubstituted divalent group selected from R and Cy. L is an optionally substituted ring as described in this disclosure, but is divalent.

[0306] In some embodiments, -Cy- is monocyclic. In some embodiments, -Cy- is bicyclic. In some embodiments, -Cy- is polycyclic. In some embodiments, -Cy- is saturated. In some embodiments, -Cy- is partially unsaturated. In some embodiments, -Cy- is aromatic. In some embodiments, -Cy- comprises a saturated cyclic moiety. In some embodiments, -Cy- comprises a partially unsaturated cyclic moiety. In some embodiments, -Cy- comprises an aromatic cyclic moiety. In some embodiments, -Cy- comprises a combination of saturated, partially unsaturated, and / or aromatic cyclic moieties. In some embodiments, -Cy- is 3-membered. In some embodiments, -Cy- is 4-membered. In some embodiments, -Cy- is 5-membered. In some embodiments, -Cy- is 6-membered. In some embodiments, -Cy- is 7-membered. In some embodiments, -Cy- is 8-membered. In some embodiments, -Cy- is 9-membered. In some embodiments, -Cy- is 10-membered. In some embodiments, -Cy- is 11-membered. In some embodiments, -Cy- is 12-membered. In some embodiments, -Cy- is 13-membered. In some embodiments, -Cy- is 14-membered. In some embodiments, -Cy- is 15-membered. In some embodiments, -Cy- is 16-membered. In some embodiments, -Cy- is 17-membered. In some embodiments, -Cy- is 18-membered. In some embodiments, -Cy- is 19-membered. In some embodiments, -Cy- is 20-membered.

[0307] In some embodiments, -Cy- is an optionally substituted divalent C 3-20 In some embodiments, -Cy- is an optionally substituted divalent saturated C 3-20 In some embodiments, -Cy- is an optionally substituted divalent moiety unsaturated C 3-20 In some embodiments, -Cy-H is an optionally substituted alicyclic ring as described in this disclosure, e.g., the alicyclic embodiments for R.

[0308] In some embodiments, -Cy- is optionally substituted C 6-20 In some embodiments, -Cy- is an optionally substituted phenylene. In some embodiments, -Cy- is an optionally substituted 1,2-phenylene. In some embodiments, -Cy- is an optionally substituted 1,3-phenylene. In some embodiments, -Cy- is an optionally substituted 1,4-phenylene. In some embodiments, -Cy- is an optionally substituted divalent naphthalene ring. In some embodiments, -Cy-H is an optionally substituted aryl as described in the present disclosure, e.g., the aryl embodiments for R.

[0309] In some embodiments, -Cy- is an optionally substituted divalent 5- to 20-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, -Cy- is an optionally substituted divalent 5- to 20-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5-6 membered heteroaryl ring having one heteroatom independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy-H is an optionally substituted heteroaryl as described in this disclosure, e.g., the heteroaryl embodiments for R. In some embodiments, -Cy- is [ka] is.

[0310] In some embodiments, -Cy- is an optionally substituted divalent 3- to 20-membered heterocyclyl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, -Cy- is an optionally substituted divalent 3- to 20-membered heterocyclyl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 3- to 6-membered heterocyclyl ring having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heterocyclyl ring having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heterocyclyl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heterocyclyl ring having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heterocyclyl ring having 1 heteroatom independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted saturated divalent heterocyclyl group. In some embodiments, -Cy- is an optionally substituted partially unsaturated divalent heterocyclyl group. In some embodiments, -Cy-H is an optionally substituted heterocyclyl as described herein, e.g., in the heterocyclyl embodiments for R.

[0311] In some embodiments, each Xaa is independently an amino acid residue. In some embodiments, each Xaa is independently an amino acid residue of an amino acid of formula AI.

[0312] In some embodiments, t is 0. In some embodiments, t is 1 to 50. In some embodiments, t is z as described in this disclosure.

[0313] In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 5. In some embodiments, z is 6. In some embodiments, z is 7. In some embodiments, z is 8. In some embodiments, z is 9. In some embodiments, z is 10. In some embodiments, z is 11. In some embodiments, z is 12. In some embodiments, z is 13. In some embodiments, z is 14. In some embodiments, z is 15. In some embodiments, z is 16. In some embodiments, z is 17. In some embodiments, z is 18. In some embodiments, z is 19. In some embodiments, z is 20. In some embodiments, z is greater than 20.

[0314] In some embodiments, R c is R' as described in this disclosure. In some embodiments, R c is R as described in this disclosure. In some embodiments, R c is -N(R')2, where each R' is independently as described in this disclosure. In some embodiments, R c is -NH. In some embodiments, R c is RC(O)—, where R is as described in this disclosure.

[0315] In some embodiments, a is 1. In some embodiments, a is 2 to 100. In some embodiments, a is 5. In some embodiments, a is 10. In some embodiments, a is 20. In some embodiments, a is 50.

[0316] In some embodiments, b is 1. In some embodiments, b is 2 to 100. In some embodiments, b is 5. In some embodiments, b is 10. In some embodiments, b is 20. In some embodiments, b is 50.

[0317] In some embodiments, a1 is 0. In some embodiments, a1 is 1.

[0318] In some embodiments, a2 is 0. In some embodiments, a2 is 1.

[0319] In some embodiments, L b is the L described in this disclosure a In some embodiments, L b In some embodiments, L b In some embodiments, L b In some embodiments, L b In some embodiments, L b includes -C(O)-N(R')-.

[0320] In some embodiments, R' is -R, -C(O)R, -C(O)OR, or -S(O)R (R is as described in this disclosure). In some embodiments, R' is R (R is as described in this disclosure). In some embodiments, R' is -C(O)R (R is as described in this disclosure). In some embodiments, R' is -C(O)OR (R is as described in this disclosure). In some embodiments, R' is -S(O)R (R is as described in this disclosure). In some embodiments, R' is hydrogen. In some embodiments, R' is not hydrogen. In some embodiments, R' is R (R is an optionally substituted C(O) group as described in this disclosure). 1-20In some embodiments, R' is R (wherein R is an optionally substituted C 1-20 In some embodiments, R' is R (wherein R is an optionally substituted C alkyl group as described in this disclosure). 6-20 In some embodiments, R' is R (wherein R is an optionally substituted C aryl as described in this disclosure). 6-20 In some embodiments, R' is R (wherein R is an optionally substituted C alkyl group as described herein). 6-20 In some embodiments, R' is R (where R is an optionally substituted 5-20 membered heteroaryl as described in this disclosure). In some embodiments, R' is R (where R is an optionally substituted 3-20 membered heterocyclyl as described in this disclosure). In some embodiments, two or more R' are R, optionally and independently, joined together to form an optionally substituted ring as described herein.

[0321] In some embodiments, each R is independently —H, or C 1-30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6-30 an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or Two R groups optionally and independently together form a covalent bond, or: two or more R groups on the same atom optionally and independently combine with that atom to form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to that atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or Two or more R groups on two or more atoms may optionally and independently be taken together with their intervening atoms to form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0322] In some embodiments, each R is independently —H, or C 1-30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6-30 an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or Two R groups optionally and independently together form a covalent bond, or: two or more R groups on the same atom optionally and independently combine with that atom to form an optionally substituted 3-30 membered monocyclic, bicyclic, or polycyclic ring having, in addition to that atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; Two or more R groups on two or more atoms may optionally and independently be taken together with their intervening atoms to form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0323] In some embodiments, each R is independently —H, or C 1-20 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1-20 Heteroaliphatic, C 6-20 Aryl, C 6-20 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6-20 an optionally substituted group selected from arylheteroaliphatic, 5-20 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-20 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or Two R groups optionally and independently together form a covalent bond, or: two or more R groups on the same atom optionally and independently combine with that atom to form an optionally substituted 3-20 membered monocyclic, bicyclic, or polycyclic ring having, in addition to that atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; Two or more R groups on two or more atoms may optionally and independently be taken together with their intervening atoms to form an optionally substituted 3- to 20-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0324] In some embodiments, each R is independently —H, or C 1-30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6-30Aryl is an optionally substituted group selected from heteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0325] In some embodiments, each R is independently —H, or C 1-20 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1-20 Heteroaliphatic, C 6-20 Aryl, C 6-20 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6-20 Aryl is an optionally substituted group selected from heteroaliphatic, 5-20 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-20 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0326] In some embodiments, R is hydrogen. In some embodiments, R is not hydrogen. In some embodiments, R is C 1-30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1-30 Heteroaliphatic, C 6-30 An optionally substituted group selected from a 5- to 30-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from aryl, oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3- to 30-membered heterocyclic ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0327] In some embodiments, R is hydrogen or C 1-20an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, an 8- to 10-membered bicyclic saturated, partially unsaturated or aryl ring, a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0328] In some embodiments, R is optionally substituted C 1-30 In some embodiments, R is an optionally substituted C 1-20 In some embodiments, R is an optionally substituted C 1-15 In some embodiments, R is an optionally substituted C 1-10 In some embodiments, R is an optionally substituted C 1-6 In some embodiments, R is an optionally substituted C 1-6In some embodiments, R is an optionally substituted hexyl, pentyl, butyl, propyl, ethyl, or methyl. In some embodiments, R is an optionally substituted hexyl. In some embodiments, R is an optionally substituted pentyl. In some embodiments, R is an optionally substituted butyl. In some embodiments, R is an optionally substituted propyl. In some embodiments, R is an optionally substituted ethyl. In some embodiments, R is an optionally substituted methyl ...

[0329] In some embodiments, R is optionally substituted C 3-30 In some embodiments, R is an optionally substituted C 3-20 In some embodiments, R is an optionally substituted C 3-10 In some embodiments, R is an optionally substituted cyclohexyl. In some embodiments, R is an optionally substituted cyclohexyl. In some embodiments, R is an optionally substituted cyclopentyl. In some embodiments, R is an optionally substituted cyclopentyl. In some embodiments, R is an optionally substituted cyclobutyl. In some embodiments, R is an optionally substituted cyclopropyl. In some embodiments, R is an optionally substituted cyclopropyl.

[0330] In some embodiments, R is an optionally substituted 3-30 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 3 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 4 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 5 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 6 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted cycloheptyl. In some embodiments, R is cycloheptyl. In some embodiments, R is an optionally substituted cyclohexyl. In some embodiments, R is cyclohexyl. In some embodiments, R is an optionally substituted cyclopentyl. In some embodiments, R is cyclopentyl. In some embodiments, R is optionally substituted cyclobutyl. In some embodiments, R is cyclobutyl. In some embodiments, R is optionally substituted cyclopropyl. In some embodiments, R is cyclopropyl.

[0331] In some embodiments, when R is or includes a ring structure, e.g., alicyclic, cycloheteroaliphatic, aryl, heteroaryl, etc., the ring structure can be monocyclic, bicyclic, or polycyclic. In some embodiments, R is or includes a monocyclic structure. In some embodiments, R is or includes a bicyclic structure. In some embodiments, R is or includes a polycyclic structure.

[0332] In some embodiments, R is an optionally substituted C group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-30In some embodiments, R is an optionally substituted C alkyl group having 1 to 10 heteroatoms. 1-20 In some embodiments, R is an optionally substituted C alkyl group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, or silicon, optionally including one or more oxidized forms of nitrogen, sulfur, phosphorus, or serine. 1-20 In some embodiments, R is [ka] optionally substituted C containing 1 to 10 groups independently selected from 1-30 It is heteroaliphatic.

[0333] In some embodiments, R is optionally substituted C 6-30 In some embodiments, R is aryl. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is phenyl. In some embodiments, R is substituted phenyl.

[0334] In some embodiments, R is an optionally substituted 8-10 membered bicyclic saturated, partially unsaturated, or aryl ring. In some embodiments, R is an optionally substituted 8-10 membered bicyclic saturated ring. In some embodiments, R is an optionally substituted 8-10 membered bicyclic partially unsaturated ring. In some embodiments, R is an optionally substituted 8-10 membered aryl ring. In some embodiments, R is optionally substituted naphthyl.

[0335] In some embodiments, R is an optionally substituted 5-30 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted 5-30 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is an optionally substituted 5-30 membered heteroaryl ring having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted 5-30 membered heteroaryl ring having 1-5 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0336] In some embodiments, R is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an unsubstituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, R is a substituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an unsubstituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0337] In some embodiments, R is an optionally substituted 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0338] In some embodiments, R is an optionally substituted 5-membered monocyclic heteroaryl ring having one heteroatom selected from nitrogen, oxygen, and sulfur, hi some embodiments, R is an optionally substituted pyrrolyl, furanyl, or thienyl.

[0339] In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5-membered heteroaryl ring having one nitrogen atom and an additional heteroatom independently selected from sulfur or oxygen. In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having four heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0340] In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1 to 4 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1 to 3 nitrogen atoms. In other embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1 to 2 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 4 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 3 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 2 nitrogen atoms. In certain embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1 nitrogen atom.

[0341] In certain embodiments, R is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 6,6-fused heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0342] In some embodiments, R is a 3-30 membered heterocyclic ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is a 3-30 membered heterocyclic ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is a 3-30 membered heterocyclic ring having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is a 3-30 membered heterocyclic ring having 1-5 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0343] In some embodiments, R is an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an unsubstituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5- to 7-membered partially unsaturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5- to 6-membered partially unsaturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 6-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 7-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 3-membered heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 4-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 7-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0344] In some embodiments, R is an optionally substituted 3-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 4-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0345] In certain embodiments, R is an optionally substituted 5-6 membered partially unsaturated monocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted tetrahydropyridinyl, dihydrothiazolyl, dihydrooxazolyl, or oxazolinyl group.

[0346] In some embodiments, R is an optionally substituted 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted indolinyl. In some embodiments, R is an optionally substituted isoindolinyl. In some embodiments, R is an optionally substituted 1,2,3,4-tetrahydroquinolinyl. In some embodiments, R is an optionally substituted 1,2,3,4-tetrahydroisoquinolinyl. In some embodiments, R is an optionally substituted azabicyclo[3.2.1]octanyl.

[0347] In some embodiments, R is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0348] In some embodiments, R is optionally substituted C 6-30 In some embodiments, R is an optionally substituted C 6-20 In some embodiments, R is an optionally substituted C 6-10 It is an arylaliphatic. In some embodiments, the aryl portion of the arylaliphatic has 6, 10, or 14 aryl carbon atoms. In some embodiments, the aryl portion of the arylaliphatic has 6 aryl carbon atoms. In some embodiments, the aryl portion of the arylaliphatic has 10 aryl carbon atoms. In some embodiments, the aryl portion of the arylaliphatic has 14 aryl carbon atoms. In some embodiments, the aryl portion is an optionally substituted phenyl.

[0349] In some embodiments, R is an optionally substituted C group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 6-30 In some embodiments, R is an optionally substituted C aryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. 6-30 In some embodiments, R is an optionally substituted C alkyl group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 6-20 In some embodiments, R is an optionally substituted C aryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. 6-20In some embodiments, R is an optionally substituted C alkyl group having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 6-10 In some embodiments, R is an optionally substituted C aryl having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, and sulfur. 6-10 Arylheteroaliphatic.

[0350] In some embodiments, two R groups optionally and independently join together to form a covalent bond. In some embodiments, -C=O is formed. In some embodiments, -C=C- is formed. In some embodiments, [ka] is formed.

[0351] In some embodiments, two or more R groups on the same atom optionally and independently combine with that atom to form an optionally substituted 3-30 membered monocyclic, bicyclic, or polycyclic ring having, in addition to that atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, two or more R groups on the same atom optionally and independently combine with that atom to form an optionally substituted 3-20 membered monocyclic, bicyclic, or polycyclic ring having, in addition to that atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, two or more R groups on the same atom optionally and independently combine with that atom to form an optionally substituted 3-10 membered monocyclic, bicyclic, or polycyclic ring having, in addition to that atom, 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, two or more R groups on the same atom optionally and independently combine with that atom to form an optionally substituted 3-6 membered monocyclic, bicyclic, or polycyclic ring having, in addition to that atom, 0-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, two or more R groups on the same atom optionally and independently combine with that atom to form an optionally substituted 3-5 membered monocyclic, bicyclic, or polycyclic ring having, in addition to that atom, 0-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0352] In some embodiments, two or more R groups on two or more atoms optionally and independently combine with their intervening atoms to form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, two or more R groups on two or more atoms optionally and independently combine with their intervening atoms to form an optionally substituted 3- to 20-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, two or more R groups on two or more atoms optionally and independently combine with their intervening atoms to form an optionally substituted 3- to 10-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, two or more R groups on two or more atoms optionally and independently combine with their intervening atoms to form an optionally substituted 3- to 10-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, two or more R groups on two or more atoms optionally and independently combine with their intervening atoms to form an optionally substituted 3- to 6-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, two or more R groups on two or more atoms optionally and independently combine with their intervening atoms to form an optionally substituted 3- to 5-membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0353] In some embodiments, heteroatoms in an R group or in the structure formed by two or more R groups taken together are selected from oxygen, nitrogen, and sulfur. In some embodiments, the ring formed is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 members. In some embodiments, the ring formed is saturated. In some embodiments, the ring formed is partially saturated. In some embodiments, the ring formed is aromatic. In some embodiments, the ring formed contains saturated, partially saturated, or aromatic ring moieties. In some embodiments, the ring formed contains 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 aromatic ring atoms. In some embodiments, the ring formed contains no more than 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 aromatic ring atoms. In some embodiments, the aromatic ring atoms are selected from carbon, nitrogen, oxygen, and sulfur.

[0354] In some embodiments, the ring formed by two or more R groups (or two or more groups selected from the variables that can be R and R) taken together is C 3-30 Alicyclic, C 6-30 aryl, a 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, or a 3- to 30-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, a ring as described for R, but which is divalent or polyvalent.

[0355] Exemplary compounds of the present invention are shown in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17]

[0356] In some embodiments, the present invention provides a compound shown in Table 1 above, or a pharmaceutically acceptable salt thereof.

[0357] 4. General Methods of Providing the Compounds The compounds of the invention may generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for similar compounds and by methods detailed in the Examples herein.

[0358] In the following schemes where specific protecting groups ("PG"), leaving groups ("LG"), or transformation conditions are illustrated, one of skill in the art will understand that other protecting groups, leaving groups, and transformation conditions are also suitable and contemplated. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M.B. Smith and J. March, 5 th Edition,John Wiley & Sons,2001,Comprehensive Organic Transformations,RCLarock,2 nd Edition, John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, TWGreene and PGMWuts, 3 rd edition, John Wiley & Sons, 1999, each of which is incorporated herein by reference in its entirety.

[0359] As used herein, the phrase "leaving group" (LG) includes, but is not limited to, halogen (e.g., fluoride, chloride, bromide, iodide), sulfonate (e.g., mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like.

[0360] As used herein, the phrase "oxygen protecting group" includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those described in, for example, Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3 rdedition, John Wiley & Sons, 1999, which is incorporated herein by reference in its entirety. Examples of suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formate, benzoylformate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethoxyacetyl), crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.

[0361] Amino protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference in its entirety. Suitable amino-protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allylamines, amides, and the like. Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.

[0362] Those skilled in the art will understand that compounds of Formula I, II, or III may contain one or more stereocenters and may exist as racemic or diastereomeric mixtures. Those skilled in the art will also recognize that there are many methods known in the art for stereoenriching these compounds or separating isomers to obtain stereopure isomers, including, but not limited to, HPLC, chiral HPLC, fractional crystallization of diastereomeric salts, kinetic enzymatic resolution (e.g., by lipases or esterases of fungal, bacterial, or animal origin), and formation of covalent diastereomeric derivatives using enantiomerically enriching reagents.

[0363] Those skilled in the art will appreciate that the various functional groups present in the compounds of the present invention, such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens, and nitriles, can be interconverted by techniques well known in the art, including, but not limited to, reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. See "March's Advanced Organic Chemistry," 5 th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, which is incorporated herein by reference in its entirety. Such interconversions may require one or more of the techniques described above, and certain methods for synthesizing compounds of the invention are described below in the Examples.

[0364] In some embodiments, the present disclosure provides compounds useful for preparing ARMs. In some embodiments, the present disclosure provides compounds useful for constructing ARM molecules via cycloaddition reactions, such as click chemistry or the like.

[0365] In some embodiments, the present disclosure provides a compound having the structure of Formula IV: [ka] or a salt thereof (wherein ABT is the antibody binding moiety; L is a linker moiety; R d -L a -R'(where R d includes -C≡C- or -N3); Each L a are independently a covalent bond or C1 to C 20 Aliphatic or C1-C with 1-5 heteroatoms 20an optionally substituted divalent radical selected from heteroaliphatic, wherein one or more methylene units of the radical are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-; Each -Cy- is independently C 3-20 Alicyclic ring, C 6-20 an optionally substituted divalent group selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; each R' is independently -R, -C(O)R, -CO2R, or -SO2R; Each R is independently -H, or C 1-30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6-30 an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or Two R groups optionally and independently together form a covalent bond, or: two or more R groups on the same atom optionally and independently combine with that atom to form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to that atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or two or more R groups on two or more atoms optionally and independently combine with their intervening atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0366] In some embodiments, the present disclosure provides a compound of formula IV-a: [ka] or a salt thereof, wherein each variable is independently as described in this disclosure.

[0367] In some embodiments, the present disclosure provides a compound of formula IV-b: [ka] or a salt thereof, wherein each variable is independently as described in this disclosure.

[0368] In some embodiments, the present disclosure provides a compound of formula IV-c: [ka] or a salt thereof, wherein each variable is independently as described in this disclosure.

[0369] In some embodiments, the present disclosure provides a compound of formula IV-d: [ka] or a salt thereof, wherein each variable is independently as described in this disclosure.

[0370] In some embodiments, the present disclosure provides a compound of formula V: [ka] or a salt thereof, wherein each variable is independently as described in this disclosure.

[0371] In some embodiments, the present disclosure provides a method for preparing a compound, comprising: providing a compound of formula IV, IV-a, IV-b, IV-c, or IV-d or a salt thereof, which compound comprises a first reactive moiety; providing a second compound of formula V or a salt thereof comprising a second reactive moiety; and reacting a first compound with a second compound, wherein the first reactive moiety reacts with the second reactive moiety via a cycloaddition reaction; The present invention provides a method comprising:

[0372] Many cycloaddition reactions can be utilized in accordance with the present disclosure. In some embodiments, the cycloaddition reaction is a [4+2] reaction. In some embodiments, the cycloaddition reaction is a [3+2] reaction. In some embodiments, the [3+2] reaction is a click chemistry reaction. In some embodiments, the first reactive moiety is -C≡C- and the second reactive moiety is -N3. In some embodiments, the first reactive moiety is -N3 and the second reactive moiety is -C≡C-.

[0373] 5. Uses, Formulation and Administration Pharmaceutically acceptable compositions According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the composition of the present invention is such that it is effective to selectively redirect endogenous antibodies to diseased cells, e.g., cancer cells, thereby inducing antibody-induced cell-mediated immunity, e.g., cytotoxicity. In certain embodiments, the amount of compound in the composition of the present invention is such that it is effective to selectively redirect endogenous antibodies to cancer cells, thereby inducing antibody-induced cell-mediated cytotoxicity in a biological sample or patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0374] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0375] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, saturated vegetable fatty acids such as glycine, sorbic acid, potassium sorbate, and protamine sulfate, water, partial glyceride mixtures of salts or electrolytes, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0376] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the invention that is capable, upon administration to a recipient, of providing, either directly or indirectly, a compound of the invention or an inhibitory active metabolite or residue thereof.

[0377] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Sterile, fixed oils are also conventionally used as solvents or suspending media.

[0378] For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides.Fatty acids such as oleic acid and its glyceride derivatives are useful for preparing injectables, as well as natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions.These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions or suspensions.Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0379] The pharmaceutically acceptable composition of the present invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include lactose and cornstarch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dry cornstarch.When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents.If desired, certain sweeteners, flavorings or coloring agents can also be added.

[0380] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum and releasing the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0381] The pharmaceutically acceptable compositions of this invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0382] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0383] For topical application, the provided pharmaceutically acceptable composition can be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.Alternatively, the provided pharmaceutically acceptable composition can be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0384] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, either with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated in an ointment, such as petrolatum.

[0385] The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0386] Most preferably, the pharmaceutically acceptable composition of the present invention is formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable composition of the present invention is administered without food. In other embodiments, the pharmaceutically acceptable composition of the present invention is administered with food.

[0387] The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0388] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the invention in the composition will also depend on the particular compound in the composition.

[0389] Uses of the Compounds and Pharmaceutically Acceptable Compositions The compounds and compositions described herein are generally useful for selectively redirecting endogenous antibodies to diseased cells, e.g., cancer cells, thereby eliciting antibody-induced cell-mediated immune responses, e.g., cytotoxicity.

[0390] In some embodiments, the present disclosure provides a method for recruiting antibodies, e.g., endogenous antibodies, to a target, comprising contacting the target with a provided agent, compound, or composition. In some embodiments, the recruited antibodies include one or more endogenous antibodies. In some embodiments, the recruited antibodies have specificity for one or more antigens. In some embodiments, the recruited antibodies have specificity for one or more peptide antigens or proteins. In some embodiments, the recruited antibodies are heterogeneous in that they are not antibodies against the same antigen or protein.

[0391] In some embodiments, the present disclosure provides a method for recruiting immune cells to a target, comprising contacting the target with a provided agent, compound, or composition.

[0392] In some embodiments, the present disclosure provides methods for inducing, generating, promoting, and / or enhancing one or more immune system activities against a target, comprising contacting the target with a provided agent, compound, or composition. In some embodiments, the immune system activity is or includes ADCC. In some embodiments, the immune system activity is or includes ADCP. In some embodiments, the immune system activity is or includes both ADCC and ADCP. In some embodiments, the immune system activity is or includes complement-dependent cytotoxicity (CDC). In some embodiments, the immune system activity is or includes ADCVI.

[0393] In some embodiments, the target is a cancer cell. In some embodiments, the target is a cancer cell in a subject. In some embodiments, the provided methods include administering a provided agent, compound, or composition to a subject.

[0394] In some embodiments, upon contact with its target, provided agents and compounds form a complex with an antibody and an Fc receptor on the target cell. In some embodiments, the present disclosure provides a complex comprising: A drug comprising: antibody binding moiety, a target binding moiety, and optionally a linker moiety, Drugs, including Fc region, and Fc receptors Including, The antibody binding moiety provides a conjugate that is a universal antibody binding moiety.

[0395] In some embodiments, the present disclosure provides a conjugate comprising two or more conjugates, each independently comprising: A drug comprising: antibody binding moiety, a target binding moiety, and optionally a linker moiety, Drugs, including Fc region, and Fc receptors Including, Provided the conjugates are of antibodies and / or fragments thereof directed against different antigens or proteins, the Fc regions of the conjugates are of antibodies and / or fragments thereof directed against different antigens or proteins.

[0396] In some embodiments, the Fc regions of the complex are from antibodies and / or fragments thereof directed against different proteins, hi some embodiments, one or more of the Fc regions are from endogenous antibodies and / or fragments thereof.

[0397] As used herein, the terms "treatment," "treat," and "treating" refer to reversing the progression of, alleviating, delaying the onset of, or inhibiting the development of a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0398] In some embodiments, the present invention provides methods for treating one or more disorders, diseases, and / or conditions, wherein the disorder, disease, or condition is cancer.

[0399] The term "neoplasm" or "cancer" is used throughout this specification to refer to a cancerous or malignant neoplasm, i.e., a pathological process that results in the formation and growth of abnormal tissue that grows by cellular proliferation, often more rapidly than normal, and continues to grow after the stimulus that initiated the new growth has ceased. Malignant neoplasms exhibit a partial or complete lack of structural organization and functional coordination with normal tissue, most infiltrate surrounding tissue, metastasize to several sites, and, unless properly treated, are likely to recur after attempted resection and cause patient death. As used herein, the term neoplasm is used to describe all cancerous disease states and includes or encompasses the pathological processes associated with malignant hematogenous, ascites, and solid tumors. Representative cancers include, for example, prostate cancer, metastatic prostate cancer, stomach, colon, rectum, liver, pancreas, lung, breast, cervix, uterine corpus, ovary, testis, bladder, kidney, brain / CNS, head and neck, throat, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth / pharynx, esophagus, larynx, kidney cancer, and lymphoma, among others, which may be treated with one or more compounds according to the present invention. In particular, the provided technology (e.g., compounds, compositions, methods, etc.) is particularly useful for the prevention and / or treatment of cancer.

[0400] Furthermore, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, or hydrate or solvate thereof, for the preparation of a medicament for the treatment of a proliferative disease.

[0401] Combination therapy Depending on the particular condition, or disease, being treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with the compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0402] In certain embodiments, the provided combinations, or compositions thereof, are administered in combination with another therapeutic agent.

[0403] Examples of drugs that may be combined with the compounds of the invention include, but are not limited to, drugs for treating Alzheimer's disease, such as Aricept® and Excelon®; drugs for treating HIV, such as ritonavir; drugs for treating Parkinson's disease, such as L-DOPA / carbidopa, entacapone, lopinrol, pramipexole, bromocriptine, pergolide, trihexefendil, and amantadine; drugs for treating multiple sclerosis (MS), such as beta interferon (e.g., drugs for treating asthma, such as albuterol and Singulair®; drugs for treating schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol; anti-inflammatory drugs, such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants, such as cyclophosphamide; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and antiparkinsonian agents; drugs for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; drugs for treating liver disease such as corticosteroids, cholestyramine, interferons, and antivirals; drugs for treating blood disorders such as corticosteroids, anti-leukemia agents, and growth factors; drugs that prolong or improve pharmacokinetics such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketophenone and ritonavir), and drugs for treating immune deficiency disorders such as gamma globulin.

[0404] In certain embodiments, the combination therapy of the invention, or a pharmaceutically acceptable composition thereof, is administered in combination with a monoclonal antibody or siRNA therapeutic.

[0405] These additional drugs can be administered separately from the combination therapy provided as part of multiple dosage regimens.Alternatively, these drugs can be part of a single dosage form that is mixed together with the compound of the present invention in a single composition.When administered as part of multiple dosage regimens, the two active agents can be administered simultaneously, sequentially, or usually within 5 hours of each other.

[0406] As used herein, the terms "combination," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a combination of the present invention may be administered together with another therapeutic agent either simultaneously or sequentially in separate unit dosage forms or in a single dosage form.

[0407] The amount of additional therapeutic agent present in the compositions of the present disclosure will not be greater than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure will be in the range of about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0408] In one embodiment, the present invention provides a composition comprising a compound of Formula I, II, or III and one or more additional therapeutic agents. The therapeutic agents may be administered together with the compound of Formula I, II, or III, or may be administered before or after the administration of the compound of Formula I, II, or III. Suitable therapeutic agents are described in more detail below. In certain embodiments, the compound of Formula I, II, or III may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, the compound of Formula I, II or III may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

[0409] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder, or condition by administering to a patient in need thereof a compound of Formula I, II, or III and one or more additional therapeutic agents. Such additional therapeutic agents can be small molecules or recombinant biological agents, including, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol, febuxostat (Ulori), and the like. c®), sulfazalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as aurothioglucose (Solganal®), aurothiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and "anti-TNF" agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (C Imzia®) and adalimumab (Humira®), "anti-IL-1" agents such as anakinra (Kineret®) and linonacept (Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), "anti-T cell" agents such as abatacept (Orencia®), "anti-IL-6" agents such as tocilizumab (Actemra®),Diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, beta 2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Qvar®), benzodiazepines (Benza ... ), and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®,Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), adacavir / lamivudine (Epzicom®), adacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Amprenavir), thiazolinone (Thiazolinone ... generase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors, For example, enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®), or any combination(s) thereof.

[0410] In another embodiment, the present invention provides a method of treating gout, comprising administering to a patient in need thereof a compound of Formula I, II or III and one or more additional therapeutic agents selected from nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colticine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, and febuxostat (Uloric®).

[0411] In another embodiment, the present invention provides a method of treating rheumatoid arthritis by administering to a patient in need thereof a compound of Formula I, II or III and nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, sulfalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as aurothioglucose (Solganal®), aurothiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and "anti-TNF" agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®), and adalimumab (Humira®), "anti-IL-1" agents, such as anakinra (Kineret®) and rilonacept (Arcalyst®), antibodies, such as rituximab (Rituxan®), "anti-T cell" agents, such as abatacept (Orencia®), and "anti-IL-6" agents, such as tocilizumab (Actemra®).

[0412] In some embodiments, the present invention provides a method of treating osteoarthritis, comprising administering to a patient in need thereof a compound of Formula I, II or III and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), and monoclonal antibodies, such as tanezumab.

[0413] In some embodiments, the present invention provides methods of treating lupus, comprising administering to a patient in need thereof a compound of Formula I, II, or III and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), anticoagulants such as heparin (Calcinparine® or Liquaemin®), and warfarin (Coumadin®).

[0414] In some embodiments, the present invention provides methods of treating inflammatory bowel disease, comprising administering to a patient in need thereof a compound of Formula I, II, or III and one or more additional therapeutic agents selected from mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®, anticholinergics or anticonvulsants such as dicyclomine (Bentyl®), anti-TNF therapeutics, steroids, and antibiotics such as flagyl or ciprofloxacin.

[0415] In some embodiments, the present invention provides a method of treating asthma by administering to a patient in need thereof a compound of Formula I, II, or III and Singulair®, beta 2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and fomoterol (Foradil®), anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as prednisone, prednisolone, beclomethasone, benzodiazepine, benzocaine ... and administering one or more additional therapeutic agents selected from tazone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgE antibodies such as omalizumab (Xolair®).

[0416] In some embodiments, the present invention provides a method of treating COPD, comprising administering to a patient in need thereof a compound of Formula I, II, or III and a beta-2 agonist such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and fomoterol (Foradil®), an anticholinergic agent such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), a methylxanthine such as benzodiazepine (BPO), ... and administering one or more additional therapeutic agents selected from theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®.

[0417] In some embodiments, the present invention provides a method of treating HIV, comprising administering to a patient in need thereof a compound of Formula I, II, or III and a nucleoside reverse transcriptase inhibitor, such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), or a combination of these two. (R), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®), and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors and administering one or more additional therapeutic agents selected from transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), and combinations thereof.

[0418] In another embodiment, the invention provides a method of treating a hematological malignancy, comprising administering to a patient in need thereof a compound of Formula I, II or III and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0419] In another embodiment, the invention provides a method of treating a solid tumor, comprising administering to a patient in need thereof a compound of Formula I, II or III and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0420] In another embodiment, the invention provides a method of treating a hematological malignancy, comprising administering to a patient in need thereof a compound of Formula I, II, or III and a hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL (Ramirez et al. "Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma," Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).

[0421] In another embodiment, the invention provides a method of treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need thereof a compound of Formula I, II or III and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.

[0422] In another embodiment, the present invention provides a method of treating multiple myeloma, comprising administering to a patient in need thereof a compound of Formula I, II or III and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor (lenalidomide (in combination with Revlimid®)).

[0423] In another embodiment, the invention provides a method of treating Waldenstrom's macroglobulinemia, comprising administering to a patient in need thereof a compound of Formula I, II or III and one or more additional therapeutic agents selected from chlorambucil (Leukeran®), cyclophosphamide (Cytoxan®, Neosar®), fludarabine (Fludara®), cladribine (Leustatin®), rituximab (Rituxan®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYK inhibitor.

[0424] In some embodiments, the present invention provides a method of treating Alzheimer's disease, comprising administering to a patient in need thereof a compound of Formula I, II or III and one or more additional therapeutic agents selected from donepezil (Aricept®), rivastigmine (Excelon®), galantamine (Razadyne®), tacrine (Cognex®), and memantine (Namenda®).

[0425] In another embodiment, the present invention provides a method of treating organ transplant rejection or graft-versus-host disease, comprising administering to a patient in need thereof a compound of Formula I, II or III and one or more additional therapeutic agents selected from steroids, cyclosporine, FK506, rapamycin, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors.

[0426] In another embodiment, the present invention provides a method for treating or lessening the severity of disease, comprising administering to a patient in need thereof a compound of Formula I, II, or III and a BTK inhibitor, wherein the method comprises administering to the patient a compound of Formula I, II, or III and a BTK inhibitor, the disease being inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, O's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjogren's syndrome, multiple sclerosis, or systemic sclerosis. , Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, autonomic neuropathy, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, drugs, foods, insect venom, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, Blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitisPneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disorders, such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer, or mast cell cancer (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, bone and joint diseases (including, but not limited to, rheumatoid arthritis, seronegative spondyloarthropathy (including ankylosing spondylitis, psoriatic arthritis, and Reiter's disease) (including cerebrovascular disease, cerebrovascular accident ... -, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis,Selected from psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory reactions (such as acute respiratory distress syndrome and ischemia-reperfusion injury), and Graves' disease.

[0427] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease selected from cancer, a neurodegenerative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, a pathological immune condition involving T-cell activation, a cardiovascular disorder, and a CNS disorder, comprising administering to a patient in need thereof a compound of Formula I, II or III and a PI3K inhibitor.

[0428] In another embodiment, the present invention provides a method of treating or lessening the severity of disease, comprising administering to a patient in need thereof a compound of Formula I, II or III and a PI3K inhibitor, wherein the disease is a benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid; sarcoma, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer; In particular, diseases including colon cancer or colon adenoma or head and neck tumors, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasms, neoplasms of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also called Hodgkin or Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia, Cowden syndrome, Lhermitte-Dacros disease, and Banayan-Zonana syndrome, or diseases in which the PI3K / PKB pathway is abnormally activated, intrinsic (non-antibody) asthma of any type or genesis, including both allergic (allergic) asthma and extrinsic (allergic) asthma, moderate asthma, severe asthma, bronchitis asthma, exercise-induced asthma, occupational asthma and asthma induced after bacterial infection, acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airway or lung disease (COPD, COAD or COLD) (including associated chronic bronchitis or dyspnea), emphysema, and exacerbations of airway hyperactivity as a result of other medications (especially other inhaled medications), bronchitis of any type or genesis (including but not limited to acute, arachic, catarrhal, croupus, chronic or tuberculous bronchitis), pneumoconiosis of any type or genesis (an inflammatory, generally occupational, lung disease, whether chronic or acute, frequently associated with airway obstruction and resulting from repeated inhalation of dust) (including, for example, aluminum lung disease, anthracosis, asbestosis, stone lung disease, trichiasis, siderosis, silicosis, tobacco poisoning and byssinosis), Löffler's syndrome, eosinophilia, pneumonia, parasitic (especially metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis,Eosinophil-related disorders of the airways resulting from or occurring concurrently with polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granulomas, and eosinophil-related disorders affecting the airways caused by drug reactions), psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, and epidermolysis bullosa acquisita , conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose (including allergic rhinitis), and inflammatory diseases involving an autoimmune response or having an autoimmune component or etiology (autoimmune hematologic disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic rheumatoid arthritis, and chronic rheumatoid arthritis). Active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal conjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, and glomerulonephritis (nephrotic syndrome) The disease is selected from neurodegenerative diseases caused by trauma, glutamate neurotoxicity, and hypoxia, including, for example, idiopathic nephrotic syndrome or minimal change nephropathy, restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, as well as neurodegenerative diseases caused by trauma, glutamate neurotoxicity, and hypoxia.

[0429] The compounds and compositions of the present invention may be administered in any amount and via any route of administration effective for treating or reducing the severity of cancer or a proliferative disorder. The exact amount required will vary from subject to subject, depending on the subject's species, age, and general condition, the severity of the infection, the specific drug, its mode of administration, and the like. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form," as used herein, refers to a physically discrete unit of drug appropriate for the patient being treated. However, the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used, and similar factors well known in the medical field. The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0430] The pharmaceutically acceptable compositions of the present invention may be administered to humans and other animals orally, rectally, intravesically, intravaginally, intraperitoneally, topically (such as by powder, ointment, or drops), bucally, as an oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention may be administered orally or parenterally in single or multiple doses at a dosage level of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg of subject body weight per day to achieve the desired therapeutic effect.

[0431] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain auxiliary agents such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and fragrances.

[0432] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. Sterile fixed oils are also commonly used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid, are also used in the preparation of injectables.

[0433] Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other injectable sterile medium before use.

[0434] To prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0435] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ordinary temperatures but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

[0436] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) humectants such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0437] Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0438] The active compound may also be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. As is common practice, such dosage forms may also contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0439] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, as needed. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. The present invention also contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0440] According to one embodiment, the present invention relates to a method for inhibiting protein kinase activity in a biological sample, comprising the step of contacting said biological sample with a compound of the present invention, or a composition comprising said compound.

[0441] The term "biological sample," as used herein, includes, but is not limited to, a cell culture or extract thereof; a biopsy or extract thereof obtained from a mammal; and blood, saliva, urine, feces, sperm, tears, or other bodily fluids or extracts thereof.

[0442] Depending on the particular condition, or disease, being treated, additional therapeutic agents, which are normally administered to treat that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0443] In particular, the compounds and / or compositions of the present disclosure can be used in combination therapy, i.e., the compounds and / or compositions of the present disclosure can be administered simultaneously with, before, or after one or more other therapeutic agents or medical treatments, particularly for the treatment of various cancers. In some embodiments, the compounds of the present invention can also be used advantageously in combination with other antiproliferative compounds. The particular combination of therapies (therapeutics or treatments) used in a combination regimen will take into account the compatibility of the other desired therapeutic agents and / or treatments and the desired therapeutic effect to be achieved. It is also understood that the therapies used can achieve the desired effect for the same disorder (e.g., a provided compound can be administered simultaneously with another anticancer agent) or they can achieve different effects (e.g., control of any adverse effects). In some embodiments, the therapeutic agent is a chemotherapeutic agent or an antiproliferative compound. Exemplary chemotherapeutic agents include, but are not limited to, alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, plant-derived alkaloids, topoisomerase inhibitors, hormone therapy agents, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, platinum complex derivatives, other immunotherapeutics, and other anticancer agents. Furthermore, the provided technology can be used together with or manufactured as a mixture with cancer treatment adjuvant leukocyte (neutropenia) agents, thrombocytopenia agents, antiemetics, and cancer analgesics to restore patient quality of life. In some embodiments, the therapeutic reagent is an antibody. In some embodiments, the therapeutic agent is an immunomodulator. In some embodiments, the immunomodulator targets a cell surface signaling molecule on an immune cell. In some embodiments, the immunomodulator targets a cell surface signaling molecule on an immune cell, and the agent is an antagonist that blocks a co-inhibitory pathway. In some embodiments, the immunomodulator is a checkpoint inhibitor. In some embodiments, the immunomodulator is an antibody that targets a cell surface signaling protein expressed by an immune cell. In some embodiments, the immunomodulatory agent is an antibody that targets a protein selected from PD-1, PD-L1, CTLA4, TIGIT, BTLA, TIM-3, LAG3, B7-H3, and B7-H4.In some embodiments, the immunomodulatory agent is a PD-1 antibody (e.g., nivolumab, pembrolizumab, pidilizumab, BMS936559, MPDL328OA, etc.). In some embodiments, the immunomodulatory agent is a PD-L1 antibody. In some embodiments, the immunomodulatory agent is a CTLA4 antibody (e.g., ipilimumab). In some embodiments, the immunomodulatory agent is a TIGIT antibody. In some embodiments, the immunomodulatory agent is a BTLA antibody. In some embodiments, the immunomodulatory agent is a Tim-3 antibody. In some embodiments, the immunomodulatory agent is a LAG3 antibody. In some embodiments, the immunomodulatory agent is a B7-H3 antibody. In some embodiments, the immunomodulatory agent is a B7-H4 antibody. In some embodiments, the immunomodulatory agent targets a cell surface signaling molecule on an immune cell and the agent is an agonist involved in a costimulatory pathway. In some embodiments, such an immunomodulatory agent is or includes an antibody that targets a costimulatory receptor. In some embodiments, the antibody activates a T cell costimulatory receptor. In some embodiments, the antibody targets a member of the tumor necrosis factor (TNF) receptor superfamily. In some embodiments, the antibody targets a protein selected from CD137 (4-1BB), CD357 (GITR, TNFRS18, AITR), CD134 (OX40), and CD40 (TNFRSF5). In some embodiments, the antibody is an anti-CD137 antibody (e.g., urelumab). In some embodiments, the antibody is an anti-CD357 antibody. In some embodiments, the antibody is an anti-CD40 antibody. In some embodiments, the antibody is an anti-CD134 antibody.Additional exemplary T cell costimulatory and co-inhibitory receptors are described in Chen L, Flies DB., Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 2013, 13(4), 227-42, and Yao S, et al., Advances in targeting cell surface signaling molecules for immune modulation. Nat. Rev. Drug Discov. 2013, 12(2), 136-40. In some embodiments, the therapeutic agent is an antibody that activates such stimulatory receptors or blocks such inhibitory receptors.

[0444] In some embodiments, the one or more other therapeutic agents are or comprise tumor-specific immune cells. In some embodiments, the one or more other therapeutic agents are or comprise tumor-specific T cells. In some embodiments, the one or more other therapeutic agents are or comprise tumor-infiltrating lymphocytes (TILs). In some embodiments, the one or more other therapeutic agents are or comprise T cells that ectopically express a known anti-tumor T cell receptor (TCR). In some embodiments, the one or more other therapeutic agents are or comprise chimeric antigen receptor (CAR) T cells. In some embodiments, provided compositions comprise an immune enhancer. Exemplary immune enhancers that may be used in combination with provided compounds, compositions, and / or methods include, but are not limited to, various cytokines and tumor antigens. Cytokines that stimulate immune responses include, for example, GM-CSF, M-CSF, G-CSF, interferon-α, β, γ, IL-1, IL-2, IL-3, and IL-12. Antibodies that block inhibitory receptors and / or activate stimulatory receptors, such as, but not limited to, B7 ligand derivatives, anti-CD3 antibodies, anti-CD28 antibodies, and anti-CTLA-4 antibodies, which are widely known in the art and described herein, may also improve immune responses. In some embodiments, the therapeutic agent is an immunomodulatory small molecule. In some embodiments, the therapeutic agent is a small molecule that mediates anti-tumor immune activity. In some embodiments, the therapeutic agent is a small molecule that targets an enzyme directly involved in immune regulation. In some embodiments, the therapeutic agent is an indoleamine 2,3-dioxygenase (IDO) inhibitor. In some embodiments, the therapeutic agent is an IDO1 inhibitor, e.g., F001287, indoximod, NLG-919, and INCB024360. In some embodiments, the therapeutic agent is a tryptophan-2,3 dioxygenase (TDO) inhibitor. In some embodiments, the therapeutic agent is a dual IDO / TDO inhibitor. In some embodiments, the therapeutic agent is an IDO-selective inhibitor. In some embodiments, in some other embodiments, the therapeutic agent is a TDO-selective inhibitor. In some embodiments, provided compositions comprise an IDO inhibitor and a first construct.In some embodiments, provided compositions comprise an IDO inhibitor, a first construct, and a second construct, and it is recognized that the immune response to the first construct and / or the second construct can be significantly enhanced by administration of the IDO inhibitor.

[0445] In some embodiments, medical treatments that may be used in combination with the compounds, compositions, and methods of the present application include, but are not limited to, surgery, radiation therapy (□-radiation, neutron radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes, to name a few), endocrine therapy, biological response modifiers (interferons, interleukins, and tumor necrosis factor (TNF)), to name a few), hyperthermia, cryotherapy, and adoptive T cell transfer (e.g., TIL therapy, transgenic TCR, CAR T cell therapy, NK cell therapy, etc.). In some embodiments, the medical treatment is surgery. In some embodiments, the medical treatment is radiation therapy.

[0446] Antiproliferative compounds include aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds that target / reduce protein or lipid kinase activity and further antiangiogenic compounds; compounds that target, reduce or inhibit the activity of protein or lipid phosphatases; gonadorelin agonists; antiandrogens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, decrease, or inhibit the activity of Flt-3; Hsp90 inhibitors, such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma Therapeutics); temozolomide (Temodal®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 (GlaxoSmithKline), or pentamidine / chlorpromazine (CombinatoRx); MEK inhibitors, such as ARRY142886 (Array BioPharma), AZD6244 (AstraZeneca), PD181461 (Pfizer), and leucovorin. The term "aromatase inhibitor", as used herein, relates to a compound which inhibits estrogen production, for example, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.The term includes, but is not limited to, steroids, particularly atamestane, exemestane, and formestane, and nonsteroids, particularly aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is commercially available under the trade name Aromasin™. Formestane is commercially available under the trade name Lentaron™. Fadrozole is commercially available under the trade name Afema™. Anastrozole is commercially available under the trade name Arimidex™. Letrozole is commercially available under the trade name Femara™ or Femar™. Aminoglutethimide is commercially available under the trade name Orimeten™. Combinations of the present invention that include a chemotherapeutic agent that is an aromatase inhibitor are particularly useful in the treatment of hormone receptor-positive tumors, such as tumors of the breast.

[0447] The term "antiestrogen," as used herein, refers to a compound that antagonizes the action of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is commercially available under the trade name Nolvadex™. Raloxifene hydrochloride is commercially available under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. The combinations of the present invention that include chemotherapeutic agents that are antiestrogens are particularly useful for treating estrogen receptor-positive tumors, such as breast tumors.

[0448] The term "antiandrogen," as used herein, refers to any substance capable of inhibiting the biological action of androgenic hormones, including, but not limited to, bicalutamide (Casodex™). The term "gonadorelin agonist," as used herein, includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin may be administered under the trade name Zoladex™.

[0449] The term "topoisomerase I inhibitor" as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, for example, in the form as it is marketed, e.g., under the trademark Camptosar™. Topotecan is marketed under the trade name Hycamptin™.

[0450] The term "topoisomerase II inhibitors," as used herein, includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulations such as Caelyx™), daunorubicin, epirubicin, idarubicin, and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is commercially available under the trade name Etopophos™. Teniposide is commercially available under the trade name VM26-Bristol. Doxorubicin is commercially available under the trade name Acriblastin™ or Adriamycin™. Epirubicin is commercially available under the trade name Farmorubicin™. Idarubicin is commercially available under the trade name Zavedos™. Mitoxantrone is commercially available under the trade name Novantron.

[0451] The term "microtubule active agent" refers to microtubule stabilizing, microtubule destabilizing compounds and microtubule polymerization inhibitors, including, but not limited to, taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolide; coticin and epothilones and their derivatives. Paclitaxel is commercially available under the trade name Taxol™. Docetaxel is commercially available under the trade name Taxotere™. Vinblastine sulfate is commercially available under the trade name Vinblastin RP™. Vincristine sulfate is commercially available under the trade name Farmistin™.

[0452] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is commercially available under the trade name Cyclostin™. Ifosfamide is commercially available under the trade name Holoxan™.

[0453] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit histone deacetylase and which possess antiproliferative activity, including, but not limited to, suberoylanilide hydroxamic acid (SAHA).

[0454] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil, i.e., 5-FU, capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folate antagonists such as pemetrexed. Capecitabine is commercially available under the trade name Xeloda™. Gemcitabine is commercially available under the trade name Gemzar™.

[0455] The term "platin compounds" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Eloxatin™.

[0456] The term "compounds which target / reduce protein or lipid kinase activity; or protein or lipid phosphatase activity; or further anti-angiogenic compounds", as used herein, includes protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds which target, reduce or inhibit the activity of platelet-derived growth factor receptors (PDGFR), e.g. compounds which target, reduce or inhibit the activity of PDGFR, in particular compounds which inhibit PDGF receptors, e.g. N-phenyl-2-pyrimidine-amine derivatives, e.g. imatinib, SU101, SU6668 and GFB-111; b) compounds which target, reduce or inhibit the activity of fibroblast growth factor receptors (FGFR); c) compounds which target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), e.g. compounds which target and reduce the activity of IGF-IR d) compounds that target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family or ephrin B4 inhibitors; e) compounds that target, reduce or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, reduce or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, reduce or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, reduce or inhibit the activity of the C-kit receptor tyrosine kinase, which is part of the PDGFR family, such as compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, in particular compounds that inhibit the c-Kit receptor, such as imatinib;i) Compounds that target, decrease or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase) and mutants, such as compounds that target, decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC680410; PD173955 (ParkeDavis); or dasatinib (BMS- 354825); j) compounds that target, decrease or inhibit the activity of members of the protein kinase C (PKC) and Raf family of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK and TEC families, and / or members of the cyclin-dependent kinase family (CDK), including staurosporine derivatives, e.g., midostaurin; further exemplary compounds include UCN-01, safin k) compounds that target, decrease, or inhibit the activity of protein-tyrosine kinase inhibitors, e.g., ... Compounds include imatinib mesylate (Gleevec™) or tyrphostins, such as tyrphostin A23 / RG-50810; AG99; tyrphostin AG213; tyrphostin AG1748; tyrphostin AG490; tyrphostin B44; tyrphostin B44 (+) enantiomer; tyrphostin AG555; AG494; tyrphostin AG556, AG957, and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC680410, adaphostin);l) Compounds which target, decrease or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their variants, e.g. compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family, in particular compounds which inhibit members of the EGF receptor tyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4, or which bind to EGF or EGF-related ligands. m) compounds that target, decrease, or inhibit the activity of the c-Met receptor, including compounds, proteins, or antibodies, CP358774, ZD1839, ZM105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives. compounds that target, decrease, or inhibit the activity of c-Met, particularly compounds that inhibit the kinase activity of the c-Met receptor, or antibodies that target the extracellular domain of c-Met or that bind to HGF; n) compounds that target, decrease, or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK) (PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, A) o) compounds that target, decrease, or inhibit the kinase activity of PI3 kinase (PI3K) (including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib);and q) compounds that target, decrease, or inhibit the signaling actions of the Hedgehog (Hh) or Smoothened Membrane Oxide (SMO) pathways (including, but not limited to, cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib));

[0457] The term "PI3K inhibitor," as used herein, includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes of the phosphatidylinositol-3-kinase family, including, but not limited to, PI3K α, PI3K γ, PI3K δ, PI3K β, PI3K-C2 α, PI3K-C2 β, PI3K-C2 γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors useful in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0458] The term "BTK inhibitor," as used herein, includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0459] The term "SYK inhibitor," as used herein, includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0460] Further examples of BTK inhibitor compounds and conditions treatable by such compounds in combination with compounds of the present invention can be found in WO2008039218 and WO2011090760, which are incorporated herein by reference in their e...

Claims

1. Compounds of Formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein: (a) ABT is an antibody binding moiety that binds to the Fc region of an antibody, wherein: (i) ABT is DCAWHLGELVWCT (wherein the two cysteine ​​residues can form a disulfide bond); Fc-III; FcBP-1; FcBP-2; CDCAWHLGELVWCTC; Fc-III-4c; or FcRM Or (ii) ABT is 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 Is it; (iii) A compound of formula I can be prepared by reacting a compound of formula II: 【Chemistry 15】 (In the formula: 【Chemistry 16】 corresponds to ABT in the compound of formula I, and the structure "L 1 -L 2 " corresponds to "-L-" in the compound of formula I; R １ , R ３ and R ５ Each of is independently hydrogen or C １－６ an optionally substituted group selected from an aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R １ and R １ ' optionally, together with their intervening carbon atoms, form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R ３ and R ３ ' optionally, together with their intervening carbon atoms, form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R attached to the same carbon atom ５ group and the R ５ ' groups optionally taken together with their intervening carbon atoms form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or Two R's ５ The groups, together with their intervening atoms, are optionally C １－１０ Divalent linear or form a branched saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of said chain are independently and optionally -S-, -SS-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O) ２ - or -Cy １ -, and each -Cy １ - is independently a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R １ ', R ３ ' and R ５ Each of ' is independently hydrogen or C １－３ is aliphatic; R ２ , R ４ and R ６ Each of is independently hydrogen, or C １－４ is aliphatic, or: R ２ and R １ optionally, together with their intervening atoms, form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R ４ and R ３ optionally, together with their intervening atoms, form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R ６ group and its adjacent R ５ groups optionally taken together with their intervening atoms form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; L １ teeth, 【Chemistry 17】 and [Chemistry 18] and the structure of the trivalent linker moiety is 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 and L ２ is a covalent bond or C １－１０ A divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of said chain are independently and optionally -S-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O) ２ -, 【Chemistry 23】 or -Cy １ -, and each -Cy １ - is independently a 5-6 membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and Each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. or (iv) The compound of formula I may be converted into a compound of formula III: 【Chemistry 24】 (In the formula: 【Chemistry 25】 corresponds to ABT in the compound of formula I; R ７ Each of is independently hydrogen or C １－６ an optionally substituted group selected from an aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R attached to the same carbon atom ７ group and the R ７ ' groups optionally, taken together with their intervening carbon atoms, form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R ７ Each of ' is independently hydrogen or C １－３ is aliphatic; R ８ Each of is independently hydrogen, or C １－４ is aliphatic, or: R ８ group and its adjacent R ７ groups optionally taken together with their intervening atoms form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R ９ is hydrogen, C １－３ Aliphatic, or —C(O)C １－３ is aliphatic; L ３ teeth, 【Chemistry 26】 is a bivalent linker moiety connecting o is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; (b) L is a covalent bond or a bivalent linker moiety connecting ABT with TBT, wherein the bivalent linker moiety is an optionally substituted linear or branched C alkyl group containing one or more aliphatic, aryl, heteroaliphatic having 1 to 20 heteroatoms, or any combination thereof. １－１００ is a group, one or more methylene units of which are optionally and independently selected from C １－６ alkylene, C2-6 alkenylene, 【Chemistry 27】 、-Cy-、-C(R’) ２ -、-O-、-S-、-S-S-、-N(R’)-、-C( O)-、-C(S)-、-C(NR’)-、-C(O)N(R’)-、-C(O)C(R’) ２ N(R’)-、-N(R’)C(O)N(R’)-、-N(R’)C(O)O-、 -S(O)-、-S(O) ２ -、-S(O) ２ N(R’)-、-C(O)S-、-C(O )O-, -P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, - P(O)(NR')-, -P(S)(OR')-, -P(S)(SR')-, -P(S) (2')-、--(82')--、-(2')--、-_(2') _、__(32')-、-_(82')--、または-li(_9-3)(2') ２ -C(R) ２ -) ｎ )- (n is 1 to 20), and -Cy- is 【Chemistry 28】 where: Each R' is independently -R, -C(O)R, -CO ２ R, or -SO ２ R; Each R is independently —H, or C １－３０ C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon １－３０ Heteroaliphatic, C ６－３０ Aryl, C ６－３０ C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon ６－３０ an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or Two R groups optionally and independently together form a covalent bond, or: two or more R groups on the same atom optionally and independently combine with said atom to form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to said atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or two or more R groups on two or more atoms optionally and independently combine with their intervening atoms to form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to said intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; and (c) TBT is a target binding moiety that binds to prostate-specific membrane antigen (PSMA), wherein the structure of TBT is 【Chemistry 29】 and In the above (a) and (b), optionally substituted R, R １ , R ３ , R ５ , R ７ or each of the optional substituents on a carbon atom in the L group is independently a halogen; ２ ) ０－４ R°, -(CH ２ ) ０－４ OR°, -O(CH ２ ) ０－４ R°, —O—(CH ２ ) ０－４ C(O)OR°, -(CH ２ ) ０－４ CH(OR°) ２ , -NO ２ , -CN, -N ３ , -(CH ２ ) ０－４ N (R°) ２ , -(CH ２ ) ０－４ N(R°)C(O)R°, -(CH ２ ) ０－４ C(O)R°, -(CH ２ ) ０－４ C(O)OR°, -(CH ２ ) ０－４ OC(O)R°, -(CH ２ ) ０－４ C(O)NR° ２ , -(CH ２ ) ０－４ OC(O)NR° ２ , -C(O)N(OR°)R°, -C(O)C(O)R°, -C(O)CH ２ C(O)R°, -C(NOR°)R°, -N(OR°)R°, -C(NH)NR° ２ , -(C １－４ Linear or branched alkylene)O-N(R°) ２ , -(C １－４ Linear or branched alkylene)C(O)O-N(R°) ２ and =O; optionally substituted R, R １ , R ３ , R ５ , R ７ or each of the optional substituents on the nitrogen atom in the L group is independently —R † , -C(O)R † , -C(O)OR † , —C(NH)NR † ２ Selected from: Each R° is independently hydrogen or C １－６ is aliphatic; and Each R ＊ are independently hydrogen or C １－６ It is aliphatic.

2. The compound of claim 1, wherein the compound has formula II: [In the formula, (a) R ２ is hydrogen; (b) R ４ is hydrogen; (c) R １ ' is hydrogen; (d) R ３ ' is hydrogen; (e) L ２ But C １－１０ a divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of said chain are independently and optionally -S-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O) ２ -, 【Transformation 30】 or -Cy １ -, where each -Cy １ - is independently a 5-6 membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or (f) a combination thereof] or a pharmaceutically acceptable salt thereof.

3. The compound of formula II has formula II-a, II-b, II-c, or II-d: 【Chemistry 31】 【Chemistry 32】 or a pharmaceutically acceptable salt thereof. Claim 4: The compound is a compound of formula III, wherein L ３ but, 【Transformation 33】 2. The compound of claim 1, wherein:

5. ABT is, DCAWHLGELVWCT (wherein the two cysteine ​​residues can form a disulfide bond); Fc-III; FcBP-1; FcBP-2; CDCAWHLGELVWCTC; Fc-III-4c; or FcRM 2. The compound of claim 1, wherein:

6. ABT is, 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 2. The compound of claim 1, wherein:

7. formula: 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Chemistry 58】 【Chemistry 59】 or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

9. A pharmaceutical composition for recruiting multiple antibodies to prostate cancer, comprising a pharmaceutically acceptable carrier, adjuvant, or vehicle and the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is contacted with prostate cancer, and wherein the pharmaceutical composition recruits multiple antibodies to the prostate cancer.

10. A pharmaceutical composition for inducing antibody-dependent cell-mediated cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP) in prostate cancer cells in a subject, comprising a pharmaceutically acceptable carrier, adjuvant, or vehicle and a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, adjuvant, or vehicle and a compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, for selectively redirecting endogenous antibodies to prostate cancer cells, thereby inducing antibody-dependent cell-mediated cytotoxicity (ADCC) in said prostate cancer cells in a biological sample, characterized in that the pharmaceutical composition is contacted with the biological sample.

12. A pharmaceutical composition for treating prostate cancer in a subject, comprising a pharmaceutically acceptable carrier, adjuvant, or vehicle and a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition described in claim 12, wherein the prostate cancer is metastatic prostate cancer.

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