WO2021216814A1

WO2021216814A1 - Btk inhibitors to treat pulmonary distress in covid-19 patients

Info

Publication number: WO2021216814A1
Application number: PCT/US2021/028553
Authority: WO
Inventors: Steven P. Treon
Original assignee: Dana-Farber Cancer Institute, Inc.
Priority date: 2020-04-23
Filing date: 2021-04-22
Publication date: 2021-10-28

Abstract

The present invention relates to a method for the treating patients diagnosed with Coronavirus Disease 19 (COVID-19) infections with BTK Inhibitors.

Description

BTK INHIBITORS TO TREAT PULMONARY DISTRESS IN COVID-19 PATIENTS RELATED APPLICATIONS [0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No: 63/014,449, filed April 23, 2020, which is incorporated herein by reference in its entirety. GOVERNMENT LICENSE RIGHTS [0002] This invention was made with government support under grant number 2P50 CA100707-16A1 awarded by the National Institutes of Health and the National Cancer Institute. The government has certain rights in the invention. BACKGROUND OF THE INVENTION [0003] Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Common symptoms include fever, cough and shortness of breath. Muscle pain, sputum production and sore throat are less common. [0004] Prior to the invention described herein, there was no standard of care for hospitalized patients experiencing COVID-19 infections beyond supportive care. Discovering/providing treatment options for patients with moderate or severe COVID-19 infection is a high priority, particularly for those with respiratory distress. SUMMARY OF THE INVENTION [0005] A first aspect of the present invention is directed to a method of treating coronavirus of 2019 (COVID-19) infection in a patient. Methods are carried out by administering to the patient a therapeutically effective amount of a Bruton’s tyrosine kinase (BTK) inhibitor. Broadly, the methods entail use of BTK inhibitors that may inhibit the activity of this kinase enzyme by any number of mechanisms, the choice of which is not critical. [0006] In some embodiments, the BTK inhibitor is ibrutinib, or an analog thereof. In some embodiments, the BTK inhibitor is acalabrutinib, or an analog thereof. In some embodiments, the BTK inhibitor is zanubrutinib, or an analog thereof. [0007] In some embodiments, the BTK inhibitor is a bispecific compound that targets BTK for selective degradation. These compounds are also known as PROTACs or degraders. [0008] In some embodiments, the BTK inhibitor is administered parenterally. In some embodiments, the BTK inhibitor is administered orally, such as by way of a solid (e.g., tablet or capsule) or a liquid (e.g., solution or suspension) dosage form. [0009] The disclosed methods are not limited to any specific subpopulation of COVID-19 patients. The patients may be at risk of COVID-19 or may have already tested positive for the virus. The patients may be symptomatic or asymptomatic. The patients may or may not have undergone prior therapy for the viral infection. [0010] In some embodiments, the patient is immune-suppressed. The patient may be suffering from or at risk of suffering from pulmonary/respiratory distress. The patient may have a pre-existing pulmonary/respiratory condition. The methods describe herein prevent, inhibit, or reduce pulmonary injury in COVID-19-infected patients, thereby reducing the requirement for oxygen supplementation and/or mechanical ventilation. [0011] The patient may be diabetic, hypertensive, obese or any combination of two or more of these factors. The patient may be at least 65 years of age. [0012] Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. [0013] All published foreign patents and patent applications cited herein are incorporated herein by reference. Genbank and NCBI submissions indicated by accession number cited herein are incorporated herein by reference. All other published references, documents, manuscripts and scientific literature cited herein are incorporated herein by reference. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. BRIEF DESCRIPTION OF THE DRAWINGS [0014] FIG. 1 is a schematic showing that entry of COVID-19 requires cleavage of S1/S2 and exposure of S2 permitting interaction with ACE2. [0015] FIG.2 is a series of photomicrographs showing inhibition of viral spread in dasatinib- treated, DENV-infected cells. An immunofluorescence assay was conducted to detect the localization of the viral envelope (E) protein in DENV-infected Vero, Huh-7, and C6/36 cells that were treated with 2.5 mM of the SRC inhibitor dasatinib or DMSO. Noninfected cells are indicated by arrowheads, and accumulation of viral E protein in the perinuclear region is indicated by arrows. Cell nuclei are stained blue with DAPI.

[0016] FIG. 3 is a heat map showing change in biomarker levels from baseline by time after ibrutinib dose in patients with chronic GVHD who failed steroids. Heat map of chemokines, cytokines, or factors associated with fibrosis that showed a significant change in levels for at least 1 time point posttreatment. The values at each time point are expressed as a proportion of the baseline value and depicted as a heat map. *P < .05; **P< .01; ***P < .001; ****P < .0001. CXCL9, C-X-C motif chemokine ligand 9; CXCL10, C-X-C motif chemokine ligand 10; EGF, epidermal growth factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN- g, interferon-y; IL-la, interleukin-la; IL-8, interleukin-8; MCP-1, monocyte chemotactic proteins 1; MCP-3, macrophage-derived chemokine, monocyte chemotactic proteins 3; MDC, macrophage-derived chemokine; MIP-la, macrophage-inflammatory proteins la; MIP-lb, macrophage-inflammatory proteins 1b; sCD25, soluble CD25; TNFa, tumor necrosis factor-a. [0017] FIG. 4 is heat map showing Serum cytokine levels for 29 patients with Waldenstrom's Macroglobulinemia prior to the start of ibrutinib therapy and after therapy with ibrutinib. [0018] FIG. 5 is a heat map showing cytokine expression by infusion related occurrence and treatment arm. Heat map of post-obinutuzumab peak cytokine expression in individual patients demonstrated more prominent reduced inflammatory cytokine expression and related infusion reactions to obinutuzumab in those patients receiving ibrutinib vs. chlorambucil.

[0019] FIG. 6A-FIG. 6B is a series of schematics showing the standard of care for a patient with COVID-19. FIG. 6A is a schematic showing the standard of care that includes treatment with the BTK inhibitor ibrutinib. FIG. 6B is a schematic showing the standard of care that includes treatment with the BTK inhibitor zanubrutinib.

[0020] FIG 7 is a schematic showing a model for the immunopathogenesis of SARS. SARS- CoV in droplets enter into the lung, where the virus binds via its S protein to ACE2 on the alveolar or bronchial epithelial cells. The virus replicates in these cells, from which new virions are released into the blood. The infected cells under the stimulation of SARS-CoV and some uninfected cells induced by viral antigens or PIC-regulatory factors produce high levels of PICs to mediate inflammatory responses for combating the virus. However, these PICs also damage the host cells. Some of the PICs, e.g. monocyte chemoattractant protein-1 (MCP-1), attract monocytes in bloodto migrate to the alveolar cavities, where the monocytes are stimulated by other PICs to become proliferative and/or activated macrophages (MF). The activated macrophages can produce more PICs and may transmit SARS-CoV to other sites. Some of the PICs, including TGF-β1andTNF-α, may induce apoptotic death of the epithelial cells, pneumocytes, and lymphocytes, or mediate pulmonary fibronosis, resulting in ALI and ARDS. The cell-free and MΦ-associated SARS-CoV in the blood can be transmitted from the lung to other organs to infect the ACE2-expressing cells in the local sites. More PICs are produced and the level of PICs in the blood is rapidly elevated, leading to multi-organ dysfunction. MΦ = macrophages; ALI = acute lung injury; PICs =pro-inflammatory cytokines [0021] FIG.8 is a schematic showing a summary of the main macrophage polarization states of activated macrophages. Different stimuli and signaling pathways have been described as inducers of M1-like or M2-like activation states, of which the most widely referenced ones are summarized here. M1-like or M2-like polarization has been reported in humans as being related to distinct defensive or healing schemas. Many roles have been ascribed to these polarization status, of which pro- and anti-inflammatory macrophage potentiation has for a long time been classically associated to the M1-like/M2-like-like dichotomy. LPS: lipopolysaccharide; MR: mannose receptor; TNF: tumor necrosis factor; IFNg: interferon gamma; IL: interleukin; MCP: monocyte chemoattractant protein; TGF: transforming growth factor; MCSF: macrophage colony stimulating-factor; ROS: reactive oxygen species; iNOS: inducible nitric oxide synthase; MHC: major histocompatibility complex. [0022] FIG. 9A-9C is a schematic showing is a series of microphotographs and a series of bar graphs showing pulmonary findings for mice treated with PBS or ibruntunib following lethal intranasal challenge with mouse dapted HIN1 influenza. FIG. 9A is a series of photomicrographs showing representative hematoxylin-eosin-stained lung sections (left and middle) and CT images (right) from mice 7 days after influenza A virus (Flu) infection [n = 10 and 5 mice for PBS- and Btk inhibitor (Inh)-treated groups, respectively]. FIG. 9B is a series of photomicrographs showing representative images of Bruton’s tyrosine kinase (Btk) in lungs of influenza A virus-infected mice. Tissue sections were analyzed by immunofluorescent staining for Btk and a PMN marker (Ly6G 1A8). White arrows indicate Ly6G/Btk double- positive cells; note differences in Btk staining between PBS- and Btk inhibitor-treated groups. FIG. 9C is a series of bar graphs showing lung volume derived from CT data (n = 10 and 5 mice for PBS- and Btk inhibitor-treated groups, respectively). Values are means ± SD; n = 3 mice in each group. *P < 0.05 (by Mann-Whitney rank sum test), and the average intensity of Btk staining expressed as fold change over control. Values are means ± SD; n = 3 mice in each group. [0023] FIG.10 is a series of line graphs showing survival and weight loss of C57BL/6 mice infected intranasally with influenza A virus (A/PR/8/34). Starting 3 days after infection, mice were treated daily with PBS (n = 7) or Bruton’s tyrosine kinase (Btk) inhibitor (Inh, n = 10) administered intranasally. Animals were monitored until death (4 mice) or weight loss of >30%, at which point they were euthanized and counted as dead (3 mice). Values for weight loss are means ± SE. Statistical significance of weight loss for days 4–9 of PBS-treated mice (n = 7) and Btk inhibitor-treated mice (n = 10) was determined by 2-way repeated-measures ANOVA with post hoc Bonferroni’s t-test: **P < 0.01. [0024] FIG.11A-FIG.11B is a series of bar graphs showing inflammatory cells observed in BAL fluids, and cytrokine levels from lung homogenates in mice treated with PBS or ibrutinib following lethal intranasal challenge with mouse-adapted HINI influenza. FIG. 11A is series of bar graphs showing bronchoalveolar lavage (BAL) protein concentration, total white blood cell (WBC) count, and number of neutrophils in BAL fluids at 7 days after influenza A virus (Flu) infection. Values are means ± SD; n = 10 and 4 mice for PBS- and Bruton’s tyrosine kinase (Btk) inhibitor (Inh)-treated groups, respectively, for BAL protein concentration and 10 and 5 mice for PBS- and Btk inhibitor-treated groups, respectively, for cell counts. **P < 0.01 (by Mann-Whitney rank sum test); ***P < 0.001 (by Student’s t-test). FIG. 11B is a series of bar graphs showing inflammatory cytokine/chemokine concentrations in lung homogenates from mice at 7 days after influenza A virus infection. Values are means ± SD; n = 10 and 5 mice for PBS- and Btk inhibitor-treated groups, respectively. *P < 0.001 (by Student’s t-test). DETAILED DESCRIPTION OF THE INVENTION [0025] The invention is based, at least in part, upon the discovery that ibrutinib, a BTK- inhibitor used to treat indolent B-cell malignancies and chronic graft versus host disease, can be used to abrogate pulmonary inflammatory cytokines, lung injury and death. [0026] Pulmonary failure is the main cause of mortality related to COVID-19 infection. Up to 80% of patients hospitalized for COVID-19 infection require supplemental oxygenation, of whom 30-40% may require mechanical ventilation. SARS-CoV-2 binds via the ACE2-receptor that is highly expressed on Alveolar Type II (ATII) cells in the lung. ATII cells constitute 5- 15% of the lung epithelium. While Alveolar Type I cells are highly adapted for gas exchange, Alveolar Type II cells have a specialized role in innate immune response. ATII cells express Toll receptors (TLRs) and can trigger inflammatory cytokines and chemo-attractants in response to pathogens that recruit and activate other immune cells including macrophages and neutrophils. [0027] Highly relevant to coronavirus infection, expression of pro-inflammatory and chemo- attractant cytokines IL1-B, IL6, IP10/CXCL10, MCP-1 and TNF-a were identified in the ACE2-positive cells from autopsy tissue of SARS-CoV-1 infected patients, that appeared causally related to the acute lung injury and pathogenesis observed with SARS-CoV-1. A similar profile of elevated cytokine levels was reported in the plasma of SARS-CoV-1 patients during the progressive and end-stage of infection, a profile consistent with an M1 polarized macrophage response. [0028] SARS-CoV-1 shares 86% homology with SARS-CoV-2. SARS-Cov-2 patients requiring intensive care also showed elevated plasma levels of inflammatory cytokines and chemo-attractants such as IL-2, IL-6, IL-7, IL-10, G-CSF, IP-10/CXCL-10, MCP-1/CCL2, MIP-1a/CCL3, and TNF-a. The importance of inflammatory cytokines to lung injury in SARS- CoV-2-infected patients has been suggested by reports of benefit with IL-6 and IL6-receptor blocking antibodies, and clinical trials to examine their use have been initiated (NCT04317092, NCT04306705, NCT04315298). [0029] This invention represents a novel standard of care for COVID-19. Pulmonary failure is the main cause of death related to COVID-19.80% of patients admitted to the hospital have respiratory distress with COVID-19. Approximately 30-40% require mechanical ventilation. The use of BTK inhibitor may prevent pulmonary injury or reduce pulmonary injury and result in decreased requirement of oxygen supplementation and mechanical ventilation. BTK Inhibitors [0030] Broadly, the methods disclosed herein are not limited to particular BTK inhibitors. They may include monospecific (e.g., traditional small molecule) inhibitors and bifunctional compounds (also known as PROTACs or degraders) alike. Representative examples of small molecule inhibitors as set forth below Small Molecule BTK Inhibitors Ibrutinib [0031] In some embodiments, the BTK inhibitor is Ibrutinib, or an analog thereof. The structure of Ibrutinib, also known as 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4- d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one, is as follows:

. This drug and its analogs are described in U.S. Patent 7,514,444, the disclosure of which is incorporated herein by reference in its entirety. [0032] Ibrutinib and its analogs are embraced by formula (I):

pharmaceutically acceptable salt or stereoisomer thereof, wherein A is N or CR5; R₁ is hydrogen, L₂-(substituted or unsubstituted alkyl), L₂-(substituted or unsubstituted cycloalkyl), L2-(substituted or unsubstituted alkenyl), L2-(substituted or unsubstituted cycloalkenyl), L₂-(substituted or unsubstituted heterocyclyl), L₂-(substituted or unsubstituted heteroaryl), or L₂-(substituted or unsubstituted aryl), where L₂ is a bond, O, S, -S(=O), -S(=O)₂, C(=O), -(substituted or unsubstituted C₁-C₆ alkyl), or -(substituted or unsubstituted C2-C6 alkenyl); R2 and R3 are independently hydrogen or substituted or unsubstituted alkyl; R₄ is L₃-X-L₄-G, wherein, L3 is optional, and when present is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; X is optional, and when present is a bond, O, -C(=O), S, -S(=O), -S(=O)₂, -NH, -NR₉, - NHC(O), -C(O)NH, -NR₉C(O), -C(O)NR₉, -S(=O)₂NH, -NHS(=O)₂, -S(=O)₂NR₉, - NR₉S(=O)₂, -OC(O)NH-, -NHC(O)O-, -OC(O)NR₉-, -NR₉C(O)O-, -CH=NO-, -ON=CH-, - NR₁₀,C(O)NR₁₀-, heteroaryl, aryl, -NR₁₀C(=NR₁)NR₁₀-, -NR₁₀C(=NR₁₁)-, -C(=NR₁)NR₁₀-, - OC(=NR1)-, or –C(=NR₁₁)O-; L₄ is optional, and when present is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl; or L₃, X and L₄ taken together form a nitrogen containing heterocyclyl;

R₆, R₇, and R₈ are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl, or R₇ and R₈ taken together form a bond; R5 is hydrogen, halogen, -L6-(substituted or unsubstituted C₁-C₃ alkyl), -L₆-(substituted or unsubstituted C₂-C₄ alkenyl), -L₆-(substituted or unsubstituted heteroaryl), or -L₆-(substituted or unsubstituted aryl), wherein L6 is a bond, O, S, -S(=O), S(=O)₂, NH, C(O), -NHC(O)O, - OC(O)NH, -NHC(O), or –C(O)NH; each R₉ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; each R10 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; or two R10 groups can together form a 5-, 6-, 7-, or 8-membered heterocyclyl; or R₉ and R10 can together form a 5-, 6-, 7-, or 8-membered heterocyclyl; and each R₁₁ is independently hydrogen, -S(=O)₂R₈, -S(=O)₂NH₂- C(O)R₈, -CN, -NO₂, heteroaryl, or heteroalkyl. [0033] In some embodiments, the compound of formula (I) is of formula (Ia):

pharmaceutically acceptable salt or stereoisomer thereof, wherein L_a is CH₂, O, NH, or S; Ar is optionally substituted aryl or optionally substituted heterocyclyl; Y is optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; Z is C(O), OC(O), NHC(O), C(S), S(O)_x, OS(O)_x, or NHS(O)_x, where x is 1 or 2; and R6, R₇, and R₈ are independently hydrogen, alkyl, heteroalkyl, carbocyclyl, or heterocyclyl, or R₇ and R₈ taken together form a bond. [0034] In some embodiments, the compounds of formula (I) are represented by any one of the following structures:

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, or a pharmaceutically acceptable salt or stereoisomer thereof. Zanubrutinib [0035] In some embodiments, the BTK inhibitor is Zanubrutinib, or an analog thereof. The structure of Zanubrutinib, also known as (7S)-2-(4-phenoxyphenyl)-7-(1-prop-2- enoylpiperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, is as

follows:

. This drug and its analogs are described in U.S. Patent 9,447,106, the disclosure of which is incorporated herein by reference in its entirety. [0036] Zanubrutinib and its analogs are embraced by formula (II):

pharmaceutically acceptable salt or stereoisomer thereof, wherein in formula (II), A is 5- or 6-membered aromatic ring comprising 0-3 heteroatoms selected from N, S or O; each W is independently - (CH₂)- or –C(O)-; L is a bond, CH₂, NR¹², O, or S; S/D is a single or double bond, wherein when S/D is a double bond, R⁵ and R⁷ are absent; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4, wherein when n is 2, 3 or 4, each R² may be different; p is 0, 1, 2, 3 or 4; R¹, R⁴, R⁵, R⁶ and R⁷ are each independently hydrogen, halogen, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkynyl, -CN, -NR¹³R¹⁴, -OR¹³, -COR¹³, - CO₂R¹³, -CONR¹³R¹⁴, -C(=NR¹³)NR¹⁴R¹⁵, -NR¹³COR¹⁴, -NR¹³CONR¹⁴R¹⁵, -NR¹³CO₂R¹⁴,- SO2R¹³, -NR¹³SO2NR¹⁴R¹⁵, or –NR¹³SO2R¹⁴, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and heterocyclyl are optionally substituted with at least one substituent R¹⁶; R² is halogen, alkyl, -S-alkyl, -CN, -NR¹³R¹⁴, -OR¹³, -COR¹³, -CO2R¹³, -CONR¹³R¹⁴, -C(=NR¹³)NR¹⁴R¹⁵, -NR¹³COR¹⁴, -NR¹³CONR¹⁴R¹⁵, -NR¹³CO₂R¹⁴,-SO₂R¹³, - NR¹³SO2NR¹⁴R¹⁵, or –NR¹³SO2R¹⁴; R¹² is hydrogen or alkyl; R¹³, R¹⁴ and R¹⁵ are each independently hydrogen, heteroalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein (R¹³ and R¹⁴) and/or (R¹⁴ and R¹⁵), together with the atom(s) to which they are attached, may independently form a ring selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl, each optionally substituted with at least one substituent R¹⁶; and R¹⁶ is halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, oxo, - CN, -OR’, -NR’R”, -COR’, -CO2R’, -CONR’R”, -C(=NR’)NR”R’”, -NR’COR”, - NR’CONR’R”, -NR’CO₂R”, -SO₂R’, -SO₂aryl, -NR’SO₂NR”R’”, or –NR’SO₂R”, wherein R’, R” and R’” are independently hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein (R’ and R”) and/or (R” and R’”), together with the atom to which they are attached, may independently form a ring selected from cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each alkyl, alkenyl and alkynyl of R¹⁶, R’, R”, and R’” is optionally substituted with at least one substituent selected from the group consisting of halogen, cycloalkyl, aryl, heteroaryl, heterocyclyl, oxo, -CN, -OR^a, -NR^aR^b, -COR^a, -CO₂R^a, - CONR^aR^b, -C(=NR^a)NR^bR^c, -NR^aCOR^b, -NR^aCONR^aR^b, -NR^aCO2R^b, -SO2R^a, -SO2aryl, - NR^aSO₂NR^bR^c, or –NR^aSO₂R^b, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl of R¹⁶, R’, R”, and R’” is optionally substituted with at least one substituent selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, oxo, -CN, -OR^a, - NR^aR^b, -COR^a, -CO₂R^a, -CONR^aR^b, -C(=NR^a)NR^bR^c, -NR^aCOR^b, -NR^aCONR^aR^b, - NR^aCO2R^b, -SO2R^a, -SO2aryl, -NR^aSO2NR^bR^c, or –NR^aSO2R^b, and wherein each R^a, R^b, and R^c is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl. [0037] In some embodiments, the compound of formula (II) is of formula (IIa):

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein R⁴, supra, includes N-containing C₁-C₈ alkyl, N-containing C₃-C₈ cycloalkyl and phenyl, for example, methylamine, aniline, azetidine, pyrrolidine, piperidine, azacycloheptenyl, each optionally substituted, particularly N-substituted with moieties such as benzyl, acyl, acryloyl, substituted acryloyl, propiolyl, substituted-propiolyl, etc., such as structures:

[0038] In some embodiments, the compounds of formula (II) are represented by any one of the following structures:

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pharmaceutically acceptable salt or stereoisomer thereof. Acalabrutinib [0039] In some embodiments, the BTK inhibitor is Acalabrutinib, or an analog thereof. The structure of Acalabrutinib, also known as 4-[8-amino-3-[(2S)-1-but-2-ynoylpyrrolidin-2- yl]imidazo[1,5-a]pyrazin-1-yl]-N-pyridin-2-ylbenzamide, is as follows:

This drug and its analogs are described in U.S. Patent 9,290,504, the disclosure of which is incorporated herein by reference in its entirety. [0040] Acalabrutinib and its analogs are embraced by formula (III):

or a pharmaceutically acceptable salt or stereoisomer

thereof, wherein X is CH, N, O or S; Y is C(R₆), N, O or S; Z is CH, N or a bond; A is CH or N; B1 is N or C(R₇); B₂ is N or C(R₈); B3 is N or C(R₉); B₄ is N or C(R₁₀); R1 is R₁₁C(O), R12S(O), R13SO2 or C₁-C₆ alkyl optionally substituted with R14; R₂ is hydrogen, C₁-C₆ alkyl or C₃-C₇ cycloalkyl; R3 is hydrogen, C₁-C₆ alkyl or C₃-C₇ cycloalkyl; or R₂ and R₃ form, together with the N and C atom that they are attached to a C₃-C₇ heterocycloalkyl optionally substituted with one or more fluorine, hydroxyl, C₁-C₃ alkyl, C₁- C₃ alkoxy or oxo; R4 is hydrogen or C₁-C₆ alkyl;

R5 is hydrogen, halogen, cyano, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₃-C₆ cycloalkyl; wherein said alkyl is optionally substituted with one or more halogen; or R₅ is C₆-C₁₀ aryl or C₂-C₆ heterocycloalkyl; R₆ is hydrogen or C₁-C₃ alkyl; or R5 and R6 together may form a C₃-C₇ cycloalkenyl, or C2-C6 heterocycloalkenyl; each optionally substituted with C₁-C₃ alkyl, or one or more halogen; R₇ is hydrogen, halogen or C₁-C₃ alkoxy; R₈ is hydrogen or C₁-C₃ alkyl; or R₇ and R₈ form, together with the carbon atom they are attached to a C6-C10 aryl or C₅-C₉ heteroaryl; R₉ is hydrogen, halogen or C₁-C₃ alkoxy; R₁₀ is hydrogen, halogen, or C₁-C₃ alkoxy; R₁₁ is independently selected from a group consisting of C₁-C₆ alkyl, C2-C6 alkenyl and C₂-C₆ alkynyl, wherein said alkyl, alkenyl or alkynyl is optionally substituted with one or more groups selected from hydroxyl, C₁-C₄ alkyl, C₃-C₇ cycloalkyl, C₁-C₄ alkylamino, (C1- C₄ alkyl)₂ amino, C₁-C₃ alkoxy, C₃-C₇ cycloalkoxy, C₆-C₁₀ aryl or C₃-C₇ heterocycloalkyl; or R₁₁ is C₁-C₃ alkyl-C(O)-S-C₁-C₃ alkyl; or R₁₁ is C5-C9 heteroaryl optionally substituted with one or more groups selected from halogen or cyano; R₁₂ and R₁₃ are independently C₂-C₆ alkenyl or C₂-C₆ alkynyl, both optionally substituted with one or more groups selected from hydroxyl, C₁-C₄ alkyl, C₃-C₇ cycloalkyl, C₁-C₄ alkylamino, (C₁-C₄ alkyl)₂ amino, C₁-C₃ alkoxy, C₃-C₇ cycloalkoxy, C₆-C₁₀ aryl or C₃-C₇ heterocycloalkyl; or C5-C9 heteroaryl optionally substituted with one or more groups selected from halogen or cyano; and each R14 is independently halogen, cyano, C2-C6 alkenyl, or C2-C6 alkynyl, wherein said alkenyl or alkynyl is optionally substituted with one or more groups selected from hydroxyl, C₁-C₄ alkyl, C₃-C₇ cycloalkyl, C₁-C₄ alkylamino, (C₁-C₄ alkyl)2 amino, C₁-C₃ alkoxy, C3- C₇ cycloalkoxy, C₆-C₁₀ aryl or C₃-C₇ heterocycloalkyl; with the proviso that: 0 to 2 atoms of X, Y, Z can simultaneously be a heteroatom; when one atom selected from X, Y is O or S, then Z is a bond and the other atom selected from X, Y cannot be O or S;

when Z is CH or N, then Y is C(R6) or N and X is CH or N; 0 to 2 atoms of Bl, B2, B3 and B₄ are N. [0041] In some embodiments, the compounds of formula (III) are represented by any one of the following structures:

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pharmaceutically acceptable salt or stereoisomer thereof.

[0042] In some embodiments, the BTK inhibitor is LCB 03-0110 dihydrochloride, or an analog thereof or a salt thereof such as a dihydrochloride salt. The structure of LCB 03-0110, also known as 3-[[2-[3-(4-morpholinylmethyl)phenyl]thieno[3,2-b]pyridin-7-yl]amino]phenol

dihydrochloride, is as follows: . This compound is described in Sun et al., J. Pharmacol. Exp. Ther. 340(3):510-519 (2012), the disclosure of which is incorporated herein by reference in its entirety. [0043] In some embodiments, the BTK inhibitor is LFM-A13, or an analog thereof. The structure of LFM-A13, also known as 2-cyano-N-(2,5-dibromophenyl)-3-hydroxy-2- butenamide, is as follows:

. This compound is described in Vassilev et al., J. Biol. Chem.274(3):1646-1656 (1999), the disclosure of which is incorporated herein by reference in its entirety. [0044] In some embodiments, the BTK inhibitor is PCI 29732, or an analog thereof. The structure of PCI 29732, also known as 1-cyclopentyl-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-amine, is as follows:

. This compound is described in Honigberg et al., Proc. Natl. Acad. Sci. USA 107(29):13075-13080 (2010), the disclosure of which is incorporated herein by reference in its entirety. [0045] In some embodiments, the BTK inhibitor is PF 06465469, or an analog thereof. The structure of PF 06465469, also known as (R)-3-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-

pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-methyl-4-(1-methylethyl))benzamide, is as follows:

. This compound is described in Zapf et al., J. Med. Chem. 55(22):10047-10063 (2012), the disclosure of which is incorporated herein by reference in its entirety. [0046] In some embodiments, the BTK inhibitor is (-)-Terreic acid, or an analog thereof. The structure of (-)-Terreic acid, also known as (1R,6S)-3-hydroxy-4-methyl-7-

oxabicyclo[4.1.0]hept-3-ene-2,5-dione, is as follows: . This compound is described in Kawakami et al., Proc. Natl. Acad. Sci. USA 96(5):2227-2232 (1999), the disclosure of which is incorporated herein by reference in its entirety. [0047] In some embodiments, the BTK inhibitor BMX-IN-1, or an analog thereof. The structure of BMX-IN-1, also known as N-[2-Methyl-5-[9-[4-[(methylsulfonyl)amino]phenyl]- 2-oxobenzo[h]-1,6-naphthyridin-1(2H)-yl]phenyl]-2-propenamide, is as follows:

. This compound is described in Li et al., Oncotarget. 8(30):49238-49252 (2017), the disclosure of which is incorporated herein by reference in its entirety. [0048] In some embodiments, the BTK inhibitor is ARQ-531, or an analog thereof. The structure of ARQ-531, also known as (2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-

(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-

yl)methanone is as follows: .This compound is described in Elgamal et al., J. Hematol. Oncol. 13:8 (2020), the disclosure of which is incorporated herein by reference in its entirety. [0049] In some embodiments, the BTK inhibitor is BI-BTK-1, or an analog thereof. The structure of BI-BTK-1, also known as 5-Amino-3-(4-phenoxyphenyl)-1-((2r,4s)-6-((E)-4- (piperidin-1-yl)but-2-enoyl)-6-azaspiro[3.4]octan-2-yl)-1H-pyrazole-4-carboxamide is as

follows: . This compound is described in Chalmers et al., Arthritis Res. Ther. 20(1):10 (2018), the disclosure of which is incorporated herein by reference in its entirety. [0050] In some embodiments, the BTK inhibitor is BMS-986142, or an analog thereof. The structure of BMS-986142, also known as 1H-Carbazole-8-carboxamide, (2S)-6-fluoro-5-[3-(8- fluoro-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl)-2-methylphenyl]-2-(2- hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide is as follows:

. This compound is described in Watterson et al., J. Med. Chem. 59(19):9173-9200, the disclosure of which is incorporated herein by reference in its entirety. [0051] In some embodiments, the BTK inhibitor is CGI-1746, or an analog thereof. The structure of CGI-1746, also known as 4-tert-butyl-N-[2-methyl-3-[4-methyl-6-[4-(morpholine- 4-carbonyl)anilino]-5-oxopyrazin-2-yl]phenyl]benzamide is as follows:

. This compound is described in Di Paolo et al., Nat. Chem. Biol.7(1):51-50 the disclosure of which is incorporated herein by reference in its entirety. [0052] In some embodiments, the BTK inhibitor is Evobrutinib, or an analog thereof. The structure of Evobrutinib, also known as 1-[4-[[[6-amino-5-(4-phenoxyphenyl)pyrimidin-4- yl]amino]methyl]piperidin-1-yl]prop-2-en-1-one is as follows:

. This compound is described in Crawford et al., J. Med. Chem. 61(6):2227-2245, the disclosure of which is incorporated herein by reference in its entirety. [0053] In some embodiments, the BTK inhibitor is Fenebrutinib, or an analog thereof. The structure of Fenebrutinib, also known as 10-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2S)-2- methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]- 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^2,6]dodeca-2(6),7-dien-9-one is as follows:

This compound is described in Crawford et al., WO 2013/067274, the disclosure of which is incorporated herein by reference in its entirety.

[0054] In some embodiments, the BTK inhibitor is GDC-0834, or an analog thereof. The structure of GDC-0834, also known as (R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2- yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7- tetrahydrobenzo[b]thiophene-2-carboxamide is as follows:

. This compound is described in Liu et al., J. Pharmacol. Exp. Ther.338(1):154-163 the disclosure of which is incorporated herein by reference in its entirety. [0055] In some embodiments, the BTK inhibitor is Olmutinib, or an analog thereof. The structure of Olmutinib, also known as N-[3-[2-[4-(4-methylpiperazin-1-yl)anilino]thieno[3,2- d]pyrimidin-4-yl]oxyphenyl]prop-2-enamide is as follows:

. This compound is described in Cha et al., U.S. Patent No. 9,345,719, the disclosure of which is incorporated herein by reference in its entirety. [0056] In some embodiments, the BTK inhibitor is PLS-123, or an analog thereof. The structure of PLS-123, also known as N-(2-((3-(2- acrylamidoacetamido)phenyl)amino)pyrimidin-5-yl)-2-methyl-5-(3- (trifluoromethyl)benzamido)benzamide is as follows:

.This compound is described in Ding et al., Oncotarget. 6(17):15122-15136 (2015), the disclosure of which is incorporated herein by reference in its entirety. [0057] In some embodiments, the BTK inhibitor is PRN1008, or an analog thereof. The structure of PRN1008, also known as (S,E)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-

1-yl)pent-2-enenitrile is as follows: . This compound is described in Smith et al., Br. J. Clin. Pharmacol.83(11):2367-2376 (2017), the disclosure of which is incorporated herein by reference in its entirety. [0058] In some embodiments, the BTK inhibitor is RN-486, or an analog thereof. The structure of RN-486, also known as 6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl- 5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-

2H-isoquinolin-1-one is as follows: . This compound is described in Zhao et al., Bioorg. Med. Chem.23(15):4344-4353 (2015), the disclosure of which is incorporated herein by reference in its entirety. [0059] In some embodiments, the BTK inhibitor is Spebrutinib, or an analog thereof. The structure of Spebrutinib, also known as N-[3-[[5-fluoro-2-[4-(2- methoxyethoxy)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide is as follows: This compound is described in Chen et al., U.S.

2019/144451, the disclosure of which is incorporated herein by reference in its entirety.

[0060] In some embodiments, the BTK inhibitor is Tirabrutinib, or an analog thereof. The structure of Tirabrutinib, also known as (R)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4- phenoxyphenyl)-7,9-dihydro-8H-purin-8-one is as follows:

. This compound is described in Izumi et al., U.S. 2018/193337, the disclosure of which is incorporated herein by reference in its entirety. [0061] In some embodiments, the BTK inhibitor is Vecabrutinib, or an analog thereof. The structure of Vecabrutinib, also known as (3R,4S)-1-(6-amino-5-fluoropyrimidin-4-yl)-3-[(3R)- 3-[3-chloro-5-(trifluoromethyl)anilino]-2-oxopiperidin-1-yl]piperidine-4-carboxamide is as follows:

. This compound is described in Hopkins et al., U.S. Patent No. 9,394,277, the disclosure of which is incorporated herein by reference in its entirety. [0062] In some embodiments, the BTK inhibitor is a N,9-diphenyl-9H-purin-2-amine derivative. N,9-diphenyl-9H-purin-2-amine derivatives are described in Yang et al., ACS Med. Chem. Lett. 7:1050-1055 (2016), the disclosure of which is incorporated herein by reference in its entirety. [0063] In some embodiments, the BTK inhibitor is a reversible inhibitor. In some embodiments, the BTK inhibitor is an irreversible inhibitor. Reversible and irreversible BTK inhibitors are described in Feng et al., Expert Opin. Ther. Pat. 29(4):217-241 (2019), the disclosure of which is incorporated herein by reference in its entirety. [0064] BTK inhibitors that may be useful in the practice of the disclosed methods may exhibit inhibitory activity toward at least one other kinase that is or may be implicated in the etiology of COVID-19, e.g., hematopoietic cell kinase (HCK). Representative examples of such compounds having multiple e.g., dual, inhibitory activity are described below. BTK/hematopoietic cell kinase (HCK) inhibitors [0065] Representative examples of BTK/HCK inhibitors include compounds of formulas IV to VI. [0066] In certain embodiments, compounds useful in the methods described herein are represented by Formula (IV): or a pharmaceutically acceptable salt

or stereoisomer thereof, wherein: Ar¹ is absent, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocycly, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;each instance of W⁴ is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –OR^a, –N(R^a)₂, –SR^a, –CN, –SCN, –C(=NR^a)R^a, – C(=NR^a)OR^a, –C(=NR^a)N(R^a)2, –C(=O)R^a, –C(=O)OR^a, –C(=O)N(R^a)2, –NO₂, – NR^aC(=O)R^a, –NR^aC(=O)OR^a, –NR^aC(=O)N(R^a)₂, –OC(=O)R^a, –OC(=O)OR^a, or – OC(=O)N(R^a)2; each instance of R^a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an

oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R^a are joined to form a substituted or unsubstituted heterocyclic ring, or substituted or unsubstituted heteroaryl ring; k is 0, 1, 2, 3, or 4, as valency permits; L is absent, –O–, –S–, –NR^b–, –C(R^c)2–, –NR^bC(=O)–, –C(=O)NR^b–, –OC(=O)–, – C(=O)O–, or a substituted or unsubstituted, C_1-6 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with –O–, –S–, –NR^b– , =N–, –N=, or –C(=O)–; each instance of R^b is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting groupAr² is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; each instance of W⁵ is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –OR^a, –N(R^a)2, –SR^a, –CN, –SCN, –C(=NR^a)R^a, –C(=NR^a)OR^a, –C(=NR^a)N(R^a)₂, –C(=O)R^a, –C(=O)OR^a, –C(=O)N(R^a)₂, –NO₂, –NR^aC(=O)R^a, –NR^aC(=O)OR^a, –NR^aC(=O)N(R^a)2, –OC(=O)R^a, –OC(=O)OR^a, or – OC(=O)N(R^a)₂; n is 0, 1, 2, 3, 4, or 5, as valency permits; bond a is a single or double bond, as valency permits; X⁵ is absent, –O–, –S–, –NR^b–, =N–, –N=, –C(R^c)₂–, –NR^bC(=O)–, –C(=O)NR^b–, – OC(=O)–, –C(=O)O–, or a substituted or unsubstituted, C1-6 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with – O–, –S–, –NR^b–, =N–, –N=, or –C(=O)–; bond b is a single or double bond, as valency permits; X⁴ is C, CR^c, or N; bond c is a single or double bond, as valency permits; X¹ is CR^c, N, –C(=O)–, –S(=O)₂–, or –P(=O)(R^a)–; each instance of R^c is independently hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, or –OR^d; each instance of R^d is independently hydrogen, substituted or unsubstituted C_1-6 alkyl, or an oxygen protecting group; X² is –C(R^e)₂– or –N(R^f)–;

each instance of R^e is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –OR^a, –N(R^a)₂, –SR^a, –CN, –SCN, –C(=NR^a)R^a, –C(=NR^a)OR^a, –C(=NR^a)N(R^a)2, –C(=O)R^a, –C(=O)OR^a, –C(=O)N(R^a)2, –NO₂, –NR^aC(=O)R^a, –NR^aC(=O)OR^a, –NR^aC(=O)N(R^a)₂, –OC(=O)R^a, –OC(=O)OR^a, or – OC(=O)N(R^a)2; R^f is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –C(=NR^a)R^a, –C(=NR^a)OR^a, –C(=NR^a)N(R^a)2, –C(=O)R^a, –C(=O)OR^a, – C(=O)N(R^a)₂, or a nitrogen protecting group; each instance of W¹ is independently halogen, substituted or unsubstituted C1-6 alkyl, or – OR^d, or two instances of W¹ at the same carbon atom are joined to form =O; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, as valency permits; p is 1 or 2; q is 1 or 2; X³ is CR^h or N; R^h is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, or –OR^d; W² is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, or –OR^d; each instance of W³ is independently hydrogen, substituted or unsubstituted C_1-6 alkyl, or a nitrogen protecting group. [0067] In certain embodiments, compounds useful in the methods described herein are represented by Formula (V):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Ar¹ is absent, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocycly, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each instance of W⁴ is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –OR^a, –N(R^a)2, –SR^a, –CN, –SCN, –C(=NR^a)R^a, –C(=NR^a)OR^a, –C(=NR^a)N(R^a)2, –C(=O)R^a, –C(=O)OR^a, –C(=O)N(R^a)2, –NO₂, –NR^aC(=O)R^a, –NR^aC(=O)OR^a, –NR^aC(=O)N(R^a)₂, –OC(=O)R^a, –OC(=O)OR^a, or – OC(=O)N(R^a)2; each instance of R^a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R^a are joined to form a substituted or unsubstituted heterocyclic ring, or substituted or unsubstituted heteroaryl ring; k is 0, 1, 2, 3, or 4, as valency permits; L is absent, –O–, –S–, –NR^b–, –C(R^c)2–, –NR^bC(=O)–, –C(=O)NR^b–, –OC(=O)–, – C(=O)O–, or a substituted or unsubstituted, C_1-6 hydrocarbon chain, optionally wherein one or

more chain atoms of the hydrocarbon chain are independently replaced with –O–, –S–, –NR^b– , =N–, –N=, or –C(=O)–; each instance of R^b is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group; Ar² is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; each instance of W⁵ is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –OR^a, –N(R^a)2, –SR^a, –CN, –SCN, –C(=NR^a)R^a, – C(=NR^a)OR^a, –C(=NR^a)N(R^a)₂, –C(=O)R^a, –C(=O)OR^a, –C(=O)N(R^a)₂, –NO₂, – NR^aC(=O)R^a, –NR^aC(=O)OR^a, –NR^aC(=O)N(R^a)2, –OC(=O)R^a, –OC(=O)OR^a, or – OC(=O)N(R^a)₂; n is 0, 1, 2, 3, 4, or 5, as valency permits; bond a is a single or double bond, as valency permits; X⁵ is absent, –O–, –S–, –NR^b–, =N–, –N=, –C(R^c)2–, –NR^bC(=O)–, –C(=O)NR^b–, – OC(=O)–, –C(=O)O–, or a substituted or unsubstituted, C_1-6 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with – O–, –S–, –NR^b–, =N–, –N=, or –C(=O)–; each instance of R^c is independently hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, or –OR^d; each instance of R^d is independently hydrogen, substituted or unsubstituted C_1-6 alkyl, or an oxygen protecting group; X² is –C(R^e)₂– or –N(R^f)–; each instance of R^e is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –OR^a, –N(R^a)₂, –SR^a, –CN, –SCN, –C(=NR^a)R^a, –C(=NR^a)OR^a, –C(=NR^a)N(R^a)2, –C(=O)R^a, –C(=O)OR^a, –C(=O)N(R^a)2, –NO₂, –NR^aC(=O)R^a, –NR^aC(=O)OR^a, –NR^aC(=O)N(R^a)₂, –OC(=O)R^a, –OC(=O)OR^a, or – OC(=O)N(R^a)2; R^f is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted

heteroaryl, –C(=NR^a)R^a, –C(=NR^a)OR^a, –C(=NR^a)N(R^a)2, –C(=O)R^a, –C(=O)OR^a, – C(=O)N(R^a)₂, or a nitrogen protecting group; each instance of W¹ is independently halogen, substituted or unsubstituted C1-6 alkyl, or – OR^d, or two instances of W¹ at the same carbon atom are joined to form =O; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, as valency permits; p is 1 or 2; q is 1 or 2; X³ is CR^h or N; R^h is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, or –OR^d; W² is hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, or –OR^d; each instance of W³ is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group; X⁶ is absent, C, CR^c, or N; bond d is absent, a single bond, or a double bond, as valency permits; W⁶ is absent, or W⁶ and W⁷ are joined to form substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; W⁷ is hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, or –OR^d; each instance of W⁸ is independently halogen, substituted or unsubstituted C1-6 alkyl, or – OR^d; and r is 0, 1, or 2. [0068] The compounds of Formulae (IV) and (V) are described U.S. Patent 10,525,060, incorporated herein by reference in its entirety. [0069] In certain embodiments, Ar¹ is absent. In certain embodiments, Ar¹ is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membed, monocyclic carbocyclyl). In certain embodiments, Ar¹ is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, or substituted or unsubstituted cyclohexyl. In certain embodiments, Ar¹ is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membed, monocyclic heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, Ar¹ is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl,

substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, Ar¹ is substituted or unsubstituted aryl (e.g., substituted or unsubstituted 6- to 14-membered aryl). In certain embodiments, Ar¹ is unsubstituted phenyl. In certain embodiments, Ar¹ is substituted phenyl. In certain embodiments, Ar¹ is substituted or unsubstituted heteroaryl. In certain embodiments, Ar¹ is substituted or unsubstituted, 5- to 6- membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur. In certain embodiments, Ar¹ is substituted or unsubstituted, 9- to 10-membed, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur. [0070] When two or more instances of W⁴ are present in a compound described herein, any two instances of W⁴ may be the same or different from each other. In certain embodiments, at least one instance of W⁴ is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of W⁴ is substituted or unsubstituted alkyl. In certain embodiments, at least one instance of W⁴ is substituted or unsubstituted C_1-6 alkyl. In certain embodiments, at least one instance of W⁴ is Me. In certain embodiments, at least one instance of W⁴ is substituted methyl, Et, substituted ethyl, Pr, substituted propyl, Bu, or substituted butyl. In certain embodiments, at least one instance of W⁴ is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C_2-6 alkenyl). In certain embodiments, at least one instance of W⁴ is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl). In certain embodiments, at least one instance of W⁴ is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membed, monocyclic carbocyclyl). In certain embodiments, at least one instance of W⁴ is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, or substituted or unsubstituted cyclohexyl. In certain embodiments, at least one instance of W⁴ is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membed, monocyclic heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of W⁴ is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of W⁴ is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of W⁴ is unsubstituted phenyl. In certain

embodiments, at least one instance of W⁴ is substituted phenyl. In certain embodiments, at least one instance of W⁴ is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of W⁴ is substituted or unsubstituted, 5- to 6-membed, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur. In certain embodiments, at least one instance of W⁴ is substituted or unsubstituted, 9- to 10-membed, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur. In certain embodiments, at least one instance of W⁴ is –OR^a (e.g., –OH, –O(substituted or unsubstituted alkyl), or –O(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of W⁴ is –SR^a (e.g., –SH, –S(substituted or unsubstituted alkyl), or –S(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of W⁴ is –N(R^a)2 (e.g., – NH₂, –NH(substituted or unsubstituted alkyl), or –N(substituted or unsubstituted alkyl)– (substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of W⁴ is – CN or –SCN. In certain embodiments, at least one instance of W⁴ is –NO₂. In certain embodiments, at least one instance of W⁴ is –C(=NR^a)R^a, –C(=NR^a)OR^a, or –C(=NR^a)N(R^a)2. In certain embodiments, at least one instance of W⁴ is –C(=O)R^a (e.g., –C(=O)(substituted or unsubstituted alkyl) or –C(=O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of W⁴ is –C(=O)OR^a (e.g., –C(=O)OH, –C(=O)O(substituted or unsubstituted alkyl), or –C(=O)O(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of W⁴ is –C(=O)N(R^a)2 (e.g., –C(=O)NH₂, – C(=O)NH(substituted or unsubstituted alkyl), –C(=O)NH(substituted or unsubstituted phenyl), –C(=O)N(substituted or unsubstituted alkyl)–(substituted or unsubstituted alkyl), or – C(=O)N(substituted or unsubstituted phenyl)–(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of W⁴ is –NR^aC(=O)R^a (e.g., –NHC(=O)(substituted or unsubstituted alkyl) or –NHC(=O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of W⁴ is –NR^aC(=O)OR^a. In certain embodiments, at least one instance of W⁴ is –NR^aC(=O)N(R^a)₂ (e.g., –NHC(=O)NH₂, –NHC(=O)NH(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of W⁴ is –OC(=O)R^a (e.g., –OC(=O)(substituted or unsubstituted alkyl) or –OC(=O)(substituted or unsubstituted phenyl)), –OC(=O)OR^a (e.g., –OC(=O)O(substituted or unsubstituted alkyl) or – OC(=O)O(substituted or unsubstituted phenyl)), or –OC(=O)N(R^a)₂ (e.g., –OC(=O)NH₂, – OC(=O)NH(substituted or unsubstituted alkyl), –OC(=O)NH(substituted or unsubstituted

phenyl), –OC(=O)N(substituted or unsubstituted alkyl)–(substituted or unsubstituted alkyl), or –OC(=O)N(substituted or unsubstituted phenyl)–(substituted or unsubstituted alkyl)). [0071] When two or more instances of R^a are present in a compound described herein, any two instances of R^a may be the same or different from each other. In certain embodiments, at least one instance of R^a is H. In certain embodiments, each instance of R^a is H. In certain embodiments, at least one instance of R^a is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-6 alkyl (e.g., Me)). In certain embodiments, at least one instance of R^a is substituted or unsubstituted acyl, substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl), or substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C_2-6 alkynyl). In certain embodiments, at least one instance of R^a is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membed, monocyclic carbocyclyl), substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membed, monocyclic heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur), substituted or unsubstituted aryl (e.g., substituted or unsubstituted phenyl), or substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membed, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R^a is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts) when attached to a nitrogen atom, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom. In certain embodiments, two instances of R^a are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring. [0072] In certain embodiments, k is 0. In certain embodiments, k is 1, 2, 3, or 4, as valency permits. [0073] In certain embodiments, when L is –(an unsymmetrical divalent moiety)–, the bond on the left-hand side of “–(an unsymmetrical divalent moiety)–” is directly attached to Ar¹, and the bond on the right-hand side of “–(an unsymmetrical divalent moiety)–” is directly attached to Ar². In certain embodiments, L is absent. In certain embodiments, L is –O–. In certain embodiments, L is –S–. In certain embodiments, L is –NR^b– (e.g., –NH–, –N(substituted or unsubstituted C_1-6 alkyl)–, or –N(nitrogen protecting group)–). In certain embodiments, L is –

C(R^c)2– (e.g., –CH₂–). In certain embodiments, L is –NR^bC(=O)– (e.g., –NHC(=O)–, – N(substituted or unsubstituted C_1-6 alkyl)C(=O)–, or –N(nitrogen protecting group)C(=O)–) or –C(=O)NR^b– (e.g., –C(=O)NH–, –C(=O)N(substituted or unsubstituted C1-6 alkyl)–, or – C(=O)N(nitrogen protecting group)–). In certain embodiments, L is –OC(=O)– or –C(=O)O–. In certain embodiments, L is a substituted or unsubstituted, C1-6 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with – O–, –S–, –NR^b–, =N–, –N=, or –C(=O)–. [0074] When two or more instances of R^b are present in a compound described herein, any two instances of R^b may be the same or different from each other. In certain embodiments, at least one instance of R^b is H. In certain embodiments, each instance of R^b is H. In certain embodiments, at least one instance of R^b is substituted or unsubstituted C1-6 alkyl (e.g., Me). In certain embodiments, at least one instance of R^b is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). [0075] In certain embodiments, Ar² is substituted or unsubstituted aryl (e.g., substituted or unsubstituted 6- to 14-membered aryl). In certain embodiments, Ar² is unsubstituted phenyl. In certain embodiments, Ar² is substituted phenyl. In certain embodiments, Ar² is substituted or unsubstituted heteroaryl. In certain embodiments, Ar² is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur. In certain embodiments, Ar² is substituted or unsubstituted, 9- to 10-membed, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur. [0076] When two or more instances of W⁵ are present in a compound described herein, any two instances of W⁵ may be the same or different from each other. In certain embodiments, at least one instance of W⁵ is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of W⁵ is substituted or unsubstituted alkyl. In certain embodiments, at least one instance of W⁵ is substituted or unsubstituted C1-6 alkyl. In certain embodiments, at least one instance of W⁵ is Me. In certain embodiments, at least one instance of W⁵ is substituted methyl, Et, substituted ethyl, Pr, substituted propyl, Bu, or substituted butyl. In certain embodiments, at least one instance of W⁵ is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl). In certain embodiments, at least one instance of W⁵ is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C_2-6 alkynyl). In certain embodiments, at least one instance of W⁵ is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membed, monocyclic carbocyclyl). In certain

embodiments, at least one instance of W⁵ is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, or substituted or unsubstituted cyclohexyl. In certain embodiments, at least one instance of W⁵ is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membed, monocyclic heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of W⁵ is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of W⁵ is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of W⁵ is unsubstituted phenyl. In certain embodiments, at least one instance of W⁵ is substituted phenyl. In certain embodiments, at least one instance of W⁵ is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of W⁵ is substituted or unsubstituted, 5- to 6-membed, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur. In certain embodiments, at least one instance of W⁵ is substituted or unsubstituted, 9- to 10-membed, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur. In certain embodiments, at least one instance of W⁵ is –OR^a (e.g., –OH, –O(substituted or unsubstituted alkyl), or –O(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of W⁵ is –SR^a (e.g., –SH, –S(substituted or unsubstituted alkyl), or –S(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of W⁵ is –N(R^a)₂ (e.g., – NH₂, –NH(substituted or unsubstituted alkyl), or –N(substituted or unsubstituted alkyl)– (substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of W⁵ is – CN or –SCN. In certain embodiments, at least one instance of W⁵ is –NO₂. In certain embodiments, at least one instance of W⁵ is –C(=NR^a)R^a, –C(=NR^a)OR^a, or –C(=NR^a)N(R^a)₂. In certain embodiments, at least one instance of W⁵ is –C(=O)R^a (e.g., –C(=O)(substituted or unsubstituted alkyl) or –C(=O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of W⁵ is –C(=O)OR^a (e.g., –C(=O)OH, –C(=O)O(substituted or unsubstituted alkyl), or –C(=O)O(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of W⁵ is –C(=O)N(R^a)2 (e.g., –C(=O)NH₂, – C(=O)NH(substituted or unsubstituted alkyl), –C(=O)NH(substituted or unsubstituted phenyl), –C(=O)N(substituted or unsubstituted alkyl)–(substituted or unsubstituted alkyl), or – C(=O)N(substituted or unsubstituted phenyl)–(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of W⁵ is –NR^aC(=O)R^a (e.g., –NHC(=O)(substituted or unsubstituted alkyl) or –NHC(=O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of W⁵ is –NR^aC(=O)OR^a. In certain embodiments, at least one instance of W⁵ is –NR^aC(=O)N(R^a)₂ (e.g., –NHC(=O)NH₂, –NHC(=O)NH(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of W⁵ is –OC(=O)R^a (e.g., –OC(=O)(substituted or unsubstituted alkyl) or –OC(=O)(substituted or unsubstituted phenyl)), –OC(=O)OR^a (e.g., –OC(=O)O(substituted or unsubstituted alkyl) or – OC(=O)O(substituted or unsubstituted phenyl)), or –OC(=O)N(R^a)₂ (e.g., –OC(=O)NH₂, – OC(=O)NH(substituted or unsubstituted alkyl), –OC(=O)NH(substituted or unsubstituted phenyl), –OC(=O)N(substituted or unsubstituted alkyl)–(substituted or unsubstituted alkyl), or –OC(=O)N(substituted or unsubstituted phenyl)–(substituted or unsubstituted alkyl)). [0077] In certain embodiments, n is 0. In certain embodiments, n is 1, 2, 3, 4, or 5, as valency permits. [0078] In certain embodiments, when X⁵ is (an unsymmetrical divalent moiety)

, the bond on the left-hand side of “

(an unsymmetrical divalent moiety) ” is directly attached to X⁴, and the bond on the right-hand side of “ (an unsymmetrical divalent moiety) ” is directly attached to Ar¹. In certain embodiments, X⁵ is absent. In certain embodiments, X⁵ is –O–. In certain embodiments, X⁵ is –S–. In certain embodiments, X⁵ is – NR^b– (e.g., –NH–, –N(substituted or unsubstituted C_1-6 alkyl)–, or –N(nitrogen protecting group)–). In certain embodiments, X⁵ is =N– or –N=. In certain embodiments, X⁵ is –C(R^c)2– (e.g., –CH₂–). In certain embodiments, X⁵ is –NR^bC(=O)– (e.g., –NHC(=O)–, –N(substituted or unsubstituted C1-6 alkyl)C(=O)–, or –N(nitrogen protecting group)C(=O)–) or –C(=O)NR^b– (e.g., –C(=O)NH–, –C(=O)N(substituted or unsubstituted C_1-6 alkyl)–, or –C(=O)N(nitrogen protecting group)–). In certain embodiments, X⁵ is –OC(=O)– or –C(=O)O–. In certain embodiments, X⁵ is a substituted or unsubstituted, C_1-6 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with –O–, –S–, –NR^b–, =N–, –N=, or –C(=O)–. In certain embodiments, X⁵ is =CH– or –CH=. In certain embodiments, X⁵ is a substituted or unsubstituted, C2 hydrocarbon chain. In certain embodiments, X⁵ is –C ^C–. In certain embodiments, X⁵ is unsubstituted ethylene or unsubstituted vinylene. In certain embodiments, X⁵ is =N–V–, wherein V is absent, –C(R^c)2–, –C(=O)–, –O–, or –N(R^b)–. In certain embodiments, X⁵ is =N–CH₂–, =N–C(=O)–, =N–O–, or

=N–NH–. In certain embodiments, X⁵ is a substituted or unsubstituted, C3 hydrocarbon chain. In certain embodiments, X⁵ is –C ^C–CH₂–. In certain embodiments, X⁵ is unsubstituted n- propylene, –CH=CH–CH₂–, –CH₂–CH=CH–, or –CH₂–C ^C–. In certain embodiments, X⁵ is a substituted or unsubstituted, C4 hydrocarbon chain, optionally one or two chain atoms of the hydrocarbon chain are independently replaced with –O–, –S–, –NR^b–, =N–, –N=, or –C(=O)– . In certain embodiments, X⁵ is –C ^C–CH₂–O–. In certain embodiments, X⁵ is –C ^C–CH₂–S– , –C ^C–CH₂–NR^b–, –C ^C–CH₂–CH₂–, –CH=CH–CH₂–O–, –CH=CH–CH₂–S–, –CH=CH– CH₂–NR^b–, –CH=CH–CH₂–CH₂–, –CH₂–CH₂–CH₂–O–, –CH₂–CH₂–CH₂–S–, –CH₂–CH₂– CH₂–NR^b–, or –CH₂–CH₂–CH₂–CH₂–. In certain embodiments, X⁵ is a substituted or unsubstituted, C_5-6 hydrocarbon chain, optionally one, two, or three chain atoms of the hydrocarbon chain are independently replaced with –O–, –S–, –NR^b–, =N–, –N=, or –C(=O)– . In certain embodiments, X⁵ is =N–V–C(=O)–CH₂–O–, wherein V is absent, –C(R^c)₂–, – C(=O)–, –O–, or –N(R^b)–. In certain embodiments, X⁵ is =N–C(=O)–CH₂–O–, =N–CH₂– C(=O)–CH₂–O–, =N–O–C(=O)–CH₂–O–, or =N–NH–C(=O)–CH₂–O–. [0079] In certain embodiments, X⁴ is C. In certain embodiments, X⁴ is CR^c. In certain embodiments, X⁴ is CH. In certain embodiments, X⁴ is N. [0080] In certain embodiments, X¹ is CR^c. In certain embodiments, X¹ is CH. In certain embodiments, X¹ is N. In certain embodiments, X¹ is –C(=O)–. In certain embodiments, X¹ is –S(=O)₂–. In certain embodiments, X¹ is –P(=O)(R^a)– (e.g., –P(=O)(substituted or unsubstituted C_1-6 alkyl)– (e.g., –P(=O)(Me)–)). When two or more instances of R^c are present in a compound described herein, any two instances of R^c may be the same or different from each other. In certain embodiments, at least one instance of R^c is H. In certain embodiments, each instance of R^c is H. In certain embodiments, at least one instance of R^c is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R^c is substituted or unsubstituted C_1-6 alkyl (e.g., Me). In certain embodiments, at least one instance of R^c is –OR^d (e.g., –OH or –OMe). [0081] When two or more instances of R^d are present in a compound described herein, any two instances of R^d may be the same or different from each other. In certain embodiments, at least one instance of R^d is H. In certain embodiments, each instance of R^d is H. In certain embodiments, at least one instance of R^d is substituted or unsubstituted C1-6 alkyl (e.g., Me). In certain embodiments, at least one instance of R^d is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl). [0082] In certain embodiments, X² is –C(R^e)2–. In certain embodiments, X² is –CH(R^e)–. In certain embodiments, X² is –CH₂–. In certain embodiments, X² is –N(R^f)–. In certain embodiments, X² is –NH–. [0083] The two instances of R^e may be the same or different from each other. In certain embodiments, at least one instance of R^e is H. In certain embodiments, each instance of R^e is H. In certain embodiments, at least one instance of R^e is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R^e is substituted or unsubstituted alkyl. In certain embodiments, at least one instance of R^e is substituted or unsubstituted C_1-6 alkyl. In certain embodiments, at least one instance of R^e is Me. In certain embodiments, at least one instance of R^e is substituted methyl, Et, substituted ethyl, Pr, substituted propyl, Bu, or substituted butyl. In certain embodiments, at least one instance of R^e is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C_2-6 alkenyl). In certain embodiments, at least one instance of R^e is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl). In certain embodiments, at least one instance of R^e is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membed, monocyclic carbocyclyl). In certain embodiments, at least one instance of R^e is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, or substituted or unsubstituted cyclohexyl. In certain embodiments, at least one instance of R^e is substituted or unsubstituted heterocyclyl. In certain embodiments, at least one instance of R^e is substituted or unsubstituted, 3- to 7-membed, monocyclic heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur. In certain embodiments, at least one instance of R^e is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, or substituted or unsubstituted morpholinyl. In certain embodiments, at least one instance of R^e is substituted or unsubstituted piperazinyl (e.g., substituted or unsubstituted 1-piperazinyl). In certain embodiments, at least one instance of R^e is

)). In certain embodiments, at least one instance of R^e is

or

. In certain embodiments, at least one instance of R^e is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In

certain embodiments, at least one instance of R^e is unsubstituted phenyl. In certain embodiments, at least one instance of R^e is substituted phenyl. In certain embodiments, at least one instance of R^e is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R^e is substituted or unsubstituted, 5- to 6-membed, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur. In certain embodiments, at least one instance of R^e is substituted or unsubstituted, 9- to 10-membed, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur. In certain embodiments, at least one instance of R^e is –OR^a (e.g., –OH, –O(substituted or unsubstituted alkyl), or –O(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R^e is –SR^a (e.g., –SH, –S(substituted or unsubstituted alkyl), or –S(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R^e is –N(R^a)₂ (e.g., – NH₂, –NH(substituted or unsubstituted alkyl), or –N(substituted or unsubstituted alkyl)– (substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of R^e is –CN or –SCN. In certain embodiments, at least one instance of R^e is –NO₂. In certain embodiments, at least one instance of R^e is –C(=NR^a)R^a, –C(=NR^a)OR^a, or –C(=NR^a)N(R^a)₂. In certain embodiments, at least one instance of R^e is –C(=O)R^a. In certain embodiments, at least one instance of R^e is –C(=O)(substituted or unsubstituted alkyl), –C(=O)(substituted or unsubstituted alkynyl), or –C(=O)(substituted or unsubstituted phenyl). In certain embodiments, at least one instance of R^e is –C(=O)(substituted or unsubstituted alkenyl) (e.g., –C(=O)(substituted or unsubstituted C_2-6 alkenyl)). In certain embodiments, at least one instance of R^e is –C(=O)(vinyl). In certain embodiments, at least one instance of R^e is – C(=O)OR^a (e.g., –C(=O)OH, –C(=O)O(substituted or unsubstituted alkyl), or – C(=O)O(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R^e is –C(=O)N(R^a)₂ (e.g., –C(=O)NH₂, –C(=O)NH(substituted or unsubstituted alkyl), – C(=O)NH(substituted or unsubstituted phenyl), –C(=O)N(substituted or unsubstituted alkyl)– (substituted or unsubstituted alkyl), or –C(=O)N(substituted or unsubstituted phenyl)– (substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of R^e is – NR^aC(=O)R^a (e.g., –NHC(=O)(substituted or unsubstituted alkyl) or –NHC(=O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R^e is –NR^aC(=O)OR^a. In certain embodiments, at least one instance of R^e is –NR^aC(=O)N(R^a)₂ (e.g., –NHC(=O)NH₂, –NHC(=O)NH(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of R^e is –OC(=O)R^a (e.g., –OC(=O)(substituted or unsubstituted alkyl) or – OC(=O)(substituted or unsubstituted phenyl)), –OC(=O)OR^a (e.g., –OC(=O)O(substituted or unsubstituted alkyl) or –OC(=O)O(substituted or unsubstituted phenyl)), or –OC(=O)N(R^a)₂ (e.g., –OC(=O)NH₂, –OC(=O)NH(substituted or unsubstituted alkyl), – OC(=O)NH(substituted or unsubstituted phenyl), –OC(=O)N(substituted or unsubstituted alkyl)–(substituted or unsubstituted alkyl), or –OC(=O)N(substituted or unsubstituted phenyl)– (substituted or unsubstituted alkyl)). [0084] In certain embodiments, R^f is H. In certain embodiments, R^f is substituted or unsubstituted alkyl. In certain embodiments, R^f is substituted or unsubstituted C_1-6 alkyl. In certain embodiments, R^f is Me. In certain embodiments, R^f is substituted methyl, Et, substituted ethyl, Pr, substituted propyl, Bu, or substituted butyl. In certain embodiments, R^f is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl). In certain embodiments, R^f is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C_2-6 alkynyl). In certain embodiments, R^f is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membed, monocyclic carbocyclyl). In certain embodiments, R^f is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, or substituted or unsubstituted cyclohexyl. In certain embodiments, R^f is substituted or unsubstituted heterocyclyl. In certain embodiments, R^f is substituted or unsubstituted, 3- to 7-membed, monocyclic heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur. In certain embodiments, R^f is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, or substituted or unsubstituted morpholinyl. In certain embodiments, R^f is substituted or unsubstituted piperazinyl (e.g., substituted or unsubstituted 1-piperazinyl). In certain embodiments, R^f is

(e.g.,

)). In certain embodiments, R^f is

. In certain embodiments, R^f is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10- membered aryl). In certain embodiments, R^f is unsubstituted phenyl. In certain embodiments, R^f is substituted phenyl. In certain embodiments, R^f is substituted or unsubstituted heteroaryl. In certain embodiments, R^f is substituted or unsubstituted, 5- to 6-membed, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are

independently nitrogen, oxygen, or sulfur. In certain embodiments, R^f is substituted or unsubstituted, 9- to 10-membed, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur. In certain embodiments, R^f is –C(=NR^a)R^a, –C(=NR^a)OR^a, or –C(=NR^a)N(R^a)₂. In certain embodiments, R^f is –C(=O)R^a. In certain embodiments, R^f is –C(=O)(substituted or unsubstituted alkyl), – C(=O)(substituted or unsubstituted alkynyl), or –C(=O)(substituted or unsubstituted phenyl). In certain embodiments, R^f is –C(=O)(substituted or unsubstituted alkenyl) (e.g., – C(=O)(substituted or unsubstituted C_2-6 alkenyl)). In certain embodiments, R^f is –C(=O)(vinyl). In certain embodiments, R^f is –C(=O)OR^a (e.g., –C(=O)OH, –C(=O)O(substituted or unsubstituted alkyl), or –C(=O)O(substituted or unsubstituted phenyl)). In certain embodiments, R^f is –C(=O)N(R^a)2 (e.g., –C(=O)NH₂, –C(=O)NH(substituted or unsubstituted alkyl), –C(=O)NH(substituted or unsubstituted phenyl), –C(=O)N(substituted or unsubstituted alkyl)–(substituted or unsubstituted alkyl), or –C(=O)N(substituted or unsubstituted phenyl)– (substituted or unsubstituted alkyl)). In certain embodiments, R^f is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). [0085] When two or more instances of W¹ are present in a compound described herein, any two instances of W¹ may be the same or different from each other. In certain embodiments, at least one instance of W¹ is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of W¹ is substituted or unsubstituted C1-6 alkyl (e.g., Me). In certain embodiments, at least one instance of W¹ is –OR^d (e.g., –OH or –OMe). In certain embodiments, two instances of W¹ at the same carbon atom are joined to form =O. In certain embodiments, two instances of W¹ at one carbon atom are joined to form =O, and another two instances of W¹ at another carbon atom are joined to form =O. [0086] In certain embodiments, m is 0. In certain embodiments, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, as valency permits. [0087] In certain embodiments, p is 1. In certain embodiments, p is 2. [0088] In certain embodiments, q is 1. In certain embodiments, q is 2. [0089] In certain embodiments, X³ is CR^h. In certain embodiments, X³ is CH. In certain embodiments, X³ is N. [0090] In certain embodiments, R^h is H. In certain embodiments, R^h is halogen (e.g., F, Cl, Br, or I). In certain embodiments, R^h is substituted or unsubstituted C_1-6 alkyl (e.g., Me). In certain embodiments, R^h is –OR^d (e.g., –OH or –OMe).

[0091] In certain embodiments, W² is H. In certain embodiments, W² is halogen (e.g., F, Cl, Br, or I). In certain embodiments, W² is substituted or unsubstituted C_1-6 alkyl (e.g., Me). In certain embodiments, W² is –OR^d (e.g., –OH or –OMe). [0092] The two instances of W³ may be the same or different from each other. In certain embodiments, at least one instance of W³ is H. In certain embodiments, each instance of W³ is H. In certain embodiments, at least one instance of W³ is substituted or unsubstituted C_1-6 alkyl (e.g., Me). In certain embodiments, at least one instance of W³ is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). [0093] In certain embodiments, X⁶ is absent. In certain embodiments, X⁶ is C. In certain embodiments, X⁶ is CR^c (e.g., CH). In certain embodiments, X⁶ is N. [0094] In certain embodiments, bond d is absent. In certain embodiments, bond d is a single bond or a double bond. [0095] In certain embodiments, W⁶ is absent. In certain embodiments, each one of X⁶, W⁶, and bonds d and e is absent. [0096] In certain embodiments, W⁶ and W⁷ are joined to form substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membed, monocyclic carbocyclyl). In certain embodiments, W⁶ and W⁷ are joined to form substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, or substituted or unsubstituted cyclohexyl. In certain embodiments, W⁶ and W⁷ are joined to form substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membed, monocyclic heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, W⁶ and W⁷ are joined to form substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, W⁶ and W⁷ are joined to form substituted or unsubstituted aryl (e.g., substituted or unsubstituted phenyl). In certain embodiments, W⁶ and W⁷ are joined to form substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membed, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen). [0097] In certain embodiments, W⁷ is H. In certain embodiments, W⁷ is halogen (e.g., F, Cl, Br, or I). In certain embodiments, W⁷ is substituted or unsubstituted C1-6 alkyl (e.g., Me). In certain embodiments, W⁷ is –OR^d (e.g., –OH or –OMe).

[0098] When two instances of W⁸ are present in a compound described herein, the two instances of W⁸ may be the same or different from each other. In certain embodiments, at least one instance of W⁸ is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of W⁸ is substituted or unsubstituted C_1-6 alkyl (e.g., Me). In certain embodiments, at least one instance of W⁸ is –OR^d (e.g., –OH or –OMe). [0099] In certain embodiments, r is 0. In certain embodiments, r is 1. In certain embodiments, r is 2. [00100] In certain embodiments, L is –O–; m is 0; W² is H; and each instance of W³ is H. [00101] In certain embodiments, k is 0; n is 0; m is 0; W² is H; and each instance of W³ is H. [00102] In certain embodiments, k is 0; L is –O–; n is 0; m is 0; W² is H; and each instance of W³ is H. [00103] In certain embodiments, k is 0; L is –O–; n is 0; X¹ is CH; m is 0; W² is H; and each instance of W³ is H. [00104] In certain embodiments, k is 0; L is –O–; n is 0; X¹ is N; m is 0; W² is H; and each instance of W³ is H. [00105] In certain embodiments, the compound of Formula (IV) is of the formula:

, or a pharmaceutically acceptable salt or stereoisomer thereof. [00106] In certain embodiments, the compound of Formula (IV) is of the formula: or a pharmaceutically acceptable salt or

stereoisomer thereof. [00107] In certain embodiments, the compound of Formula (IV) is of the formula: or a pharmaceutically acceptable salt or

stereoisomer thereof. [00108] In certain embodiments, the compound of Formula (IV) is of the formula:

or a pharmaceutically acceptable salt or stereoisomer thereof. [00109] In certain embodiments, the compound of Formula (IV) is of the formula: or a pharmaceutically acceptable salt or

stereoisomer thereof. [00110] In certain embodiments, the compound of Formula (IV) is of the formula:

, or a pharmaceutically acceptable salt or stereoisomer thereof. [00111] In certain embodiments, the compound of Formula (IV) is of the formula:

, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R^g is H, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group. In certain embodiments, R^g is H. In certain embodiments, R^g is substituted or unsubstituted C1-6 alkyl. In certain embodiments, R^g is Me. In certain embodiments, R^g is substituted methyl, Et, substituted ethyl, Pr, substituted propyl, Bu, or substituted butyl. In certain embodiments, R^g is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). [00112] In certain embodiments, the compound of Formula (IV) is of the formula:

, or a pharmaceutically acceptable salt or stereoisomer thereof. [00113] In certain embodiments, the compound of Formula (IV) is of the formula: or a pharmaceutically acceptable salt or

stereoisomer thereof. [00114] In certain embodiments, the compound of Formula (IV) is of the formula:

, or a pharmaceutically acceptable salt or stereoisomer thereof. [00115] In certain embodiments, the compound of Formula (IV) is of the formula:

or a pharmaceutically acceptable salt or stereoisomer thereof. [00116] In certain embodiments, the compound of Formula (IV) is of the formula:

, or a pharmaceutically acceptable salt or stereoisomer thereof. [00117] In certain embodiments, the compound of Formula (IV) is of the formula:

, or a pharmaceutically acceptable salt or stereoisomer thereof. [00118] In certain embodiments, the compound of Formula (IV) is of the formula:

or a pharmaceutically or stereoisomer thereof. [00119] In certain embodiments, the compound of Formula (IV) is of the formula:

or a pharmaceutically acceptable salt or stereoisomer thereof. [00120] In certain embodiments, the compound of Formula (IV) is of the formula:

, or a pharmaceutically acceptable salt or stereoisomer thereof. [00121] In certain embodiments, the compound of Formula (IV) is of the formula:

, or a pharmaceutically acceptable salt or stereoisomer thereof. [00122] In certain embodiments, the compound of Formula (IV) is of the formula:

or a pharmaceutically acceptable salt or stereoisomer thereof. [00123] In certain embodiments, the compound of Formula (IV) is of the formula:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein V is absent, –C(R^c)₂–, –C(=O)–, –O–, or –N(R^b)–. [00124] In certain embodiments, the compound of Formula (IV) is of the formula:

, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein V is absent, –C(R^c)2–, –C(=O)–, –O–, or –N(R^b)–. [00125] In certain embodiments, the compound of Formula (IV) is of the formula:

or a pharmaceutically acceptable salt or stereoisomer thereof. [00126] In certain embodiments, the compound of Formula (IV) is of the formula:

, , or a pharmaceutically acceptable salt or stereoisomer thereof. [00127] In certain embodiments, the compound of Formula (V) is of the formula:

, or a pharmaceutically acceptable salt or stereoisomer thereof. [00128] In certain embodiments, the compound of Formula (V) is of the formula:

,

,

, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: each instance of W⁹ is independently halogen, substituted or unsubstituted C1-6 alkyl, or – OR^d; s is 0, 1, 2, 3, or 4; and W¹⁰ is hydrogen, substituted or unsubstituted C_1-6 alkyl, or a nitrogen protecting group. [00129] Exemplary compounds of Formula (IV) include:

pharmaceutically acceptable salts and stereoisomers thereof. [00130] In certain embodiments, the exemplary compound of Formula (IV) is A419259 (trihydrochloride of compound 1), or or stereoisomer thereof. [00131] In certain embodiments, compounds useful in the methods described herein are represented by the following structure:

, or a pharmaceutically acceptable salt or stereoisomer thereof. [00132] In certain embodiments, compounds useful in the methods described herein are represented by Formula (VI):

pharmaceutically acceptable salt or stereoisomer thereof, wherein: R is optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –O–

optionally substituted carbocyclyl, –CH₂–O–optionally substituted carbocyclyl, –O–optionally substituted aryl, –CH₂–O–optionally substituted aryl, –O–optionally substituted heteroaryl, or –CH₂–O–optionally substituted heteroaryl; R¹ is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; each occurrence of R² is independently hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –OR^a, –N(R^a)2, or –SR^a, wherein R^a is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom; each occurrence of R³ is independently hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –OR^b, –N(R^b)2, or –SR^b, wherein R^b is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom; J is a bond or alkynylene; m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits; n is 1, 2, 3, 4, 5, 6, 7, or 8, as valency permits; A is an optionally substituted mono- or bicyclic-heteroaryl, or optionally substituted bicyclic heterocyclyl; provided that when J is a bond, R is substituted phenyl, R¹ is methyl, R² is H, and R³ is H, then ring A is not of the formula:

[00133] Formula (VI), as described herein, contains the substituent R. In certain embodiments, R is optionally substituted alkynyl. In certain embodiments, R is optionally substituted carbocyclyl. In certain embodiments, R is optionally substituted heterocyclyl. In certain embodiments, R is optionally substituted aryl. In certain embodiments, R is optionally substituted phenyl. In certain embodiments, R is 4-phenoxyphenyl. In certain embodiments, R is optionally substituted heteroaryl. In certain embodiments, R is –O–optionally substituted carbocyclyl. In certain embodiments, R is –CH₂–O–optionally substituted carbocyclyl. In certain embodiments, R is –O–optionally substituted aryl. In certain embodiments, R is –CH₂– O–optionally substituted aryl. In certain embodiments, R is –CH₂–O–optionally substituted phenyl. In certain embodiments, R is –CH₂–O–unsubstituted phenyl. In certain embodiments, R is –O–optionally substituted heteroaryl. In certain embodiments, R is –CH₂–O–optionally substituted heteroaryl. [00134] Formula (VI) contains the substituent R¹. In certain embodiments, R¹ is hydrogen. In certain embodiments, R¹ is optionally substituted acyl. In certain embodiments, R¹ is optionally substituted alkyl (e.g., Me, Et, Pr). In certain embodiments, R¹ is optionally substituted methyl. In certain embodiments, R¹ is unsubstituted methyl. In certain embodiments, R¹ is optionally substituted alkenyl. In certain embodiments, R¹ is optionally substituted alkynyl. In certain embodiments, R¹ is optionally substituted carbocyclyl. In certain embodiments, R¹ is optionally substituted heterocyclyl. In certain embodiments, R¹ is optionally substituted aryl. In certain embodiments, R¹ is optionally substituted heteroaryl. In certain embodiments, R¹ is a nitrogen protecting group. [00135] In certain embodiments, R¹ is methyl. [00136] Formula (VI) contains the substituent R². In certain embodiments, at least one of R² is hydrogen. In certain embodiments, at least one instance of R² is halogen. In certain embodiments, at least one instance of R² is optionally substituted acyl. In certain embodiments, at least one instance of R² is optionally substituted alkyl. In certain embodiments, at least one instance of R² is optionally substituted alkenyl. In certain embodiments, at least one instance of R² is optionally substituted alkynyl. In certain embodiments, at least one instance of R² is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R² is

optionally substituted heterocyclyl. In certain embodiments, at least one instance of R² is optionally substituted aryl. In certain embodiments, at least one instance of R² is optionally substituted heteroaryl. In certain embodiments, at least one instance of R² is –OR^a. In certain embodiments, at least one instance of R² is –N(R^a)₂. [00137] In certain embodiments, R² is H. [00138] In certain embodiments, there are m instances of R². In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6. In certain embodiments, m is 7. In certain embodiments, m is 8. In certain embodiments, m is 9. In certain embodiments, m is 10. [00139] In certain embodiments, R² is H; and m is 1. [00140] Formula (VI) contains the substituents R³. In certain embodiments, at least one instance of R³ is hydrogen. In certain embodiments, at least one instance of R³ is halogen. In certain embodiments, at least one instance of R³ is optionally substituted acyl. In certain embodiments, at least one instance of R³ is optionally substituted alkyl. In certain embodiments, at least one instance of R³ is optionally substituted alkenyl. In certain embodiments, at least one instance of R³ is optionally substituted alkynyl. In certain embodiments, at least one instance of R³ is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R³ is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R³ is optionally substituted aryl. In certain embodiments, at least one instance of R³ is optionally substituted heteroaryl. In certain embodiments, at least one instance of R³ is –OR^b. In certain embodiments, at least one instance of R³ is –N(R^b)2. In certain embodiments, at least one instance of R³ is –SR^b. [00141] In certain embodiments, R³ is H. [00142] In certain embodiments, there are n instances of R³. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain embodiments, n is 7. In certain embodiments, n is 8. [00143] In certain embodiments, R³ is H; and n is 1. [00144] In certain embodiments, R² and R³ are the same. In certain embodiments, R² and R³ are different. In certain embodiments, R² is H; and R³ is H. [00145] Formula (VI) contains the substituent J. In certain embodiments, J is a bond. In certain embodiments, J is alkynylene. [00146] Formula (VI) contains ring A. In certain embodiments, ring A is of the formula:

. In certain embodiments, ring A is of the formula: In certain

embodiments, ring A is of the formula:

In certain embodiments, ring A is of the formula:

certain embodiments, ring A is of the formula:

certain embodiments, ring A is of the formula:

certain embodiments, ring A is of the formula: . In certain embo

diments, ring A is of the formula: . In certain embodiments, ring A is of the formula: In certain embodiments, ring A

is of the formula:

. In certain embodiments, ring A is of the formula: In certain embodiments, ring A is of the formula: In

certain embodiments, ring A is of the formula:

In certain embodiments, ring A is of the formula:

In certain embodiments, ring A is of the formula:

. In certain embodiments, ring A is of the formula:

In certain embodiments, ring A is of the formula:

. In certain embodiments, J is alkynyl; and ring A is of the formula:

In certain embodiments, J is alkynyl ring A is of the formula:

In certain embodiments, J is alkynyl and ring A is of the formula:

. In certain embodiments, J is alkynyl ring A is of the formula:

certain embodiments, J is alkynyl and ring A is of the formula:

. [00147] In certain embodiments, Ring A comprises the substituent R⁴. In certain embodiments, each instance of R⁴ is the same. In certain embodiments, each instance of R⁴ is

different. In certain embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ is halogen. In certain embodiments, R⁴ is optionally substituted acyl. In certain embodiments, R⁴ is optionally substituted alkyl (e.g., Me, Et, Pr). In certain embodiments, R⁴ is –CN. In certain embodiments, R⁴ is –SCN. In certain embodiments, R⁴ is –NO₂. In certain embodiments, R⁴ is –C(=O)R^c. In certain embodiments, R⁴ is –C(=O)N(R^c)2. In certain embodiments, R⁴ is –OR^c. In certain embodiments, R⁴ is –N(R^c)₂. In certain embodiments, R⁴ is –C(=NR^c)R^c. In certain embodiments, R⁴ is –C(=NR^c)OR^c. In certain embodiments, R⁴ is –C(=NR^c)N(R^c)2. In certain embodiments, R⁴ is –C(=O)OR^c. In certain embodiments, R⁴ is –NR^cC(=O)R^c. In certain embodiments, R⁴ is –NR^cC(=O)OR^c. In certain embodiments, R⁴ is –NR^cC(=O)N(R^c)2. In certain embodiments, R⁴ is –OC(=O)R^c. In certain embodiments, R⁴ is –OC(=O)OR^c. In certain embodiments, R⁴ is –OC(=O)N(R^c)2. In certain embodiments, R⁴ is –SR^c, wherein R^c is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom. [00148] In certain embodiments, R⁴ is H. [00149] In certain embodiments, R⁴ is –C(=O)N(R^c)₂. In certain embodiments, R⁴ is – C(=O)NH₂. [00150] In certain embodiments, Ring A comprises the substituent R⁵. In certain embodiments, at R⁵ is hydrogen. In certain embodiments, R⁵ is halogen. In certain embodiments, R⁵ is optionally substituted acyl. In certain embodiments, R⁵ is optionally substituted alkyl (e.g., Me, Et, Pr). In certain embodiments, R⁵ is –CN. In certain embodiments, R⁵ is –SCN. In certain embodiments, R⁵ is –NO₂. In certain embodiments, R⁵ is –C(=O)R^d. In certain embodiments, R⁵ is –C(=O)N(R^d)₂. In certain embodiments, R⁵ is –OR^d. In certain embodiments, R⁵ is –N(R^d)2. In certain embodiments, R⁵ is –C(=NR^d)R^d. In certain embodiments, R⁵ is –C(=NR^d)OR^d. In certain embodiments, R⁵ is –C(=NR^d)N(R^d)₂. In certain embodiments, R⁵ is –C(=O)OR^d. In certain embodiments, R⁵ is –NR^dC(=O)R^d. In certain embodiments, R⁵ is –NR^dC(=O)OR^d. In certain embodiments, R⁵ is –NR^dC(=O)N(R^d)₂. In certain embodiments, R⁵ is –OC(=O)R^d. In certain embodiments, R⁵ is –OC(=O)OR^d. In certain embodiments, R⁵ is –OC(=O)N(R^d)₂. In certain embodiments, R⁵ is –SR^d, wherein R^d is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom.

[00151] In certain embodiments, R⁵ is H. In certain embodiments, R⁵ is –N(R^d)2. In certain embodiments, R⁵ is –NH₂. [00152] In certain embodiments, R⁴ is –C(=O)N(R^c)2; and R⁵ is –N(R^d)2. In certain embodiments, R⁴ is –C(=O)NH₂; and R⁵ is –N(R^d)₂. In certain embodiments, R⁴ is – C(=O)N(R^c)2; and R⁵ is –NH₂. In certain embodiments, R⁴ is –C(=O)NH₂; and R⁵ is –NH₂. [00153] In certain embodiments, Ring A comprises the substituent R⁶. In certain embodiments, at R⁶ is hydrogen. In certain embodiments, R⁶ is halogen. In certain embodiments, R⁶ is optionally substituted acyl. In certain embodiments, R⁶ is optionally substituted alkyl (e.g., Me, Et, Pr). In certain embodiments, R⁶ is –CN. In certain embodiments, R⁶ is –SCN. In certain embodiments, R⁶ is –NO₂. In certain embodiments, R⁶ is –C(=O)R^e. In certain embodiments, R⁶ is –C(=O)N(R^e)2. In certain embodiments, R⁶ is –OR^e. In certain embodiments, R⁶ is –N(R^e)₂. In certain embodiments, R⁶ is –C(=NR^e)R^e. In certain embodiments, R⁶ is –C(=NR^e)OR^e. In certain embodiments, R⁶ is –C(=NR^e)N(R^e)2. In certain embodiments, R⁶ is –C(=O)OR^e. In certain embodiments, R⁶ is –NR^eC(=O)R^e. In certain embodiments, R⁶ is –NR^eC(=O)OR^e. In certain embodiments, R⁶ is –NR^eC(=O)N(R^e)2. In certain embodiments, R⁶ is –OC(=O)R^e. In certain embodiments, R⁶ is –OC(=O)OR^e. In certain embodiments, R⁶ is –OC(=O)N(R^e)2. In certain embodiments, R⁶ is –SR^e, wherein R^e is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom. [00154] In certain embodiments, R⁶ is H. [00155] In certain embodiments, ring A contains the substituent X¹. In certain embodiments, X¹ =N–. In certain embodiments, X¹ is =C(R^f)–. In certain embodiments, R^f is hydrogen, halogen, or substituted or unsubstituted C1-6 alkyl. In certain embodiments, X¹ is =C(H)–. [00156] In certain embodiments, ring A contains the substituent X². In certain embodiments, X² =N–. In certain embodiments, X² is =C(R^g)–. In certain embodiments, R^g is hydrogen, halogen, or substituted or unsubstituted C_1-6 alkyl. In certain embodiments, X² is =C(H)–. [00157] In certain embodiments, ring A contains the substituent X³. In certain embodiments, X³ =N–. In certain embodiments, X³ is =C(R^g)–. In certain embodiments, R^g is hydrogen, halogen, or substituted or unsubstituted C1-6 alkyl. In certain embodiments, X² is =C(H)–. [00158] In certain embodiments, ring A contains the substituent X⁴. In certain embodiments, X⁴ =N–. In certain embodiments, X⁴ is =C(R^f)–. In certain embodiments, R^f is hydrogen, halogen, or substituted or unsubstituted C_1-6 alkyl. In certain embodiments, X¹ is =C(H)–.

[00159] In certain embodiments, ring A contains the substituent X⁴. In certain embodiments, X⁴ is =N–. In certain embodiments, X⁴ is =C(Rⁱ)–. In certain embodiments, X⁴ is =C(H)–. In certain embodiments, Rⁱ is hydrogen, halogen, or substituted or unsubstituted C1-6 alkyl (e.g., Me, Et, Pr). [00160] In certain embodiments, X⁴ is =N–; and R is –CH₂–O–optionally substituted aryl. In certain embodiments, X⁴ is =C(R^f)–; and R is –CH₂–O–optionally substituted aryl. In certain embodiments, X⁴ is =C(H)–; and R is –CH₂–O–optionally substituted aryl. In certain embodiments, X⁴ is =N–; and R is –CH₂–O–unsubstituted phenyl. In certain embodiments, X⁴ is =C(Rⁱ)–; and R is –CH₂–O–unsubstituted phenyl. In certain embodiments, X⁴ is =C(H)–; and R is –CH₂–O–unsubstituted phenyl. [00161] In certain embodiments, ring A is of the formula:

. In certain embodiments, ring A is of the formula:

certain embodiments, ring A is of the formula:

certain embodiments, ring A is of the formula:

certain embodiments, ring A is of the formula:

certain embodiments, ring A is of the formula:

certain embodiments, ring A is of the formula:

certain embodiments, ring A is of the formula:

certain embodiments, ring A

is of the formula:

. In certain embodiments, ring A is of the formula:

. certain embodiments, ring A is of the formula:

. [00162] In certain embodiments, ring A is not of the formula:

[00163] In certain embodiments, ring A is not of the formula:

. In certain embodiments, ring A is not of the formula:

certain embodiments, ring A is not of the formula: . In certain embodiments, ring A is not of the formula:

. [00164] In certain embodiments, J is a bond; and ring A is not of the formula:

. In certain embodiments, J is a bond; and ring A is not of the formula:

certain embodiments, J is a bond; and ring A is not of the formula:

. In certain embodiments, J is a bond; and ring A is not of the formula:

. [00165] In certain embodiments, a compound of Formula (VI) is of the Formula (VI-a):

( ), or a pharmaceutically acceptable salt or stereoisomer thereof. [00166] In certain embodiments, a compound of Formula (VI) is of the Formula (VI-b):

or a pharmaceutically acceptable salt or stereoisomer thereof. [00167] In certain embodiments, a compound of Formula (VI) is of the Formula (VI-c):

or a pharmaceutically acceptable salt or stereoisomer thereof. [00168] In certain embodiments, a compound of Formula (VI) is of the formula:

pharmaceutically acceptable salt or stereoisomer thereof. [00169] In certain embodiments, a compound of Formula (I) is of the formula:

pharmaceutically acceptable salt or stereoisomer thereof. [00170] In certain embodiments, a compound of Formula (VI) is of the Formula (VI-d):

or a pharmaceutically acceptable salt or stereoisomer thereof. [00171] In certain embodiments, the compound of Formula (VI) is of the formula:

a pharmaceutically acceptable salt or stereoisomer thereof. [00172] In certain embodiments, the compound of Formula (VI) is of the formula: or a pharmaceutically acceptable salt or stereoisomer thereof.

[00173] In certain embodiments, a compound of Formula (VI) is of the formula:

( ), or a pharmaceutically acceptable salt or stereoisomer thereof. [00174] In certain embodiments, a compound of Formula (VI) is of the formula:

pharmaceutically acceptable salt or stereoisomer thereof. [00175] In certain embodiments, a compound of Formula (VI) is of the Formula (VI-e):

pharmaceutically acceptable salt or stereoisomer thereof. [00176] In certain embodiments, a compound of Formula (I) is of the formula: or a pharmaceutically acceptable

salt or stereoisomer thereof. [00177] In certain embodiments, a compound of Formula (VI) is of the formula:

pharmaceutically acceptable salt or stereoisomer thereof. [00178] In certain embodiments, a compound of Formula (VI) is a compound, or pharmaceutically acceptable salt thereof, of any one of structures:

BTK Degraders [00179] Representative examples of BTK degraders that may be useful in the practice of the disclosed methods are set forth below. [00180] In one embodiment, the BTK degrader is a bifunctional compound of Formula VII:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: the Targeting Ligand is capable of binding BTK; the Linker is a group that covalently binds to the Targeting Ligand and the Degron; and the Degron is capable of binding to a ubiquitin ligase, such as an E3 ubiquitin ligase (e.g., cereblon,Von Hippel–Lindau tumor suppressor (VHL)). [00181] In one embodiment, the BTK degrader is a compound of Formula VIII:

Targeting Ligand or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: R1, R2, R3b, R4, X1, X2, n1, n2, n3, and n4 are each as defined herein; the Linker is a group that covalently binds to X₂ and the Degron; and the Degron is capable of binding to a ubiquitin ligase, such as an E3 ubiquitin ligase. [00182] In one embodiment, the BTK degrader is a compound of Formula IX:

Targeting Ligand wherein: R5, R6, R₇, A, B, Y2, Y3, o1, and o2 are each as defined herein; the Linker is a group that covalently binds to and the Degron; and

the Degron is capable of binding to a ubiquitin ligase, such as an E3 ubiquitin ligase (e.g., cereblon). [00183] In one embodiment, the BTK degrader is a compound of Formula X:

Targeting Ligand or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, Z, s1, s2, s3, and s4 are each as defined herein; the Linker is a group that covalently binds to Z and the Degron; and the Degron is capable of binding to a ubiquitin ligase, such as an E3 ubiquitin ligase (e.g., cereblon). [00184] Referring to formula VII, in one embodiment, the Targeting Ligand is a compound of Formula TL-I:

each R₁ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂; each R₂ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, CN, OH, or NH₂; R_3a and R_3b are each independently H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl; each R4 is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂; n1 and n2 are each independently 0, 1, or 2; n3 is 0, 1, 2, 3 or 4; and n4 is 1, 2, 3 or 4, wherein the Targeting Ligand is bonded to the Linker via the

next to X₂. [00185] In some embodiments, X1 is O. In another embodiment, X1 is NR3a. [00186] In some embodiments, R_3a is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. In other embodiments, R3a is H or (C₁-C₄) alkyl. In other embodiments, R3a is H, methyl, ethyl, n- propyl, or i-propyl. In other embodiments, R_3a is H, methyl or ethyl. In other embodiments, R3a is (C₁-C₄) alkyl. In other embodiments, R3a is methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R_3a is methyl or ethyl. In other embodiments, R_3a is (C₁-C₄) alkyl or (C₁-C₄) haloalkyl. In other embodiments, R3a is H. [00187] In some embodiments, X2 is O. In another embodiment, X2 is

. [00188] In some embodiments, each R₁ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. In other embodiments, each R1 is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments, each R1 is independently halogen, OH, or NH₂. In other embodiments, each R1 is independently (C₁-C₃) alkoxy or (C₁-C₃) haloalkoxy. In other embodiments, each R1 is independently (C₁-C₃) alkoxy. In other embodiments, each R1 is independently methoxy, ethoxy, n-propoxy, or i-propoxy. In other embodiments, each R1 is independently methoxy or ethoxy. In other embodiments, at least one R₁ is methoxy. [00189] In some embodiments, each R2 is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, CN, OH, or NH₂. In other embodiments, each R2 is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments, each R₂ is independently halogen, CN, OH, or NH₂. In other embodiments, each R2 is independently CN, OH, or NH₂. In other embodiments, at least one R₂ is CN. [00190] In some embodiments, R3b is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. In other embodiments, R_3b is H or (C₁-C₄) alkyl. In other embodiments, R_3b is H, methyl, ethyl, n- propyl, or i-propyl. In other embodiments, R3b is H, methyl or ethyl. In other embodiments,

R3b is (C₁-C₄) alkyl. In other embodiments, R3b is methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R_3b is methyl or ethyl. In other embodiments, R_3b is (C₁-C₄) alkyl or (C₁-C₄) haloalkyl. In other embodiments, R3b is H. [00191] In some embodiments, each R₄ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. In other embodiments, each R4 is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, or halogen. In other embodiments, each R4 is independently halogen, OH, or NH₂. In other embodiments, each R₄ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁- C3) haloalkoxy, or halogen. In other embodiments, each R4 is independently (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. In other embodiments, each R₄ is independently (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, or halogen. In other embodiments, each R4 is independently (C₁-C₃) alkoxy or halogen. In other embodiments, each R₄ is independently methoxy, ethoxy, n-propoxy, i-propoxy, F, or Cl. In other embodiments, each R4 is independently methoxy, ethoxy, F, or Cl. In other embodiments, each R₄ is independently methoxy or Cl. In other embodiments, at least one R4 is methoxy and at least one R4 is Cl. [00192] In some embodiments, n1 is 0. In other embodiments, n1 is 1. In other embodiments, n1 is 2. In other embodiments, n1 is 0 or 1. In other embodiments, n1 is 1 or 2. [00193] In some embodiments, n2 is 0. In other embodiments, n2 is 1. In other embodiments, n2 is 2. In other embodiments, n2 is 0 or 1. In other embodiments, n2 is 1 or 2. [00194] In some embodiments, n3 is 0. In other embodiments, n3 is 1. In other embodiments, n3 is 2. In other embodiments, n3 is 3. In other embodiments, n3 is 4. In other embodiments, n3 is 0 or 1. In other embodiments, n3 is 1 or 2. In other embodiments, n3 is 0, 1 or 2. In other embodiments, n3 is 1, 2 or 3. In other embodiments, n3 is 2, 3 or 4. In other embodiments, n3 is 1, 2, 3, or 4. In other embodiments, n3 is 0, 1, 2 or 3. [00195] In some embodiments, n4 is 1. In other embodiments, n4 is 2. In other embodiments, n4 is 3. In other embodiments, n4 is 4. In other embodiments, n4 is 1 or 2. In other embodiments, n4 is 3 or 4. In other embodiments, n4 is 1, 2 or 3. In other embodiments, n4 is 2, 3 or 4. [00196] Any of the groups described herein for any of X₁, X₂, R₁, R₂, R_3a, R_3b, R₄, n1, n2, n3, and n4 can be combined with any of the groups described herein for one or more of the remainder of X₁, X₂, R₁, R₂, R_3a, R_3b, R₄, n1, n2, n3, and n4, and may further be combined with any of the groups described herein for the Linker. [00197] For a Targeting Ligand of Formula TL-I: (1) In one embodiment, X1 is NR3a and X2 is O. (2) In one embodiment, X1 is NR3a and X2 is

(3) In one embodiment, X1 is NR3a, X2 is O, and each R1 is independently (C₁-C₄) alkoxy. (4) In one embodiment, X1 is NR3a, X2 is

, and each R1 is independently (C1- C₄) alkoxy. (5) In one embodiment, X1 is NR3a, X2 is O, each R1 is independently (C₁-C₄) alkoxy, and at least one R2 is CN. (6) In one embodiment, X1 is NR3a, X2 is

, each R1 is independently (C₁-C₄) alkoxy, and at least one R₂ is CN. (7) In one embodiment, X1 is NR3a, X2 is O, each R1 is independently (C₁-C₄) alkoxy, at least one R₂ is CN, and R_3b is H. (8) In one embodiment, X₁ is NR_3a, X₂ is

, each R₁ is independently (C₁-C₄) alkoxy, at least one R2 is CN, and R3b is H. (9) In one embodiment, X₁ is NR_3a, X₂ is O, each R₁ is independently (C₁-C₄) alkoxy, at least one R2 is CN, R3b is H, and each R4 is independently (C₁-C₄) alkoxy or halogen. (10) In one embodiment, X1 is NR3a, X2 is

, each R1 is independently (C₁-C₄) alkoxy, at least one R₂ is CN, R_3b is H, and each R₄ is independently (C₁-C₄) alkoxy or halogen. (11) In one embodiment, X1 is O and X2 is O. (12) In one embodiment, X1 is O and X2 is

(13) In one embodiment, X₁ is O, X₂ is O, and each R₁ is independently (C₁-C₄) alkoxy. (14) In one embodiment, X₁ is O, X₂ is

, and each R₁ is independently (C₁-C₄) alkoxy. (15) In one embodiment, X₁ is O, X₂ is O, each R₁ is independently (C₁-C₄) alkoxy, and at least one R2 is CN. (16) In one embodiment, X1 is O, X2 is

, each R1 is independently (C₁-C₄) alkoxy, and at least one R₂ is CN.

(17) In one embodiment, X1 is O, X2 is O, each R1 is independently (C₁-C₄) alkoxy, at least one R₂ is CN, and R_3b is H. (18) In one embodiment, X₁ is O, X₂ is

, each R₁ is independently (C₁-C₄) alkoxy, at least one R2 is CN, and R3b is H. (19) In one embodiment, X₁ is O, X₂ is O, each R₁ is independently (C₁-C₄) alkoxy, at least one R2 is CN, R3b is H, and each R4 is independently (C₁-C₄) alkoxy or halogen. (20) In one embodiment, X1 is O, X2 is

, each R1 is independently (C₁-C₄) alkoxy, at least one R₂ is CN, R_3b is H, and each R₄ is independently (C₁-C₄) alkoxy or halogen. (21) In one embodiment, each R1 is independently (C₁-C₄) alkoxy. (22) In one embodiment, each R₁ is independently (C₁-C₄) alkoxy and at least one R₂ is CN. (23) In one embodiment, X₂ is

and each R₁ is independently (C₁-C₄) alkoxy. (24) In one embodiment, X2 is O and each R1 is independently (C₁-C₄) alkoxy. (25) In one embodiment, X2 is

, each R1 is independently (C₁-C₄) alkoxy, and at least one R₂ is CN. (26) In one embodiment, X2 is O, each R1 is independently (C₁-C₄) alkoxy, and at least one R2 is CN. (27) In one embodiment, X₂ is

, each R₁ is independently (C₁-C₄) alkoxy, and R3b is H. (28) In one embodiment, X₂ is O, each R₁ is independently (C₁-C₄) alkoxy, and R_3b is H. (29) In one embodiment, X₂ is

, each R₁ is independently (C₁-C₄) alkoxy, R_3b is H, and each R4 is independently (C₁-C₄) alkoxy or halogen. (30) In one embodiment, X₂ is O, each R₁ is independently (C₁-C₄) alkoxy, R_3b is H, and each R4 is independently (C₁-C₄) alkoxy or halogen. (31) In one embodiment, each R₁ is independently (C₁-C₄) alkoxy, at least one R₂ is CN, and R3b is H. (32) In one embodiment, R₁, R₂, R_3a, R_3b, R₄, X₁, and X₂ are each as defined, where applicable, in any one of (1)-(31), and n1 is 1.

(33) In one embodiment, R1, R2, R3a, R3b, R4, X1, and X2 are each as defined, where applicable, in any one of (1)-(31), and n2 is 1. (34) In one embodiment, R1, R2, R3a, R3b, R4, X1, and X2 are each as defined, where applicable, in any one of (1)-(31), and n3 is 1. (35) In one embodiment, R1, R2, R3a, R3b, R4, X1, and X2 are each as defined, where applicable, in any one of (1)-(31), and n3 is 2. (36) In one embodiment, R1, R2, R3a, R3b, R4, X1, and X2 are each as defined, where applicable, in any one of (1)-(31), and n3 is 3. (37) In one embodiment, R1, R2, R3a, R3b, R4, X1, and X2 are each as defined, where applicable, in any one of (1)-(31), and n4 is 1. (38) In one embodiment, R1, R2, R3a, R3b, R4, X1, and X2 are each as defined, where applicable, in any one of (1)-(31), and n4 is 2. (39) In one embodiment, R1, R2, R3a, R3b, R4, X1, and X2 are each as defined, where applicable, in any one of (1)-(31), and n4 is 3. (40) In one embodiment, R1, R2, R3a, R3b, R4, X1, and X2 are each as defined, where applicable, in any one of (1)-(31), n1 is 1, and n2 is 1. (41) In one embodiment, R1, R2, R3a, R3b, R4, X1, and X2 are each as defined, where applicable, in any one of (1)-(31), n1 is 1, n2 is 1, and n3 is 3. (42) In one embodiment, R1, R2, R3a, R3b, R4, X1, and X2 are each as defined, where applicable, in any one of (1)-(31), n1 is 1, n2 is 1, n3 is 3, and n4 is 3. [00198] In one embodiment, the targeting ligand of Formula TL-I is of Formula TL-Ia:

wherein X₂, R₁, R₄, n3, and n4 are each as defined above in Formula TL-I. [00199] For a Targeting Ligand of Formula TL-Ia: (1) In one embodiment, R₁ is (C₁-C₄) alkoxy and each R₄ is independently (C₁-C₄) alkoxy or halogen. (2) In one embodiment, R₁ is (C₁-C₃) alkoxy and each R₄ is independently (C₁-C₃) alkoxy or halogen. (3) In one embodiment, R1 is methoxy and each R4 is independently methoxy, F or Cl. (4) In one embodiment, R1 is methoxy and each R4 is independently methoxy or Cl. (5) In one embodiment, X₂ is O. (6) In one embodiment, X₂ is

(7) In one embodiment, R1 is (C₁-C₄) alkoxy, each R4 is independently (C₁-C₄) alkoxy or halogen, and X₂ is O. (8) In one embodiment, R1 is (C₁-C₄) alkoxy, each R4 is independently (C₁-C₄) alkoxy or halogen, and X2 is

(9) In one embodiment, R₁, R₄, and X₂ are each as defined, where applicable, in any one of (1)- (8), and n4 is 3. (10) In one embodiment, R₁, R₄, and X₂ are each as defined, where applicable, in any one of (1)-(8), and n3 is 3. (11) In one embodiment, R₁, R₄, and X₂ are each as defined, where applicable, in any one of (1)-(8), n3 is 3, and n4 is 3. (12) In one embodiment, X₂ is O and n4 is 3. (13) In one embodiment, X₂ is

and n4 is 3. (14) In one embodiment, X2 is O and n3 is 3. (15) In one embodiment, X2 is

and n3 is 3. [00200] X₂, R₁, R₄, n3, and n4 can each be selected from any of the groups and combined as described above in Formula TL-I or TL-Ia. [00201] In another embodiment, the targeting ligand of Formula TL-I is of Formula TL-Ib:

wherein X2, R1, and n4 are each as defined above in Formula TL-I. [00202] For a Targeting Ligand of Formula TL-Ib: (1) In one embodiment, R1 is (C₁-C₃) alkoxy. (2) In one embodiment, R₁ is methoxy. (3) In one embodiment, R1 is (C₁-C₃) alkoxy, and n4 is 3.

(4) In one embodiment, R1 is methoxy and n4 is 1, 2, or 3. (5) In one embodiment, R₁ is (C₁-C₃) alkoxy and X₂ is O. (6) In one embodiment, R₁ is (C₁-C₃) alkoxy and X₂ is

. (7) In one embodiment, R1 is methoxy and X2 is O. (8) In one embodiment, R₁ is methoxy and X₂ is

. (9) In one embodiment, R1 is (C₁-C₃) alkoxy, X2 is O, and n4 is 3. (10) In one embodiment, R1 is (C₁-C₃) alkoxy, X2 is

, and n4 is 3. (11) In one embodiment, R1 is methoxy, X2 is O, and n4 is 3. (12) In one embodiment, R1 is methoxy, X2 is

, and n4 is 3. [00203] R₁, X₂, and n4 can each be selected from any of the groups and combined as described above in Formula TL-I or TL-Ib. [00204] Referring to formula VII, in one embodiment, a Targeting Ligand is a compound of Formula TL-II:

wherein: A is phenyl or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S, wherein the phenyl or heteroaryl is optionally substituted with 1 to 3 R₈; B is phenyl or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S, wherein the phenyl or heteroaryl is optionally substituted with 1 to 3 R₉; Y2 is NR10a or O; Y₃ is C(O)NR_10b or NR_10bC(O); Y4 is NR5’ or, when B is bonded to Y4, N; R₅’ is H, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, or halogen; each R5 is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, or oxo; R6 is H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl; each R₇ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, (C₁-C₄) hydroxyalkyl, halogen, OH, or NH₂; each R₈ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, NH₂, or (C₃-C₆) cycloalkyl; or two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring; or R₈ and R_10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁; each R₉ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, or halogen; R10a and R10b are each independently H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl; or R₈ and R10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁; each R₁₁ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂; and o1 and o2 are each independently 0, 1, 2, or 3, wherein the Targeting Ligand is bonded to the Linker via the

[00205] In some embodiments, A is phenyl optionally substituted with 1 to 3 R₈. In other embodiments, A is 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S optionally substituted with 1 to 3 R₈. In other embodiments, A is phenyl or thiophenyl wherein each is optionally substituted with 1 to 3 R₈. In other embodiments, A is phenyl or thiophenyl wherein each is substituted with 1 to 3 R₈. In other embodiments, A is phenyl or thiophenyl wherein each is optionally substituted with 1 to 2 R₈. In other embodiments, A is phenyl or thiophenyl wherein each is substituted with 1 to 2 R₈. In other embodiments, A is phenyl substituted with 1 to 2 R₈. In other embodiments, A is phenyl substituted with 3 R₈. In other embodiments, A is thiophenyl substituted with 1 to 2 R₈. [00206] In some embodiments, B is phenyl optionally substituted with 1 to 3 R₉. In other embodiments, B is 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S, optionally substituted with 1 to 3 R₉. In other embodiments, B is 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S, optionally substituted with 1

to 3 R₉. In other embodiments, B is 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S, optionally substituted with 1 to 3 R₉. In other embodiments, B is 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S. In other embodiments, B is 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S. In other embodiments, B is 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S. In other embodiments, B is pyridinyl optionally substituted with 1 to 3 R₉. In other embodiments, B is phenyl. In other embodiments, B is pyridinyl. [00207] In some embodiments, Y₂ is NR_10a. In other embodiments, Y₂ is O. [00208] In some embodiments, Y3 is C(O)NR10b. In other embodiments, Y3 is NR10bC(O). [00209] In some embodiments, Y₄ is NR₅’. In other embodiments, Y₄ is N. [00210] In some embodiments, R5’ is (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C1- C₃) haloalkoxy, or halogen. In other embodiments, R₅’ is (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁- C3) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments, R5’ is (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, or halogen. In other embodiments, R₅’ is (C₁-C₃) alkyl or halogen. In other embodiments, R5’ is methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R5’ is methyl or ethyl. In other embodiments, R₅’ is methyl. [00211] In some embodiments, each R5 is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, or oxo. In other embodiments, each R₅ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments, each R5 is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, halogen, or oxo. In other embodiments, each R₅ is independently (C₁-C₃) alkyl, halogen, or oxo. In other embodiments, each R5 is independently (C₁-C₃) alkyl or oxo. In other embodiments, each R5 is independently methyl, ethyl, n-propyl, i-propyl, or oxo. In other embodiments, each R₅ is independently methyl, ethyl, or oxo. In other embodiments, each R5 is independently methyl or oxo. [00212] In some embodiments, R6 is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. In other embodiments, R₆ is H or (C₁-C₄) alkyl. In other embodiments, R₆ is H or (C₁-C₃) alkyl. In other embodiments, R6 is H, methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R6 is H, methyl, or ethyl. In other embodiments, R₆ is (C₁-C₄) alkyl. In other embodiments, R₆ is methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R6 is H. In other embodiments, R6 is methyl or ethyl. In other embodiments, R₆ is methyl. [00213] In some embodiments, each R₇ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, (C₁-C₃) hydroxyalkyl, halogen, OH, or NH₂. In other

embodiments, each R₇ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C1- C₄) haloalkoxy, (C₁-C₄) hydroxyalkyl, halogen, or OH. In other embodiments, each R₇ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, (C₁-C₄) hydroxyalkyl, or OH. In other embodiments, each R₇ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) hydroxyalkyl, halogen, or OH. In other embodiments, each R₇ is independently (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄) hydroxyalkyl, or OH. In other embodiments, each R₇ is independently (C₁-C₄) alkyl, (C₁-C₄) hydroxyalkyl, or OH. In other embodiments, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl. In other embodiments, each R₇ is independently (C₁-C₃) alkyl or (C₁-C₃) hydroxyalkyl. In other embodiments, each R₇ is independently (C₁-C₃) alkyl. In other embodiments, each R₇ is independently (C₁-C₃) hydroxyalkyl. In other embodiments, each R₇ is independently methyl, ethyl, n-propyl, i-propyl, or (C₁-C₃) hydroxyalkyl. In other embodiments, each R₇ is independently methyl, ethyl, n-propyl, i-propyl, CH₂OH, CH₂CH₂OH, CH₂CH₂CH₂OH, CH(OH)CH₃, CH(OH)CH₂CH₃, or CH₂CH(OH)CH₃. In other embodiments, each R₇ is independently methyl, ethyl, CH₂OH, CH₂CH₂OH, or CH(OH)CH3. In other embodiments, each R₇ is independently methyl, ethyl, CH₂OH, or CH₂CH₂OH. In other embodiments, each R₇ is independently methyl or CH₂OH. [00214] In some embodiments, each R₈ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, NH₂, or (C₃-C₆) cycloalkyl. In other embodiments, each R₈ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C1- C₄) haloalkoxy, or halogen. In other embodiments, each R₈ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, or (C₃-C₆) cycloalkyl. In other embodiments, each R₈ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, halogen, or (C₃-C₆) cycloalkyl. In other embodiments, each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl. In other embodiments, each R₈ is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, F, Cl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In other embodiments, each R₈ is independently n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, F, Cl, cyclopropyl, cyclobutyl, or cyclopentyl. In other embodiments, each R₈ is independently i- propyl, i-butyl, t-butyl, F, or cyclopropyl. In other embodiments, each R₈ is independently i- propyl, t-butyl, F, or cyclopropyl. In other embodiments, each R₈ is independently t-butyl, F, or cyclopropyl. In other embodiments, at least one R₈ is t-butyl. In other embodiments, at least one R₈ is F. In other embodiments, at least one R₈ is cyclopropyl. In other embodiments, at least one R₈ is F, and at least one R₈ is cyclopropyl.

[00215] In some embodiments, two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. In some embodiments, two R₈ together with the atoms to which they are attached form a cyclopentyl ring. In some embodiments, two R₈ together with the atoms to which they are attached form a cyclohexyl ring. [00216] In some embodiments, each R₉ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, or halogen. In other embodiments, each R₉ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, or halogen. In other embodiments, each R₉ is independently (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, or halogen. In other embodiments, each R₉ is independently (C₁-C₃) alkyl, (C₁-C₃) alkoxy, or halogen. In other embodiments, each R₉ is independently (C₁-C₃) alkyl, or halogen. In other embodiments, each R₉ is independently methyl, ethyl, n-propyl, i-propyl, F or Cl. [00217] In some embodiments, R₈ and R_10b together with the atoms to which they are attached form a 5-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. In other embodiments, R₈ and R10b together with the atoms to which they are attached form a 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. In other embodiments, R₈ and R10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. In other embodiments, R₈ and R10b together with the atoms to which they are attached form a 5- or 6- membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. [00218] In other embodiments, R₈ and R_10b together with the atoms to which they are attached form a 5-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. In other embodiments, R₈ and R_10b together with the atoms to which they are attached form a 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. In other embodiments, R₈ and R10b together with the atoms to which they are attached form a 5- membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. In other embodiments, R₈ and R10b together with the atoms to which they are attached form a 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁.

[00219] In some embodiments, R10a is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. In other embodiments, R_10a is (C₁-C₄) alkyl or (C₁-C₄) haloalkyl. In other embodiments, R_10a is H or (C₁-C₄) alkyl. In other embodiments, R10a is H, methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R_10a is H, methyl or ethyl. In other embodiments, R_10a is (C₁-C₄) alkyl. In other embodiments, R10a is methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R10a is methyl or ethyl. In other embodiments, R_10a is H. [00220] In some embodiments, R10b is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. In other embodiments, R_10b is (C₁-C₄) alkyl or (C₁-C₄) haloalkyl. In other embodiments, R_10b is H or (C₁-C₄) alkyl. In other embodiments, R10b is H, methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R_10b is H, methyl or ethyl. In other embodiments, R_10b is (C₁-C₄) alkyl. In other embodiments, R10b is methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R10b is methyl or ethyl. In other embodiments, R_10b is H. [00221] In some embodiments, each R₁₁ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. In other embodiments, each R₁₁ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, or halogen. In other embodiments, each R₁₁ is independently halogen, OH, or NH₂. In other embodiments, each R₁₁ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments, each R₁₁ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, or halogen. In other embodiments, each R₁₁ is independently methyl, ethyl, n- propyl, i-propyl, F, or Cl. [00222] In some embodiments, o1 is 0. In other embodiments, o1 is 1. In other embodiments, o1 is 2. In other embodiments, o1 is 3. In other embodiments, o1 is 0 or 1. In other embodiments, o1 is 1 or 2. In other embodiments, o1 is 2 or 3. In other embodiments, o1 is 0, 1 or 2. In other embodiments, o1 is 1, 2, or 3. [00223] In some embodiments, o2 is 0. In other embodiments, o2 is 1. In other embodiments, o2 is 2. In other embodiments, o2 is 3. In other embodiments, o2 is 0 or 1. In other embodiments, o2 is 1 or 2. In other embodiments, o2 is 2 or 3. In other embodiments, o2 is 0, 1 or 2. In other embodiments, o2 is 1, 2, or 3. [00224] Any of the groups described herein for any of A, B, Y₂, Y₃, Y₄, R₅, R₅’, R₆, R₇, R₈, R₉, R10a, R10b, R₁₁, o1, and o2 can be combined with any of the groups described herein for one or more of the remainder of A, B, Y₂, Y₃, Y₄, R₅, R₅’, R₆, R₇, R₈, R₉, R_10a, R_10b, R₁₁, o1, and o2, and may further be combined with any of the groups described herein for the Linker. [00225] For a Targeting Ligand of Formula TL-II:

(1) In one embodiment, B is phenyl and Y2 is NR10a. (2) In one embodiment, B is phenyl, Y₂ is NR_10a, and R₆ is (C₁-C₄) alkyl. (3) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl. (4) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl. (5) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) hydroxyalkyl. (6) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and Y₃ is C(O)NR_10b. (7) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and Y₃ is C(O)NR_10b. (8) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and Y₃ is C(O)NR_10b. (9) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (10) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl. (11) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁-C₄) alkyl. (12) In one embodiment, B is phenyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and each R₈ is independently halogen or (C₃-C₆) cycloalkyl. (13) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (14) In one embodiment, B is phenyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C3- C6) cycloalkyl, or two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (15) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃- C6) cycloalkyl. (16) In one embodiment, B is phenyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl. (17) In one embodiment, B is phenyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y3 is C(O)NR10b, and each R₈ is independently halogen or (C₃-C₆) cycloalkyl. (18) In one embodiment, B is phenyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y3 is C(O)NR10b, and two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (19) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the atoms to which they are attached form a (C₅- C₇) cycloalkyl ring. (20) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl. (21) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁-C₄) alkyl. (22) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently halogen or (C₃-C₆) cycloalkyl. (23) In one embodiment, B is phenyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (24) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the atoms to which they are attached form a (C₅- C₇) cycloalkyl ring.

(25) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl. (26) In one embodiment, B is phenyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (27) In one embodiment, B is phenyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen or (C₃-C₆) cycloalkyl. (28) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (29) In one embodiment, B is phenyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (30) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl. (31) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl. (32) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently halogen or (C₃-C₆) cycloalkyl. (33) In one embodiment, B is phenyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (34) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (35) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl. (36) In one embodiment, B is phenyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl.

(37) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen or (C₃-C₆) cycloalkyl. (38) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (39) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(38), and A is phenyl. (40) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(38), and A is thiophenyl. (41) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(38), and R10a is H. (42) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(38), and R10b is H. (43) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(38), R10a is H, and R10b is H. (44) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(38), A is phenyl, and R10a is H. (45) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(38), A is phenyl, and R10b is H. (46) In one embodiment, B, Y2, Y3, R6, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(38), A is phenyl, R_10a is H, and R_10b is H. (47) In one embodiment, B, Y2, Y3, R6, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(38), A is thiophenyl, and R_10a is H. (48) In one embodiment, B, Y2, Y3, R6, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(38), A is thiophenyl, and R_10b is H. (49) In one embodiment, B, Y2, Y3, R6, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(38), A is thiophenyl, R_10a is H, and R_10b is H. (50) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and R₈ and R_10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁.

(51) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is C(O)NR_10b, and R₈ and R_10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. (52) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and R₈ and R_10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. (53) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and R₈ and R_10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. (54) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and R₈ and R_10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. (55) In one embodiment, B is phenyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and R₈ and R_10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. (56) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_10b are each as defined, where applicable, in any one of (50)-(55), and A is phenyl. (57) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_10b are each as defined, where applicable, in any one of (50)-(55), and A is thiophenyl. (58) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_10b are each as defined, where applicable, in any one of (50)-(55), and R10a is H. (59) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_10b are each as defined, where applicable, in any one of (50)-(55), A is phenyl, and R10a is H. (60) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_10b are each as defined, where applicable, in any one of (50)-(55), A is thiophenyl, and R10a is H. (61) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_10b are each as defined, where applicable, in any one of (50)-(55), and R10a is H. (62) In one embodiment, B is pyridinyl and Y₂ is NR_10a.

(63) In one embodiment, B is pyridinyl, Y2 is NR10a, and R6 is (C₁-C₄) alkyl. (64) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl. (65) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl. (66) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) hydroxyalkyl. (67) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and Y3 is C(O)NR10b. (68) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and Y3 is C(O)NR10b. (69) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and Y3 is C(O)NR10b. (70) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (71) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl. (72) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl. (73) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently halogen or (C₃-C₆) cycloalkyl. (74) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (75) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring.

(76) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl. (77) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl. (78) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y3 is C(O)NR10b, and each R₈ is independently halogen or (C3- C₆) cycloalkyl. (79) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is C(O)NR_10b, and two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (80) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (81) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl. (82) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl. (83) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently halogen or (C₃-C₆) cycloalkyl. (84) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (85) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring.

(86) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl. (87) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (88) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen or (C₃-C₆) cycloalkyl. (89) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (90) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (91) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl. (92) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl. (93) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently halogen or (C₃-C₆) cycloalkyl. (94) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (95) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the atoms to which they are attached form a (C₅- C7) cycloalkyl ring. (96) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl.

(97) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (98) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen or (C₃-C₆) cycloalkyl. (99) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (100) In one embodiment, B, Y2, Y3, R6, R₇, and R₈ are each as defined, where applicable, in any one of (62)-(99), and A is phenyl. (101) In one embodiment, B, Y2, Y3, R6, R₇, and R₈ are each as defined, where applicable, in any one of (62)-(99), and A is thiophenyl. (102) In one embodiment, B, Y2, Y3, R6, R₇, and R₈ are each as defined, where applicable, in any one of (62)-(99), and R_10a is H. (103) In one embodiment, B, Y2, Y3, R6, R₇, and R₈ are each as defined, where applicable, in any one of (62)-(99), and R_10b is H. (104) In one embodiment, B, Y2, Y3, R6, R₇, and R₈ are each as defined, where applicable, in any one of (62)-(99), R_10a is H, and R_10b is H. (105) In one embodiment, B, Y2, Y3, R6, R₇, and R₈ are each as defined, where applicable, in any one of v, A is phenyl, and R10a is H. (106) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (62)-(99), A is phenyl, and R10b is H. (107) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (62)-(99), A is phenyl, R10a is H, and R10b is H. (108) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (62)-(99), A is thiophenyl, and R10a is H. (109) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (62)-(99), A is thiophenyl, and R10b is H. (110) In one embodiment, B, Y₂, Y₃, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (62)-(99), A is thiophenyl, R10a is H, and R10b is H. (111) In one embodiment, B is pyridinyl, Y₂ is NR_10a, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and R₈ and R10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl

or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. (112) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is C(O)NR_10b, and R₈ and R_10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. (113) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and R₈ and R_10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. (114) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and R₈ and R_10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. (115) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and R₈ and R_10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. (116) In one embodiment, B is pyridinyl, Y2 is NR10a, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and R₈ and R10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. (117) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_10b are each as defined, where applicable, in any one of (111)-(116), and A is phenyl. (118) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_10b are each as defined, where applicable, in any one of (111)-(116), and A is thiophenyl. (119) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_10b are each as defined, where applicable, in any one of (111)-(116), and R10a is H. (120) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_10b are each as defined, where applicable, in any one of (111)-(116), A is phenyl, and R10a is H. (121) In one embodiment, B, Y₂, Y₃, R₆, R₇, R₈, and R_10b are each as defined, where applicable, in any one of (111)-(116), A is thiophenyl, and R10a is H.

(122) In one embodiment, B, Y2, Y3, R6, R₇, R₈, and R10b are each as defined, where applicable, in any one of (111)-(116), and R_10a is H. (123) In one embodiment, B is pyridinyl and A is phenyl. (124) In one embodiment, B is pyridinyl and A is thiophenyl. (125)In one embodiment, B is phenyl and A is phenyl. (126) In one embodiment, B is phenyl and A is thiophenyl. (127) In one embodiment, B is pyridinyl, A is phenyl, and R6 is methyl. (128) In one embodiment, B is pyridinyl, A is thiophenyl, and R₆ is methyl. (129) In one embodiment, B is phenyl, A is phenyl, and R6 is methyl. (130) In one embodiment, B is phenyl, A is thiophenyl, and R₆ is methyl. (131) In one embodiment, B is pyridinyl, A is phenyl, and Y2 is NR10a. (132) In one embodiment, B is pyridinyl, A is thiophenyl, and Y₂ is NR_10a. (133) In one embodiment, B is phenyl, A is phenyl, and Y2 is NR10a. (134) In one embodiment, B is phenyl, A is thiophenyl, and Y₂ is NR_10a. (135) In one embodiment, B is pyridinyl, A is phenyl, and Y3 is C(O)NR10b. (136) In one embodiment, B is pyridinyl, A is thiophenyl, and Y₃ is C(O)NR_10b. (137) In one embodiment, B is phenyl, A is phenyl, and Y3 is C(O)NR10b. (138) In one embodiment, B is phenyl, A is thiophenyl, and Y₃ is C(O)NR_10b. (139) In one embodiment, A, B, Y2, Y3, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(138), o1 is 0. (140) In one embodiment, A, B, Y₂, Y₃, R₆, R₇, R₈, R_10a, and R_10b are each as defined, where applicable, in any one of (1)-(138), o1 is 1. (141) In one embodiment, A, B, Y₂, Y₃, R₆, R₇, R₈, R_10a, and R_10b are each as defined, where applicable, in any one of (1)-(138), o1 is 2. (142) In one embodiment, A, B, Y₂, Y₃, R₆, R₇, R₈, R_10a, and R_10b are each as defined, where applicable, in any one of (1)-(138), o1 is 2, and R5 is (C₁-C₄) alkyl or oxo. (143) In one embodiment, A, B, Y₂, Y₃, R₆, R₇, R₈, R_10a, and R_10b are each as defined, where applicable, in any one of (1)-(138), o2 is 1. (144) In one embodiment, A, B, Y₂, Y₃, R₆, R₇, R₈, R_10a, and R_10b are each as defined, where applicable, in any one of (1)-(138), o2 is 2. (145) In one embodiment, A, B, Y₂, Y₃, R₆, R₇, R₈, R_10a, and R_10b are each as defined, where applicable, in any one of (1)-(138), o1 is 0 and o2 is 1.

(146) In one embodiment, A, B, Y2, Y3, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(138), o1 is1 and o2 is 1. (147) In one embodiment, A, B, Y2, Y3, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(138), o1 is 2 and o2 is 1. [00226] In one embodiment, the compound of Formula TL-II is of Formula TL-IIa, TL-IIb, or TL-IIc:

wherein A, B, Y4, R5, R6, R₇, R10b, and o1 are each as defined above in Formula TL-II. [00227] For a Targeting Ligand of Formula TL-IIa: (1) In one embodiment, B is phenyl. (2) In one embodiment, B is phenyl and R₆ is (C₁-C₄) alkyl. (3) In one embodiment, B is phenyl, R6 is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl. (4) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl. (5) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) hydroxyalkyl. (6) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆)

cycloalkyl, or two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (7) In one embodiment, B is phenyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl. (8) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (9) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen or (C₃-C₆) cycloalkyl. (10) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (11) In one embodiment, B is phenyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (12) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl. (13) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl. (14) In one embodiment, B is phenyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently halogen or (C₃-C₆) cycloalkyl. (15) In one embodiment, B is phenyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (16) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (17) In one embodiment, B is phenyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl. (18) In one embodiment, B is phenyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (19) In one embodiment, B is phenyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen or (C₃-C₆) cycloalkyl.

(20) In one embodiment, B is phenyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (21) In one embodiment, B, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(20), and A is phenyl. (22) In one embodiment, B, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(20), and A is thiophenyl. (23) In one embodiment, B, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(20), and R10b is H. (24) In one embodiment, B, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(20), A is phenyl, and R10b is H. (25) In one embodiment, B, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(20), A is thiophenyl, and R10b is H. (26) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and R₈ and R10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. (27) In one embodiment, B is phenyl, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and R₈ and R10b together with the atoms to which they are attached form a 5- or 6- membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. (28) In one embodiment, B is phenyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and R₈ and R_10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. (29) In one embodiment, B, R6, R₇, R₈, and R10b are each as defined, where applicable, in any one of (26)-(28), and A is phenyl. (30) In one embodiment, B, R6, R₇, R₈, and R10b are each as defined, where applicable, in any one of (26)-(28), and A is thiophenyl. (31) In one embodiment, B is pyridinyl. (32) In one embodiment, B is pyridinyl and R₆ is (C₁-C₄) alkyl. (33) In one embodiment, B is pyridinyl, R6 is (C₁-C₄) alkyl, and each R₇ is independently (C1- C₄) alkyl or (C₁-C₄) hydroxyalkyl.

(34) In one embodiment, B is pyridinyl, R6 is (C₁-C₄) alkyl, and each R₇ is independently (C1- C₄) alkyl. (35) In one embodiment, B is pyridinyl, R6 is (C₁-C₄) alkyl, and each R₇ is independently (C1- C₄) hydroxyalkyl. (36) In one embodiment, B is pyridinyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (37) In one embodiment, B is pyridinyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl. (38) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (39) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen or (C₃-C₆) cycloalkyl. (40) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (41) In one embodiment, B is pyridinyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (42) In one embodiment, B is pyridinyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl. (43) In one embodiment, B is pyridinyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl. (44) In one embodiment, B is pyridinyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently halogen or (C₃-C₆) cycloalkyl. (45) In one embodiment, B is pyridinyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (46) In one embodiment, B is pyridinyl, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl, or two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring.

(47) In one embodiment, B is pyridinyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl, halogen, or (C₃-C₆) cycloalkyl. (48) In one embodiment, B is pyridinyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (49) In one embodiment, B is pyridinyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen or (C₃-C₆) cycloalkyl. (50) In one embodiment, B is pyridinyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and two R₈ together with the atoms to which they are attached form a (C₅-C₇) cycloalkyl ring. (51) In one embodiment, B, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (31)-(50), and A is phenyl. (52) In one embodiment, B, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (31)-(50), and A is thiophenyl. (53) In one embodiment, B, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (31)-(50), and R10b is H. (54) In one embodiment, B, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (31)-(50), A is phenyl, and R10b is H. (55) In one embodiment, B, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (31)-(50), A is thiophenyl, and R10b is H. (56) In one embodiment, B is pyridinyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and R₈ and R_10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. (57) In one embodiment, B is pyridinyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and R₈ and R_10b together with the atoms to which they are attached form a 5- or 6- membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. (58) In one embodiment, B is pyridinyl, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and R₈ and R_10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R₁₁. (59) In one embodiment, B, R6, R₇, R₈, and R10b are each as defined, where applicable, in any one of (56)-(58), and A is phenyl.

(60) In one embodiment, B, R6, R₇, R₈, and R10b are each as defined, where applicable, in any one of (56)-(58), and A is thiophenyl. (61) In one embodiment, B is pyridinyl and A is phenyl. (62) In one embodiment, B is pyridinyl and A is thiophenyl. (63) In one embodiment, B is phenyl and A is phenyl. (64) In one embodiment, B is phenyl and A is thiophenyl. (65) In one embodiment, B is pyridinyl, A is phenyl, and R6 is methyl. (66) In one embodiment, B is pyridinyl, A is thiophenyl, and R₆ is methyl. (67) In one embodiment, B is phenyl, A is phenyl, and R6 is methyl. (68) In one embodiment, B is phenyl, A is thiophenyl, and R₆ is methyl. (69) In one embodiment, B is pyridinyl, and A is phenyl. (70) In one embodiment, B is pyridinyl, and A is thiophenyl. (71) In one embodiment, B is phenyl, and A is phenyl. (72) In one embodiment, B is phenyl, and A is thiophenyl. (73) In one embodiment, A, B, R6, R₇, R₈, and R10b are each as defined, where applicable, in any one of (1)-(72), o1 is 0. (74) In one embodiment, A, B, R6, R₇, R₈, and R10b are each as defined, where applicable, in any one of (1)-(72), o1 is 1. (75) In one embodiment, A, B, R6, R₇, R₈, and R10b are each as defined, where applicable, in any one of (1)-(72), o1 is 2. (76) In one embodiment, A, B, R₆, R₇, R₈, and R_10b are each as defined, where applicable, in any one of (1)-(72), o1 is 2, and R5 is (C₁-C₄) alkyl or oxo. [00228] A, B, R₅, R₆, R₇, R₈, R_10b, and o1 can each be selected from any of the groups and combined as described above in Formula TL-II. [00229] Referring to formula VII, in one embodiment, the Targeting Ligand is a compound of Formula TL-III:

each R₁₂ is independently H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl; R13 is H, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, or CN; each R₁₄ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, O-phenyl, OH, or NH₂; R₁₅ is H, (C₁-C₄) alkyl, halogen, or CN; each R₁₆ is independently H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl; R17 is H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl; each R₁₈ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, or oxo; s1 and s5 are each independently 0, 1, 2 or 3; and s2, s3, and s4 are each independently 0 or 1, wherein the Targeting Ligand is bonded to the Linker via the

next to Z. [00230] In some embodiments, Z is NR17. In other embodiments, Z is In

other embodiments, Z is In other embodiments, Z is NR₁₇ or

. In other embodiments, Z is NR₁₇ or

. In other embodiments, Z is

. [00231] In some embodiments, R₁₇ is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. In other embodiments, R17 is (C₁-C₃) alkyl or (C₁-C₃) haloalkyl. In other embodiments, R17 is H or (C1- C₃) alkyl. In other embodiments, R₁₇ is H, methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R17 is H, methyl, or ethyl. In other embodiments, R17 is methyl. [00232] In some embodiments, each R₁₈ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, or oxo. In other embodiments, each R18 is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, or halogen. In other embodiments, each R18 is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, halogen, or oxo. In other embodiments, each R18 is independently (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, or oxo. In other embodiments, each R₁₈ is independently halogen or oxo. In other embodiments, each R18 is independently (C₁-C₃) alkyl, halogen, or oxo. In other embodiments, each R₁₈ is independently methyl, ethyl, n-propyl, i-propyl, F, Cl, Br, I, or oxo. In other embodiments, each R18 is independently methyl, ethyl, n-propyl, i-propyl, F, Cl, or oxo. [00233] In some embodiments, each R12 is independently H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. In other embodiments, each R₁₂ is independently (C₁-C₃) alkyl or (C₁-C₃) haloalkyl. In other embodiments, each R12 is independently H or (C₁-C₃) alkyl. In other embodiments, each R₁₂ is independently H, methyl, ethyl, n-propyl, or i-propyl. In other embodiments, each R12 is independently H, methyl, or ethyl. In other embodiments, each R12 is independently H or methyl. In other embodiments, each R₁₂ is H. [00234] In some embodiments, R13 is H, (C₁-C₃) alkyl, (C₁-C₃) haloalkyl or CN. In other embodiments, R₁₃ is (C₁-C₃) alkyl, (C₁-C₃) haloalkyl or CN. In other embodiments, R₁₃ is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. In other embodiments, R13 is (C₁-C₃) alkyl or (C₁-C₃) haloalkyl. In other embodiments, R₁₃ is H or CN. In other embodiments, R₁₃ is H. [00235] In some embodiments, each R14 is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, O-phenyl, OH, or NH₂. In other embodiments, each R₁₄ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, or halogen. In other embodiments, each R14 is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl,

(C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, or O-phenyl. In other embodiments, each R14 is independently (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, O-phenyl, or OH. In other embodiments, each R14 is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments, each R₁₄ is independently O-phenyl, OH, or NH₂. In other embodiments, each R14 is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, halogen, or O-phenyl. In other embodiments, each R₁₄ is independently (C₁-C₄) alkyl, halogen, or O-phenyl. In other embodiments, each R14 is independently methyl, ethyl, n-propyl, i- propyl, F, Cl, Br, I, or O-phenyl. In other embodiments, each R₁₄ is independently methyl, F, Cl, or O-phenyl. In other embodiments, each R14 is independently F, Cl, Br, I, or O-phenyl. In other embodiments, each R₁₄ is independently F, Cl, or O-phenyl. In other embodiments, each R14 is independently F or O-phenyl. [00236] In some embodiments, R₁₅ is H, (C₁-C₃) alkyl, halogen, or CN. In other embodiments, R15 is (C₁-C₃) alkyl, halogen, or CN. In other embodiments, R15 is H, (C₁-C₃) alkyl, or CN. In other embodiments, R₁₅ is H, methyl, ethyl, n-propyl, i-propyl, or CN. In other embodiments, R15 is H, methyl, ethyl, or CN. In other embodiments, R15 is H, methyl, or CN. In other embodiments, R₁₅ is H or CN. [00237] In some embodiments, each R16 is independently H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. In other embodiments, each R₁₆ is independently (C₁-C₃) alkyl or (C₁-C₃) haloalkyl. In other embodiments, each R16 is independently H or (C₁-C₃) alkyl. In other embodiments, each R16 is independently H, methyl, ethyl, n-propyl, or i-propyl. In other embodiments, each R₁₆ is independently H, methyl, or ethyl. In other embodiments, each R₁₆ is independently H or methyl. In other embodiments, each R16 is H. In other embodiments, each R16 is methyl. In other embodiments, one R₁₆ is H and the other R₁₆ is methyl. [00238] In some embodiments, s1 is 0. In other embodiments, s1 is 1. In other embodiments, s1 is 2. In other embodiments, s1 is 3. In other embodiments, s1 is 0 or 1. In other embodiments, s1 is 1 or 2. In other embodiments, s1 is 2 or 3. In other embodiments, s1 is 0, 1, or 2. In other embodiments, s1 is 1, 2, or 3. [00239] In some embodiments, s2 is 0. In other embodiments, s2 is 1. [00240] In some embodiments, s3 is 0. In other embodiments, s3 is 1. [00241] In some embodiments, s4 is 0. In other embodiments, s4 is 1. [00242] In some embodiments, s5 is 0. In other embodiments, s5 is 1. In other embodiments, s5 is 2. In other embodiments, s5 is 3. In other embodiments, s5 is 0 or 1. In other

embodiments, s5 is 1 or 2. In other embodiments, s5 is 2 or 3. In other embodiments, s5 is 0, 1, or 2. In other embodiments, s5 is 1, 2, or 3. [00243] Any of the groups described herein for any of Z, R12, R13, R14, R15, R16, R17, R18, s1, s2, s3, s4, and s5 can be combined with any of the groups described herein for one or more of the remainder of Z, R12, R13, R14, R15, R16, R17, R18, s1, s2, s3, s4, and s5, and may further be combined with any of the groups described herein for the Linker. [00244] For a Targeting Ligand of Formula TL-III: (1) In one embodiment, each R₁₂ is H and R₁₃ is H. (2) In one embodiment, each R12 is H, R13 is H, and s2 is 0. (3) In one embodiment, each R₁₂ is H, R₁₃ is H, and s2 is 1. (4) In one embodiment, each R12 is H, R13 is H, s2 is 0, and s3 is 0. (5) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 1, and s3 is 0. (6) In one embodiment, each R12 is H, R13 is H, s2 is 0, and s3 is 1. (7) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 1, and s3 is 1. (8) In one embodiment, each R12 is H, R13 is H, s2 is 0, s3 is 0, and each R14 is independently halogen or O-phenyl. (9) In one embodiment, each R12 is H, R13 is H, s2 is 1, s3 is 0, and each R14 is independently halogen or O-phenyl. (10) In one embodiment, each R12 is H, R13 is H, s2 is 0, s3 is 1, and each R14 is independently halogen or O-phenyl. (11) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 1, s3 is 1, and each R₁₄ is independently halogen or O-phenyl. (12) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 0, s3 is 0, each R₁₄ is independently halogen or O-phenyl, and R15 is H or CN. (13) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 1, s3 is 0, each R₁₄ is independently halogen or O-phenyl, and R15 is H or CN. (14) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 0, s3 is 1, each R₁₄ is independently halogen or O-phenyl, and R15 is H or CN. (15) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 1, s3 is 1, each R₁₄ is independently halogen or O-phenyl, and R15 is H or CN. (16) In one embodiment, each R₁₂ is H, R₁₃ is H, s2 is 0, s3 is 0, each R₁₄ is independently halogen or O-phenyl, R15 is H or CN, and each R16 is independently H or (C₁-C₄) alkyl. (17) In one embodiment, each R12 is H, R13 is H, s2 is 1, s3 is 0, each R14 is independently halogen or O-phenyl, R₁₅ is H or CN, and each R₁₆ is independently H or (C₁-C₄) alkyl. (18) In one embodiment, each R12 is H, R13 is H, s2 is 0, s3 is 1, each R14 is independently halogen or O-phenyl, R₁₅ is H or CN, and each R₁₆ is independently H or (C₁-C₄) alkyl. (19) In one embodiment, each R12 is H, R13 is H, s2 is 1, s3 is 1, each R14 is independently halogen or O-phenyl, R₁₅ is H or CN, and each R₁₆ is independently H or (C₁-C₄) alkyl. (20) In one embodiment, Z is NR17 and R17 is H or (C₁-C₃) alkyl. (21) In one embodiment, Z is NR₁₇ and R₁₇ is H, methyl or ethyl. (21) In one embodiment, Z is NR17 and R17 is H. (23) In one embodiment, Z is NR₁₇ and R₁₇ is methyl or ethyl. (24) In one embodiment, Z is

and R17 is H or (C₁-C₃) alkyl. (25) In one embodiment, Z is

and R₁₇ is H, methyl or ethyl. (26) In one embodiment, Z is

and R17 is H. (27) In one embodiment,

and R₁₇ is methyl or ethyl. (28) In one embodiment, Z is

and s5 is 0. (29) In one embodiment, Z is NR₁₇, R₁₇ is H or (C₁-C₃) alkyl, and R₁₅ is H or CN. (30) In one embodiment, Z is NR17, R17 is H, methyl or ethyl, and R15 is H or CN. (31) In one embodiment, Z is NR₁₇, R₁₇ is H, and R₁₅ is H or CN. (32) In one embodiment, Z is NR17, R17 is methyl or ethyl, and R15 is H or CN. (33) In one embodiment, Z is

, R₁₇ is H or (C₁-C₃) alkyl, and R₁₅ is H or CN. (34) In one embodiment, Z is

R17 is H, methyl or ethyl, and R15 is H or CN. (35) In one embodiment, Z is , R₁₇ is H, and R₁₅ is H or CN.

(36) In one embodiment, Z is

, R17 is methyl or ethyl, and R15 is H or CN. (37) In one embodiment, Z is

s5 is 0, and R15 is H or CN. (38) In one embodiment, each R₁₆ is methyl. In other embodiments, each R₁₆ is H. In yet other embodiments one R16 is H and the other R16 is methyl. (49) In one embodiment, Z is NR₁₇ and s2 is 0. (40) In one embodiment, Z is NR17 and s2 is 1. (41) In one embodiment, Z is NR17 and s3 is 0. (42) In one embodiment, Z is NR17 and s3 is 1. (43) In one embodiment, Z is NR17, s2 is 0, and s3 is 0. (44) In one embodiment, Z is NR₁₇, s2 is 1, and s3 is 0. (45) In one embodiment, Z is NR17, s2 is 0, and s3 is 1. (46) In one embodiment, Z is NR₁₇, s2 is 1, and s3 is 1. (47) In one embodiment, Z is

and s2 is 0. (48) In one embodiment, Z is

and s2 is 1. (49) In one embodiment, Z is

and s3 is 0. (50) In one embodiment, Z is

and s3 is 1. (51) In one embodiment, Z is s2 is 0, and s3 is 0.

(52) In one embodiment, Z is

, s2 is 1, and s3 is 0. (53) In one embodiment, Z is

, s2 is 0, and s3 is 1. (54) In one embodiment, Z is s2 is 1, and s3 is 1.

(55) In one embodiment, Z is

and s2 is 0. (56) In one embodiment, Z is

and s2 is 1. (57) In one embodiment, Z is

and s3 is 0. (58) In one embodiment, Z is

and s3 is 1. (59) In one embodiment, Z is

s2 is 0, and s3 is 0. (60) In one embodiment, Z is

s2 is 1, and s3 is 0. (61) In one embodiment, Z is

s2 is 0, and s3 is 1. (62) In one embodiment, Z is

, s2 is 1, and s3 is 1. (63)In one embodiment, Z, R12, R13, R14, R15, R16, R17, s2, s3 and s5 are each as defined, where applicable, in any one of (1)-(62), s1 is 1. (64) In one embodiment, Z, R12, R13, R14, R15, R16, R17, s2, s3 and s5 are each as defined, where applicable, in any one of (1)-(62), s1 is 2. (65) In one embodiment, Z, R12, R13, R14, R15, R16, R17, s2, s3 and s5 are each as defined, where applicable, in any one of (1)-(62), s4 is 0. (66) In one embodiment, Z, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, s2, s3 and s5 are each as defined, where applicable, in any one of (1)-(62), s4 is 1. [00245] Z, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, s1, s2, s3, s4, and s5 can each be selected from any of the groups and combined as described above in Formula TL-III. [00246] In one embodiment, the targeting ligand of Formula TL-III is of Formula TL-IIIa:

wherein Z, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, s2, s3, s4, and s5 are each as defined above in Formula TL- III. [00247] For a Targeting Ligand of Formula TL-IIIa: (1) In one embodiment, s2 is 0, and s3 is 0. (2) In one embodiment, s2 is 1, and s3 is 0. (3) In one embodiment, s2 is 0, and s3 is 1. (4) In one embodiment, s2 is 1, and s3 is 1. (5) In one embodiment, s2 is 0, s3 is 0, and each R14 is independently halogen or O-phenyl. (6) In one embodiment, s2 is 1, s3 is 0, and each R₁₄ is independently halogen or O-phenyl. (7) In one embodiment, s2 is 0, s3 is 1, and each R14 is independently halogen or O-phenyl. (8) In one embodiment, s2 is 1, s3 is 1, and each R₁₄ is independently halogen or O-phenyl. (9) In one embodiment, s2 is 0, s3 is 0, each R14 is independently halogen or O-phenyl, and R15 is H or CN. (10) In one embodiment, s2 is 1, s3 is 0, each R14 is independently halogen or O-phenyl, and R15 is H or CN. (11) In one embodiment, s2 is 0, s3 is 1, each R₁₄ is independently halogen or O-phenyl, and R15 is H or CN. (12) In one embodiment, s2 is 1, s3 is 1, each R₁₄ is independently halogen or O-phenyl, and R15 is H or CN. (13) In one embodiment, s2 is 0, s3 is 0, each R₁₄ is independently halogen or O-phenyl, R₁₅ is H or CN, and each R16 is independently H or (C₁-C₄) alkyl. (14) In one embodiment, s2 is 1, s3 is 0, each R₁₄ is independently halogen or O-phenyl, R₁₅ is H or CN, and each R16 is independently H or (C₁-C₄) alkyl. (15) In one embodiment, s2 is 0, s3 is 1, each R₁₄ is independently halogen or O-phenyl, R₁₅ is H or CN, and each R16 is independently H or (C₁-C₄) alkyl. (16) In one embodiment, s2 is 1, s3 is 1, each R14 is independently halogen or O-phenyl, R15 is H or CN, and each R₁₆ is independently H or (C₁-C₄) alkyl. (17) In one embodiment, Z is NR17 and R17 is H or (C₁-C₃) alkyl. (18) In one embodiment, Z is NR₁₇ and R₁₇ is H, methyl or ethyl. (19) In one embodiment, Z is NR17 and R17 is H. (20) In one embodiment, Z is NR₁₇ and R₁₇ is methyl or ethyl. (21) In one embodiment, Z is

and R17 is H or (C₁-C₃) alkyl. (22) In one embodiment, Z is

R₁₇ is H, methyl or ethyl. (23) In one embodiment, Z is and R17 is H. (24) In one embodiment, Z is

and R₁₇ is methyl or ethyl. (25) In one embodiment, Z is

and s5 is 0. (26) In one embodiment, Z is NR17, R17 is H or (C₁-C₃) alkyl, and R15 is H or CN. (27) In one embodiment, Z is NR17, R17 is H, methyl or ethyl, and R15 is H or CN. (28) In one embodiment, Z is NR17, R17 is H, and R15 is H or CN. (29) In one embodiment, Z is NR17, R17 is methyl or ethyl, and R15 is H or CN. (30) In one embodiment, Z is

, R₁₇ is H or (C₁-C₃) alkyl, and R₁₅ is H or CN. (31) In one embodiment, Z is

, R17 is H, methyl or ethyl, and R15 is H or CN. (32) In one embodiment, Z is R17 is H, and R15 is H or CN.

(33) In one embodiment, Z is

, R₁₇ is methyl or ethyl, and R₁₅ is H or CN. (34) In one embodiment, Z is s5 is 0, and R15 is H or CN.

(35) In one embodiment, each R16 is methyl. In other embodiments, each R16 is H. In yet other embodiments one R₁₆ is H and the other R₁₆ is methyl. (36) In one embodiment, Z is NR17 and s2 is 0. (37) In one embodiment, Z is NR₁₇ and s2 is 1. (38) In one embodiment, Z is NR17 and s3 is 0. (39) In one embodiment, Z is NR₁₇ and s3 is 1. (40) In one embodiment, Z is NR17, s2 is 0, and s3 is 0. (41) In one embodiment, Z is NR₁₇, s2 is 1, and s3 is 0. (42) In one embodiment, Z is NR17, s2 is 0, and s3 is 1. (43) In one embodiment, Z is NR₁₇, s2 is 1, and s3 is 1. (44) In one embodiment, Z is

and s2 is 0. (45) In one embodiment, Z is

and s2 is 1. (46) In one embodiment, Z is

nd s3 is 0. (47) In one embodiment, Z is

and s3 is 1. (48) In one embodiment, Z is

s2 is 0, and s3 is 0. (49) In one embodiment, Z is s2 is 1, and s3 is 0.

(50) In one embodiment, Z is

s2 is 0, and s3 is 1. (51) In one embodiment, Z is s2 is 1, and s3 is 1.

(52) In one embodiment, Z is and s2 is 0.

(53) In one embodiment, Z is and s2 is 1.

(54) In one embodiment, Z is

and s3 is 0. (55) In one embodiment, Z is

and s3 is 1. (56) In one embodiment, Z is

s2 is 0, and s3 is 0. (57) In one embodiment, Z is , s2 is 1, and s3 is 0. (58) In one embodiment, Z is s2 is 0, and s3 is 1. (59) In one embodiment, Z is

, s2 is 1, and s3 is 1. (60) In one embodiment, Z, R14, R15, R16, R17, R18, s2, s3, and s5 are each as defined, where applicable, in any one of (1)-(59), s4 is 0. (61) In one embodiment, Z, R₁₄, R₁₅, R₁₆, R₁₇, s2, s3 and s5 are each as defined, where applicable, in any one of (1)-(59), s4 is 1. [00248] Z, R₁₄, R₁₅, R₁₆, R₁₇, s2, s3, s4, and s5 can each be selected from any of the groups and combined as described above in Formula TL-III or TL-IIIa. [00249] In one embodiment, the targeting ligand of Formula TL-III is of Formula TL-IIIb:

wherein Z, R15, R16, R17, R18, s2, s3, s4, and s5 are each as defined above in Formula TL-III. [00250] For a Targeting Ligand of Formula TL-IIIb: (1) In one embodiment, s2 is 0, and s3 is 0. (2) In one embodiment, s2 is 1, and s3 is 0. (3) In one embodiment, s2 is 0, and s3 is 1. (4) In one embodiment, s2 is 1, and s3 is 1. (5) In one embodiment, s2 is 0, s3 is 0, and R15 is H or CN. (6) In one embodiment, s2 is 1, s3 is 0, and R₁₅ is H or CN. (7) In one embodiment, s2 is 0, s3 is 1, and R15 is H or CN. (8) In one embodiment, s2 is 1, s3 is 1, and R₁₅ is H or CN. (9) In one embodiment, s2 is 0, s3 is 0, R15 is H or CN, and each R16 is independently H or (C1- C₄) alkyl. (10) In one embodiment, s2 is 1, s3 is 0, R15 is H or CN, and each R16 is independently H or (C₁-C₄) alkyl. (11) In one embodiment, s2 is 0, s3 is 1, R15 is H or CN, and each R16 is independently H or (C₁-C₄) alkyl. (12) In one embodiment, s2 is 1, s3 is 1, R15 is H or CN, and each R16 is independently H or (C₁-C₄) alkyl. (13) In one embodiment, Z is NR17 and R17 is H or (C₁-C₃) alkyl. (14) In one embodiment, Z is NR₁₇ and R₁₇ is H, methyl or ethyl. (15) In one embodiment, Z is NR17 and R17 is H. (16) In one embodiment, Z is NR17 and R17 is methyl or ethyl. (17) In one embodiment, Z is

and R17 is H or (C₁-C₃) alkyl. (18) In one embodiment, Z is and R17 is H, methyl or ethyl.

(19) In one embodiment, Z is

and R17 is H. (20) In one embodiment, Z is

and R₁₇ is methyl or ethyl. (21) In one embodiment, Z is

and s5 is 0. (22) In one embodiment, Z is NR₁₇, R₁₇ is H or (C₁-C₃) alkyl, and R₁₅ is H or CN. (23) In one embodiment, Z is NR17, R17 is H, methyl or ethyl, and R15 is H or CN. (24)In one embodiment, Z is NR17, R17 is H, and R15 is H or CN. (25) In one embodiment, Z is NR₁₇, R₁₇ is methyl or ethyl, and R₁₅ is H or CN. (26) In one embodiment, Z is

, R17 is H or (C₁-C₃) alkyl, and R15 is H or CN. (27) In one embodiment, Z is

, R17 is H, methyl or ethyl, and R15 is H or CN. (28) In one embodiment, Z is

R₁₇ is H, and R₁₅ is H or CN. (29) In one embodiment, Z is

R17 is methyl or ethyl, and R15 is H or CN. (30) In one embodiment, Z is

, s5 is 0, and R₁₅ is H or CN. (31) In one embodiment, each R16 is methyl. In other embodiments, each R16 is H. In yet other embodiments one R₁₆ is H and the other R₁₆ is methyl. (32) In one embodiment, Z is NR17 and s2 is 0. (33) In one embodiment, Z is NR₁₇ and s2 is 1. (34) In one embodiment, Z is NR17 and s3 is 0. (35) In one embodiment, Z is NR17 and s3 is 1. (36) In one embodiment, Z is NR17, s2 is 0, and s3 is 0. (37) In one embodiment, Z is NR17, s2 is 1, and s3 is 0. (38) In one embodiment, Z is NR₁₇, s2 is 0, and s3 is 1. (39) In one embodiment, Z is NR17, s2 is 1, and s3 is 1. (40) In one embodiment, Z is and s2 is 0.

(41) In one embodiment, Z is

and s2 is 1. (42) In one embodiment, Z is and s3 is 0.

(43) In one embodiment, Z is and s3 is 1.

(44) In one embodiment, Z is

s2 is 0, and s3 is 0. (45) In one embodiment, Z is

, s2 is 1, and s3 is 0. (46) In one embodiment, Z is

, s2 is 0, and s3 is 1. (47) In one embodiment, Z is

, s2 is 1, and s3 is 1. (48) In one embodiment, Z is

and s2 is 0. (49) In one embodiment, Z is

and s2 is 1. (50) In one embodiment, Z is and s3 is 0. (51) In one embodiment, Z is and s3 is 1. (52) In one embodiment, Z is s2 is 0, and s3 is 0. (53) In one embodiment, Z is s2 is 1, and s3 is 0. (54) In one embodiment, Z is s2 is 0, and s3 is 1. (55) In one embodiment, Z is

s2 is 1, and s3 is 1. (56) In one embodiment, Z, R15, R16, R17, R18, s2, s3, and s5 are each as defined, where applicable, in any one of (1)-(55), s4 is 0. (57) In one embodiment, Z, R15, R16, R17, R18, s2, s3, and s5 are each as defined, where applicable, in any one of (1)-(55), s4 is 1. [00251] Z, R₁₅, R₁₆, R₁₇, R₁₈, s2, s3, s4, and s5 can each be selected from any of the groups and combined as described above in Formula TL-III or TL-IIIb. [00252] In one embodiment, the BTK degrader is a compound of Formula XI:

or a pharmaceutically acceptable salt or stereoisomer thereof wherein: R5, R6, R₇, B, Y1, Y2, Y3, o1, o2, and o3 are each as defined herein; the Linker is a group that covalently binds to

and the Degron; and the Degron is capable of binding to a ubiquitin ligase, such as an E3 ubiquitin ligase (e.g., cereblon). [00253] In one embodiment, a Targeting Ligand is a compound of Formula TL-IV:

wherein: B is phenyl or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S, wherein the phenyl or heteroaryl is optionally substituted with 1 to 3 R₉, wherein when Y1 is absent, B is bonded to a carbon atom or Y4 in

Y₁ is absent or C(O), wherein Y₁ is bonded to a carbon atom or Y₄ in

Y2 is NR10a or O; Y₃ is C(O)NR_10b or NR_10bC(O); Y4 is NR5’ or, when Y1 is bonded to Y4 or when Y1 is absent and B is bonded to Y4, Y4 is N; R5’ is H, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, or halogen; each R₅ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, or oxo; R₆ is H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl; each R₇ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, (C₁-C₄) hydroxyalkyl, halogen, OH, or NH₂; each R₈ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, OH, or NH₂; each R₉ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, or halogen; R10a and R10b are each independently H, (C₁-C₄) alkyl, or (C₁-C₄) haloalkyl; and o1, o2, and o3 are each independently 0, 1, 2, or 3; wherein the Targeting Ligand is bonded to the Linker via the

next to

. [00254] In some embodiments, B is phenyl optionally substituted with 1 to 3 R₉. In other embodiments, B is 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S, optionally substituted with 1 to 3 R₉. In other embodiments, B is 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S, optionally substituted with 1 to 3 R₉. In other embodiments, B is 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S, optionally substituted with 1 to 3 R₉. In other embodiments, B is 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S. In other embodiments, B is 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S. In other embodiments, B is 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S. In other embodiments, B is pyridinyl optionally substituted with 1 to 3 R₉. In other embodiments, B is pyridinyl. In other embodiments, B is phenyl. [00255] In some embodiments, Y₁ is absent. In other embodiments, Y₁ is C(O). [00256] In some embodiments, Y2 is NR10a. In other embodiments, Y2 is O. [00257] In some embodiments, Y₃ is C(O)NR_10b. In other embodiments, Y₃ is NR_10bC(O).

[00258] In some embodiments, Y4 is NR5’. In other embodiments, Y4 is N. [00259] In some embodiments, R₅’ is (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁- C3) haloalkoxy, or halogen. In other embodiments, R5’ is (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C1- C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments, R₅’ is (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, or halogen. In other embodiments, R5’ is (C₁-C₃) alkyl or halogen. In other embodiments, R₅’ is methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R₅’ is methyl or ethyl. In other embodiments, R5’ is methyl. [00260] In some embodiments, each R₅ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, or oxo. In other embodiments, each R5 is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, or (C₁-C₃) haloalkoxy. In other embodiments, each R5 is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, halogen, or oxo. In other embodiments, each R₅ is independently (C₁-C₃) alkyl, halogen, or oxo. In other embodiments, each R5 is independently (C₁-C₃) alkyl or oxo. In other embodiments, each R5 is independently methyl, ethyl, n-propyl, i-propyl, or oxo. In other embodiments, each R₅ is independently methyl, ethyl, or oxo. In other embodiments, each R5 is independently methyl or oxo. [00261] In some embodiments, R6 is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. In other embodiments, R₆ is H or (C₁-C₄) alkyl. In other embodiments, R₆ is H or (C₁-C₃) alkyl. In other embodiments, R6 is H, methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R6 is H, methyl, or ethyl. In other embodiments, R6 is (C₁-C₄) alkyl. In other embodiments, R6 is methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R₆ is H. In other embodiments, R₆ is methyl or ethyl. In other embodiments, R6 is methyl. [00262] In some embodiments, each R₇ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, (C₁-C₃) hydroxyalkyl, halogen, OH, or NH₂. In other embodiments, each R₇ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁- C4) haloalkoxy, (C₁-C₄) hydroxyalkyl, halogen, or OH. In other embodiments, each R₇ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, (C₁-C₄) hydroxyalkyl, or OH. In other embodiments, each R₇ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) hydroxyalkyl, halogen, or OH. In other embodiments, each R₇ is independently (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄) hydroxyalkyl, or OH. In other embodiments, each R₇ is independently (C₁-C₄) alkyl, (C₁-C₄) hydroxyalkyl, or OH. In other embodiments, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl. In other embodiments, each R₇ is independently (C₁-C₃) alkyl or (C₁-C₃) hydroxyalkyl. In other

embodiments, each R₇ is independently (C₁-C₃) alkyl. In other embodiments, each R₇ is independently (C₁-C₃) hydroxyalkyl. In other embodiments, each R₇ is independently methyl, ethyl, n-propyl, i-propyl, or (C₁-C₃) hydroxyalkyl. In other embodiments, each R₇ is independently methyl, ethyl, n-propyl, i-propyl, CH₂OH, CH₂CH₂OH, CH₂CH₂CH₂OH, CH(OH)CH3, CH(OH)CH₂CH3, or CH₂CH(OH)CH3. In other embodiments, each R₇ is independently methyl, ethyl, CH₂OH, CH₂CH₂OH, or CH(OH)CH₃. In other embodiments, each R₇ is independently methyl, ethyl, CH₂OH, or CH₂CH₂OH. In other embodiments, each R₇ is independently methyl or CH₂OH. In other embodiments, each R₇ is independently methyl, ethyl, n-propyl, or i-propyl. In other embodiments, each R₇ is independently methyl or ethyl. In other embodiments, at least one R₇ is methyl. [00263] In some embodiments, each R₈ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, halogen, OH, or NH₂. In other embodiments, each R₈ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, or halogen. In other embodiments, each R₈ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁- C4) alkoxy, (C₁-C₄) haloalkoxy, or halogen. In other embodiments, each R₈ is independently (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, or halogen. In other embodiments, each R₈ is independently (C₁-C₄) alkyl or halogen. In other embodiments, each R₈ is independently methyl, ethyl, n- propyl, i-propyl, n-butyl, i-butyl, t-butyl, F, or Cl. In other embodiments, each R₈ is independently n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, F, or Cl. In other embodiments, each R₈ is independently i-propyl, i-butyl, t-butyl, or F. In other embodiments, each R₈ is independently i-propyl, t-butyl, or F. In other embodiments, each R₈ is independently t-butyl or F. In other embodiments, at least one R₈ is F. In other embodiments, at least one R₈ is t- butyl. [00264] In some embodiments, each R₉ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, or halogen. In other embodiments, each R₉ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, or halogen. In other embodiments, each R₉ is independently (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, or halogen. In other embodiments, each R₉ is independently (C₁-C₃) alkyl, (C₁-C₃) alkoxy, or halogen. In other embodiments, each R₉ is independently (C₁-C₃) alkyl, or halogen. In other embodiments, each R₉ is independently methyl, ethyl, n-propyl, i-propyl, F or Cl. [00265] In some embodiments, R_10a is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. In other embodiments, R10a is (C₁-C₄) alkyl or (C₁-C₄) haloalkyl. In other embodiments, R10a is H or (C₁-C₄) alkyl. In other embodiments, R_10a is H, methyl, ethyl, n-propyl, or i-propyl. In other

embodiments, R10a is H, methyl or ethyl. In other embodiments, R10a is (C₁-C₄) alkyl. In other embodiments, R_10a is methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R_10a is methyl or ethyl. In other embodiments, R10a is H. [00266] In some embodiments, R_10b is H, (C₁-C₃) alkyl, or (C₁-C₃) haloalkyl. In other embodiments, R10b is (C₁-C₄) alkyl or (C₁-C₄) haloalkyl. In other embodiments, R10b is H or (C₁-C₄) alkyl. In other embodiments, R_10b is H, methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R10b is H, methyl or ethyl. In other embodiments, R10b is (C₁-C₄) alkyl. In other embodiments, R_10b is methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R_10b is methyl or ethyl. In other embodiments, R10b is H. [00267] In some embodiments, o1 is 0. In other embodiments, o1 is 1. In other embodiments, o1 is 2. In other embodiments, o1 is 3. In other embodiments, o1 is 0 or 1. In other embodiments, o1 is 1 or 2. In other embodiments, o1 is 2 or 3. In other embodiments, o1 is 0, 1 or 2. In other embodiments, o1 is 1, 2, or 3. [00268] In some embodiments, o2 is 0. In other embodiments, o2 is 1. In other embodiments, o2 is 2. In other embodiments, o2 is 3. In other embodiments, o2 is 0 or 1. In other embodiments, o2 is 1 or 2. In other embodiments, o2 is 2 or 3. In other embodiments, o2 is 0, 1 or 2. In other embodiments, o2 is 1, 2, or 3. [00269] In some embodiments, o3 is 0. In other embodiments, o3 is 1. In other embodiments, o3 is 2. In other embodiments, o3 is 3. In other embodiments, o3 is 0 or 1. In other embodiments, o3 is 1 or 2. In other embodiments, o3 is 2 or 3. In other embodiments, o3 is 0, 1 or 2. In other embodiments, o3 is 1, 2, or 3. [00270] Any of the groups described herein for any of B, Y1, Y2, Y3, Y4, R5, R5’, R6, R₇, R₈, R₉, R_10a, R_10b, o1, o2, and o3 can be combined with any of the groups described herein for one or more of the remainder of B, Y1, Y2, Y3, Y4, R5, R5’, R6, R₇, R₈, R₉, R10a, R10b, o1, o2, and o3, and may further be combined with any of the groups described herein for the Linker. [00271] For a Targeting Ligand of Formula TL-IV (1) In one embodiment, B is phenyl and Y₂ is NR_10a. (2) In one embodiment, B is phenyl, Y2 is NR10a, and Y1 is C(O). (3) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is C(O), and R₆ is (C₁-C₄) alkyl. (4) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl. (5) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl.

(6) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) hydroxyalkyl. (7) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and Y₃ is C(O)NR_10b. (8) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and Y₃ is C(O)NR_10b. (9) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and Y₃ is C(O)NR_10b. (10) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁-C₄) alkyl or halogen. (11) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl. (12) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently halogen. (13) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl or halogen. (14) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl. (15) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y3 is C(O)NR10b, and each R₈ is independently halogen. (16) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl or halogen. (17) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁-C₄) alkyl. (18) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and each R₈ is independently halogen. (19) In one embodiment, B is phenyl, Y₂ is NR_10a, and Y₁ is absent.

(20) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is absent, and R6 is (C₁-C₄) alkyl. (21) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is absent, R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl. (22) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is absent, R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl. (23) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is absent, R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) hydroxyalkyl. (24) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and Y3 is C(O)NR10b. (25) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and Y3 is C(O)NR10b. (26) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and Y3 is C(O)NR10b. (27) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl or halogen. (28) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁-C₄) alkyl. (29) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently halogen. (30) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl or halogen. (31) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁-C₄) alkyl. (32) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is C(O)NR_10b, and each R₈ is independently halogen. (33) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁-C₄) alkyl or halogen.

(34) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁-C₄) alkyl. (35) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and each R₈ is independently halogen. (36) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (37) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (38) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (39) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (40) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl. (41) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently halogen. (42) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (43) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (44) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (45) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (46) In one embodiment, B is phenyl, Y₂ is NR_10a, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (47) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen.

(48) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (49) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl. (50) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently halogen. (51) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (52) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (53) In one embodiment, B is phenyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (54) In one embodiment, B, Y1, Y2, Y3, R6, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(53), and R_10a is H. (55) In one embodiment, B, Y1, Y2, Y3, R6, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(53), and R_10b is H. (56) In one embodiment, B, Y1, Y2, Y3, R6, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(53), R_10a is H, and R_10b is H. (57) In one embodiment, B is pyridinyl and Y2 is NR10a. (58) In one embodiment, B is pyridinyl, Y2 is NR10a, and Y1 is absent. (59) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is absent, and R₆ is (C₁-C₄) alkyl. (60) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl. (61) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl. (62) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) hydroxyalkyl. (63) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and Y₃ is C(O)NR_10b. (64) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and Y₃ is C(O)NR_10b. (65) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and Y₃ is C(O)NR_10b.

(66) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁-C₄) alkyl or halogen. (67) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl. (68) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently halogen. (69) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl or halogen. (70) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁-C₄) alkyl. (71) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is C(O)NR_10b, and each R₈ is independently halogen. (72) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁- C4) alkyl or halogen. (73) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁- C4) alkyl. (74) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and each R₈ is independently halogen. (75) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁- C4) alkyl or halogen. (76) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C1- C₄) alkyl.

(77) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (78) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (79) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl. (80) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently halogen. (81) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (82) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (83) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (84) In one embodiment, B is pyridinyl, Y2 is NR10a, and Y1 is C(O). (85) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is C(O), and R₆ is (C₁-C₄) alkyl. (86) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl. (87) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl. (88) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) hydroxyalkyl. (89) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and Y3 is C(O)NR10b. (90) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and Y3 is C(O)NR10b. (91) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and Y3 is C(O)NR10b. (92) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl or halogen.

(93) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁-C₄) alkyl. (94) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and each R₈ is independently halogen. (95) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁-C₄) alkyl or halogen. (96) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y3 is C(O)NR10b, and each R₈ is independently (C₁-C₄) alkyl. (97) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, Y3 is C(O)NR10b, and each R₈ is independently halogen. (98) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y3 is C(O)NR10b, and each R₈ is independently (C1- C₄) alkyl or halogen. (99) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently (C₁- C4) alkyl. (100) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, Y₃ is C(O)NR_10b, and each R₈ is independently halogen. (101) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C1- C₄) alkyl or halogen. (102) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁- C4) alkyl. (103) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (104) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen.

(105) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl. (106) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently halogen. (107) In one embodiment, B is pyridinyl, Y2 is NR10a, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (108) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (109) In one embodiment, B is pyridinyl, Y₂ is NR_10a, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (110) In one embodiment, B, Y₁, Y₂, Y₃, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (57)-(109), and R10a is H. (111) In one embodiment, B, Y₁, Y₂, Y₃, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (57)-(109), and R10b is H. (112) In one embodiment, B, Y₁, Y₂, Y₃, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (57)-(109), R10a is H, and R10b is H. (113) In one embodiment, B is pyridinyl and R₆ is methyl. (114) In one embodiment, B is phenyl and R6 is methyl. (115) In one embodiment, R6 is methyl and Y2 is NR10a. (116) In one embodiment, B is pyridinyl and Y₁ is absent. (117) In one embodiment, B is phenyl and Y1 is absent. (118) In one embodiment, B is pyridinyl and Y₁ is C(O). (119) In one embodiment, B is phenyl and Y1 is C(O). (120) In one embodiment, B is pyridinyl and Y₃ is C(O)NR_10b. (121) In one embodiment, B is phenyl and Y3 is C(O)NR10b. (122) In one embodiment, B, Y₁, Y₂, Y₃, R₆, R₇, R₈, R_10a, and R_10b are each as defined, where applicable, in any one of (1)-(121), o1 is 0. (123) In one embodiment, B, Y₁, Y₂, Y₃, R₆, R₇, R₈, R_10a, and R_10b are each as defined, where applicable, in any one of (1)-(121), o1 is 1. (124) In one embodiment, B, Y₁, Y₂, Y₃, R₆, R₇, R₈, R_10a, and R_10b are each as defined, where applicable, in any one of (1)-(121), o1 is 2.

(125) In one embodiment, B, Y1, Y2, Y3, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(121), o1 is 2, and R₅ is (C₁-C₄) alkyl or oxo. (126) In one embodiment, B, Y1, Y2, Y3, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(121), o2 is 1. (127) In one embodiment, B, Y1, Y2, Y3, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(121), o2 is 2. (128) In one embodiment, B, Y1, Y2, Y3, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(121), o1 is 0 and o2 is 1. (129) In one embodiment, B, Y1, Y2, Y3, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(121), o1 is1 and o2 is 1. (130) In one embodiment, B, Y1, Y2, Y3, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(121), o1 is 2 and o2 is 1. (131) In one embodiment, B, Y1, Y2, Y3, R5, R6, R₇, R₈, R10a, R10b, o1, and o2 are each as defined, where applicable, in any one of (1)-(130), and Y1 is bonded to Y4. [00272] In one embodiment, the compound of Formula TL-IV is of Formula TL-IVa:

wherein B, Y₁, Y₂, Y₄, R₅, R₆, R₇, R₈, R_10b, o1, o2, and o3 are each as defined above in Formula TL-VI. [00273] For a Targeting Ligand of Formula TL-IVa: (1) In one embodiment, B is phenyl. (2) In one embodiment, B is phenyl, and Y₁ is C(O). (3) In one embodiment, B is phenyl, Y1 is C(O), and R6 is (C₁-C₄) alkyl. (4) In one embodiment, B is phenyl, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl. (5) In one embodiment, B is phenyl, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl. (6) In one embodiment, B is phenyl, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) hydroxyalkyl.

(7) In one embodiment, B is phenyl, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (8) In one embodiment, B is phenyl, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (9) In one embodiment, B is phenyl, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (10) In one embodiment, B is phenyl, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (11) In one embodiment, B is phenyl, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl. (12) In one embodiment, B is phenyl, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently halogen. (13) In one embodiment, B is phenyl, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (14) In one embodiment, B is phenyl, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (15) In one embodiment, B is phenyl, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (16) In one embodiment, B is phenyl, and Y₁ is absent. (17) In one embodiment, B is phenyl, Y1 is absent, and R6 is (C₁-C₄) alkyl. (18) In one embodiment, B is phenyl, Y₁ is absent, R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl. (19) In one embodiment, B is phenyl, Y₁ is absent, R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl. (20) In one embodiment, B is phenyl, Y₁ is absent, R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) hydroxyalkyl. (21) In one embodiment, B is phenyl, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen.

(22) In one embodiment, B is phenyl, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (23) In one embodiment, B is phenyl, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (24) In one embodiment, B is phenyl, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (25) In one embodiment, B is phenyl, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl. (26) In one embodiment, B is phenyl, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently halogen. (27) In one embodiment, B is phenyl, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (28) In one embodiment, B is phenyl, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (29) In one embodiment, B is phenyl, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (30) In one embodiment, B, Y₁, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(29), and Y2 is NR10a. (31) In one embodiment, B, Y1, R6, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(29), and Y₂ is O. (32) In one embodiment, B, Y1, R6, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(29), and R_10a is H. (33) In one embodiment, B, Y1, R6, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(29), and R_10b is H. (34) In one embodiment, B, Y1, R6, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(29), and Y₂ is NR_10a and R_10a is H. (35) In one embodiment, B is pyridinyl. (36) In one embodiment, B is pyridinyl, and Y₁ is C(O). (37) In one embodiment, B is pyridinyl, Y1 is C(O), and R6 is (C₁-C₄) alkyl. (38) In one embodiment, B is pyridinyl, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl.

(39) In one embodiment, B is pyridinyl, Y1 is C(O), R6 is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl. (40) In one embodiment, B is pyridinyl, Y1 is C(O), R6 is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) hydroxyalkyl. (41) In one embodiment, B is pyridinyl, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (42) In one embodiment, B is pyridinyl, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (43) In one embodiment, B is pyridinyl, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (44) In one embodiment, B is pyridinyl, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (45) In one embodiment, B is pyridinyl, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl. (46) In one embodiment, B is pyridinyl, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently halogen. (47) In one embodiment, B is pyridinyl, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (48) In one embodiment, B is pyridinyl, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (49) In one embodiment, B is pyridinyl, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (50) In one embodiment, B is pyridinyl, and Y₁ is absent. (51) In one embodiment, B is pyridinyl, Y1 is absent, and R6 is (C₁-C₄) alkyl. (52) In one embodiment, B is pyridinyl, Y₁ is absent, R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl. (53) In one embodiment, B is pyridinyl, Y₁ is absent, R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) alkyl. (54) In one embodiment, B is pyridinyl, Y₁ is absent, R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁-C₄) hydroxyalkyl.

(55) In one embodiment, B is pyridinyl, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (56) In one embodiment, B is pyridinyl, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (57) In one embodiment, B is pyridinyl, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (58) In one embodiment, B is pyridinyl, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (59) In one embodiment, B is pyridinyl, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl. (60) In one embodiment, B is pyridinyl, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently halogen. (61) In one embodiment, B is pyridinyl, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (62) In one embodiment, B is pyridinyl, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (63) In one embodiment, B is pyridinyl, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (64) In one embodiment, B, Y₁, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (35)-(63), and Y2 is NR10a. (65) In one embodiment, B, Y₁, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (35)-(63), and Y2 is O. (66) In one embodiment, B, Y₁, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (35)-(63), and R10a is H. (67) In one embodiment, B, Y₁, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (35)-(63), and R10b is H. (68) In one embodiment, B, Y₁, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (35)-(63), and Y2 is NR10a and R10a is H. (69) In one embodiment, B is pyridinyl and R₆ is methyl. (70) In one embodiment, B is phenyl and R6 is methyl. (71) In one embodiment, R₆ is methyl and Y₁ is absent.

(72) In one embodiment, R6 is methyl and Y1 is C(O). (73) In one embodiment, R₆ is methyl and Y₂ is NR_10a. (74) In one embodiment, B, Y1, Y2, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(73), o1 is 0. (75) In one embodiment, B, Y1, Y2, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(73), o1 is 1. (76) In one embodiment, B, Y1, Y2, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(73), o1 is 2. (77) In one embodiment, B, Y1, Y2, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(73), o3 is 1. (78) In one embodiment, B, Y1, Y2, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(73), o3 is 1. (79) In one embodiment, B, Y1, Y2, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(73), o1 is 0 and o2 is 1. (80) In one embodiment, B, Y1, Y2, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(73), o2 is 1 and o3 is 1. (81) In one embodiment, B, Y1, Y2, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(73), o1 is 0, o2 is 1, and o3 is 1. (82) In one embodiment, B, Y1, Y2, R6, R₇, R₈, R10a,and R10b are each as defined, where applicable, in any one of (1)-(73), o1 is 2, and R5 is (C₁-C₄) alkyl or oxo. (83) In one embodiment, B, Y1, Y2, R5, R6, R₇, R₈, R10a, R10b, o1, and o2 are each as defined, where applicable, in any one of (1)-(82), and Y₁ is bonded to Y₄. [00274] B, Y1, Y2, R5, R6, R₇, R₈, R10a, R10b, o1, o2, and o3 can each be selected from any of the groups and combined as described above in Formula TL-IV or TL-IVa. [00275] In one embodiment, the targeting ligand of Formula TL-IV is of Formula TL-IVb or

wherein Y1, Y4, R5, R6, R₇, R₈, R10a, R10b, o1, o2, and o3 are each as defined above in Formula TL-IV. [00276] For a Targeting Ligand of Formula TL-IVb and TL-IVc: (1) In one embodiment, Y₁ is C(O). (2) In one embodiment, Y1 is C(O), and R6 is (C₁-C₄) alkyl. (3) In one embodiment, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁- C4) alkyl or (C₁-C₄) hydroxyalkyl. (4) In one embodiment, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁- C4) alkyl. (5) In one embodiment, Y1 is C(O), R6 is (C₁-C₄) alkyl, and each R₇ is independently (C1- C₄) hydroxyalkyl. (6) In one embodiment, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (7) In one embodiment, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (8) In one embodiment, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (9) In one embodiment, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (10) In one embodiment, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl. (11) In one embodiment, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently halogen. (12) In one embodiment, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (13) In one embodiment, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (14) In one embodiment, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen.

(15) In one embodiment, Y1 is absent. (16) In one embodiment, Y₁ is absent and R₆ is (C₁-C₄) alkyl. (17) In one embodiment, Y1 is absent, R6 is (C₁-C₄) alkyl, and each R₇ is independently (C1- C₄) alkyl or (C₁-C₄) hydroxyalkyl. (18) In one embodiment, Y1 is absent, R6 is (C₁-C₄) alkyl, and each R₇ is independently (C1- C₄) alkyl. (19) In one embodiment, Y1 is absent, R6 is (C₁-C₄) alkyl, and each R₇ is independently (C1- C₄) hydroxyalkyl. (20) In one embodiment, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (21) In one embodiment, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (22) In one embodiment, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (23) In one embodiment, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (24) In one embodiment, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl. (25) In one embodiment, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently halogen. (26) In one embodiment, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (27) In one embodiment, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (28) In one embodiment, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (29) In one embodiment, Y₁, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(28), and R10a is H. (30) In one embodiment, Y₁, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(28), and R10b is H. (31) In one embodiment, Y₁, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(28), and Y2 is NR10a and R10a is H. (32) In one embodiment, R₆ is methyl.

(33) In one embodiment, R6 is methyl and Y1 is absent. (34) In one embodiment, R₆ is methyl and Y₁ is C(O). (35) In one embodiment, Y1, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(34), o1 is 0. (36) In one embodiment, Y1, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(34), o1 is 1. (37) In one embodiment, Y1, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(34), o1 is 2. (38) In one embodiment, Y1, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(34), o3 is 1. (39) In one embodiment, Y1, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(34), o3 is 1. (40) In one embodiment, Y1, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(34), o1 is 0 and o2 is 1. (41) In one embodiment, Y1, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(34), o2 is 1 and o3 is 1. (42) In one embodiment, Y1, R6, R₇, R₈, R10a, and R10b are each as defined, where applicable, in any one of (1)-(34), o1 is 0, o2 is 1, and o3 is 1. (43) In one embodiment, Y1, R6, R₇, R₈, R10a,and R10b are each as defined, where applicable, in any one of (1)-(34), o1 is 2, and R5 is (C₁-C₄) alkyl or oxo. (44) In one embodiment, Y₁, R₅, R₆, R₇, R₈, R_10a, R_10b, o1, o2, and o3 are each as defined, where applicable, in any one of (1)-(43), and Y1 is bonded to Y4. [00277] Y₁, R₅, R₆, R₇, R₈, R_10a, R_10b, o1, o2, and o3 can each be selected from any of the groups and combined as described above in Formula TL-IV, TL-IVb, or TL-IVc. [00278] In one embodiment, the targeting ligand of Formula TL-IV is of Formula TL-IVd or TL-IVe:

wherein Y1, R5, R6, R₇, R₈, o1, and o3 are each as defined above in Formula TL-IV. [00279] For a Targeting Ligand of Formula TL-IVd and TL-IVe: (1) In one embodiment, Y1 is C(O). (2) In one embodiment, Y₁ is C(O), and R₆ is (C₁-C₄) alkyl. (3) In one embodiment, Y1 is C(O), R6 is (C₁-C₄) alkyl, and each R₇ is independently (C1- C₄) alkyl or (C₁-C₄) hydroxyalkyl. (4) In one embodiment, Y1 is C(O), R6 is (C₁-C₄) alkyl, and each R₇ is independently (C1- C₄) alkyl. (5) In one embodiment, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁- C4) hydroxyalkyl. (6) In one embodiment, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (7) In one embodiment, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (8) In one embodiment, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (9) In one embodiment, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (10) In one embodiment, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl. (11) In one embodiment, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently halogen. (12) In one embodiment, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (13) In one embodiment, Y₁ is C(O), R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (14) In one embodiment, Y1 is C(O), R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (15) In one embodiment, Y1 is absent.

(16) In one embodiment, Y1 is absent and R6 is (C₁-C₄) alkyl. (17) In one embodiment, Y₁ is absent, R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁- C4) alkyl or (C₁-C₄) hydroxyalkyl. (18) In one embodiment, Y₁ is absent, R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁- C4) alkyl. (19) In one embodiment, Y₁ is absent, R₆ is (C₁-C₄) alkyl, and each R₇ is independently (C₁- C4) hydroxyalkyl. (20) In one embodiment, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (21) In one embodiment, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (22) In one embodiment, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl or (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (23) In one embodiment, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (24) In one embodiment, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently (C₁-C₄) alkyl. (25) In one embodiment, Y₁ is absent, R₆ is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) alkyl, and each R₈ is independently halogen. (26) In one embodiment, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl or halogen. (27) In one embodiment, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently (C₁-C₄) alkyl. (28) In one embodiment, Y1 is absent, R6 is (C₁-C₄) alkyl, each R₇ is independently (C₁-C₄) hydroxyalkyl, and each R₈ is independently halogen. (29) In one embodiment, R6 is methyl. (30) In one embodiment, R₆ is methyl and Y₁ is absent. (31) In one embodiment, R6 is methyl and Y1 is C(O). (32) In one embodiment, Y₁, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(31), o1 is 0. (33) In one embodiment, Y₁, R₆, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(31), o1 is 1. (34) In one embodiment, Y1, R6, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(31), o3 is 1. (35) In one embodiment, Y1, R6, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(31), o3 is 1. (36) In one embodiment, Y1, R6, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(31), o1 is 0 and o3 is 1. (37) In one embodiment, Y1, R6, R₇, and R₈ are each as defined, where applicable, in any one of (1)-(31), o1 is 2, and R₅ is (C₁-C₄) alkyl or oxo. [00280] Y1, R5, R6, R₇, R₈, o1, and o3 can each be selected from any of the groups and combined as described above in Formula TL-IV, TL-IVd, or TL-IVe. [00281] In one embodiment, the BTK degraders are represented by Formula (XII): Ricrado, should this be XII? or a pharmaceutically acceptable salt or

stereoisomer thereof, wherein: each instance of R¹ is independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR^D1, -N(R^D1a)2, -SR^D1, -NO₂, or -SCN; R^D1 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; each occurrence of R^D1a is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; or optionally two instances of R^D1a are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; each instance of R² is independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR^D1, -N(R^D1a)₂, -SR^D1, -NO₂, or -SCN; each instance of R³ is independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR^D1, -N(R^D1a)₂, -SR^D1, -NO₂, or -SCN; each instance of R⁴ is independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR^D1, -N(R^D1a)₂, -SR^D1, -NO₂, or -SCN; each instance of R⁵ is independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR^D1, -N(R^D1a)₂, -SR^D1, -NO₂, or -SCN; L1 is a linker;

is a single bond or a double bond, as valency permits; W is =C(R^A)- or =N-; X is =C(R^A)- or =N-; Y is O, –N(R^Y)-, or S;

each instance of R^A is independently hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR^A1, -N(R^A1a)₂, or –SR^A1; R^A1 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; each occurrence of R^A1a is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; or optionally two instances of R^A1a are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; R^Y is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or a nitrogen protecting group; a is 0, 1, 2, 3, 4, or 5; b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; c is 0, 1, 2, 3, 4, 5, 6, 7, or 8; p is 0, 1, 2, or 3; w is 0, 1, 2, 3, or 4; x is 0, 1, or 2; y is 0, 1, 2, or 3; D, the degron, is an E3 ubiquitin ligase binding moiety; l^X indicates the point of attachment to the moiety of formula

l^Y indicates the point of attachment to L2

l^W indicates the point of attachment to Ring A; andl^Z indicates the point of attachment to the moiety of formula

. Degron [00282] The Degron serves to link a targeted protein, through a Linker and a Targeting Ligand, to a ubiquitin ligase for proteosomal degradation. In one embodiment, the Degron is capable of binding to a ubiquitin ligase, such as an E3 ubiquitin ligase. [00283] In one embodiment, the Degron is capable of binding to cereblon. [00284] In one embodiment, the Degron is of Formula D1:

wherein: Y is a bond, (CH₂)_1-6, (CH₂)_0-6-O, (CH₂)_0-6-C(O)NR₂₆, (CH₂)_0-6-NR₂₆C(O), (CH₂)_0-6-NH, or (CH₂)0-6-NR27; Z₃ is C(O) or C(R₂₈)₂;R₂₆ is H or C₁-C₆ alkyl; R27 is C₁-C₆ alkyl or C(O)-C₁-C₆ alkyl; each R₂₈ is independently H or C₁-C₃ alkyl; each R29 is independently C₁-C₃ alkyl; R₃₀ is H, deuterium, C₁-C₃ alkyl, F, or Cl; each R31 is independently halogen, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy; q is 0, 1, or 2; and v is 0, 1, 2, or 3. [00285] In one embodiment, Z₃ is C(O). [00286] In one embodiment, Z3 is C(O) or CH₂. [00287] In one embodiment, Z₃ is C(R₂₈)₂; and each R₂₈ is H. In one embodiment, Z₃ is C(R28)2; and one of R28 is H, and the other is C₁-C₃ alkyl selected from methyl, ethyl, and propyl. In one embodiment, Z₃ is C(R₂₈)₂; and each R₂₈ is independently selected from methyl, ethyl, and propyl. [00288] In one embodiment, Y is a bond. [00289] In one embodiment, Y is a bond, O, or NH.

[00290] In one embodiment, Y is (CH₂)1, (CH₂)2, (CH₂)3, (CH₂)4, (CH₂)5, or (CH₂)6. In one embodiment, Y is (CH₂)₁, (CH₂)₂, or (CH₂)₃. In one embodiment, Y is (CH₂)₁ or (CH₂)₂. [00291] In one embodiment, Y is O, CH₂-O, (CH₂)2-O, (CH₂)3-O, (CH₂)4-O, (CH₂)5-O, or (CH₂)₆-O. In one embodiment, Y is O, CH₂-O, (CH₂)₂-O, or (CH₂)₃-O. In one embodiment, Y is O or CH₂-O. In one embodiment, Y is O. [00292] In one embodiment, Y is C(O)NR₂₆, CH₂-C(O)NR₂₆, (CH₂)₂-C(O)NR₂₆, (CH₂)₃- C(O)NR26, (CH₂)4-C(O)NR26, (CH₂)5-C(O)NR26, or (CH₂)6-C(O)NR26. In one embodiment, Y is C(O)R₂₆, CH₂-C(O)NR₂₆, (CH₂)₂-C(O)NR₂₆, or (CH₂)₃-C(O)NR₂₆. In one embodiment, Y is C(O)NR26 or CH₂-C(O)NR26. In one embodiment, Y is C(O)NR26. [00293] In one embodiment, Y is NR₂₆C(O), CH₂-NR₂₆C(O), (CH₂)₂-NR₂₆C(O), (CH₂)₃- NR26C(O), (CH₂)4-NR26C(O), (CH₂)5-NR26C(O), or (CH₂)6-NR26C(O). In one embodiment, Y is NR₂₆C(O), CH₂-NR₂₆C(O), (CH₂)₂-NR₂₆C(O), or (CH₂)₃-NR₂₆C(O). In one embodiment, Y is NR26C(O) or CH₂-NR26C(O). In one embodiment, Y is NR26C(O). [00294] In one embodiment, R₂₆ is H. In one embodiment, R₂₆ is selected from methyl, ethyl, propyl, butyl, i-butyl, t-butyl, pentyl, i-pentyl, and hexyl. In one embodiment, R26 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl. [00295] In one embodiment, Y is NH, CH₂-NH, (CH₂)2-NH, (CH₂)3-NH, (CH₂)4-NH, (CH₂)₅-NH, or (CH₂)₆-NH. In one embodiment, Y is NH, CH₂-NH, (CH₂)₂-NH, or (CH₂)₃- NH. In one embodiment, Y is NH or CH₂-NH. In one embodiment, Y is NH. [00296] In one embodiment, Y is NR27, CH₂-NR27, (CH₂)2-NR27, (CH₂)3-NR27, (CH₂)4-NR27, (CH₂)₅-NR₂₇, or (CH₂)₆-NR₂₇. In one embodiment, Y is N R₂₇, CH₂-NR₂₇, (CH₂)₂-NR₂₇, or (CH₂)3-NR27. In one embodiment, Y is NR27 or CH₂-NR27. In one embodiment, Y is NR27. [00297] In one embodiment, R₂₇ is selected from methyl, ethyl, propyl, butyl, i-butyl, t-butyl, pentyl, i-pentyl, and hexyl. In one embodiment, R27 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl. [00298] In one embodiment, R27 is selected from C(O)-methyl, C(O)-ethyl, C(O)-propyl, C(O)-butyl, C(O)-i-butyl, C(O)-t-butyl, C(O)-pentyl, C(O)-i-pentyl, and C(O)-hexyl. In one embodiment, R27 is C(O)-C₁-C₃ alkyl selected from C(O)-methyl, C(O)-ethyl, and C(O)- propyl. [00299] In one embodiment, R28 is H. [00300] In one embodiment, R₂₈ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl. In one embodiment, R28 is methyl. [00301] In one embodiment, q is 0.

[00302] In one embodiment, q is 1. [00303] In one embodiment, q is 2. [00304] In one embodiment, each R29 is independently C₁-C₃ alkyl selected from methyl, ethyl, and propyl. [00305] In one embodiment, v is 0. [00306] In one embodiment, v is 1. [00307] In one embodiment, v is 2. [00308] In one embodiment, v is 3. [00309] In one embodiment, each R31 is independently selected from halogen (e.g., F, Cl, Br, and I), OH, C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, butyl, i-butyl, t-butyl, pentyl, i-pentyl, and hexyl), and C₁-C₆ alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, i-butoxy, t-butoxy, and pentoxy). In a further embodiment, each R₃₁ is independently selected from F, Cl, OH, methyl, ethyl, propyl, butyl, i-butyl, t-butyl, methoxy, and ethoxy. [00310] In one embodiment, R₃₀ is H, deuterium, or C₁-C₃ alkyl. In another embodiment, R30 is H or C₁-C₃ alkyl. In a further embodiment, R30 is in the (S) or (R) configuration. In a further embodiment, R₃₀ is in the (S) configuration. In one embodiment, the compound comprises a racemic mixture of (S)-R30 and (R)-R30. [00311] In one embodiment, R₃₀ is H. [00312] In one embodiment, R30 is deuterium. [00313] In one embodiment, R30 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl. In one embodiment, R₃₀ is methyl. [00314] In one embodiment, R30 is F or Cl. In a further embodiment, R30 is in the (S) or (R) configuration. In a further embodiment, R₃₀ is in the (R) configuration. In one embodiment, the compound comprises a racemic mixture of (S)-R30 and (R)-R30. In one embodiment, R30 is F. [00315] Any of the groups described herein for any of Y, Z3, R26, R27, R28, R29, R30, R31, q and v can be combined with any of the groups described herein for one or more of the remainder of Y, Z3, R26, R27, R28, R29, R30, R31, q and v, and may further be combined with any of the groups described herein for the Linker. [00316] For a Degron of Formula D1: (1) In one embodiment, Z₃ is C(O) and Y is a bond. (2) In one embodiment, Z3 is C(O) and Y is NH. (3) In one embodiment, Z₃ is C(O) and Y is (CH₂)_0-6-O. In a further embodiment, Y is O.

(4) In one embodiment, Z3 is C(O); Y is a bond; and q and v are each 0. (5) In one embodiment, Z₃ is C(O); Y is NH; and q and v are each 0. (6) In one embodiment, Z3 is C(O); Y is (CH₂)0-6-O; and q and v are each 0. In a further embodiment, Y is O. (7) In one embodiment, Z3 is C(O); Y is a bond; and R28 is H. (8) In one embodiment, Z₃ is C(O); Y is a bond; and R₂₈ is H. (9) In one embodiment, Z3 is C(O); Y is NH; and R28 is H. (10) In one embodiment, Z₃ is C(O); Y is NH; and R₃₀ is H. (11) In one embodiment, Z3 is C(O); Y is a bond; R28 is H; and R30 is H. (12) In one embodiment, Z₃ is C(O); Y is NH; R₂₈ is H; and R₃₀ is H. (13) In one embodiment, Z3 is C(O); Y is (CH₂)0-6-O; and R28 is H. In a further embodiment, Y is O. (14) In one embodiment, Z3 is C(O); Y is (CH₂)0-6-O; and R30 is H. In a further embodiment, Y is O. (15) In one embodiment, Z3 is C(O); Y is (CH₂)0-6-O; R28 is H; and R30 is H. In a further embodiment, Y is O. (16) In one embodiment, q and v are each 0; and Y, Z3, R28, R30, and R31 are each as defined in any of (1) – (3) and (7) – (15). (17) In one embodiment, Z3 is CH₂ and Y is a bond. (18) In one embodiment, Z3 is CH₂ and Y is NH. (19) In one embodiment, Z₃ is CH₂ and Y is (CH₂)_0-6-O. In a further embodiment, Y is O. (20) In one embodiment, Z3 is CH₂; Y is a bond; and q and v are each 0. (21) In one embodiment, Z₃ is CH₂; Y is NH; and q and v are each 0. (22) In one embodiment, Z3 is CH₂; Y is (CH₂)0-6-O; and q and v are each 0. In a further embodiment, Y is O. (23) In one embodiment, Z3 is CH₂; Y is a bond; and R28 is H. (24) In one embodiment, Z₃ is CH₂; Y is a bond; and R₃₀ is H. (25) In one embodiment, Z3 is CH₂; Y is NH; and R28 is H. (26) In one embodiment, Z₃ is CH₂; Y is NH; and R₃₀ is H. (27) In one embodiment, Z3 is CH₂; Y is a bond; R28 is H; and R30 is H. (28) In one embodiment, Z₃ is CH₂; Y is NH; R₂₈ is H; and R₃₀ is H. (29) In one embodiment, Z3 is CH₂; Y is (CH₂)0-6-O; and R28 is H. In a further embodiment, Y is O.

(30) In one embodiment, Z3 is CH₂; Y is (CH₂)0-6-O; and R30 is H. In a further embodiment, Y is O. (31) In one embodiment, Z3 is CH₂; Y is (CH₂)0-6-O; R28 is H; and R30 is H. In a further embodiment, Y is O. (32) In one embodiment, q and v are each 0; and Y, Z₃, R₂₈, R₃₀, and R₃₁ are each as defined in any of (17) – (19) and (23) – (31). [00317] In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g,

R31, q, and v are each as defined above in Formula D1, and can be selected from any moieties or combinations thereof described above.

[00318] In one embodiment, Y is a bond, O, or NH. In one embodiment, Y is a bond. In one embodiment, Y is O. In one embodiment, Y is NH. [00319] In one embodiment, the Degron binds VHL and is of Formula D2:

wherein: each R32 is independently C₁-C₃ alkyl; q' is 0, 1, 2, 3 or 4; and R33 is H or C₁-C₃ alkyl. [00320] In one embodiment, q' is 0. [00321] In one embodiment, q' is 1. [00322] In one embodiment, q' is 2. [00323] In one embodiment, q' is 3. [00324] In one embodiment, each R₃₂ is independently C₁-C₃ alkyl selected from methyl, ethyl, and propyl. [00325] In one embodiment, R33 is methyl, ethyl, or propyl. In one embodiment, R33 is methyl. [00326] In one embodiment, the Degron is of Formula D2a:

wherein: each R32 is independently C₁-C₃ alkyl; q' is 0, 1, 2, 3 or 4; and R33 is H or C₁-C₃ alkyl. [00327] In one embodiment, q' is 0. [00328] In one embodiment, q' is 1.

[00329] In one embodiment, q' is 2. [00330] In one embodiment, q' is 3. [00331] In one embodiment, each R32 is independently C₁-C₃ alkyl selected from methyl, ethyl, and propyl. [00332] In one embodiment, R33 is methyl, ethyl, or propyl. In one embodiment, R33 is methyl. [00333] In one embodiment, the Degron is of Formula D2b:

wherein: each R32 is independently C₁-C₃ alkyl; q' is 0, 1, 2, 3 or 4; and R33 is H or C₁-C₃ alkyl. [00334] In one embodiment, q' is 0. [00335] In one embodiment, q' is 1. [00336] In one embodiment, q' is 2. [00337] In one embodiment, q' is 3. [00338] In one embodiment, each R32 is independently C₁-C₃ alkyl selected from methyl, ethyl, and propyl. [00339] In one embodiment, R33 is methyl, ethyl, or propyl. In one embodiment, R33 is methyl. [00340] In one embodiment, the Degron is of Formula D2c:

[00341] In one embodiment, the Degron is of Formula D2d:

[00342] In certain embodiments, D is of formula D3:

wherein: R^3A is hydrogen or C₁-C₃ alkyl; each R³′ is independently C₁-C₃ alkyl; each R⁶′ is independently halogen, -OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy; n1 is 0, 1, 2, 3, 4, or 5; and m1 is 0, 1, 2, 3, 4, or 5. [00343] In certain embodiments, R^3A is hydrogen. In certain embodiments, R^3A is C₁-C₃ alkyl (e.g., methyl, ethyl, propyl). In certain embodiments, at least one instance of R^{3 ^} is C₁-C₃ alkyl (e.g., methyl, ethyl, propyl). In certain embodiments, at least one instance of R^{6 ^} is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R^{6 ^} is –OH. In certain embodiments, at least one instance of R^{6 ^} is C₁-C₆ alkyl (e.g., methyl, ethyl, propyl). In certain embodiments, at least one instance of R^{6 ^} is C₁-C₆ alkoxy (e.g., -O(methyl), -O(ethyl), - O(propyl)). [00344] In certain embodiments, there are zero instances of R^{3 ^} on the compound of formula: . In certain embodiments, there are one or more instances of R^{3 ^} on the

compound of formula:

In certain embodiments, there are zero instances of R^{6 ^} on the compound of formula:

In certain embodiments, there are one or more instances of R^{6 ^} on the compound of formula:

. In certain embodiments, n1 is 0. In certain embodiments, n1 is 1. In certain embodiments, n1 is 2. In certain embodiments, n1 is 3. In certain embodiments, n1 is 4. In certain embodiments, n1 is 5. In certain embodiments, m1 is 0. In certain embodiments, m1 is 1. In certain embodiments, m1 is 2. In certain embodiments, m1 is 3. In certain embodiments, m1 is 4. In certain embodiments, m1 is 5. In certain embodiments, m1 is 0 and n1 is 0. In certain embodiments, D is of formula:

. Linker [00345] The Linker is a bond, a carbon chain, carbocyclic ring, or heterocyclic ring that serves to link the Targeting Ligand with the Degron. In one embodiment, the carbon chain optionally comprises one, two, three, or more heteroatoms selected from N, O, and S. In one embodiment, the carbon chain comprises only saturated chain carbon atoms. In one embodiment, the carbon chain optionally comprises two or more unsaturated chain carbon atoms

In one embodiment, one or more chain carbon atoms in the carbon chain are optionally substituted with one or more substituents (e.g., oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₃ alkoxy, OH, halogen, NH₂, NH(C₁-C₃ alkyl), N(C₁-C₃ alkyl)2, CN, C3-C8 cycloalkyl, heterocyclyl, phenyl, and heteroaryl). [00346] In one embodiment, the Linker comprises at least 5 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises less than 25 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises less than 20 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises 5, 7, 9, 11, 13, 15, 17, or 19 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises 5, 7, 9, or 11 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises 11, 13, 15, 17, or 19 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises 11, 13, 15, 17, 19, 21, or 23 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises 6, 8, 10, 12, 14, 16, 18, or 20 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises 6, 8, 10, or 12 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises 12, 14, 16, 18, or 20 chain atoms (e.g., C, O, N, and S). [00347] In one embodiment, the Linker comprises from 11 to 19 chain atoms (e.g., C, O, N, and S). [00348] In one embodiment, the Linker is a carbon chain optionally substituted with non- bulky substituents (e.g., oxo, C₁-C₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C₁-C₃ alkoxy, OH, halogen, NH₂, NH(C₁-C₃ alkyl), N(C₁-C₃ alkyl)₂, and CN). In one embodiment, the non-bulky substitution is located on the chain carbon atom proximal to the Degron (i.e., the carbon atom is separated from the carbon atom to which the Degron is bonded by at least 3, 4, or 5 chain atoms in the Linker). In one embodiment, the non-bulky substitution is located on the chain carbon atom proximal to the Targeting Ligand (i.e., the carbon atom is separated from the carbon atom to which the Degron is bonded by at least 3, 4, or 5 chain atoms in the Linker). [00349] In one embodiment, the Linker is of Formula L1:

wherein: p1 is an integer selected from 0 to 12; p2 is an integer selected from 0 to 12; p3 is an integer selected from 1 to 6; each W is independently absent, CH₂, O, S, or NR24; Z1 is absent, C(O), CH₂, O, (CH₂)jNR24, O(CH₂)jC(O)NR24, C(O)NR24, (CH₂)jC(O)NR24, NR₂₄C(O), (CH₂)_jNR₂₄C(O), (CH₂)_kNR₂₄(CH₂)_jC(O)NR₂₄, or NR₂₄(CH₂)_jC(O)NR₂₄; each R24 is independently H or C₁-C₃ alkyl; j is 1, 2, or 3; k is 1, 2, or 3; and Q₁ is absent, C(O), NHC(O)CH₂, OCH₂C(O), or O(CH₂)_1-2; wherein the Linker is covalently bonded to a Degron via the

next to Q1, and covalently bonded to a Targeting Ligand via the

next to Z₁. [00350] In one embodiment, the total number of chain atoms in the Linker is less than 30. In a further embodiment, the total number of chain atoms in the Linker is less than 20. [00351] For a Linker of Formula L1: (1) In one embodiment, p1 is an integer selected from 0 to 10. (2) In one embodiment, p1 is an integer selected from 1 to 10. (3) In one embodiment, p1 is selected from 1, 2, 3, 4, 5, and 6. (4) In one embodiment, p1 is 0, 1, 3, or 5. (5) In one embodiment, p1 is 0, 1, 2, or 3. (6) In one embodiment, p1 is 0. (7) In one embodiment, p1 is 1. (8) In one embodiment, p1 is 2. (9) In one embodiment, p1 is 3. (10) In one embodiment, p1 is 4. (11) In one embodiment, p1 is 5. (12) In one embodiment, p2 is an integer selected from 0 to 10. (13) In one embodiment, p2 is selected from 0, 1, 2, 3, 4, 5, and 6.

(14) In one embodiment, p2 is 0, 1, 2, or 3. (15) In one embodiment, p2 is 0. (16) In one embodiment, p2 is 1. (17) In one embodiment, p2 is 2. (18) In one embodiment, p2 is 3. (19) In one embodiment, p3 is an integer selected from 1 to 5. (20) In one embodiment, p3 is 2, 3, 4, or 5. (21) In one embodiment, p3 is 0, 1, 2, or 3. (22) In one embodiment, p3 is 0. (23) In one embodiment, p3 is 1. (24) In one embodiment, p3 is 2. (25) In one embodiment, p3 is 3. (26) In one embodiment, p3 is 4. (27) In one embodiment, at least one W is CH₂. (28) In one embodiment, at least one W is O. (29) In one embodiment, at least one W is S. (30) In one embodiment, at least one W is NH. (31) In one embodiment, at least one W is NR₂₄; and each R₂₄ is independently C₁-C₃ alkyl selected from methyl, ethyl, and propyl. (32) In one embodiment, each W is O. (33) In one embodiment, each W is CH₂. (34) In one embodiment, j is 1, 2, or 3. (35) In one embodiment, j is 1. (36) In one embodiment, j is 2. (37) In one embodiment, j is 3. (38) In one embodiment, j is 2 or 3. (39) In one embodiment, j is 1 or 2. (40) In one embodiment, k is 1, 2, or 3. (41) In one embodiment, k is 1. (42) In one embodiment, k is 2. (43) In one embodiment, k is 3. (44) In one embodiment, k is 2 or 3. (45) In one embodiment, k is 1 or 2.

(46) In one embodiment, Q1 is absent. (47) In one embodiment, Q₁ is NHC(O)CH₂. (48) In one embodiment, Q1 is O(CH₂)1-2. (49) In one embodiment, Q₁ is OCH₂. (50) In one embodiment, Q1 is OCH₂CH₂. (51) In one embodiment, Q₁ is OCH₂C(O). (52) In one embodiment, Q1 is C(O). (53) In one embodiment, Z₁ is absent. (54) In one embodiment, Z1 is O(CH₂)jC(O)NR24; and R24 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl. (55) In one embodiment, Z1 is O(CH₂)jC(O)NR24; and R24 is H. (56) In one embodiment, Z₁ is O(CH₂)_jC(O)NR₂₄; R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is 1. (57) In one embodiment, Z₁ is O(CH₂)_jC(O)NR₂₄; R₂₄ is H; and j is 1. (58) In one embodiment, Z1 is O(CH₂)jC(O)NR24; R24 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is 2. (59) In one embodiment, Z1 is O(CH₂)jC(O)NR24; R24 is H; and j is 2. (60) In one embodiment, Z₁ is O(CH₂)_jC(O)NR₂₄; R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is 3. (61) In one embodiment, Z1 is O(CH₂)jC(O)NR24; and R24 is H; and j is 3. (62) In one embodiment, Z₁ is C(O)NR₂₄; and R₂₄ is H. (63) In one embodiment, Z1 is C(O)NR24; and R24 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl. (64) In one embodiment, Z1 is (CH₂)jC(O)NR24; and R24 is H. (65) In one embodiment, Z₁ is (CH₂)_jC(O)NR₂₄; and R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl. (66) In one embodiment, Z₁ is (CH₂)_jC(O)NR₂₄; R₂₄ is H; and j is 1. (67) In one embodiment, Z1 is (CH₂)jC(O)NR24; R24 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is 1 (68) In one embodiment, Z1 is (CH₂)jC(O)NR24; R24 is H; and j is 2. (69) In one embodiment, Z₁ is (CH₂)_jC(O)NR₂₄; R₂₄is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is 2. (70) In one embodiment, Z₁ is (CH₂)_jC(O)NR₂₄; R₂₄ is H; and j is 3.

(71) In one embodiment, Z1 is (CH₂)jC(O)NR24; R24 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is 3. (72) In one embodiment, Z1 is NR24C(O); and R24 is H. (73) In one embodiment, Z₁ is NR₂₄C(O); and R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl. (74) In one embodiment, Z₁ is (CH₂)_jNR₂₄C(O); and R₂₄ is H. (75) In one embodiment, Z1 is (CH₂)jNR24C(O); and R24 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl. (76) In one embodiment, Z1 is (CH₂)jNR24C(O); R24 is H; and j is 1. (77) In one embodiment, Z₁ is (CH₂)_jNR₂₄C(O); R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is 1 (78) In one embodiment, Z₁ is (CH₂)_jNR₂₄C(O); R₂₄ is H; and j is 2. (79) In one embodiment, Z1 is (CH₂)jNR24C(O); R24 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is 2. (80) In one embodiment, Z1 is (CH₂)jNR24C(O); R24 is H; and j is 3. (81) In one embodiment, Z₁ is (CH₂)_jNR₂₄C(O); R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is 3. (82) In one embodiment, Z₁ is (CH₂)_kNR₂₄(CH₂)_jC(O)NR₂₄; and each R₂₄ is independently H or C₁-C₃ alkyl selected from methyl, ethyl, and propyl. (83) In one embodiment, Z1 is (CH₂)kNR24(CH₂)jC(O)NR24; and one of R24 is H and one of R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl. In one embodiment, Z₁ is (CH₂)kNR24(CH₂)jC(O)NH. (84) In one embodiment, Z₁ is (CH₂)_kNR₂₄(CH₂)_jC(O)NR₂₄; each R₂₄ is independently H or C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is 1. (85) In one embodiment, Z₁ is (CH₂)_kNR₂₄(CH₂)_jC(O)NR₂₄; each R₂₄ is independently H or C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and k is 1. (86) In one embodiment, Z₁ is (CH₂)_kNR₂₄(CH₂)_jC(O)NR₂₄; each R₂₄ is independently H or C₁-C₃ alkyl selected from methyl, ethyl, and propyl; j is 1; and k is 1. (87) In one embodiment, Z₁ is (CH₂)_kNR₂₄(CH₂)_jC(O)NR₂₄; one of R₂₄ is H and one of R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is 1. In one embodiment, Z1 is (CH₂)_kNR₂₄(CH₂)C(O)NH.

(88) In one embodiment, Z1 is (CH₂)kNR24(CH₂)jC(O)NR24; one of R24 is H and one of R24 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and k is 1. In one embodiment, Z₁ is (CH₂)NR24(CH₂)jC(O)NH. (89) In one embodiment, Z₁ is (CH₂)_kNR₂₄(CH₂)_jC(O)NR₂₄; one of R₂₄ is H and one of R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; j is 1; and k is 1. In one embodiment, Z₁ is (CH₂)NR₂₄(CH₂)C(O)NH. In one embodiment, Z₁ is (CH₂)N(CH₃)(CH₂)C(O)NH. (90) In one embodiment, Z1 is (CH₂)kNR24(CH₂)jC(O)NR24; each R24 is independently H or C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is 2. (91) In one embodiment, Z1 is (CH₂)kNR24(CH₂)jC(O)NR24; each R24 is independently H or C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and k is 2. (92) In one embodiment, Z1 is (CH₂)kNR24(CH₂)jC(O)NR24; one of R24 is H and one of R24 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is 2. In one embodiment, Z₁ is (CH₂)kNR24(CH₂)2C(O)NH. (93) In one embodiment, Z₁ is (CH₂)_kNR₂₄(CH₂)_jC(O)NR₂₄; one of R₂₄ is H and one of R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and k is 2. In one embodiment, Z1 is (CH₂)₂NR₂₄(CH₂)_jC(O)NH. (94) In one embodiment, Z1 is (CH₂)kNR24(CH₂)jC(O)NR24; each R24 is independently H or C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is 3. (95) In one embodiment, Z1 is (CH₂)kNR24(CH₂)jC(O)NR24; each R24 is independently H or C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and k is 3. (96) In one embodiment, Z₁ is (CH₂)_kNR₂₄(CH₂)_jC(O)NR₂₄; one of R₂₄ is H and one of R₂₄ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j is 3. In one embodiment, Z1 is (CH₂)_kNR₂₄(CH₂)₃C(O)NH. (97) In one embodiment, Z1 is (CH₂)kNR24(CH₂)jC(O)NR24; one of R24 is H and one of R24 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and k is 3. In one embodiment, Z₁ is (CH₂)3NR24(CH₂)jC(O)NH. (98) In one embodiment, Z₁ is NR₂₄(CH₂)_jC(O)NR₂₄; and each R₂₄ is independently H or C₁-C₃ alkyl selected from methyl, ethyl, and propyl. (99) In one embodiment, Z₁ is NR₂₄(CH₂)_jC(O)NR₂₄; and each R₂₄ is H. (100) In one embodiment, Z1 is NR24(CH₂)jC(O)NR24; one of R24 is H and one of R24 is C1- C₃ alkyl selected from methyl, ethyl, and propyl; and j is 1. (101) In one embodiment, Z1 is NR24(CH₂)jC(O)NR24; R24 is H; and j is 1.

(102) In one embodiment, Z1 is NR24(CH₂)jC(O)NR24; one of R24 is H and one of R24 is C1- C₃ alkyl selected from methyl, ethyl, and propyl; and j is 2. (103) In one embodiment, Z1 is NR24(CH₂)jC(O)NR24; R24 is H; and j is 2. (104) In one embodiment, Z₁ is NR₂₄(CH₂)_jC(O)NR₂₄; one of R₂₄ is H and one of R₂₄ is C₁- C3 alkyl selected from methyl, ethyl, and propyl; and j is 3. (105) In one embodiment, Z₁ is absent and p3 is 1. (106) In one embodiment, Z1 is absent and p3 is 2. (107) In one embodiment, Z₁ is absent and p3 is 3. (108) In one embodiment, Z1 is absent, p3 is 1, and p1 is 1-8. (109) In one embodiment, Z₁ is absent, p3 is 1, and p1 is 1. (110) In one embodiment, Z1 is absent, p3 is 1, and p1 is 2. (111) In one embodiment, Z₁ is absent, p3 is 1, and p1 is 3. (112) In one embodiment, Z1 is absent, p3 is 1, and p1 is 4. (113) In one embodiment, Z₁ is absent, p3 is 1, and p1 is 5. (114) In one embodiment, Z1 is absent, p3 is 1, and p1 is 6. (115) In one embodiment, Z₁ is absent, p3 is 1, and p1 is 7. (116) In one embodiment, Z1 is absent, p3 is 1, and p1 is 8. (117) In one embodiment, Z₁ is absent, p3 is 1, and W is O. (118) In one embodiment, Z1 is absent, p3 is 1, p1 is 1, and W is O. (119) In one embodiment, Z1 is absent, p3 is 1, p1 is 2, and W is O. (120) In one embodiment, Z₁ is absent, p3 is 1, p1 is 3, and W is O. (121) In one embodiment, Z1 is absent, p3 is 1, p1 is 4, and W is O. (122) In one embodiment, Z₁ is absent, p3 is 1, p1 is 5, and W is O. (123) In one embodiment, Z1 is absent, p3 is 1, p1 is 6, and W is O. (124) In one embodiment, Z₁ is absent, p3 is 1, p1 is 7, and W is O. (125) In one embodiment, Z1 is absent, p3 is 1, p1 is 8, and W is O. (126) In one embodiment, Z₁ is absent, p3 is 1, p1 is 1, and W is CH₂. (127) In one embodiment, Z1 is absent, p3 is 1, p1 is 2, and W is CH₂. (128) In one embodiment, Z₁ is absent, p3 is 1, p1 is 3, and W is CH₂. (129) In one embodiment, Z1 is absent, p3 is 1, p1 is 4, and W is CH₂. (130) In one embodiment, Z₁ is absent, p3 is 1, p1 is 5, and W is CH₂. (131) In one embodiment, Z1 is absent, p3 is 1, p1 is 6, and W is CH₂. (132) In one embodiment, Z₁ is absent, p3 is 1, p1 is 7, and W is CH₂.

(133) In one embodiment, Z1 is absent, p3 is 1, p1 is 8, and W is CH₂. (134) In one embodiment, Z₁ is absent, p3 is 2, p1 is 1, and W is O. (135) In one embodiment, Z1 is absent, p3 is 2, p1 is 2, and W is O. (136) In one embodiment, Z₁ is absent, p3 is 2, p1 is 3, and W is O. (137) In one embodiment, Z1 is absent, p3 is 2, p1 is 4, and W is O. (138) In one embodiment, Z₁ is absent, p3 is 2, p1 is 5, and W is O. (139) In one embodiment, Z1 is absent, p3 is 2, p1 is 6, and W is O. (140) In one embodiment, Z₁ is absent, p3 is 2, p1 is 7, and W is O. (141) In one embodiment, Z1 is absent, p3 is 2, p1 is 8, and W is O. (142) In one embodiment, Z₁ is absent, p3 is 2, p1 is 1, and W is CH₂. (143) In one embodiment, Z1 is absent, p3 is 2, p1 is 2, and W is CH₂. (144) In one embodiment, Z₁ is absent, p3 is 2, p1 is 3, and W is CH₂. (145) In one embodiment, Z1 is absent, p3 is 2, p1 is 4, and W is CH₂. (146) In one embodiment, Z₁ is absent, p3 is 2, p1 is 5, and W is CH₂. (147) In one embodiment, Z1 is absent, p3 is 2, p1 is 6, and W is CH₂. (148) In one embodiment, Z₁ is absent, p3 is 2, p1 is 7, and W is CH₂. (149) In one embodiment, Z1 is absent, p3 is 2, p1 is 8, and W is CH₂. (150) In one embodiment, Z₁ is absent, p3 is 3, p1 is 1, and W is O. (151) In one embodiment, Z1 is absent, p3 is 3, p1 is 2, and W is O. (152) In one embodiment, Z1 is absent, p3 is 3, p1 is 3, and W is O. (153) In one embodiment, Z₁ is absent, p3 is 3, p1 is 4, and W is O. (154) In one embodiment, Z1 is absent, p3 is 3, p1 is 5, and W is O. (155) In one embodiment, Z₁ is absent, p3 is 3, p1 is 6, and W is O. (156) In one embodiment, Z1 is absent, p3 is 3, p1 is 7, and W is O. (157) In one embodiment, Z₁ is absent, p3 is 3, p1 is 8, and W is O. (158) In one embodiment, Z1 is absent, p3 is 3, p1 is 1, and W is CH₂. (159) In one embodiment, Z₁ is absent, p3 is 3, p1 is 2, and W is CH₂. (160) In one embodiment, Z1 is absent, p3 is 3, p1 is 3, and W is CH₂. (161) In one embodiment, Z₁ is absent, p3 is 3, p1 is 4, and W is CH₂. (162) In one embodiment, Z1 is absent, p3 is 3, p1 is 5, and W is CH₂. (163) In one embodiment, Z₁ is absent, p3 is 3, p1 is 6, and W is CH₂. (164) In one embodiment, Z1 is absent, p3 is 3, p1 is 7, and W is CH₂. (165) In one embodiment, Z₁ is absent, p3 is 3, p1 is 8, and W is CH₂.

(166) In one embodiment, p1, Z1, p3, and W are each as defined, where applicable, in any one of (1)-(165), and p2 is 0. (167) In one embodiment, p1, Z1, p3, and W are each as defined, where applicable, in any one of (1)-(165), and p2 is 1. (168) In one embodiment, p1, Z1, p3, and W are each as defined, where applicable, in any one of (1)-(165), and p2 is 2. (169) In one embodiment, p1, Z1, p3, p2, and W are each as defined, where applicable, in any one of (1)-(168), and Q₁ is absent. (170) In one embodiment, p1, Z1, p3, p2, and W are each as defined, where applicable, in any one of (1)-(168), and Q₁ is NHC(O)CH₂. (171) In one embodiment, p1, Z1, p3, p2, and W are each as defined, where applicable, in any one of (1)-(168), and Q₁ is O(CH₂)_1-2. (172) In one embodiment, p1, Z1, p3, p2, and W are each as defined, where applicable, in any one of (1)-(168), and Q₁ is O(CH₂). (173) In one embodiment, p1, Z1, p3, p2, and W are each as defined, where applicable, in any one of (1)-(168), and Q₁ is O(CH₂CH₂). (174) In one embodiment, p1, Z1, p3, p2, and W are each as defined, where applicable, in any one of (1)-(168), and Q₁ is C(O). (175) In one embodiment, p1, Z1, p3, p2, and W are each as defined, where applicable, in any one of (1)-(168), and Q₁ is OCH₂C(O). [00352] In one embodiment, the Linker–Targeting Ligand (TL) has the structure selected from Table L: Table L: Linker Formulas

wherein Z1, W, Q1, TL, p1, and p3 are each as described

above. [00353] In one embodiment, the Degron is of Formula D1, and the Linker is selected from L1a – L1o. In one embodiment, Degron is of Formula D1, and the Linker is selected from L1a. In one embodiment, the Degron is of Formula D1, and the Linker is selected from L1b – L1d. In one embodiment, the Degron is of Formula D1, and the Linker is selected from L1e-L1g. In one embodiment, the Degron is of Formula D1, and the Linker is L1h-L1j. In one embodiment, the Degron is of Formula D1, and the Linker is L1p or L1q. In one embodiment, the Degron is of Formula D1, and the Linker is L1a, L1b, L1e, L1h, L1k, L1l or L1o. In one embodiment, the Degron is of Formula D1, and the Linker is L1c, L1d, L1f, L1g, L1i, L1j, L1m, or L1n. In one embodiment, the Degron is of Formula D1, and the Linker is L1k. In one embodiment, the Degron is of Formula D1, and the Linker is L11 or L1o. In one embodiment, the Degron is of Formula D1, and the Linker is L1c or L1d. In one embodiment, the Degron is of Formula D1, and the Linker is L1f or L1g. In one embodiment, the Degron is of Formula D1, and the Linker is L1i or L1j. In one embodiment, the Degron is of Formula D1, and the Linker is L1m or L1n. [00354] In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L1a – L1o. In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L1a. In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L1b – L1d. In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L1e-L1g. In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1h-L1j. In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1p or L1q. In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1a, L1b, L1e, L1h, L1k, L1l or L1o. In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1c, L1d, L1f, L1g, L1i, L1j, L1m, or L1n. In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1k. In

one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L11 or L1o. In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1c or L1d. In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1f or L1g. In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1i or L1j. In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1m or L1n. [00355] In one embodiment, the Degron is of Formula D2, and the Linker is selected from L1a – L1o. In one embodiment, the Degron is of Formula D2, and the Linker is selected from L1a. In one embodiment, the Degron is of Formula D2, and the Linker is selected from L1b – L1d. In one embodiment, the Degron is of Formula D2, and the Linker is selected from L1e- L1g. In one embodiment, the Degron is of Formula D2, and the Linker is L1h-L1j. In one embodiment, the Degron is of Formula D2, and the Linker is L1p or L1q. In one embodiment, the Degron is of Formula D2, and the Linker is L1a, L1b, L1e, L1h, L1k, L1l or L1o. In one embodiment, the Degron is of Formula D2, and the Linker is L1c, L1d, L1f, L1g, L1i, L1j, L1m, or L1n. In one embodiment, the Degron is of Formula D2, and the Linker is L1k. In one embodiment, the Degron is of Formula D2, and the Linker is L11 or L1o. In one embodiment, the Degron is of Formula D2, and the Linker is L1c or L1d. In one embodiment, the Degron is of Formula D2, and the Linker is L1f or L1g. In one embodiment, the Degron is of Formula D2, and the Linker is L1i or L1j. In one embodiment, the Degron is of Formula D2, and the Linker is L1m or L1n. [00356] In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is selected from L1a – L1o. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is selected from L1a. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is selected from L1b – L1d. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is selected from L1e-L1g. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is L1h-L1j. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is L1p or L1q. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is L1a, L1b, L1e, L1h, L1k, L1l or L1o. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is L1c, L1d, L1f, L1g, L1i, L1j, L1m, or L1n. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is L1k. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is L11 or L1o. In one embodiment, the

Degron is of Formula D2a or D2b, and the Linker is L1c or L1d. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is L1f or L1g. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is L1i or L1j. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is L1m or L1n. [00357] In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is selected from L1a – L1o. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is selected from L1a. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is selected from L1b – L1d. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is selected from L1e-L1g. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is L1h-L1j. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is L1p or L1q. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is L1a, L1b, L1e, L1h, L1k, L1l or L1o. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is L1c, L1d, L1f, L1g, L1i, L1j, L1m, or L1n. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is L1k. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is L11 or L1o. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is L1c or L1d. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is L1f or L1g. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is L1i or L1j. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is L1m or L1n. [00358] In one embodiment, the Linker is of Formula L2:

wherein p4 and p4' are each independently an integer selected from 0 to 12; p5 is an integer selected from 0 to 12; p6 is an integer selected from 1 to 6; each W1 is independently absent, CH₂, O, S, or NR25;

each W3 is independently absent, CH₂, O, S, or NR25; Z2 is absent, C(O), CH₂, O, (CH₂)j1NR25, O(CH₂)j1C(O)NR25, C(O)NR25, (CH₂)_j1C(O)NR₂₅, NR₂₅C(O), (CH₂)_j1NR₂₅C(O), (CH₂)_k1NR₂₅(CH₂)_j1C(O)NR₂₅,or NR25(CH₂)j1C(O)NR25; each R₂₅ is independently H or C₁-C₃ alkyl; j1 is 1, 2, or 3; k1 is 1, 2, or 3; and Q2 is absent, C(O), NHC(O)CH₂, or O(CH₂)1-2; wherein the Linker is covalently bonded to a Degron via the

next to Q₂, and covalently bonded to a Targeting Ligand via the

next to Z2. [00359] For a Linker of Formula L2: (1) In one embodiment, p4 is an integer selected from 0 to 10 (2) In one embodiment, p4 is an integer selected from 1 to 10. (3) In one embodiment, p4 is selected from 1, 2, 3, 4, 5, and 6. (4) In one embodiment, p4 is 0, 1, 3, or 5. (5) In one embodiment, p4 is 0, 1, 2, or 3. (6) In one embodiment, p4 is 0. (7) In one embodiment, p4 is 1. (8) In one embodiment, p4 is 2. (9) In one embodiment, p4 is 3. (10) In one embodiment, p4 is 4. (11) In one embodiment, p4 is 5. (12) In one embodiment, p4' is an integer selected from 0 to 10. (13) In one embodiment, p4' is an integer selected from 1 to 10. (14) In one embodiment, p4' is selected from 1, 2, 3, 4, 5, and 6. (15) In one embodiment, p4' is 0, 1, 3, or 5. (16) In one embodiment, p4' is 0, 1, 2, or 3. (17) In one embodiment, p4' is 0. (18) In one embodiment, p4' is 1. (19) In one embodiment, p4' is 2. (20) In one embodiment, p4' is 3. (21) In one embodiment, p4' is 4. (22) In one embodiment, p4' is 5. (23) In one embodiment, p5 is an integer selected from 0 to 10. (24) In one embodiment, p5 is selected from 0, 1, 2, 3, 4, 5, and 6. (25) In one embodiment, p5 is 0, 1, 2, or 3. (26) In one embodiment, p5 is 0. (27) In one embodiment, p5 is 1. (28) In one embodiment, p5 is 2. (29) In one embodiment, p5 is 3. (30) In one embodiment, p6 is an integer selected from 1 to 5. (31) In one embodiment, p6 is 2, 3, 4, or 5. (32) In one embodiment, p6 is 0, 1, 2, or 3. (33) In one embodiment, p6 is 0. (34) In one embodiment, p6 is 1. (35) In one embodiment, p6 is 2. (36) In one embodiment, p6 is 3. (37) In one embodiment, p6 is 4. (38) In one embodiment, at least one W1 is CH₂. (39) In one embodiment, at least one W₁ is O. (40) In one embodiment, at least one W1 is S. (41) In one embodiment, at least one W1 is NH. (42) In one embodiment, at least one W₁ is NR₂₅; and each R₂₅ is independently C₁-C₃ alkyl selected from methyl, ethyl, and propyl. (43) In one embodiment, each W₁ is O. (44) In one embodiment, each W1 is CH₂. (45) In one embodiment, W₂ is NR₂₅C(O)CH_2.; and R₂₅ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl. (46) In one embodiment, W₂ is NR₂₅C(O)CH_2.; and R₂₅ is H. (47) In one embodiment, W₂ is

(48) In one embodiment, W₂ is

(49) In one embodiment, W2 is

(50) In one embodiment, at least one W₃ is CH₂. (51) In one embodiment, at least one W3 is O. (52) In one embodiment, at least one W3 is S. (53) In one embodiment, at least one W₃ is NH. (54) In one embodiment, at least one W3 is NR25; and each R25 is independently C₁-C₃ alkyl selected from methyl, ethyl, and propyl. (55) In one embodiment, each W3 is O. (56) In one embodiment, each W₃ is CH₂. (57) In one embodiment, j1 is 1, 2, or 3. (58) In one embodiment, j1 is 1. (59) In one embodiment, j1 is 2. (60) In one embodiment, j1 is 3. (61) In one embodiment, j1 is 2 or 3. (62) In one embodiment, j1 is 1 or 2. (63) In one embodiment, k1 is 1, 2, or 3. (64) In one embodiment, k1 is 1. (65) In one embodiment, k1 is 2. (66) In one embodiment, k1 is 3. (67) In one embodiment, k1 is 2 or 3. (68) In one embodiment, k1 is 1 or 2. (69) In one embodiment, Q2 is absent. (70) In one embodiment, Q2 is NHC(O)CH₂. (71) In one embodiment, Q2 is O(CH₂)1-2. (72) In one embodiment, Q2 is OCH₂. (73) In one embodiment, Q₂ is OCH₂CH₂. (74) In one embodiment, Q2 is OCH₂C(O). (75) In one embodiment, Q₂ is C(O). (76) In one embodiment, Z2 is absent. (77) In one embodiment, Z₂ is O(CH₂)_j1C(O)NR₂₅; and R₂₅ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl. (78) In one embodiment, Z₂ is O(CH₂)_j1C(O)NR₂₅; and R₂₅ is H.

(79) In one embodiment, Z2 is O(CH₂)j1C(O)NR25; R25 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j1 is 1. (80) In one embodiment, Z2 is O(CH₂)j1C(O)NR25; R25 is H; and j1 is 1. (81) In one embodiment, Z₂ is O(CH₂)_j1C(O)NR₂₅; R₂₅ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j1 is 2. (82) In one embodiment, Z₂ is O(CH₂)_j1C(O)NR₂₅; R₂₅ is H; and j1 is 2. (83) In one embodiment, Z2 is O(CH₂)j1C(O)NR25; R25 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j1 is 3. (84) In one embodiment, Z2 is O(CH₂)j1C(O)NR25; and R25 is H; and j1 is 3. (85) In one embodiment, Z₂ is C(O)NR₂₅; and R₂₅ is H. (86) In one embodiment, Z2 is C(O)NR25; and R25 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl. (87) In one embodiment, Z2 is (CH₂)j1C(O)NR25; and R25 is H. (88) In one embodiment, Z₂ is (CH₂)_j1C(O)NR₂₅; and R₂₅ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl. (89) In one embodiment, Z₂ is (CH₂)_j1C(O)NR₂₅; R₂₅ is H; and j1 is 1. (90) In one embodiment, Z2 is (CH₂)j1C(O)NR25; R25 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j1 is 1 (91) In one embodiment, Z2 is (CH₂)j1C(O)NR25; R25 is H; and j1 is 2. (92) In one embodiment, Z2 is (CH₂)j1C(O)NR25; R25 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j1 is 2. (93) In one embodiment, Z2 is (CH₂)j1C(O)NR25; R25 is H; and j1 is 3. (94) In one embodiment, Z₂ is (CH₂)_j1C(O)NR₂₅; R₂₅ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j1 is 3. (95) In one embodiment, Z₂ is NR₂₅C(O); and R₂₅ is H. (96) In one embodiment, Z2 is NR25C(O); and R25 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl. (97) In one embodiment, Z2 is (CH₂)j1NR25C(O); and R25 is H. (98) In one embodiment, Z₂ is (CH₂)_j1NR₂₅C(O); and R₂₅ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl. (99) In one embodiment, Z₂ is (CH₂)_j1NR₂₅C(O); R₂₅ is H; and j1 is 1. (100) In one embodiment, Z2 is (CH₂)j1NR25C(O); R25 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j1 is 1

(101) In one embodiment, Z2 is (CH₂)j1NR25C(O); R25 is H; and j1 is 2. (102) In one embodiment, Z₂ is (CH₂)_j1NR₂₅C(O); R₂₅ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j1 is 2. (103) In one embodiment, Z₂ is (CH₂)_j1NR₂₅C(O); R₂₅ is H; and j1 is 3. (104) In one embodiment, Z2 is (CH₂)j1NR25C(O); R25 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j1 is 3. (105) In one embodiment, Z2 is (CH₂)k1NR25(CH₂)j1C(O)NR25; and each R25 is independently H or C₁-C₃ alkyl selected from methyl, ethyl, and propyl. (106) In one embodiment, Z2 is (CH₂)k1NR25(CH₂)j1C(O)NR25; and one of R25 is H and one of R₂₅ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl. In one embodiment, Z₂ is (CH₂)k1NR25(CH₂)j1C(O)NH. (107) In one embodiment, Z₂ is (CH₂)_k1NR₂₅(CH₂)_j1C(O)NR₂₅; each R₂₅ is independently H or C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j1 is 1. (108) In one embodiment, Z₂ is (CH₂)_k1NR₂₅(CH₂)_j1C(O)NR₂₅; each R₂₅ is independently H or C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and k1 is 1. (109) In one embodiment, Z₂ is (CH₂)_k1NR₂₅(CH₂)_j1C(O)NR₂₅; each R₂₅ is independently H or C₁-C₃ alkyl selected from methyl, ethyl, and propyl; j1 is 1; and k1 is 1. (110) In one embodiment, Z₂ is (CH₂)_k1NR₂₅(CH₂)_j1C(O)NR₂₅; one of R₂₅ is H and one of R₂₅ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j1 is 1. In one embodiment, Z2 is (CH₂)k1NR25(CH₂)C(O)NH. (111) In one embodiment, Z₂ is (CH₂)_k1NR₂₅(CH₂)_j1C(O)NR₂₅; one of R₂₅ is H and one of R₂₅ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and k1 is 1. In one embodiment, Z2 is (CH₂)NR₂₅(CH₂)_j1C(O)NH. (112) In one embodiment, Z2 is (CH₂)k1NR25(CH₂)j1C(O)NR25; one of R25 is H and one of R25 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; j1 is 1; and k1 is 1. In one embodiment, Z2 is (CH₂)NR25(CH₂)C(O)NH. In one embodiment, Z2 is (CH₂)N(CH3)(CH₂)C(O)NH. (113) In one embodiment, Z₂ is (CH₂)_k1NR₂₅(CH₂)_j1C(O)NR₂₅; each R₂₅ is independently H or C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j1 is 2. (114) In one embodiment, Z₂ is (CH₂)_k1NR₂₅(CH₂)_j1C(O)NR₂₅; each R₂₅ is independently H or C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and k1 is 2. (115) In one embodiment, Z₂ is (CH₂)_k1NR₂₅(CH₂)_j1C(O)NR₂₅; one of R₂₅ is H and one of R₂₅ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j1 is 2. In one embodiment, Z2 is (CH₂)_k1NR₂₅(CH₂)₂C(O)NH.

(116) In one embodiment, Z2 is (CH₂)k1NR25(CH₂)j1C(O)NR25; one of R25 is H and one of R25 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and k1 is 2. In one embodiment, Z₂ is (CH₂)2NR25(CH₂)j1C(O)NH. (117) In one embodiment, Z₂ is (CH₂)_k1NR₂₅(CH₂)_j1C(O)NR₂₅; each R₂₅ is independently H or C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j1 is 3. (118) In one embodiment, Z₂ is (CH₂)_k1NR₂₅(CH₂)_j1C(O)NR₂₅; each R₂₅ is independently H or C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and k1 is 3. (119) In one embodiment, Z₂ is (CH₂)_k1NR₂₅(CH₂)_j1C(O)NR₂₅; one of R₂₅ is H and one of R₂₅ is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and j1 is 3. In one embodiment, Z2 is (CH₂)_k1NR₂₅(CH₂)₃C(O)NH. (120) In one embodiment, Z2 is (CH₂)k1NR25(CH₂)j1C(O)NR25; one of R25 is H and one of R25 is C₁-C₃ alkyl selected from methyl, ethyl, and propyl; and k1 is 3. In one embodiment, Z₂ is (CH₂)3NR25(CH₂)j1C(O)NH. (121) In one embodiment, Z₂ is NR₂₅(CH₂)_j1C(O)NR₂₅; and each R₂₅ is independently H or C₁-C₃ alkyl selected from methyl, ethyl, and propyl. (122) In one embodiment, Z₂ is NR₂₅(CH₂)_j1C(O)NR₂₅; and each R₂₅ is H. (123) In one embodiment, Z2 is NR25(CH₂)j1C(O)NR25; one of R25 is H and one of R25 is C1- C₃ alkyl selected from methyl, ethyl, and propyl; and j1 is 1. (124) In one embodiment, Z2 is NR25(CH₂)j1C(O)NR25; R25 is H; and j1 is 1. (125) In one embodiment, Z2 is NR25(CH₂)j1C(O)NR25; one of R25 is H and one of R25 is C1- C₃ alkyl selected from methyl, ethyl, and propyl; and j1 is 2. (126) In one embodiment, Z2 is NR25(CH₂)j1C(O)NR25; R25 is H; and j1 is 2. (127) In one embodiment, Z₂ is NR₂₅(CH₂)_j1C(O)NR₂₅; one of R₂₅ is H and one of R₂₅ is C₁- C3 alkyl selected from methyl, ethyl, and propyl; and j1 is 3. (128) In one embodiment, Z₂ is absent and p6 is 1. (129) In one embodiment, Z2 is absent and p6 is 2. (130) In one embodiment, Z₂ is absent and p6 is 3. (131) In one embodiment, Z2 is absent, p6 is 1, and p4 is 1-5. (132) In one embodiment, Z₂ is absent, p6 is 1, and p4 is 1. (133) In one embodiment, Z2 is absent, p6 is 1, and p4 is 2. (134) In one embodiment, Z₂ is absent, p6 is 1, and p4 is 3. (135) In one embodiment, Z2 is absent, p6 is 1, and p4 is 4. (136) In one embodiment, Z₂ is absent, p6 is 1, and p4 is 5.

(137) In one embodiment, Z2 is absent, p6 is 2, and p4 is 1-5. (138) In one embodiment, Z₂ is absent, p6 is 2, and p4 is 1. (139) In one embodiment, Z2 is absent, p6 is 2, and p4 is 2. (140) In one embodiment, Z₂ is absent, p6 is 2, and p4 is 3. (141) In one embodiment, Z2 is absent, p6 is 2, and p4 is 4. (142) In one embodiment, Z₂ is absent, p6 is 2, and p4 is 5. (143) In one embodiment, Z2 is absent, p6 is 2, and p4 is 1-5. (144) In one embodiment, Z₂ is absent, p6 is 2, and p4 is 1. (145) In one embodiment, Z2 is absent, p6 is 2, and p4 is 2. (146) In one embodiment, Z₂ is absent, p6 is 2, and p4 is 3. (147) In one embodiment, Z2 is absent, p6 is 2, and p4 is 4. (148) In one embodiment, Z₂ is absent, p6 is 2, and p4 is 5. (149) In one embodiment, Z2 is absent, p6 is 1, p4 is 1, and p4' is 1. (150) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, and p4' is 2. (151) In one embodiment, Z2 is absent, p6 is 1, p4 is 1, and p4' is 3. (152) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, and p4' is 4. (153) In one embodiment, Z2 is absent, p6 is 1, p4 is 1, and p4' is 5. (154) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, and p4' is 1. (155) In one embodiment, Z2 is absent, p6 is 1, p4 is 2, and p4' is 2. (156) In one embodiment, Z2 is absent, p6 is 1, p4 is 2, and p4' is 3. (157) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, and p4' is 4. (158) In one embodiment, Z2 is absent, p6 is 1, p4 is 2, and p4' is 5. (159) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, and p4' is 1. (160) In one embodiment, Z2 is absent, p6 is 1, p4 is 3, and p4' is 2. (161) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, and p4' is 3. (162) In one embodiment, Z2 is absent, p6 is 1, p4 is 3, and p4' is 4. (163) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, and p4' is 5. (164) In one embodiment, Z2 is absent, p6 is 1, p4 is 4, and p4' is 1. (165) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, and p4' is 2. (166) In one embodiment, Z2 is absent, p6 is 1, p4 is 4, and p4' is 3. (167) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, and p4' is 4. (168) In one embodiment, Z2 is absent, p6 is 1, p4 is 4, and p4' is 5. (169) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, and p4' is 1.

(170) In one embodiment, Z2 is absent, p6 is 1, p4 is 5, and p4' is 2. (171) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, and p4' is 3. (172) In one embodiment, Z2 is absent, p6 is 1, p4 is 5, and p4' is 4. (173) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, and p4' is 5. (174) In one embodiment, Z2 is absent, p6 is 2, p4 is 1, and p4' is 1. (175) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, and p4' is 2. (176) In one embodiment, Z2 is absent, p6 is 2, p4 is 1, and p4' is 3. (177) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, and p4' is 4. (178) In one embodiment, Z2 is absent, p6 is 2, p4 is 1, and p4' is 5. (179) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, and p4' is 1. (180) In one embodiment, Z2 is absent, p6 is 2, p4 is 2, and p4' is 2. (181) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, and p4' is 3. (182) In one embodiment, Z2 is absent, p6 is 2, p4 is 2, and p4' is 4. (183) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, and p4' is 5. (184) In one embodiment, Z2 is absent, p6 is 2, p4 is 3, and p4' is 1. (185) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, and p4' is 2. (186) In one embodiment, Z2 is absent, p6 is 2, p4 is 3, and p4' is 3. (187) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, and p4' is 4. (188) In one embodiment, Z2 is absent, p6 is 2, p4 is 3, and p4' is 5. (189) In one embodiment, Z2 is absent, p6 is 2, p4 is 4, and p4' is 1. (190) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, and p4' is 2. (191) In one embodiment, Z2 is absent, p6 is 2, p4 is 4, and p4' is 3. (192) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, and p4' is 4. (193) In one embodiment, Z2 is absent, p6 is 2, p4 is 4, and p4' is 5. (194) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, and p4' is 1. (195) In one embodiment, Z2 is absent, p6 is 2, p4 is 5, and p4' is 2. (196) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, and p4' is 3. (197) In one embodiment, Z2 is absent, p6 is 2, p4 is 5, and p4' is 4. (198) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, and p4' is 5. (199) In one embodiment, Z2 is absent, p6 is 1, and W1 is O. (200) In one embodiment, Z₂ is absent, p6 is 2, and W₁ is O. (201) In one embodiment, Z2 is absent, p6 is 3, and W1 is O. (202) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, and p4' is 1.

(203) In one embodiment, Z2 is absent, p6 is 1, p4 is 1, p4' is 1, and W1 is O. (204) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, p4' is 2, and W₁ is O. (205) In one embodiment, Z2 is absent, p6 is 1, p4 is 1, p4' is 3, and W1 is O. (206) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, p4' is 4, and W₁ is O. (207) In one embodiment, Z2 is absent, p6 is 1, p4 is 1, p4' is 5, and W1 is O. (208) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, p4' is 1, and W₁ is O. (209) In one embodiment, Z2 is absent, p6 is 1, p4 is 2, p4' is 2, and W1 is O. (210) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, p4' is 3, and W₁ is O. (211) In one embodiment, Z2 is absent, p6 is 1, p4 is 2, p4' is 4, and W1 is O. (212) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, p4' is 5, and W₁ is O. (213) In one embodiment, Z2 is absent, p6 is 1, p4 is 3, p4' is 1, and W1 is O. (214) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, p4' is 2, and W₁ is O. (215) In one embodiment, Z2 is absent, p6 is 1, p4 is 3, p4' is 3, and W1 is O. (216) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, p4' is 4, and W₁ is O. (217) In one embodiment, Z2 is absent, p6 is 1, p4 is 3, p4' is 5, and W1 is O. (218) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, p4' is 1, and W₁ is O. (219) In one embodiment, Z2 is absent, p6 is 1, p4 is 4, p4' is 2, and W1 is O. (220) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, p4' is 3, and W₁ is O. (221) In one embodiment, Z2 is absent, p6 is 1, p4 is 4, p4' is 4, and W1 is O. (222) In one embodiment, Z2 is absent, p6 is 1, p4 is 4, p4' is 5, and W1 is O. (223) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, p4' is 1, and W is O. (224) In one embodiment, Z2 is absent, p6 is 1, p4 is 5, p4' is 2, and W is O. (225) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, p4' is 3, and W is O. (226) In one embodiment, Z2 is absent, p6 is 1, p4 is 5, p4' is 4, and W is O. (227) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, p4' is 5, and W is O. (228) In one embodiment, Z2 is absent, p6 is 1, p4 is 1, p4' is 1, and W1 is CH₂. (229) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, p4' is 2, and W₁ is CH₂. (230) In one embodiment, Z2 is absent, p6 is 1, p4 is 1, p4' is 3, and W1 is CH₂. (231) In one embodiment, Z₂ is absent, p6 is 1, p4 is 1, p4' is 4, and W₁ is CH₂. (232) In one embodiment, Z2 is absent, p6 is 1, p4 is 1, p4' is 5, and W1 is CH₂. (233) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, p4' is 1, and W₁ is CH₂. (234) In one embodiment, Z2 is absent, p6 is 1, p4 is 2, p4' is 2, and W1 is CH₂. (235) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, p4' is 3, and W₁ is CH₂.

(236) In one embodiment, Z2 is absent, p6 is 1, p4 is 2, p4' is 4, and W1 is CH₂. (237) In one embodiment, Z₂ is absent, p6 is 1, p4 is 2, p4' is 5, and W₁ is CH₂. (238) In one embodiment, Z2 is absent, p6 is 1, p4 is 3, p4' is 1, and W1 is CH₂. (239) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, p4' is 2, and W₁ is CH₂. (240) In one embodiment, Z2 is absent, p6 is 1, p4 is 3, p4' is 3, and W1 is CH₂. (241) In one embodiment, Z₂ is absent, p6 is 1, p4 is 3, p4' is 4, and W₁ is CH₂. (242) In one embodiment, Z2 is absent, p6 is 1, p4 is 3, p4' is 5, and W1 is CH₂. (243) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, p4' is 1, and W₁ is CH₂. (244) In one embodiment, Z2 is absent, p6 is 1, p4 is 4, p4' is 2, and W1 is CH₂. (245) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, p4' is 3, and W₁ is CH₂. (246) In one embodiment, Z2 is absent, p6 is 1, p4 is 4, p4' is 4, and W1 is CH₂. (247) In one embodiment, Z₂ is absent, p6 is 1, p4 is 4, p4' is 5, and W₁ is CH₂. (248) In one embodiment, Z2 is absent, p6 is 1, p4 is 5, p4' is 1, and W is CH₂. (249) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, p4' is 2, and W is CH₂. (250) In one embodiment, Z2 is absent, p6 is 1, p4 is 5, p4' is 3, and W is CH₂. (251) In one embodiment, Z₂ is absent, p6 is 1, p4 is 5, p4' is 4, and W is CH₂. (252) In one embodiment, Z2 is absent, p6 is 1, p4 is 5, p4' is 5, and W is CH₂. (253) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, p4' is 1, and W₁ is O. (254) In one embodiment, Z2 is absent, p6 is 2, p4 is 1, p4' is 2, and W1 is O. (255) In one embodiment, Z2 is absent, p6 is 2, p4 is 1, p4' is 3, and W1 is O. (256) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, p4' is 4, and W₁ is O. (257) In one embodiment, Z2 is absent, p6 is 2, p4 is 1, p4' is 5, and W1 is O. (258) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, p4' is 1, and W₁ is O. (259) In one embodiment, Z2 is absent, p6 is 2, p4 is 2, p4' is 2, and W1 is O. (260) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, p4' is 3, and W₁ is O. (261) In one embodiment, Z2 is absent, p6 is 2, p4 is 2, p4' is 4, and W1 is O. (262) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, p4' is 5, and W₁ is O. (263) In one embodiment, Z2 is absent, p6 is 2, p4 is 3, p4' is 1, and W1 is O. (264) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, p4' is 2, and W₁ is O. (265) In one embodiment, Z2 is absent, p6 is 2, p4 is 3, p4' is 3, and W1 is O. (266) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, p4' is 4, and W₁ is O. (267) In one embodiment, Z2 is absent, p6 is 2, p4 is 3, p4' is 5, and W1 is O. (268) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, p4' is 1, and W₁ is O.

(269) In one embodiment, Z2 is absent, p6 is 2, p4 is 4, p4' is 2, and W1 is O. (270) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, p4' is 3, and W₁ is O. (271) In one embodiment, Z2 is absent, p6 is 2, p4 is 4, p4' is 4, and W1 is O. (272) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, p4' is 5, and W₁ is O. (273) In one embodiment, Z2 is absent, p6 is 2, p4 is 5, p4' is 1, and W is O. (274) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, p4' is 2, and W is O. (275) In one embodiment, Z2 is absent, p6 is 2, p4 is 5, p4' is 3, and W is O. (276) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, p4' is 4, and W is O. (277) In one embodiment, Z2 is absent, p6 is 2, p4 is 5, p4' is 5, and W is O. (278) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, p4' is 1, and W₁ is CH₂. (279) In one embodiment, Z2 is absent, p6 is 2, p4 is 1, p4' is 2, and W1 is CH₂. (280) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, p4' is 3, and W₁ is CH₂. (281) In one embodiment, Z2 is absent, p6 is 2, p4 is 1, p4' is 4, and W1 is CH₂. (282) In one embodiment, Z₂ is absent, p6 is 2, p4 is 1, p4' is 5, and W₁ is CH₂. (283) In one embodiment, Z2 is absent, p6 is 2, p4 is 2, p4' is 1, and W1 is CH₂. (284) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, p4' is 2, and W₁ is CH₂. (285) In one embodiment, Z2 is absent, p6 is 2, p4 is 2, p4' is 3, and W1 is CH₂. (286) In one embodiment, Z₂ is absent, p6 is 2, p4 is 2, p4' is 4, and W₁ is CH₂. (287) In one embodiment, Z2 is absent, p6 is 2, p4 is 2, p4' is 5, and W1 is CH₂. (288) In one embodiment, Z2 is absent, p6 is 2, p4 is 3, p4' is 1, and W1 is CH₂. (289) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, p4' is 2, and W₁ is CH₂. (290) In one embodiment, Z2 is absent, p6 is 2, p4 is 3, p4' is 3, and W1 is CH₂. (291) In one embodiment, Z₂ is absent, p6 is 2, p4 is 3, p4' is 4, and W₁ is CH₂. (292) In one embodiment, Z2 is absent, p6 is 2, p4 is 3, p4' is 5, and W1 is CH₂. (293) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, p4' is 1, and W₁ is CH₂. (294) In one embodiment, Z2 is absent, p6 is 2, p4 is 4, p4' is 2, and W1 is CH₂. (295) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, p4' is 3, and W₁ is CH₂. (296) In one embodiment, Z2 is absent, p6 is 2, p4 is 4, p4' is 4, and W1 is CH₂. (297) In one embodiment, Z₂ is absent, p6 is 2, p4 is 4, p4' is 5, and W₁ is CH₂. (298) In one embodiment, Z2 is absent, p6 is 2, p4 is 5, p4' is 1, and W is CH₂. (299) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, p4' is 2, and W₁ is CH₂. (300) In one embodiment, Z2 is absent, p6 is 2, p4 is 5, p4' is 3, and W1 is CH₂. (301) In one embodiment, Z₂ is absent, p6 is 2, p4 is 5, p4' is 4, and W₁ is CH₂. (302) In one embodiment, Z2 is absent, p6 is 2, p4 is 5, p4' is 5, and W1 is CH₂. (303) In one embodiment, p4, p4', Z₂, p6, W₁, W₂, and W₃ are each as defined, where applicable, in any one of (1)-(302), and p5 is 0. (304) In one embodiment, p4, p4', Z₂, p6, W₁, W₂, and W₃ are each as defined, where applicable, in any one of (1)-(302), and p5 is 1. (305) In one embodiment, p4, p4', Z₂, p6, W₁, W₂, and W₃ are each as defined, where applicable, in any one of (1)-(302), and p5 is 2. (306) In one embodiment, p4, p4', Z₂, p6, p5, W₁, and W₃ are each as defined, where applicable, in any one of (1)-(44) and (50)-(305), and W2 is O. (307) In one embodiment, p4, p4', Z₂, p6, p5, W₁, and W₃ are each as defined, where applicable, in any one of (1)-(44) and (50)-(305), and W2 is CH₂. (308) In one embodiment, p4, p4', Z₂, p6, p5, W_1, and W₂ are each as defined, where applicable, in any one of (1)-(49) and (57)-(307), and W3 is NR25C(O)CH₂. (309) In one embodiment, p4, p4', Z₂, p6, p5, W_1, and W₂ are each as defined, where applicable, in any one of (1)-(49) and (57)-(307), and W3 is NHC(O)CH₂. (310) In one embodiment, p4, p4', Z₂, p6, p5, W_1, and W₂ are each as defined, where applicable, in any one of (1)-(49) and (57)-(307), and W₃ is

(311) In one embodiment, p4, p4', Z2, p6, p5, W1, and W2 are each as defined, where applicable, in any one of (1)-(49) and (57)-(307), and W3 is

(312) In one embodiment, p4, p4', Z₂, p6, p5, and W₁ are each as defined, where applicable, in any one of (1)-(311), and Q2 is absent. (313) In one embodiment, p4, p4', Z₂, p6, p5, W_1, W_2, and W₃ are each as defined, where applicable, in any one of (1)-(311), and Q2 is NHC(O)CH₂. (314) In one embodiment, p4, p4', Z₂, p6, p5, W_1, W_2, and W₃ are each as defined, where applicable, in any one of (1)-(311), and Q2 is O(CH₂)1-2. (315) In one embodiment, p4, p4', Z₂, p6, p5, W_1, W_2, and W₃ are each as defined, where applicable, in any one of (1)-(311), and Q2 is O(CH₂). (316) In one embodiment, p4, p4', Z2, p6, p5, W1, W2, and W3 are each as defined, where applicable, in any one of (1)-(311), and Q₂ is O(CH₂CH₂). (317) In one embodiment, p4, p4', Z2, p6, p5, W1, W2, and W3 are each as defined, where applicable, in any one of (1)-(311), and Q₂ is C(O).

(318) In one embodiment, p4, p4', Z₂, p6, p5, W_1, W_2, and W₃ are each as defined, where applicable, in any one of (1)-(311), and Q2 is OCH₂C(O). [00360] In one embodiment, the Linker–Targeting Ligand (TL) has any one of the structures set forth in Table M: Table M: Linker Formulas

R₂₅, p4, p4', and p6 are each as described above. [00361] In certain embodiments, L1 is of formula:

,

indicates the point of attachment to the moiety of formula:

indicates the point of attachment to D; n1 is 1, 2, 3, 4, 5, or 6; n2 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n3 is 1, 2, 3, 4, 5, or 6; and g is 1, 2, 3, 4, 5, or 6. In certain embodiments, n1 is 1. In certain embodiments, n1 is 2. In certain embodiments, n1 is 3. In certain embodiments, n1 is 4. In certain embodiments, n1 is 5. In certain embodiments, n1 is 6. In certain embodiments, n2 is 1. In certain embodiments, n2 is 2. In certain embodiments, n2 is 3. In certain embodiments, n2 is 4. In certain embodiments, n2 is 5. In certain embodiments, n2 is 6. In certain embodiments, n2 is 7. In certain embodiments, n2 is 8. In certain embodiments, n2 is 9. In certain embodiments, n2 is 10. In certain embodiments, n3 is 1. In certain embodiments, n3 is 2. In certain embodiments, n3 is 3. In certain embodiments, n3 is 4. In certain embodiments, n3 is 5. In certain embodiments, n3 is 6. In certain embodiments, g is 1. In certain embodiments, g is 2. In certain embodiments, g is 3. In certain embodiments, g is 4. In certain embodiments, g is 5. In certain embodiments, g is 6. [00362] In certain embodiments, L1 is of formula:

,

, , o . [00363] In certain embodiments, L1 is of formula: In certain

embodiments, L1 is of formula:

. In certain embodiments, L1 is of formula:

In certain embodiments, L1 is of formula:

In certain embodiments, L1 is of formula:

wherein: n1 is 1, 2, or 3; n2 is 4, 5, 6, 7, 8, or 9; n3 is 1, 2, 3, or 4; and g is 1, 2, 3, 4, or 5. In certain embodiments, L1 is of formula:

, ,

wherein: n1 is 1, 2, or 3; n2 is 4, 5, 6, 7, 8; n3 is 2, 3, or 4; and g is 1, 2, or 3. In certain embodiments, n1 is 1. In certain embodiments, n1 is 2. In certain embodiments, n1 is 3. In certain embodiments, n2 is 4. In certain embodiments, n2 is 5. In certain embodiments, n2 is 6. In certain embodiments, n2 is 7. In certain embodiments, n2 is 8. In certain embodiments, n2 is 9. In certain embodiments, n3 is 1. In certain embodiments, n3 is 2. In certain embodiments, n3 is 3. In certain embodiments, n3 is 4. In certain embodiments, g is 1. In certain embodiments, g is 2. In certain embodiments, g is 3. In certain embodiments, g is 4. In certain embodiments, g is 5. [00364] In certain embodiments, L1 is of formula:

,

. In certain embodiments, L1 is of formula: In certain embodiments, L1 is of formula: In certain embodiments, L1 is of formula: In certain embodiments, L1 is of formula:

In certain embodiments, L1 is of formula:

In certain embodiments, L1 is of formula:

. [00365] Any one of the Degrons described herein can be covalently bound to any one of the Linkers described herein. Any one of the Targeting Ligands described herein can be covalently bound to any one of the Linkers described herein. [00366] In one embodiment, the Degron is of Formula D1, and the Linker is selected from L2a – L2x. In one embodiment, the Degron is of Formula D1, and the Linker is selected from L2a-L2c. In one embodiment, the Degron is of Formula D1, and the Linker is selected from L2d-L2g. In one embodiment, the Degron is of Formula D1, and the Linker is selected from

L2h-L2k. In one embodiment, the Degron is of Formula D1, and the Linker is selected from L2l-L2m. In one embodiment, the Degron is of Formula D1, and the Linker is selected from L2n -L2p. In one embodiment, the Degron is of Formula D1, and the Linker is selected from L2q-L2t. In one embodiment, the Degron is of Formula D1, and the Linker is selected from L2u-L2x. [00367] In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L2a – L2x. In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L2a-L2c. In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L2d-L2g. In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L2h-L2k. In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L2l-L2m. In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L2n - L2p. In one embodiment, the Degron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L2q-L2t. In one embodiment, the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L2u-L2x. [00368] In one embodiment, the Degron is of Formula D2, and the Linker is selected from L2a – L2x. In one embodiment, the Degron is of Formula D2, and the Linker is selected from L2a-L2c. In one embodiment, the Degron is of Formula D2, and the Linker is selected from L2d-L2g. In one embodiment, the Degron is of Formula D2, and the Linker is selected from L2h-L2k. In one embodiment, the Degron is of Formula D2, and the Linker is selected from L2l-L2m. In one embodiment, the Degron is of Formula D2, and the Linker is selected from L2n -L2p. In one embodiment, the Degron is of Formula D2, and the Linker is selected from L2q-L2t. In one embodiment, the Degron is of Formula D2, and the Linker is selected from L2u-L2x. [00369] In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is selected from L2a – L2x. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is selected from L2a-L2c. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is selected from L2d-L2g. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is selected from L2h-L2k. In one embodiment, the Degron is of Formula D2a

or D2b, and the Linker is selected from L2l-L2m. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is selected from L2n -L2p. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is selected from L2q-L2t. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is selected from L2u-L2x. [00370] In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is selected from L2a – L2x. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is selected from L2a-L2c. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is selected from L2d-L2g. In one embodiment, Degron is of Formula D2c or D2d, and the Linker is selected from L2h-L2k. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is selected from L2l-L2m. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is selected from L2n -L2p. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is selected from L2q-L2t. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is selected from L2u-L2x. [00371] In one embodiment, the Linker is designed and optimized based on SAR (structure- activity relationship) and X-ray crystallography of the Targeting Ligand with regard to the location of attachment for the Linker. [00372] In one embodiment, the optimal Linker length and composition vary by the Targeting Ligand and can be estimated based upon X-ray structure of the Targeting Ligand bound to its target. Linker length and composition can be also modified to modulate metabolic stability and pharmacokinetic (PK) and pharmacodynamics (PD) parameters. [00373] In some embodiments, the BTK degraders have any one of the structures set forth in Tables A-D:

[00374] Table A

[00375] Table B

[00376] TABLE C

[00377] TABLE D

[00378] In certain embodiments, the BTK degrader is a compound of Formula (XI) and is represented by any one of formulae: ,

,

, or a pharmaceutically acceptable salt or stereoisomer thereof. [00379] In certain embodiments, the compound of Formula (XI) is of the formula:

, or a pharmaceutically acceptable salt acceptable salt or stereoisomer thereof. [00380] In certain embodiments, the compound of Formula (XI) is of the formula: or a pharmaceutically acceptable salt or

stereoisomer thereof. [00381] In certain embodiments, the compound of Formula (XI) is of the formula:

, or a pharmaceutically acceptable salt or stereoisomer thereof. [00382] In certain embodiments, the compound of Formula (XI) is of the formula:

or a pharmaceutically acceptable salt or stereoisomer thereof. [00383] In certain embodiments, the compound of Formula (XI) is of the formula:

or a pharmaceutically acceptable salt or stereoisomer thereof. [00384] In certain embodiments, the compound of Formula (XI) is of the formula:

or a pharmaceutically acceptable salt or stereoisomer thereof. [00385] In certain embodiments, the compound of Formula (XI) is of the formula:

, ,

,

,

stereoisomer thereof. [00386] In certain embodiments, the compound of Formula (XI) is of the formula:

,

or a pharmaceutically

acceptable salt or stereoisomer thereof. [00387] In certain embodiments, the compound of Formula (XI) is of the formula:

pharmaceutically acceptable salt or stereoisomer thereof. [00388] In certain embodiments, the compound of Formula (XI) is of the formula:

,

a pharmaceutically acceptable salt or stereoisomer thereof. [00389] In certain embodiments, the compound of Formula (XI) is of the formula:

, or a pharmaceutically

acceptable salt or stereoisomer thereof. [00390] In certain embodiments, the compound of Formula (XI) is of the formula:

or a pharmaceutically acceptable salt or stereoisomer thereof. [00391] In certain embodiments, the compound of Formula (XI) is of the formula:

, or a pharmaceutically acceptable salt or stereoisomer thereof. [00392] In certain embodiments, the compound of Formula (XI) is of the formula:

pharmaceutically acceptable salt or stereoisomer thereof; wherein n1 is 1, 2, 3, 4, 5, or 6; n2 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n3 is 1, 2, 3, 4, 5, or 6; and g is 1, 2, 3, 4, 5, or 6. [00393] In certain embodiments, the compound of Formula (XI) is any one of structures: ,

,

pharmaceutically acceptable salt or stereoisomer thereof. [00394] BTK inhibitors useful in the practice of the inventive methods may be in the form of a free acid or free base, or a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable" in the context of a salt refers to a salt of the compound that does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the compound in salt form may be administered to a subject without causing undesirable biological effects (such as dizziness or gastric upset) or interacting in a deleterious manner with any of the other components of the composition in which it is contained. The term

"pharmaceutically acceptable salt" refers to a product obtained by reaction of the compound of the present invention with a suitable acid or a base. Examples of pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4- methylbenzenesulfonate or p-toluenesulfonate salts and the like. Certain compounds of the invention can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin. [00395] BTK inhibitors useful in the practice of the inventive methods may have at least one chiral center and thus may be in the form of a stereoisomer, which as used herein, embraces all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers which include the (R-) or (S-) configurations of the compounds), mixtures of mirror image isomers (physical mixtures of the enantiomers, and racemates or racemic mixtures) of compounds, geometric (cis/trans or E/Z, R/S) isomers of compounds and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers). The chiral centers of the compounds may undergo epimerization in vivo; thus, for these compounds, administration of the compound in its (R-) form is considered equivalent to administration of the compound in its (S-) form. Accordingly, the compounds of the present invention may be made and used in the form of individual isomers and substantially free of other isomers, or in the form of a mixture of various isomers, e.g., racemic mixtures of stereoisomers. [00396] In some embodiments, an BTK inhibitor useful in the practice of the inventive methods may be is an isotopic derivative in that it has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. In one embodiment, the compound includes deuterium or multiple deuterium atoms. Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and thus may be advantageous in some circumstances.

[00397] In addition, BTK inhibitors useful in the practice of the inventive methods embrace the use of N-oxides, crystalline forms (also known as polymorphs), active metabolites of the compounds having the same type of activity, tautomers, and unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, of the compounds. The solvated forms of the conjugates presented herein are also considered to be disclosed herein. Pharmaceutical Compositions [00398] BTK inhibitors may be formulated in a pharmaceutical composition that includes a therapeutically effective amount of the BTK inhibitor or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier,” as known in the art, refers to a pharmaceutically acceptable material, composition or vehicle, suitable for administering the BTK inhibitor to mammals. Suitable carriers may include, for example, liquids (both aqueous and non-aqueous alike, and combinations thereof), solids, encapsulating materials, gases, and combinations thereof (e.g., semi-solids), and gases, that function to carry or transport the compound from one organ, or portion of the body, to another organ, or portion of the body. A carrier is “acceptable” in the sense of being physiologically inert to and compatible with the other ingredients of the formulation and not injurious to the subject or patient. Depending on the type of formulation, the composition may further include one or more pharmaceutically acceptable excipients. [00399] Broadly, BTK inhibitors and their pharmaceutically acceptable salts and stereoisomers useful in the practice of the inventive methods may be formulated into a given type of composition in accordance with conventional pharmaceutical practice such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping and compression processes (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York). The type of formulation depends on the mode of administration which may include enteral (e.g., oral, buccal, sublingual and rectal), parenteral (e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), and intrasternal injection, or infusion techniques, intra-ocular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, interdermal, intravaginal, intraperitoneal, mucosal, nasal, intratracheal instillation, bronchial instillation, and inhalation) and topical (e.g., transdermal). In general, the most appropriate route of administration will depend upon a variety of factors including,

for example, the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). For example, parenteral (e.g., intravenous) administration may also be advantageous in that the bifunctional compound may be administered relatively quickly such as in the case of a single-dose treatment and/or an acute condition. [00400] In some embodiments, the BTK inhibitors are formulated for oral or intravenous administration (e.g., systemic intravenous injection). [00401] Accordingly, BTK inhibitors may be formulated into solid compositions (e.g., powders, tablets, dispersible granules, capsules, cachets, and suppositories), liquid compositions (e.g., solutions in which the compound is dissolved, suspensions in which solid particles of the compound are dispersed, emulsions, and solutions containing liposomes, micelles, or nanoparticles, syrups and elixirs); semi-solid compositions (e.g., gels, suspensions and creams); and gases (e.g., propellants for aerosol compositions). Compounds may also be formulated for rapid, intermediate or extended release. [00402] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with a carrier such as sodium citrate or dicalcium phosphate and an additional carrier or excipient such as a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as crosslinked polymers (e.g., crosslinked polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl cellulose (croscarmellose sodium), sodium starch glycolate, 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) wetting agents 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 include buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage

forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings. They may further contain an opacifying agent. [00403] In some embodiments, BTK inhibitors may be formulated in a hard or soft gelatin capsule. Representative excipients that may be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearyl fumarate, lactose anhydrous, microcrystalline cellulose and croscarmellose sodium. Gelatin shells may include gelatin, titanium dioxide, iron oxides and colorants. [00404] Liquid dosage forms for oral administration include solutions, suspensions, emulsions, micro-emulsions, syrups and elixirs. In addition to the compound, the liquid dosage forms may contain an aqueous or non-aqueous carrier (depending upon the solubility of the compounds) commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Oral compositions may also include an excipients such as wetting agents, suspending agents, coloring, sweetening, flavoring, and perfuming agents. [00405] Injectable preparations may include sterile aqueous solutions or oleaginous suspensions. They may be formulated according to standard techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-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 sterile injectable medium prior to use. The effect of the compound may be prolonged by slowing its absorption, which may be accomplished by the use of a liquid suspension or crystalline or amorphous material with poor water solubility. Prolonged absorption of the compound from a parenterally

administered formulation may also be accomplished by suspending the compound in an oily vehicle. [00406] In certain embodiments, BTK inhibitors may be administered in a local rather than systemic manner, for example, via injection of the conjugate directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Injectable depot forms are made by forming microencapsule matrices of the compound in a biodegradable polymer, e.g., polylactide- polyglycolides, poly(orthoesters) and poly(anhydrides). The rate of release of the compound may be controlled by varying the ratio of compound to polymer and the nature of the particular polymer employed. Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. Furthermore, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. [00407] The compounds may be formulated for buccal or sublingual administration, examples of which include tablets, lozenges and gels. [00408] The compounds may be formulated for administration by inhalation. Various forms suitable for administration by inhalation include aerosols, mists or powders. Pharmaceutical compositions may be delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In some embodiments, the dosage unit of a pressurized aerosol may be determined by providing a valve to deliver a metered amount. In some embodiments, capsules and cartridges including gelatin, for example, for use in an inhaler or insufflator, may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. [00409] BTK inhibitors may be formulated for topical administration which as used herein, refers to administration intradermally by application of the formulation to the epidermis. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions and sprays. [00410] Representative examples of carriers useful in formulating compositions for topical application include solvents (e.g., alcohols, poly alcohols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffered solutions (e.g.,

hypotonic or buffered saline). Creams, for example, may be formulated using saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmito-oleic acid, cetyl, or oleyl alcohols. Creams may also contain a non-ionic surfactant such as polyoxy-40-stearate. [00411] In some embodiments, the topical formulations may also include an excipient, an example of which is a penetration enhancing agent. These agents are capable of transporting a pharmacologically active compound through the stratum corneum and into the epidermis or dermis, preferably, with little or no systemic absorption. A wide variety of compounds have been evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin. See, for example, Percutaneous Penetration Enhancers, Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which surveys the use and testing of various skin penetration enhancers, and Buyuktimkin et al., Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh T. K., Pfister W. R., Yum S. I. (Eds.), Interpharm Press Inc., Buffalo Grove, Ill. (1997). Representative examples of penetration enhancing agents include triglycerides (e.g., soybean oil), aloe compositions (e.g., aloe-vera gel), ethyl alcohol, isopropyl alcohol, octolyphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N- decylmethylsulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate), and N-methylpyrrolidone. [00412] Representative examples of yet other excipients that may be included in topical as well as in other types of formulations (to the extent they are compatible), include preservatives, antioxidants, moisturizers, emollients, buffering agents, solubilizing agents, skin protectants, and surfactants. Suitable preservatives include alcohols, quaternary amines, organic acids, parabens, and phenols. Suitable antioxidants include ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents like EDTA and citric acid. Suitable moisturizers include glycerin, sorbitol, polyethylene glycols, urea, and propylene glycol. Suitable buffering agents include citric, hydrochloric, and lactic acid buffers. Suitable solubilizing agents include quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates. Suitable skin protectants include vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide. [00413] Transdermal formulations typically employ transdermal delivery devices and transdermal delivery patches wherein the compound is formulated in lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. Patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

Transdermal delivery of the compounds may be accomplished by means of an iontophoretic patch. Transdermal patches may provide controlled delivery of the compounds wherein the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Absorption enhancers may be used to increase absorption, examples of which include absorbable pharmaceutically acceptable solvents that assist passage through the skin. [00414] Ophthalmic formulations include eye drops. [00415] Formulations for rectal administration include enemas, rectal gels, rectal foams, rectal aerosols, and retention enemas, which may contain conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. Compositions for rectal or vaginal administration may also be formulated as suppositories which can be prepared by mixing the compound with suitable non-irritating carriers and excipients such as cocoa butter, mixtures of fatty acid glycerides, polyethylene glycol, suppository waxes, and combinations thereof, all of which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound. Dosage Amounts [00416] As used herein, the term, "therapeutically effective amount" refers to an amount of a BTK inhibitor or a pharmaceutically acceptable salt or a stereoisomer thereof that is effective in producing the desired therapeutic response in a COVID-19 patient. The term "therapeutically effective amount" thus includes the amount of the BTK inhibitor or a pharmaceutically acceptable salt or a stereoisomer thereof, that when administered, induces a positive modification in COVID-19, or is sufficient to prevent development or progression of COVID- 19, or alleviate to some extent, one or more of the symptoms of COVID-19 in the patient, or which simply kills or inhibits the propagation of the virus in cells. [00417] The total daily dosage of the BKT inhibitor may be decided in accordance with standard medical practice, e.g., by the attending physician using sound medical judgment. The specific therapeutically effective dose for any particular subject will depend upon a variety of factors including the severity of the infection (e.g., its present status); the activity of the BTK inhibitor employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the BTK inhibitor employed; the duration of the treatment; drugs used in combination or coincidental with the specific BTK inhibitor employed; and like factors well

known in the medical arts (see, for example, Hardman et al., eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th Edition, McGraw-Hill Press, 155-173, 2001). [00418] The BTK inhibitor may be effective over a wide dosage range. In some embodiments, the total daily dosage (e.g., for adult humans) may range from about 0.001 to about 1600 mg, from 0.01 to about 1600 mg, from 0.01 to about 500 mg, from about 0.01 to about 100 mg, from about 0.5 to about 100 mg, from 1 to about 100-400 mg per day, from about 1 to about 50 mg per day, and from about 5 to about 40 mg per day, and in yet other embodiments from about 10 to about 30 mg per day. Individual dosage may be formulated to contain the desired dosage amount depending upon the number of times the compound is administered per day. By way of example, capsules may be formulated with from about 1 to about 200 mg of compound (e.g., 1, 2, 2.5, 3, 4, 5, 10, 15, 20, 25, 50, 100, 150, and 200 mg). In some embodiments, capsules may be formulated with about 70 mg, about 80 mg, about 100 mg, or about 140 mg of compound. In some embodiments, tablets may be formulated with about 140 mg, about 280 mg, about 420, or about 560 mg of compound. In some embodiments, individual dosages may be formulated to contain the desired dosage amount depending upon the number of times the compound is administered per day. In some embodiments, the dosage is 4, 10, 25, 100, 200, 300, 400, 500, or 600 mg/day. In some embodiments, the dosage is 160, 200, 320, 420 or 560 mg/day. [00419] The administration of a BTK inhibitor or a pharmaceutical composition thereof to the patient may occur in a single dose or in multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20, or more doses). In some embodiments, the frequency of administration ranges from about once a day for 1, 2, 3, 4, 5, 6 or more weeks, or at least until an abatement of symptoms is observed. In some embodiments, the frequency of administration is twice a day for 1, 2, 3, 4, 5, 6 or more weeks, or at least until an abatement of symptoms is observed. Methods of Use [00420] The present invention is directed to methods of treating a COVID-19 patient that entails administration of a therapeutically effective amount of a BTK inhibitor or a pharmaceutically acceptable salt or stereoisomer thereof, to a patient in need thereof. [00421] In some embodiments, the patient is suffering from respiratory distress associated with COVID-19 or is at risk of developing respiratory distress. Patients suffering from respiratory distress associated with COVID-19 infection may be identified in accordance with established art-recognized symptoms. For example, the patients may show signs that they are having to work harder to breathe or are not getting enough oxygen. As persons skilled in the

art would appreciate, signs that may indicate that a person is suffering from respiratory distress include one or more of the following: • Breathing rate. An increase in the number of breaths per minute may mean that a person is having trouble breathing or not getting enough oxygen. • Color changes. A bluish color seen around the mouth, on the inside of the lips, or on the fingernails may happen when a person is not getting as much oxygen as needed. The color of the skin may also appear pale or gray. • Grunting. A grunting sound can be heard each time the person exhales. This grunting is the body's way of trying to keep air in the lungs so they will stay open. • Nose flaring. The openings of the nose spreading open while breathing may mean that a person is having to work harder to breathe. • Retractions. The chest appears to sink in just below the neck or under the breastbone with each breath or both. This is one way of trying to bring more air into the lungs, and can also be seen under the rib cage or even in the muscles between the ribs. • Sweating. There may be increased sweat on the head, but the skin does not feel warm to the touch. More often, the skin may feel cool or clammy. This may happen when the breathing rate is very fast. • Wheezing. A tight, whistling or musical sound heard with each breath can mean that the air passages may be smaller (tighter), making it harder to breathe. • Body position. A person may spontaneously lean forward while sitting to help take deeper breaths. This is a warning sign that he or she is about to collapse. A patient at risk of respiratory distress may, in fact, be asymptomatic. In other embodiments, an at-risk patient may be symptomatic and exhibit one or more of the constellation of symptoms associated with COVID-19 short of respiratory distress such as high fever. [00422] The BTK inhibitor may be administered to a COVID-19 patient, as a monotherapy or by way of combination therapy. Therapy may be "front/first-line", i.e., as an initial treatment in patients who have undergone no prior anti-viral treatment regimens, either alone or in combination with other treatments; or "second-line", as a treatment in patients who have undergone a prior anti-viral treatment regimen, either alone or in combination with other treatments; or as "third-line", "fourth-line", etc. treatments, either alone or in combination with other treatments. Therapy may also be given to patients who have had previous treatments which were unsuccessful or partially successful but who became intolerant to the particular treatment. Therapy may also be given as an adjuvant treatment, i.e., to prevent reoccurrence of

COVID-19 in patients with no currently detectable disease or after surgical removal of COVID- 19. Thus, in some embodiments, the BTK inhibitors may be administered to a patient who has received another anti-COVID-19 therapy. [00423] The methods of the present invention may entail administration of a BTK inhibitor or a pharmaceutical composition to the patient in a single dose or in multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20, or more doses). For example, the frequency of administration may range from once a day up to about once every eight weeks. In some embodiments, the frequency of administration ranges from about once a day for 1, 2, 3, 4, 5, or 6 weeks, and in other embodiments entails at least one 28-day cycle which includes daily administration for 3 weeks (21 days) followed by a 7-day “off” period. In other embodiments, the bifunctional compound may be dosed twice a day (BID) over the course of two and a half days (for a total of 5 doses) or once a day (QD) over the course of two days (for a total of 2 doses). In other embodiments, the bifunctional compound may be dosed once a day (QD) over the course of five days. [00424] The disclosed methods are not limited to any specific subpopulation of COVID-19 patients. The patients may be at risk of COVID-19 or may have already tested positive for the virus. The patients may be symptomatic or asymptomatic. In some embodiments, the patient is immune-suppressed. [00425] The patient may be diabetic, hypertensive, obese or any combination of two or more of these factors. The patient may be at least 65 years of age. [00426] The patient may have a pre-existing pulmonary/respiratory condition. The methods describe herein may reduce or inhibit, or even prevent pulmonary injury in COVID-19-infected patients, thereby reducing the requirement for oxygen supplementation and/or mechanical ventilation. Combination Therapy [00427] BTK inhibitors may be used in combination or concurrently with at least one other active anti-COVID-19 agent. The terms “in combination” and “concurrently” in this context mean that the agents are co-administered, which includes substantially contemporaneous administration, by way of the same or separate dosage forms, and by the same or different modes of administration, or sequentially, e.g., as part of the same treatment regimen, or by way of successive treatment regimens. Thus, if given sequentially, at the onset of administration of the second compound, the first of the two compounds is in some cases still detectable at effective concentrations at the site of treatment. The sequence and time interval may be

determined such that they can act together (e.g., synergistically) to provide an increased benefit than if they were administered otherwise. For example, the therapeutics may be administered at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they may be administered sufficiently close in time so as to provide the desired therapeutic effect, which may be in a synergistic fashion. Thus, the terms are not limited to the administration of the active agents at exactly the same time. [00428] Representative examples of additional active agents and treatment regimens include anti-viral therapeutics (e.g., Remdesivir), convalescent plasma, immunomodulators, and therapeutic antibodies (e.g., artificial antibodies against COVID-19). [00429] In some embodiments, a BTK inhibitor and the additional anti-COVID-19 therapeutic may be administered less than 5 minutes apart, less than 30 minutes apart, less than 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours part. The two or more (e.g., anti-viral) therapeutics may be administered within the same patient visit. EXAMPLES [00430] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of the therapeutic methods of the invention, and are not intended to limit the scope of what the inventors regard as their invention. [00431] Example 1: The BTK-Inhibitor Ibrutinib Protects Against Pulmonary Injury in COVID-19 Infected Patients [00432] The BTK-inhibitor ibrutinib is used to treat indolent B-cell malignancies and chronic graft versus host disease. The potential for ibrutinib to abrogate pulmonary inflammatory cytokines, lung injury and death was previously demonstrated in a highly relevant, lethal flu

animal model (Florence, et al., Am. J. Physiol. Lung Cell Mol. Physiol.315:L52-L58 (2018)). The impact of ibrutinib in COVID-19 patients was investigated. 600-800 Waldenstrom’s Macroglobulinemia (WM) patients per year were cared for; approximately 300 of whom are on a BTK-inhibitor. Six patients were identified for receiving ibrutinib for Waldenstrom’s Macroglobulinemia who were diagnosed with COVID-19. Their clinical characteristics appear in Table 1. Their median age was 66 years, and five were on the recommended treatment dose of 420 mg/day; the sixth patient was on a reduced dose of 140 mg/day because of arthralgias. For all patients, the median time on ibrutinib was 52 months. Their median time with COVID- 19 related symptoms prior to diagnostic testing was 5 days, and since diagnosis of COVID-19 was 22 days. All 6 patients experienced cough and fever as prodromal symptoms. The 5 patients on ibrutinib at 420 mg/day experienced no dyspnea and required no hospitalization. Their course was marked by steady improvement, and resolution or near resolution of COVID- 19 related symptoms in all five of these patients during the follow-up period.

Table 1: Clinical characteristics of 6 patients with Waldenstrom’s Macroglobulinemia on ibrutinib with COVID-19 infection. WM, Waldenstrom’s Macroglobulinemia; HC, hydrochloroquine; AZ, azithromycin; TOCI, tocilizumab; Y = yes; N = No.

[00433] The patient on reduced dose ibrutinib (Patient 6; Table 1) experienced progressive dyspnea and hypoxia prompting hospitalization. Chest CT showed bilateral ground glass opacities and a pleural effusion on admission prompting a hold on ibrutinib during which his

hypoxia acutely worsened necessitating supplemental oxygen use. Hydroxychloroquine (HCQ) and azithromycin were administered. Azithromycin was stopped after 3 days due to wide QRS complex tachyarrhythmia, HCQ was given for a total of 5 days. Hypoxia worsened and fever persisted during HCQ course. Ibrutinib was restarted at 140 mg/day and tocilizumab 400 mg was co-administered on hospital day 5 with improved oxygenation, and decreased C-reactive protein (CRP) levels (83 to 9 mg/L). Intravenous immunoglobulin was also given on hospital days 6-10. On day 10 of hospitalization, the patient experienced worsening hypoxia accompanied by increased CRP (28 mg/L) and required mechanical ventilation. Given the lack of hypoxia in the other COVID-19 infected WM patients on full dose ibrutinib, ibrutinib was increased to 420 mg/day on days 11 and day 12. A rapid improvement in oxygenation followed, and the patient was successfully extubated late on day 12 and maintained oxygen saturations of 94-96% on 3 liters/min supplemental oxygen by nasal cannula. The next day supplemental oxygen was decreased to 2 liters/min, with oxygen saturations of 96-98%, and CRP level of 10 mg/L. On day 14, oxygen saturation was 95% on room air, repeat CRP level was 6 mg/L, and the patient was discharged home off supplemental oxygen on 420 mg/day of ibrutinib. Seven days later the patient continues to do well, without fever, cough or dyspnea at rest. The patient remains on ibrutinib at 420 mg/day and tolerating therapy well. [00434] Pulmonary failure is the main cause of mortality related to COVID-19 infection (Wang et al., JAMA 323:1061-69 (2020); Bhatraju et al., N. Engl. J. Med. 382:2012-2022 (2020)). Up to 80% of patients hospitalized for COVID-19 infection require supplemental oxygenation, of whom 30-40% may require mechanical ventilation (Wang et al., JAMA 323:1061-69 (2020); Cao et al., N. Engl. J. Med. 382:1787-1799 (2020); Wu et al., JAMA 180(7):934-943 (2020)). SARS-CoV-2 binds via the ACE2-receptor that is highly expressed on Alveolar Type II (ATII) cells in the lung (Hoffman et al., Cell 181:271–280 (2020)). ATII cells constitute 5-15% of the lung epithelium. While Alveolar Type I cells are highly adapted for gas exchange, Alveolar Type II cells have a specialized role in innate immune response (Pechkovsky et al., Resp. Res. 6:75 (2005); Thorley et al., PLOS ONE 6:e21827 (2011); Chuquimia et al., Infection and Immunity 81:381-389 (2013)). ATII cells express Toll receptors (TLRs) and can trigger inflammatory cytokines and chemo-attractants in response to pathogens that recruit and activate other immune cells including macrophages and neutrophils (Pechkovsky et al., Resp. Res. 6:75 (2005); Thorley et al., PLOS ONE 6:e21827 (2011); Chuquimia et al., Infection and Immunity 81:381-389 (2013)). Highly relevant to coronavirus infection, expression of pro-inflammatory and chemo-attractant cytokines IL1-B, IL6,

IP10/CXCL10, MCP-1 and TNF-a were identified in the ACE2-positive cells from autopsy tissue of SARS-CoV-1 infected patients, that appeared causally related to the acute lung injury and pathogenesis observed with SARS-CoV-1 (He et al., J. Pathology 210:288-297 (2006)). A similar profile of elevated cytokine levels was reported in the plasma of SARS-CoV-1 patients during the progressive and end-stage of infection (Jiang et al., Am. J. Respir. Care Med. 171:850-857 (2005)), a profile consistent with an M1 polarized macrophage response (Ley K., J. Immunology 199:2191-2193 (2017)). [00435] SARS-CoV-1 shares 86% homology with SARS-CoV-2. SARS-Cov-2 patients requiring intensive care also showed elevated plasma levels of inflammatory cytokines and chemo-attractants such as IL-2, IL-6, IL-7, IL-10, G-CSF, IP-10/CXCL-10, MCP-1/CCL2, MIP-1a/CCL3, and TNF-a (Huang et al., Lancet 395:565-574 (2020)). The importance of inflammatory cytokines to lung injury in SARS-CoV-2 infected patients has been suggested by reports of benefit with IL-6 and IL6-receptor blocking antibodies, and clinical trials to examine their use have been initiated (NCT04317092, NCT04306705, NCT04315298). [00436] It was previously shown that BTK, and its upstream activator HCK, were involved in TLR-mediated signaling (Jeffries et al., J. Biol. Chem. 278:26258-26264 (2003); Yang et al., Blood 122:1222-1232 (2013)). Yang et al., Blood 127:3237-3252 (2016)). Both BTK and HCK are triggered by MYD88, a TLR-adaptor protein that signals for all Toll receptors except TLR3 in response to viral and bacterial pathogens, including coronaviruses (Wang et al., mBio. 7(1):e01872-15 (2016). ATII cells express TLRs, as do alveolar macrophages that coordinate inflammatory responses with ATII cells (Pechkovsky et al., Resp. Res.6:75 (2005); Thorley et al., PLOS ONE 6:e21827 (2011); Chuquimia et al., Infection and Immunity 81:381- 389 (2013)). As components of TLR/MYD88 signaling, BTK and HCK can drive inflammatory cytokine production through ERK1/2 (Chen et al., Blood 131:2047-2059 (2018)). [00437] In a transgenic mouse model, activated HCK over-expression promoted extensive pulmonary inflammation and an enhanced innate immune response, particularly in older mice (Ernst et al., J. Exp. Med. 196:589-604 (2002)). Elevated levels of TNF-a were identified in the bronchoalveolar lavage fluids of these mice following LPS challenge. The pulmonary pathology findings from these mice show great overlap with those described in the lungs of patients with COVID-19 infection which showed serous and fibrin exudation with alveolar infiltration consisting mostly of macrophages and monocytes (Yao et al., Zhonghua Bing Li Xue Za Zhi.49(5):411-417 (2020)).

[00438] Ibrutinib is a highly potent, covalent inhibitor of BTK (biochemical IC500.5 nM). Ibrutinib is also a potent reversible inhibitor of HCK (IC₅₀49 nM). The IC₅₀ levels for BTK and HCK are within the pharmacologically attainable dosimetry of orally administered ibrutinib (Yang et al., Blood 127:3237-3252 (2016)). Serially collected blood samples from patients with chronic lymphocytic leukemia (CLL), Waldenstrom’s Macroglobulinemia (WM), and chronic graft versus host disease (cGVHD) on ibrutinib monotherapy showed marked reductions in pro-inflammatory and chemo-attractant cytokines that greatly overlapped with those reported elevated in the plasma of SARS-Cov-1 and SARS-COV-2 patients, and in ACE2+ cells from lung tissue of SARS-CoV-1 patients (Table 2) (He et al., J. Pathology 210:288-297 (2006); Jiang et al., Am. J. Respir. Care Med.171:850-857 (2005); Huang et al., Lancet 395:565-574 (2020); Niemann et al., Clin. Cancer Res. 22:1572-1582 (2016); Vos et al., Haematologica 102:e455 (2017); Miklos et al., Blood 130:2243-2250 (2017); (Greil et al., Hematological Oncology 37(2); 210-212 (2019)). Table 2. Summary of pro-inflammatory and chemo-attractant cytokine patterns in patients infected with SARS-CoV-1 and SARS-CoV-2 (highlighted in red), and following ibrutinib treatment in patients with CLL, WM, and cGVHD (highlighted in green).

[00439] In the iLLUMINATE randomized study, CLL subjects treated with ibrutinib immediately prior to infusion with obinutuzumab also showed significantly decreased levels of inflammatory cytokines associated with infusion related reactions (a cytokine release syndrome) (Greil et al., Hematological Oncology 37(2); 210-212 (2019)). These findings are consistent with a shift from an M1 to M2 polarized macrophage response following ibrutinib, and are supported by pre-clinical and clinical studies showing dependence of macrophage lineage commitment on BTK function (Fiorcari et al., Oncotarget 7:65968-65981 (2016)). [00440] The potential for ibrutinib to abrogate lung injury and death was also demonstrated in an experimental model wherein mice challenged with a lethal intranasal inoculum of a mouse adapted strain of H1N1 influenza virus were protected against lung injury. Control mice developed respiratory failure, along with histological and CT findings consistent with lung injury in sharp contrast to the mice that received ibrutinib (Florence et al., Am. J. Physiol. Lung Cell Mol. Physiol.315:L52-L58 (2018)). Control mice also lost weight and died, whereas those treated with ibrutinib recovered their weight after a brief loss and all survived (Florence et al., Am. J. Physiol. Lung Cell Mol. Physiol. 315:L52-L58 (2018)). Notably, mice treated with ibrutinib also showed decreased inflammatory cell infiltration as well as pro-inflammatory cytokines in lung tissues that included pro-inflammatory and chemo-attractant cytokines such as IL-1β, IL-6, KC/CXCL1, TNFα, and MCP-1 observed in SARS-Cov-1 and SARS-CoV-2 patients (Florence et al., Am. J. Physiol. Lung Cell Mol. Physiol. 315:L52-L58 (2018)). The findings provide rationale that an exaggerated cytokine release syndrome triggered by ATII cells and resident macrophages by SARS-CoV-2 may underlie pulmonary injury associated with COVID-19. [00441] Ibrutinib and possibly other BTK-inhibitors may therefore provide protection against lung injury, and even improve pulmonary function in hypoxic patients with COVID- 19 as observed in this series of WM patients on ibrutinib. Patients on ibrutinib, and possibly other BTK-inhibitors may well benefit with continuation of their therapy despite the diagnosis of COVID-19. It will be important to further validate these findings in other patient populations on BTK-inhibitors, including CLL patients. Clinical trials examining the benefit of BTK- inhibitors are being carried out in COVID-19 patients in pulmonary distress, and the outcome of these prospective, randomized studies will be needed to confirm these observations.

[00442] Example 2: Treatment of Patients with Moderate or Severe COVID-19 Infection with Ibrutinib [00443] Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Common symptoms include fever, cough and shortness of breath. Muscle pain, sputum production and sore throat are less common. While the majority of cases result in mild symptoms, some progress to severe pneumonia and multi-organ failure (Guan et al., N. Engl. J. Med.382:1708-1720 (2020)). The rate of deaths per number of diagnosed cases is estimated to be 2-4%, with older individuals >70 years, and those with other co-morbid conditions being at higher risk. Coronaviruses are enveloped single stranded RNA viruses that express four structural proteins including Spiked Proteins (S1,S2), Envelope Protein, Membrane protein, and Nucleocapsid Protein. Binding of SARS-CoV-2 is dependent on cleavage of its S1 protein, that leads to display of S2 protein that permits binding to ACE2, which is highly expressed on alveolar type II cells, the primary target of COVID-19 (FIG.1) (Shen et al., Biochimie 142:1-10 (2017)) TMPSRR2, a serine protease facilitates S1-S2 cleavage of SARS-CoV-2, and blockage of TMPSSR2 by a serine protease inhibitor blocks SARS-CoV-2 pseudoviral particle cell entry (Hoffman et al., Cell 181(2):271- 280 (2020)). TMPSSR2 and the serine protease ADAMS17 also can cleave ACE2, and permit fusion of coronaviruses to the cellular membrane (Heurich et al., J. Virology 88:1293-1307 (2014)). [00444] The SRC family comprises kinases that enable single stranded RNA virion assembly, and entry exemplified by the dengue virus. Use of kinases that target SRC family members such as dasatinib blocks single stranded RNA dengue virus assembly and dissemination (FIG.2) (Chu et al., Proc. Natl. Acad. Sci. USA 104:3520-3525 (2007)). HCK, is an important member of the SRC family that is highly expressed in lung tissues (Lee et al., EBioMedicine 28:151-161 (2018)). [00445] HCK regulates ADAMS17 (Ernst et al., J. Exp. Med. 196:589-604 (2002)), and along with BTK is expressed in resident lung macrophages/monocytes (Tian et al., J. Thorac. Oncol. 15(5):700-704 (2020)). Both HCK and BTK can be activated in response to the innate immune response triggered by TOLL-receptor/MYD88 activation. Transgenic mouse overexpression of activated HCK promotes extensive pulmonary inflammation and enhanced innate immune response characterized by extensive eosinophilic and mononuclear cell infiltration within the lung parenchyma, alveolar airspaces, and around blood vessels, as well as marked epithelial mucus metaplasia in conducting airways (Yao et al., Zhonghua Bing Li

Xue Za Zhi. 49:E009 (2020)). Lungs from these mice show areas of emphysema and pulmonary fibrosis, which together with inflammation results in altered lung function and respiratory distress, particularly in aging mice (Yao et al., Zhonghua Bing Li Xue Za Zhi. 49:E009 (2020)). These pulmonary findings show great overlap with those recently described in the lungs of patients with COVID-19 infection which serous and fibrin exudation with alveolar infiltration consisting majorly of macrophages and monocytes. The blood vessels of alveolar septum were congested, edematous and widened, with modest infiltration of monocytes and lymphocytes (He et al., J. Pathology 210:288-297 (2006); Chen et al., Blood 131:2047-2059 (2018)). Expression of elevated levels of pro-inflammatory cytokines including IL-6, TNF-a, IL-1B MCP-1, TGF-B1 was shown in ACE2-positive cells from autopsy tissue of SARS-1 patients, that may have been causally related to acute lung injury and pathogenesis of SARS-COV-1 that shares 70% homology and a similar pathogenetic mechanism to SARS- COV-2 (12). BTK and HCK can drive inflammatory cytokine production through ERK1/2 and are highly expressed in macrophages and monocytes (Yang et al., Blood 127:3237-3252 (2016)). [00446] Ibrutinib is a highly potent, covalent inhibitor of BTK (biochemical IC₅₀0.5 nM). Ibrutinib is also a potent non-covalent inhibitor of HCK (IC5049 nM) (Byrd et al., N. Engl. J. Med.369:32-42 (2013)). Both BTK and HCK are well within the pharmacologically attainable dosimetry of orally administered ibrutinib (Miklos et al., Blood 130:2243-2250 (2017)). Serially collected blood samples from patients on ibrutinib shows significant reductions in pro-inflammatory cytokines in patients with chronic GVHD (FIG. 3), Waldenstrom's Macroglobulinemia (FIG.4) (Vos et al., Haematologica 102:e455 (2017)), and significantly more so for those patients with CLL randomized to ibrutinib containing arm on the ILLUMINATE STUDY (FIG. 5) (Greil et al., Hematological Oncology 37(2); 210-212 (2019)). The ability to block inflammatory cytokine production to limit pulmonary injury has been observed in patients with severe COVID-19 infections who received treatment with the IL-6 blocking antibody tocilizumab, and a clinical trial examining the use of tocilizumab NCT04306705). The potential for ibrutinib to more broadly inhibit inflammatory cytokines through BTK and HCK suppression, as well as to block serine protease dependent COVI D-19 virus entry may be recognized in patients with moderate or severe COVI D-19 infection.

[00447] Example 3: Utilizing BTK Inhibitors to Treat COVID-19 [00448] Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Common symptoms include fever, cough and shortness of breath. Muscle pain, sputum production and sore throat are less common. While most cases result in mild symptoms, some progress to severe pneumonia and multi-organ failure (Guan et al., N. Engl. J. Med. 382:1708-1720 (2020)). The rate of deaths per number of diagnosed cases is estimated to be 2-4%, with older individuals >70 years, and those with other co-morbid conditions being at higher risk. Coronaviruses are enveloped single stranded RNA viruses that express four structural proteins including Spike Proteins (S1,S2), Envelope Protein, Membrane protein, and Nucleocapsid Protein. During viral infection, host cell proteases cleave the SARS-CoV-2 S protein at the S1/S2 cleavage site, thus allowing the N-terminal S1-ectodomain to recognize the ACE2 receptor, while the C-terminal S2- membrane-anchored protein is involved in viral entry. The ACE2 receptor is highly expressed on alveolar type II cells, the primary target of COVID-19 (Hoffman et al., Cell 181(2):271-280 (2020)). Alveolar Type II cells constitute 5-15% of the lung epithelium. While Alveolar Type I cells are highly adapted for gas exchange, Alveolar Type II cells have a specialized role in innate immune response (Fujino et al., Lab Invest.91:363-378 (2010)). Alveolar Type II cells express Toll receptors and can trigger inflammatory cytokines and chemo-attractants in response to viral and bacterial pathogens that recruit and activate other immune cells including macrophages and neutrophils (Pechkovsky et al., Resp. Res. 6:75 (2005); Wang et al., J. Immunology 182:1296-1304 (2009); Thorley et al., PLOS ONE 6:e21827 (2011); Chuquimia et al., Infection and Immunity 81:381-389 (2013); Werner et al., J. Immunology 193:3842- 3850 (2014)). Highly relevant to coronavirus infection, expression of pro-inflammatory and chemo-attractant cytokines IL1-B, IL6, IP10/CXCL10, MCP-1 and TNF-a were identified in the ACE2-positive cells from autopsy tissue of SARS-CoV-1 infected patients, that appeared causally related to the acute lung injury and pathogenesis observed with SARS-CoV-1 (FIG. 7) (He et al., J. Pathology 210:288-297 (2006)). A similar profile of elevated cytokine levels of IL6, IL8, IP10/CXCL10 and MCP-1 was also reported in the plasma of SARS-CoV-1 patients during the progressive and end stage of infection ((Jiang et al., Am. J. Respir. Care Med.171:850-857 (2005)), a profile more consistent with M1 polarized macrophage response (FIG. 8) (Ley K., J. Immunology 199:2191-2193 (2017); Atri et al., Int. J. Mol. Sci. 19:1801 (2018)).

[00449] SARS-CoV-1 shares 86% homology and has a similar pathogenetic mechanism to SARS-CoV-2 (Chan et al., Emerg. Microbes Infect. 9:221-236 (2020); Heurich et al., J. Virology 88:1293-1307 (2014)). Similar to SARS-CoV-1 patients, SARS-Cov-2 patients that required intensive care showed elevated plasma levels of inflammatory cytokines and chemo- attractants such as IL-2, IL-6, IL-7, IL-10, G-CSF, IP-10/CXCL-10, MCP-1/CCL2, MIP- 1a/CCL3, and TNF-a (Huang et al., Lancet 395:565-574 (2020)). The importance of inflammatory cytokines to lung injury in SARS-CoV-2 infected patients has been suggested by reports of benefit with IL-6 and IL6-receptor blocking antibodies, and clinical trials to examine their use have been initiated (NCT04317092, NCT04306705, NCT04315298). [00450] Previous studies have showed an important role for the TEC family member BTK, and its upstream activator, HCK, a SRC family member in triggering Toll receptor (TLR) mediated signaling (Jeffries et al., J. Biol. Chem.278:26258-26264 (2003); Yang et al., Blood 122:1222-1232 (2013); Yang et al., Blood 127:3237-3252 (2016)). Both BTK and HCK can be triggered by MYD88, a TLR-adaptor protein that signals for all Toll receptors except TLR3 in response to viral and bacterial pathogens, including coronaviruses (Wang et al., mBio. 7(1):e01872-15 (2016)). Alveolar Type II cells express Toll-receptors, as do alveolar macrophages that coordinate inflammatory responses with Alveolar Type II cells (Pechkovsky et al., Resp. Res.6:75 (2005); Wang et al., J. Immunology 182:1296-1304 (2009); Thorley et al., PLOS ONE 6:e21827 (2011); Chuquimia et al., Infection and Immunity 81:381-389 (2013); Werner et al., J. Immunology 193:3842-3850 (2014)). As components of Toll/MYD88 signaling, BTK and HCK can drive inflammatory cytokine production through ERK1/2 (Chen et al., Blood 131:2047-2059 (2018)). [00451] In a transgenic mouse model, overexpression of activated HCK promoted extensive pulmonary inflammation and enhanced innate immune response characterized by extensive eosinophilic and mononuclear cell infiltration within the lung parenchyma, alveolar airspaces, and around blood vessels, as well as marked epithelial mucus metaplasia in conducting airways (Ernst et al., J. Exp. Med. 196:589-604 (2002)). Lungs from these mice show areas of emphysema and pulmonary fibrosis, which together with inflammation resulted in altered lung function and respiratory distress, particularly in aging mice (Ernst et al., J. Exp. Med.196:589- 604 (2002)). Elevated levels of TNF-a were also identified in the bronchoalveolar lavage fluids of these mice following LPS challenge. The pulmonary pathology findings from these mice show great overlap with those described in the lungs of patients with COVID-19 infection which showed serous and fibrin exudation with alveolar infiltration consisting majorly of

macrophages and monocytes. The blood vessels of alveolar septum were also congested, edematous and widened, with modest infiltration of monocytes and lymphocytes (Tian et al., J. Thorac. Oncol. 15(5):700-704 (2020); Yao et al., Zhonghua Bing Li Xue Za Zhi. 49:E009 (2020)). [00452] Ibrutinib is a highly potent, covalent inhibitor of BTK (biochemical IC500.5 nM). Ibrutinib is also a potent reversible inhibitor of HCK (IC₅₀ 49 nM) (Yang et al., Blood 127:3237-3252 (2016); lincs.hms.harvard.edu/db/datasets/20222/results?page=1). The IC50 levels for BTK and HCK are well within the pharmacologically attainable dosimetry of orally administered ibrutinib, although HCK inhibition has not yet been demonstrated in patients under ibrutinib therapy, possibly due to the rapid clearance (Byrd et al., N. Engl. J. Med. 369:32-42 (2013)). Serially collected blood samples from patients with chronic lymphocytic leukemia (CLL), Waldenstrom’s Macroglobulinemia (WM), and chronic graft versus host disease (cGVHD) on ibrutinib monotherapy showed marked reductions in pro-inflammatory and chemo-attractant cytokines that greatly overlapped with those reported elevated in the plasma of SARS-Cov-1 and SARS-COV-2 patients, and in ACE2+ cells from lung tissue of SARS-CoV-1 patients (Table 2) (He et al., J. Pathology 210:288-297 (2016); Jiang et al., Am. J. Respir. Care Med.171:850-857 (2005); Huang et al., Lancet 395:565-574 (2020); Niemann et al., Clin. Cancer Res. 22:1572-1582 (2015); Vos et al., Haematologica 102:e455 (2017); Miklos et al., Blood 130:2243-2250 (2017)). In the iLLUMINATE randomized study, CLL subjects treated with ibrutinib immediately prior to infusion with obinutuzumab also showed significantly decreased levels of inflammatory cytokines associated with infusion related reactions (a cytokine release syndrome) ((Greil et al., Hematological Oncology 37(2); 210-212 (2019)). [00453] The potential for ibrutinib to abrogate lung injury and death was demonstrated in an experimental model wherein mice challenged with a lethal intranasal inoculum of a mouse adapted strain of H1N1 influenza virus were protected against lung injury. Control mice that received phosphate buffered saline (PBS) developed respiratory failure, along with histological and CT findings consistent with lung injury in sharp contrast to the mice that received ibrutinib (FIG.9A-9C) (Florence et al., Am. J. Physiol. Lung Cell Mol. Physiol.315:L52-L58 (2018)). [00454] Mice treated with PBS also lost weight and died, whereas those treated with ibrutinib recovered their weight after a brief loss and all survived (Figure 10) (Florence et al., Am. J. Physiol. Lung Cell Mol. Physiol. 315:L52-L58 (2018)). Notably, mice treated with ibrutinib also showed decreased inflammatory cell infiltration as well as pro-inflammatory cytokines in

lung tissues that included pro-inflammatory and chemo-attractant cytokines such as IL-1β, IL- 6, KC/CXCL1, TNFα, and MCP-1 observed in SARS-Cov-1 and SARS-CoV-2 patients (FIG 11A-11B) (Florence et al., Am. J. Physiol. Lung Cell Mol. Physiol.315:L52-L58 (2018)). [00455] The above findings support the rationale that an exaggerated cytokine response triggered by Alveolar Type II cells and resident macrophages in response to SARS-CoV-2 is etiological for the pulmonary injury and respiratory failure associated with COVID-19 infection. The importance of inflammatory cytokines to lung injury in SARS-CoV-2 infected patients has been suggested by reports of benefit with IL-6 and IL6-receptor blocking antibodies, and clinical trials to examine their use have been initiated (NCT04317092, NCT04306705, NCT04315298). The ability to block inflammatory cytokine production to limit pulmonary injury has been observed in patients with severe COVID-19 infections who received treatment with the IL-6 blocking antibody tocilizumab. [00456] Ibrutinib blocks Toll-receptor signaling, and cytokines associated with SARS-CoV- 2, including those found in Alveolar Type II (ACE2+) cells. Importantly, in a relevant experimental mouse model, ibrutinib protected mice subjected to lethal intranasal inoculums of mouse adapted H1N1 influenza and suppressed inflammatory cell recruitment and pathological cytokines that overlapped with many of those observed in SARS-CoV-2 infected patients. Ibrutinib and other BTK inhibitors provides protection against lung injury in patients with COVID-19 related pulmonary distress. [00457] Example 4: Treatment of Patients Hospitalized for Covid-19 Infection And Pulmonary Distress With Ibrutinib OBJECTIVES Study Design [00458] There is currently no standard of care for hospitalized patients experiencing COVID- 19 infections beyond supportive care. Numerous studies examining various study interventions are underway. Discovering/providing treatment options for patients with moderate or severe COVID-19 infection is a high priority, particularly for those with respiratory distress. Exaggerated cytokine response triggered by Alveolar Type II cells and resident macrophages in response to SARS-CoV-2 appears etiological for the pulmonary injury and respiratory failure associated with COVID-19 infection. Ibrutinib blocks Toll-receptor signaling, and cytokines associated with SARS-CoV-2, including those found in Alveolar Type II (ACE2+) cells. Importantly, in a relevant experimental mouse model, ibrutinib protected mice subjected

to lethal intranasal inoculums of mouse adapted H1N1 influenza and suppressed inflammatory cell recruitment and pathological cytokines that overlapped with many of those observed in SARS-CoV-2 infected patients. Based on this, it is hypothesized that Ibrutinib and possibly other BTK-inhibitors may potentially provide protection against lung injury. Ibrutinib is an oral agent approved by the U.S. FDA, European Medicines Agency, and other global health authorities for the treatment of various B-cell malignancies. For those subjects/patients whose health care providers feel that they qualify to participate in this study, who meet inclusion/exclusion criteria and sign an associated consent form, they will be offered ibrutinib at 560 mg a day for 14 days followed by 420 mg daily for the remaining 14 days, for up to 28 days so long as patient is able to tolerate therapy. An extension of 28 days of ibrutinib is permitted in patients who have recurring symptoms consistent with COVID-19 after completing 28 days of therapy. See, FIG.6A. Primary Objectives [00459] To evaluate if the addition of ibrutinib to supportive care leads to more rapid improvement in fever and pulmonary function through day 14 in hospitalized COVID-19 infected patients experiencing pulmonary distress. Secondary Objective [00460] To assess the safety and tolerability of ibrutinib as an adjuvant therapy to supportive care in hospitalized COVID-19 infected patients experiencing pulmonary distress. Study Disease(s) [00461] Screening evaluations for COVID-19 for eligibility are to be conducted within 4 days prior to start of ibrutinib including RT-polymerase chain reaction (PCR) from nasopharyngeal swabs. Hospitalized patients with COVID-19 infection will be defined as all of the following: [00462] Currently hospitalized with fever defined as temperature ≥ 36.6°C armpit, ≥ 37.2°C oral, or ≥ 37.8°C rectal or tympanic. [00463] Peripheral capillary oxygen saturation (SpO2) ≤ 92% on room air at screening. [00464] Radiographic evidence of pulmonary infiltrates. IND Agent [00465] Ibrutinib is an irreversible inhibitor of Bruton’s Tyrosine Kinase (BTK) that is approved by the U.S. FDA for the treatment of adult patients with: [00466] Mantle cell lymphoma (MCL) who have received at least one prior therapy.

[00467] Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. [00468] Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL). [00469] Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion. [00470] Waldenström's macroglobulinemia (WM). [00471] Marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy. [00472] Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. [00473] Chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy. PARTICIPANT SELECTION Eligibility Criteria [00474] Inclusion Criteria [00475] Age > 18 years. [00476] Willing and able to provide written informed consent prior to therapy. [00477] Patient requires hospitalization for COVID-19. [00478] Patient has Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection confirmed by polymerase chain reaction (PCR) test before study entry including all three following features: [00479] Currently hospitalized with fever defined as temperature ≥ 36.6°C armpit, ≥ 37.2°C oral, or ≥ 37.8°C rectal or tympanic. [00480] Peripheral capillary oxygen saturation (SpO2) ≤ 92% on room air at screening. [00481] Radiographic evidence of pulmonary infiltrates. [00482] Females of childbearing potential (FCBP) must use one reliable form of contraception or have complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) while participating in the study; and 2) for at least 90 days after discontinuation from the study. FCBP must be referred to a qualified provider of contraceptive methods if needed. FCBP must have a negative serum pregnancy test as of screening.

[00483] Men must agree to use a latex condom during treatment and for up to 90 days after the last dose of ibrutinib during sexual contact with a FCBP. [00484] Adequate hematologic function defined as: [00485] Absolute neutrophil count (ANC) > 750 cells/mm3 (0.75 x 109/L) [00486] Platelet count > 50,000 cells/mm3 (50 x 109/L) [00487] Adequate hepatic and renal function defined as: [00488] Estimated Creatinine Clearance (CrCl) ≥30 mL/min (Cockcroft-Gault). [00489] Bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non- hepatic origin). [00490] Prothrombin time (PT)/International normal ratio (INR) < 1.5 x (upper limit of normal) ULN and PTT (activated partial thromboplastin time [aPTT]) < 1.5 x ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder). When treated with warfarin or other vitamin K antagonists, then INR ≤ 3.0). [00491] Key Exclusion Criteria [00492] Participation in any other clinical trial of an experimental treatment for COVID-19 [00493] Concurrent treatment with other agents with actual or possible direct acting antiviral activity against SARS-CoV-2 is prohibited < 24 hours prior to study entry (e.g remdesivir or the antiparasitic agent, chloroquine, and hydroxy chloroquine (with or without Z-Pac) [00494] Requiring mechanical ventilation at screening [00495] Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction [00496] Known bleeding disorders (e.g., von Willebrand’s disease or hemophilia) [00497] Patients in whom surgery is anticipated to be necessary within 72 hours. [00498] History of stroke or intracranial hemorrhage within 6 months prior to enrollment. [00499] Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded. [00500] Major surgery within 4 weeks of study entry in patients whom surgery is anticipated to be necessary within 72 hours.

[00501] Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization. [00502] Asymptomatic arrythmias (e.g NSVT, bradycardia HR less <50, or AV block, or any other atrial or ventricular arrythmia) and or EF <40% on a baseline echo. [00503] Subjects receiving a strong cytochrome P450 (CYP) 3A4 inhibitor with the exception of those receiving anti-fungal therapy/prophylaxis. [00504] Subjects with chronic liver disease and hepatic impairment meeting Child Pugh class C. [00505] Female subjects who are pregnant, or breastfeeding, or planning to become pregnant while enrolled in this study or within 1 month of last dose of study drug. Male subjects who plan to father a child while enrolled in this study or within 3 months after the last dose of study drug. [00506] Unwilling or unable to participate in all required study evaluations and procedures [00507] Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations). [00508] Inclusion of Women and Minorities [00509] Both men and women of all races and ethnic groups are eligible for this trial. REGISTRATION [00510] General Guidelines for DF/HCC Institutions [00511] Institutions will register eligible participants in the Clinical Trials Management System (CTMS) OnCore. Registrations must occur prior to the initiation of any protocol- specific therapy or intervention. Any participant not registered to the protocol before protocol- specific therapy or intervention begins will be considered ineligible and registration will be denied. [00512] An investigator will confirm eligibility criteria and a member of the study team will complete the protocol-specific eligibility checklist. [00513] An email confirmation of the registration will be sent to the study coordinator(s) from the registering site, treating investigator and registering person immediately following the registration and/or randomization.

[00514] Following registration, participants may begin protocol-specific therapy and/or intervention. Issues that would cause treatment delays should be discussed with the Principal Investigator (PI) of the registering site. If the subject does not receive protocol therapy following registration, the subject must be taken off study in the CTMS (OnCore) with an appropriate date and reason entered. [00515] Registration Process for DF/HCC Institutions [00516] Applicable DF/HCC policy (REGIST-101) must be followed. TREATMENT PLAN [00517] Once registered, patients will begin ibrutinib at 560 mg/day by mouth for 14 days. Thereafter patients will receive ibrutinib at 420 mg/day for an additional 14 days. Patients may receive an additional 28 days of ibrutinib treatment at 420 mg/day if they experience symptom recurrence related to COVID-19. Dose-escalation will also be permitted to 560 mg/day if patients experience symptom recurrence related to COVID-19 following dose de-escalation to 420 mg/day. Nasogastric tube administration of ibrutinib is permitted for patients unable to take ibrutinib orally. Dose-de-escalation for toxicity is permitted (see below). Patients may receive any supportive care treatments and/or interventions, however, infection prophylaxis and dose modifications may be necessary in certain situations (see below). Other investigational agents should not be administered with the intent to treat COVID-19 infection. Administration of ibrutinib therapy and dosing should be recorded in the patient’s medical record. A diary will be provided for discharged patients to record daily dosing. Treatment Criteria [00518] Treatment should be withheld for adverse events as outlined below: [00519] Grade 3 or 4 nausea, vomiting, or diarrhea (if persistent despite optimal antiemetic [00520] and/or antidiarrheal therapy) related to ibrutinib. [00521] Grade 4 or unmanageable nonhematologic grade 3 toxicities related to ibrutinib [00522] Neutrophil count </=500/μL [00523] In subjects without baseline thrombocytopenia: [00524] Platelet count </= 50,000/μL in the presence of bleeding [00525] Platelet count </= 25,000 μL without bleeding [00526] For AEs that are felt to be related to worsening Covid-19 infection, the investigator may continue ibrutinib, however, in patients with hepatic or cardiac dysfunction, bleeding, or multiple infections related to Covid-19 infection, the risks of continuing ibrutinib may outweigh the potential benefit of continuing treatment with ibrutinib.

Agent Administration [00527] Ibrutinib 420 mg or 560 mg is administered orally once daily. The capsules are to be taken around the same time each day with a glass of water. The capsules should be swallowed intact and subjects should not attempt to open capsules or dissolve them in water. For patients who require NGT placement while on study, ibrutinib may be administered by opening the capsules, mixing with water, and flushing down the NGT. Though the use of strong CYP3A inhibitors/inducers, and grapefruit and Seville oranges should be avoided for the duration of treatment, treatment with antifungal prophylaxis (e.g. voriconazole, posaconazole) is permitted; however, dose reductions of ibrutinib are necessary (see below). If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. The subject should not take extra capsules to make up the missed dose. [00528] While binding to BTK is covalent, inhibition of SRC family members including HCK, FYN and LYN is non-covalent, and maintenance of sufficient drug levels may be necessary to maintain their inhibition. For this reason, patients will be initiated at 560 mg/day for 14 days, and thereafter dose de-escalated to 420 mg/day for 14 additional days. For patients experiencing recurrence of symptoms deemed related to COVID-19 infection, an additional treatment period of 28 days will be permitted at the dose of 420 mg/day. Dose escalation will also be permitted from 420 mg/day to 560 mg/day if the patient at any time experiences recurrence of symptoms deemed related to COVID-19 infection following dose de-escalation. [00529] Dose reductions for toxicity will be permitted (see below). Dose re-escalation to the start dose will also be permitted for patients reduced below 420 mg/day if toxicities that prompted dose de-escalation have resolved. [00530] For hospitalized patients, ibrutinib will be administered by nursing staff. For patients discharged from the hospital, ibrutinib will be self-administered, and participants will be instructed to write in a diary daily, documenting that the drug was taken and adverse events experienced. Patients should be instructed to take the study drug with a glass of water at approximately the same time each day. Patients taking ibrutinib at home will be instructed on how to complete the diary by study staff prior to discharge. If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. The subject should not take extra capsules to make up the missed dose. The missed dose will not be made up and must be returned at the next scheduled visit. The patient will be instructed to document missed drug doses in the study diary. Furthermore,

they will be instructed to call their provider, the principal investigator or research nurse if vomiting occurs or they have recurrence of their COVID-19 symptoms or any other adverse events consistent with the product label. If the pills are vomited, this should be noted on the patient diary, but a replacement dose should not be taken that day. All dosages prescribed and dispensed to the patient, and all dose changes during the study should be recorded. Diaries will be collected at the treatment period. In the event of circumstances that prevent a patient from coming to clinic, the principal investigator may permit up to 28 day supply of drug to be sent to the patient by a trackable delivery service, and receipt confirmed. A log book of such supplies shall be kept by the study team that will include shipping information, telephone log confirming receipt, and reason that emergency supply was dispatched to the subject. [00531] Drug accountability will be done at each clinic visit; unused drug and diaries will be collected from the patient, unused drug will be counted and returned to the pharmacy to be destroyed. A new prescription for dispensing ibrutinib for at home use, as detailed above, will be filled by the study pharmacy. Medication labels will comply with US legal requirements and be printed in English. Ibrutinib is formulated as capsules for oral administration and will be available for this study in 140mg and 70mg capsules. Overdose [00532] Any dose of study drug in excess of that specified in this protocol is considered to be an overdose. Signs and symptoms of an overdose that meet any Serious Adverse Event criterion must be reported as a Serious Adverse Event in the appropriate time frame and documented as clinical sequelae to an overdose. There is no specific experience in the management of ibrutinib overdose in patients. There are limited data on the effects of ibrutinib overdose. No maximum tolerated dose (MTD) was reached in the Phase 1 study in which subjects received up to 12.5 mg/kg/day (1,400 mg/day). In a separate study 1 healthy subject who received a dose of 1,680 mg experienced reversible Grade 4 hepatic enzyme increases (AST and ALT). Refer to the IB for additional details about this case. There is no specific antidote to ibrutinib. Subjects who ingest more than the recommended dosage should be closely monitored and given appropriate supportive treatment. General Concomitant Medication and Supportive Care Guidelines [00533] Supportive care medications and intervention for COVID-19 infection, including use of a ventilator support as clinically indicated is permitted at the treating physician’s discretion. Careful monitoring for signs and symptoms of bleeding are indicated, consistent with the safety profile of ibrutinib. Anti-emetics are permitted if clinically indicated. All concomitant

medications during the treatment period should be recorded. The following restrictions apply during the entire duration of the study: [00534] No other investigational therapy for COVID-19 should be given to participants. [00535] For cancer patients, no other anti-neoplastic therapy including radiation therapy should be given to participants during the treatment period. If such agents are required, then the patient must first be withdrawn from receiving ibrutinib. [00536] The use of concomitant steroids if possible, should be avoided or minimized (if medically possible). If steroids are necessary, strongly consider treatment with an appropriate anti-fungal prophylaxis agent (e.g voriconazole/posaconazole). Consider the addition of anti- bacterial prophylaxis as clinically necessary [00537] Growth factors (i.e. G-CSF, GM-CSF, erythropoietin, platelets growth factors etc.) and transfusion support is permitted. [00538] Concomitant use of anti-platelet agents and anticoagulants should be avoided (if possible) due to the anti-platelet effects of ibrutinib, however their use may be clinically necessary. [00539] The use of DVT prophylaxis is permitted. Participants receiving anti-platelet agents in conjunction with ibrutinib should be observed closely for any signs of bleeding or bruising, and ibrutinib should be withheld in the event of any grade 2 or higher bleeding events until complete resolution to < grade 1. Participants with any grade CNS bleeding should have treatment discontinued. [00540] Subjects requiring the initiation of therapeutic anticoagulation therapy (eg, atrial fibrillation), consider the risks and benefits of continuing ibrutinib treatment. If therapeutic anticoagulation is clinically indicated, treatment with ibrutinib should be held and not be restarted until the subject is clinically stable and has no signs of bleeding. Subjects should be observed closely for signs and symptoms of bleeding. No dose reduction is required when study drug is restarted. [00541] Supplements such as fish oils and vitamin E preparations should be avoided. [00542] Use ibrutinib with caution in subjects requiring other anticoagulants or medications that inhibit platelet function. [00543] Medications to be Used with Caution [00544] CYP3A Enzyme Inhibitors/Inducers [00545] Ibrutinib is primarily metabolized by CYP3A4. Concomitant use of ibrutinib and drugs that strongly or moderately inhibit CYP3A can increase ibrutinib exposure, and strong

CYP3A inhibitors should be avoided. Avoid grapefruit and Seville oranges during ibrutinib treatment as these contain moderate inhibitors of CYP3A. Dose adjustment of ibrutinib due to concomitant use of CYP3A inhibitors should follow Table 3 below as applicable. Table 3. Ibrutinib Dose Modification Guidance for Co-Administration with CYP3A Inhibitors

[00546] Monitor for adverse reactions to IMBRUVICA and interrupt or modify dose as recommended (see Dosage and Administration). [00547] Posaconazole at higher doses (posaconazole suspension 200 mg three times daily or 400 mg twice daily, posaconazole IV injection 300 mg once daily, posaconazole delayed- release tablets 300 mg once daily).

[00548] A list of common CYP3A inhibitors and inducers is provided in. For further information, the current version of the ibrutinib IB and examples of inhibitors, inducers, and substrates can be found at medicine.iupui.edu/clinpharm/ddis/main-table/. [00549] This website is continually revised and should be checked frequently for updates. [00550] Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib [00551] In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp) nor other major transporters, except OCT2. The dihydrodiol metabolite and other metabolites are P-gp substrates. Ibrutinib is a mild inhibitor of P-gp and breast cancer resistance protein (BCRP). Ibrutinib is not expected to have systemic drug-drug interactions with P-gp substrates. However, it cannot be excluded that ibrutinib could inhibit intestinal P-gp and BCRP after a therapeutic dose. There is no clinical data available. To minimize a potential interaction in the GI tract, narrow therapeutic range P-gp substrates such as digoxin or methotrexate, should be taken at least 6 hours before or after ibrutinib. Ibrutinib may also inhibit BCRP systemically and increase the exposure of drugs that undergo BCRP-mediated hepatic efflux, such as rosuvastatin. [00552] Antiplatelet Agents and Anticoagulants (Section [00550] ) [00553] Use ibrutinib with caution in subjects requiring anticoagulants or medications that inhibit platelet function. In an in vitro platelet function study, inhibitory effects of ibrutinib on collagen induced platelet aggregation were observed. Supplements such as fish oil and vitamin E preparations should be avoided during treatment with ibrutinib. Bleeding events of any grade, including bruising and petechiae, occurred in subjects treated with ibrutinib. Ibrutinib should be held at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding. Subjects with congenital bleeding diathesis have not been studied. [00554] Guidelines for Ibrutinib Management with Surgeries or Procedures (Section [00554] ) [00555] Ibrutinib may increase risk of bleeding with invasive procedures or surgery. The following guidance should be applied to the use of ibrutinib in the perioperative period for subjects who require surgical intervention or an invasive procedure while receiving ibrutinib. [00556] Minor Surgical Procedures [00557] For minor procedures (except as noted below) that are urgently needed, consider transfusion with platelets just prior to procedure otherwise consider holding ibrutinib for 1-3 days prior to the procedure and should not be restarted for 1-3 days after the procedure depending on anticipated bleeding risk of procedure.

[00558] For central line placement, NGT placement, bronchoscopy, or endotracheal intubation, ibrutinib should be temporarily stopped for 24 hours before the procedure, if possible. If there is evidence of bleeding at the time of the procedure a platelet transfusion should be given. If bleeding does occur, ibrutinib should be temporarily stopped and the primary investigator should be contacted. If there is no evidence of bleeding during or post- procedure, ibrutinib may be resumed. [00559] For subjects who require endotracheal intubation after enrollment on the trial, ibrutinib may be continued if, in the opinion of the investigator, the patient appears to be benefiting from treatment with ibrutinib and the risk of continuing therapy with ibrutinib outweighs the risks associated with ibrutinib (e.g. bleeding). [00560] Major Surgical Procedures [00561] For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib should be held at least 7 days prior to the intervention (except for emergency procedures) and should be held at least 7 days after the procedure and restarted at the discretion of the investigator when the surgical site is reasonably healed without serosanguineous drainage or the need for drainage tubes. [00562] Emergency Procedures [00563] For emergency procedures, ibrutinib should be held after the procedure until the surgical site is reasonably healed, or for at least 7 days after the urgent surgical procedure, whichever is longer. Consider the use of platelet transfusions to reduce bleeding risk or active bleeding. [00564] Duration of Therapy [00565] Duration of therapy will depend on individual response, evidence of pulmonary disease progression and tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue until one of the following criteria applies: [00566] Intercurrent illness that in the medical judgment of the treating physician prevents further administration of treatment [00567] Unacceptable adverse event(s) [00568] Patient demonstrates an inability or unwillingness to comply with the oral medication regimen and/or documentation requirements [00569] Patient decides to withdraw from the protocol therapy [00570] General or specific changes in the participant's condition render the participant unacceptable for further treatment in the judgment of the treating investigator

[00571] Patients will be removed from the protocol therapy when any of these criteria apply. The reason for removal from protocol therapy, and the date the participant was removed, must be documented in the medical record. Alternative care options will be discussed with the participant. [00572] When a participant is removed from protocol therapy and/or is off of the study, the participant’s status must be updated in OnCore in accordance with REGIST-OP-1. [00573] Duration of Follow Up [00574] Participants will be followed for 4 weeks after completion of therapy or until death, whichever occurs first. Participants removed from protocol therapy for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event. [00575] Criteria for Taking a Participant Off Study [00576] Participants will be removed from study when any of the following criteria apply: [00577] Lost to follow-up [00578] Withdrawal of consent for data submission [00579] Death [00580] The reason for taking a participant off study, and the date the participant was removed, must be documented in the case report form (CRF). In addition, the study team will ensure the participant’s status is updated in OnCore in accordance with REGIST-OP-1. [00581] DOSING DELAYS/DOSE MODIFICATIONS [00582] Dose delays and modifications will be made using above. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose modifications. A copy of the CTCAE version 5.0 can be downloaded from the CTEP website: ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. [00583] In the case of toxicity, appropriate medical treatment should be used (including anti- emetics, antidiarrheals, etc.). All adverse events experienced by patients that at least may be possibly related to ibrutinib will be collected from the time of the first dose of study treatment, through the end of therapy should be documented in the medical record. If patients continue to experience ibrutinib toxicity at the end of treatment, they may be contacted for additional assessments until the toxicity has resolved or is deemed irreversible. Dose de-escalations for toxicity will be performed as follows:

[00584] Dosing will be held for any of the following conditions: [00585] Grade 4 ANC (< 500/μL). Neutrophil growth factors may be used for ANC recovery. [00586] Grade 3 Platelets (< 50,000/μL) in the presence of clinically significant bleeding events; or [00587] Grade 4 Platelets (< 25,000/μL). Platelet transfusions may be used for platelet recovery. [00588] Grade 3 or 4 nausea, vomiting, or diarrhea (if persistent despite optimal antiemetic and/or antidiarrheal therapy). [00589] Any other ibrutinib related grade 4 toxicities and any unmanageable non- hematologic Grade 3 or higher toxicities. [00590] For Grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade, consider the risks and benefits of restarting and continuing ibrutinib treatment. If clinically indicated, the use of non-warfarin or vitamin k antagonist anticoagulants or antiplatelet agents may be considered for the thromboprophylaxis of atrial fibrillation. [00591] For AEs that are felt to be related to worsening Covid-19 infection, the investigator may continue ibrutinib, however, in patients with hepatic or cardiac dysfunction, bleeding, or

multiple infections related to Covid-19 infection, the risks of continuing ibrutinib may outweigh the potential benefit of continuing treatment with ibrutinib. [00592] Dose Modification for Hepatic Impaired Patients [00593] Subjects who develop acute hepatic toxicity as reflected by an increase in bilirubin should be treated as outlined in Table 4 below. Table 4: Dose Modification Guidance for Acute Hepatic Impaired Subjects

[00594] For subjects with mild chronic liver impairment (Child-Pugh class A), the recommended dose is 280mg daily. For subjects with moderate chronic liver impairment (Child-Pugh class B), the recommended dose is 140mg daily. Monitor subjects for signs of ibrutinib toxicity and follow dose modification guidance as needed. It is not recommended to administer ibrutinib to subjects with severe hepatic impairment Subjects with clinically significant chronic hepatic impairment at the time of Screening (Child- Pugh class C) are excluded from study participation. Concomitant use of strong CYP inhibitors is not permitted in subjects with chronic hepatic impairment. Table 5 shows dose modifications due to chronic hepatic impairment.

Table 5: Dose Modification Guidance for Chronic Hepatic Impaired Subjects

[00595] * If further reduction is needed due to non-hepatic toxicity, dose may be reduced to 140 mg. In the event that additional reduction is needed, ibrutinib should be held for non- hepatic toxicity until resolution. [00596] ** If further reduction is needed due to non-hepatic toxicity, ibrutinib should be held until resolution. [00597] ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS (Section 7.0) [00598] Adverse event (AE) deemed at least possibly related to ibrutinib will be collected. Additionally, lab abnormalities which are clinically significant will be collected. The following list of reported and/or potential AEs and the characteristics of an observed AE will determine whether the event requires expedited reporting in addition to routine reporting. [00599] Adverse Event List for Ibrutinib [00600] Risks [00601] Bleeding-related events [00602] There have been reports of hemorrhagic events in subjects treated with ibrutinib both with and without thrombocytopenia. These include primarily minor hemorrhagic events such as contusion, epistaxis, and petechiae; and major hemorrhagic events, some fatal, including gastrointestinal bleeding, intracranial hemorrhage and hematuria. Use of ibrutinib in subjects requiring other anticoagulants or medications that inhibit platelet function may increase the risk of bleeding. In an in vitro platelet function study, inhibitory effects of ibrutinib on

collagen-induced platelet aggregation were observed. A higher risk for major bleeding was observed with anticoagulant than with antiplatelet agents. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with ibrutinib. Monitor for signs and symptoms of bleeding. Supplements such as fish oil and vitamin E preparations should be avoided. Subjects with congenital bleeding diathesis have not been studied. See Section [00550] for guidance on concomitant use of anticoagulants, antiplatelet therapy and/or supplements. See Section [00554] for guidance on ibrutinib management with surgeries or procedures. [00603] Cardiac Arrhythmias [00604] Atrial fibrillation, atrial flutter, and cases of ventricular tachyarrhythmia including some fatal events, have been reported in subjects treated with ibrutinib, particularly in subjects with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmia. Periodically monitor subjects clinically for cardiac arrhythmia. Subjects who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest discomfort or new onset of dyspnea) should be evaluated clinically, and if indicated, have an ECG performed. For cardiac arrhythmias which persist, consider the risks and benefits of ibrutinib treatment and follow the protocol dose modification guidelines [00605] Hypertension [00606] Hypertension has occurred in subjects treated with ibrutinib. Regularly monitor blood pressure in subjects treated with ibrutinib and initiate or adjust antihypertensive medication throughout treatment with ibrutinib as appropriate. [00607] Cerebrovascular Accidents [00608] Although causality has not been established, cases of cerebrovascular accident, transient ischemic attack, and ischemic stroke including fatalities have been reported with the use of ibrutinib in the post-marketing setting, with and without concomitant atrial fibrillation and/or hypertension. Regular monitoring and appropriate treatment of conditions that can contribute to the occurrence of these events is recommended. [00609] Cytopenias [00610] Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) have been reported in subjects treated with ibrutinib. [00611] Diarrhea [00612] Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and combination therapy. Other frequently reported gastrointestinal events

include nausea, vomiting, and constipation. These events are rarely severe and are generally managed with supportive therapies including antidiarrheals and antiemetics. Subjects should be monitored carefully for gastrointestinal AEs and cautioned to maintain fluid intake to avoid dehydration. Medical evaluation should be made to rule out other etiologies such as Clostridium difficile or other infectious agents. Should symptoms be severe or prolonged, follow the protocol dose modification guidelines. [00613] Infections [00614] Infections (including sepsis, bacterial, viral, or fungal infections) were observed in subjects treated with ibrutinib therapy. Some of these infections have been associated with hospitalization and death. Consider prophylaxis according to standard of care in subjects who are at increased risk for opportunistic infections. Although causality has not been established, cases of progressive multifocal leukoencephalopathy and hepatitis B reactivation have occurred in subjects treated with ibrutinib. Subjects should be monitored for signs and symptoms (fever, chills, weakness, confusion, vomiting and jaundice) and appropriate therapy should be instituted as indicated. [00615] Non-Melanoma Skin Cancer [00616] Non-melanoma skin cancers have occurred in patients treated with ibrutinib. Monitor patients for the appearance of non-melanoma skin cancer. [00617] Rash [00618] Rash has been commonly reported in subjects treated with either single agent ibrutinib or in combination with chemotherapy. In a randomized Phase 3 study (PCYC-1112- CA), rash occurred at a higher rate in the ibrutinib arm than in the control arm. Most rashes were mild to moderate in severity. Isolated cases of severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) have been reported in subjects treated with ibrutinib. Subjects should be closely monitored for signs and symptoms suggestive of SCAR including SJS. Subjects receiving ibrutinib should be observed closely for rashes and treated symptomatically, including interruption of the suspected agent as appropriate. In addition, hypersensitivity-related events including erythema, urticaria, and angioedema have been reported. [00619] Interstitial Lung Disease (ILD) [00620] Cases of interstitial lung disease (ILD) have been rarely reported in patients treated with ibrutinib. It may be difficult to separate from those of COVID-19. Monitor patients for pulmonary symptoms indicative of ILD, and if suspected to be ibrutinib related, discontinue

therapy. If symptoms develop, interrupt ibrutinib and manage ILD appropriately. If symptoms persist, consider the risks and benefits of ibrutinib treatment and follow the protocol dose modification guidelines [00621] Pregnancy [00622] Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy. However, should a pregnancy occur in a female study subject, consent to provide follow-up information regarding the outcome of the pregnancy and the health of the infant until 30 days old will be requested. A female subject must immediately inform their treating physician if she becomes pregnant from the time of consent to 30 days after the last dose of ibrutinib. A male subject must immediately inform the treating physician if his partner becomes pregnant from the time of consent to 90 days after the last dose of ibrutinib. Any female subjects receiving study drug(s) who become pregnant must immediately discontinue ibrutinib. The Investigator should counsel the subject, discussing any risks of continuing the pregnancy and any possible effects on the fetus. Although pregnancy itself is not regarded as an adverse event, the outcome will need to be documented. Any pregnancy occurring in a subject or subject’s partner from the time of consent to 30 days (or 90 days for male partners) after the last dose of study drug must be reported. Any congenital anomaly/birth defect noted in the infant must be reported as a serious adverse event. [00623] Other Malignancies [00624] All new malignant tumors including solid tumors, skin malignancies and hematologic malignancies will be reported for the duration of study treatment and during any protocol specified follow-up periods including post-progression follow-up for overall survival. If observed, enter data in the corresponding eCRF.

T

[00625] Adverse Event Characteristics [00626] CTCAE term (AE description) and grade: The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. [00627] For expedited reporting purposes only: [00628] AEs for the agent(s) that are listed above should be reported only if the adverse event varies in nature, intensity or frequency from the expected toxicity information which is provided. [00629] Other AEs for the protocol that do not require expedited reporting are outlined in the next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-Specific Expedited Adverse Event Reporting Exclusions. [00630] Attribution of the AE: [00631] Definite – The AE is clearly related to the study treatment. [00632] Probable – The AE is likely related to the study treatment. [00633] Possible – The AE may be related to the study treatment. [00634] Unlikely – The AE is doubtfully related to the study treatment. [00635] Unrelated – The AE is clearly NOT related to the study treatment. [00636] Expedited Adverse Event Reporting [00637] Investigators must report to the Overall PI any serious adverse event (SAE) that occurs after the initial dose of ibrutinib, during treatment, or up to 30 days of the last dose of treatment on the local institutional SAE form. [00638] Investigative sites will report SAEs directly to the DFCI Office for Human Research Studies (OHRS) per the DFCI IRB reporting policy. Grade 3 and 4 expected hematologic events that have not induced clinical signs or symptoms do not require separate reporting as serious adverse events. [00639] Expedited Reporting Guidelines [00640] Use the protocol number and the protocol-specific participant ID assigned during trial registration on all reports. Note: A death on study requires both routine and expedited reporting regardless of causality, unless as noted below. Attribution to treatment or other cause must be provided. [00641] Expedited Reporting to FDA

[00642] Expedited Reporting to Hospital Risk Management [00643] Participating investigators will report to their local Risk Management office any participant safety reports or sentinel events that require reporting according to institutional policy. [00644] Routine Adverse Event Reporting [00645] Information on all Grade 2 or higher adverse events that at least are possibly related to ibrutinib will be reported in routine study data submissions to the Overall PI on the toxicity case report forms. AEs reported through expedited processes (e.g., reported to the IRB, FDA, etc.) must also be reported in routine study data submissions. [00646] PHARMACEUTICAL INFORMATION [00647] Ibrutinib [00648] Description [00649] Ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl]-1- piperidinyl]-2-propen-1-one and has a molecular weight of 440.50 g/mole (anhydrous basis). Ibrutinib exhibited 18% to 23% oral bioavailability in rats and 7% to 11% oral bioavailability in dogs. The mean terminal half-life of ibrutinib after oral administration ranged from 1.7 to 3.1 hours in mice, 1 to 4.7 hours in rats, and 3.3 to 6.4 hours in dogs. Preliminary results suggest a 1.5- to 2.5-hour half-life of ibrutinib in humans. The effects of renal and/or hepatic impairment on drug clearance are not known at this time. In vitro studies have indicated that ibrutinib is metabolized extensively by cytochrome P450 (CYP) 3A4. [00650] Form [00651] Ibrutinib is a white to off-white crystalline solid. Ibrutinib has a single chiral center and is the R-enantiomer. Ibrutinib product is is an oral formulation containing micronized ibrutinib and the following compendial excipients: microcrystalline cellulose (NF); croscarmellose sodium (NF); sodium lauryl sulfate (NF); may contain magnesium stearate (NF). The 140 mg strength contains 140 mg of the active ingredient, ibrutinib, adjusted for water content and purity in a size 0, gray, hard gelatin capsule. Capsules are packaged in 60-cc high-density polyethylene (HDPE) bottles with an induction seal and a child resistant screw

top cap. The number of capsules per bottle is indicated on the label. The HDPE bottles are labeled with the appropriate information and intended for distribution to participants. [00652] Storage and Stability [00653] The recommended storage condition for ibrutinib PO Hard Gelatin Capsule is at 15°C to 25°C [59°F to 77°F] with excursions permitted to 30°C (86°F). Under these conditions, the drug product is expected to remain within specifications for at least 6 months. Total accumulative excursions between 25°C and 30°C must not exceed 12 months. Formal ICH stability studies are ongoing to determine the shelf-life of the product. [00654] Handling [00655] Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the environment, should undertake the preparation, handling, and safe disposal of the chemotherapeutic agent in a self-contained and protective environment. [00656] Administration [00657] Ibrutinib should be self-administered daily by the participant and should be taken at approximately the same time each day. Ibrutinib is intended to be administered orally once daily with 8 ounces (approximately 240 mL) of water (avoid GRAPEFRUIT JUICE and Seville Orange Juice Products due to CYP4503A4 inhibition). The capsules should be swallowed intact and participants should not attempt to open capsules or dissolve them in water. [00658] If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. The subject should not take extra capsules to make up the missed dose. The missed dose will not be made up and must be returned to the site at the next scheduled visit. If the pills are vomited this should be noted on the diary, but a replacement dose should not be taken that day. A study diary will be used to aid with study drug administration compliance for patients taking drug in a non-hospital setting. [00659] Accountability [00660] The investigator, or a responsible party designated by the investigator, should maintain a careful record of the inventory and disposition of the agent using the NCI Drug Accountability Record Form (DARF) or another comparable drug accountability form. (See the NCI Investigator’s Handbook for Procedures for Drug Accountability and Storage). [00661] Destruction and Return [00662] Unused ibrutinib capsules will be returned by the participant, collected and counted at each study visit and will be returned to pharmacy for destruction. Unused supplies of ibrutinib will be destroyed according to institutional policies.

[00663] STUDY CALENDAR [00664] Screening evaluations for eligibility are to be conducted within 4 days prior to start of ibrutinib including RT-PCR assay for COVID-19; O2 saturation on room air; and CT scans or Chest X-Rays. Assessments must be performed prior to administration of any study agent. [00665] STUDY CALENDAR

[00666] BIOMARKER STUDIES [00667] Two green tops will be collected for cytokine analysis using multiplex quantitative assessment for inflammatory cytokines as per Vos et al, Ref.26. Green tops will be collected at screening, and on day 3 and day 7 +/- 1 day. Patients who are medically unstable for additional blood collection will be excluded from biomarker sampling. Samples will be sent to the Treon Laboratory for analysis. Exploratory analysis will be performed to delineate cytokine suppression associated with ibrutinib activity. [00668] DATA REPORTING / REGULATORY REQUIREMENTS [00669] Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse Events: List and Reporting Requirements).

[00670] Data Reporting [00671] The DF/HCC Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the data for this study. Responsibility for Data Submission [00672] Investigative sites are responsible for submitting data and/or data forms to the Office of Data Quality (ODQ) in accordance with DF/HCC policies. [00673] Data Safety Monitoring [00674] A Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and accrual data from this study on an ongoing basis. The DSMC will be composed of physicians with extensive expertise in the administration, efficacy and safety of ibrutinib: [00675] Steven Coutre MD, Professor of Medicine Hematology/Oncology Stanford University Hospitals [00676] Kieron Dunleavy MD, Hematology/Oncology, George Washington University Hospital [00677] Adrian Wiestner MD PhD, Laboratory of Lymphoid Malignancies, NIH/NHLBI [00678] The DSMC will initially meet weekly with the timing of subsequent meetings determined by the outcome of previous meetings/reviews and enrollment rate. Information to be provided to the committee may include: up-to-date participant accrual; current dose level information; DLT information; all grade 2 or higher adverse events that have been reported across all sites as well as a summary of all deaths occurring within 30 days of the last day of study drug treatment. In addition to safety results, all response/efficacy information (including laboratory results, scans etc) will be reviewed to better assess the risk/benefit of the study intervention. Should any major concerns arise, the DSMB, after meeting in a closed session, will offer recommendations regarding whether or not to suspend or amend the study. PCYC/JBI should receive all data summaries and outcome of the DSMB meeting within 7 days of its occurrence. STATISTICAL CONSIDERATIONS [00679] Study Design and Endpoints [00680] As no standard for treatment of COVID-19 currently exists and new treatment options are urgently needed given the high mortality rate associated with COVD-19 infection, this study will be exploratory in nature. Data acquired as part of this study will be used to inform future studies. Up to 34 patients will be enrolled with response assessments for treatment efficacy that include:

[00681] Duration of fever in days, i.e until start of normalization of temperature to < 36.6°C armpit, <37.2°C oral, or < 37.8°C rectal for 48 hours [00682] Days until attainment of peripheral capillary oxygen saturation (SpO2) > 92% on room air [00683] Days until supplemental oxygen is no longer required i.e. until start of period in which supplemental oxygen is not required for a duration of at least 24 hours [00684] Improvement or resolution of radiographic evidence of pulmonary infiltrates during treatment follow-up. [00685] Survival [00686] Proportion of patients needing a ventilator based on clinical condition of patient [00687] Ventilator-free survival in days [00688] Duration in days on ventilator [00689] Tolerability of therapy [00690] These endpoints are in alignment with other ongoing studies in COVID-19 subjects with pulmonary complications (clinicaltrials.gov/ct2/show/NCT04280705; clinicaltrials.gov/ct2/show/NCT04315298?term=sarilumab&draw=2&rank=4) [00691] Sample Size, Accrual Rate and Study Duration [00692] Up to 34 patients will be randomized at an allocation of 1:1 to ibrutinib plus SOC and SOC, alone. Enrollment is anticipated to be complete within 3-6 months. The study is expected to be complete in 6-12 months after activation. If the standardized treatment effect is 1.2 at alpha_1-sided=0.025, 28 subjects would need to be treated to maintain a power of 0.863. [00693] The standardized treatment effect allows for sample size to be calculated based on the proportion of the difference in mean days of fever between the treatment group, divided by the standard deviation of fever duration in the population. If it was assumed that the mean duration of fever in the moderate to severe population is 16.5 days, with a standard deviation of 1.25 (in which case fever for most subjects would last between 14 and 19 days), than at a standardized treatment effect of 1.2, it would be expected that the ibrutinib plus SOC arm would reduce the mean duration of fever by 1.5 days compared to the SOC, only, arm. [00694] Fever is selected as an important parameter based on the investigators’ experience in a study of Waldenstrom's Macroglobulinemia (WM) patients who held drug and developed constitutional symptoms upon withdrawal, resolution of these withdrawal symptoms including fever occurred within a day of ibrutinib being restarted. WM patients like COVID-19 patients have activated TOLL-receptor/MYD88 signaling; in the case of WM due to MYD88 activating

mutations, in the case of COVID-19, activation by virus. Fever is also reasonable corollary to improvement in cytokine release associated with ibrutinib (Castillo et al., Haematologica 103:e307-e310 (2018)). [00695] Of note, as COVID-19 symptom duration is still being characterized, this sample size justification and study design allow for uncertainty in the mean length of symptoms while providing guidance on the minimum improvement detectable between the study arms given population variability. The same sample size would be required if the standard deviation is twice as large, if the effect size is also doubled, i.e. a 3 day difference in fever between arms with a 2.5 standard deviation. A standardized effect size of 1.25 provides sufficient power to detect a moderate improvement in the experimental study arm. [00696] Per FDA guidance on adaptive design, if the pooled standard deviation is greater than 1.25, sample size may increase to maintain study power. The timing of this interim calculation would be once 20 subjects have been randomized and the calculation will be performed without unblinding the datapoints to the statistician of the study. No reduction of sample size will be made, should the actual standard deviation be under 1.25. [00697] Inhibitors and Inducers of CYP3A [00698] NOTE: Itraconazole and ketoconazole can be replaced with voriconazole for study subjects.



[00699] Child-Pugh Score for Subjects with Liver Impairment

[00700] Source references: 1. Child CG, Turcotte JG. Surgery and portal hypertension. In Child CG. The liver and portal hypertension. Philadelphia:Saunders.1964;50-64. 2. Pugh RN, Murray-Lyon IM, Dawson L, et al. Transection of the oesophagus for bleeding oesophageal varices. The British journal of surgery, 1973;60:646-9. [00701] Example 5: Treatment of Patients Hospitalized for Covid-19 Infection and Pulmonary Distress with Zanubrutinib [00702] OBJECTIVES [00703] Study Design [00704] There is currently no standard of care for hospitalized patients experiencing COVID- 19 infections beyond supportive care. Numerous studies examining various study interventions are underway. Discovering/providing treatment options for patients with moderate or severe COVID-19 infection is a high priority, particularly for those with respiratory distress. Exaggerated cytokine response triggered by Alveolar Type II cells and resident macrophages in response to SARS-CoV-2 appears etiological for the pulmonary injury and respiratory failure associated with COVID-19 infection. Ibrutinib blocks Toll-receptor signaling, and cytokines associated with SARS-CoV-2, including those found in Alveolar Type II (ACE2+)

cells. Importantly, in a relevant experimental mouse model, ibrutinib protected mice subjected to lethal intranasal inoculums of mouse adapted H1N1 influenza and suppressed inflammatory cell recruitment and pathological cytokines that overlapped with many of those observed in SARS-CoV-2 infected patients. Based on this, it is hypothesized that BTK inhibitors may potentially provide protection against lung injury. Zanubrutinib is an oral agent approved by the U.S. FDA, for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. For those subjects/patients whose health care providers feel that they qualify to participate in this study, who meet inclusion/exclusion criteria and sign an associated consent form, they will be enrolled and randomized 3:1 to receive supportive care plus zanubrutinib for up to 28 days or supportive care alone. For patients randomized to receive zanubrutinib, the dose of zanubrutinib will be 320 mg once daily day for the 28 days. Up to 40 patients will be enrolled in this study. See, FIG.6B. [00705] Primary Objectives [00706] To evaluate if the addition of zanubrutinib to supportive care leads to more rapid improvement in fever and pulmonary function through day 14 in hospitalized COVID-19 infected patients experiencing pulmonary distress. [00707] Secondary Objective [00708] To assess the safety and tolerability of zanubrutinib as an adjuvant therapy to supportive care in hospitalized COVID-19 infected patients experiencing pulmonary distress. [00709] To assess the feasibility of administering zanubrutinib via a nasogastric or feeding tube. [00710] BACKGROUND [00711] Study Disease(s) [00712] Screening evaluations for COVID-19 for eligibility are to be conducted within 4 days prior to start of zanubrutinib including RT-polymerase chain reaction (PCR) from nasopharyngeal swabs. Hospitalized patients with COVID-19 infection will be defined as all of the following: [00713] Currently hospitalized with fever defined as temperature ≥ 36.6°C armpit, ≥ 37.2°C oral, or ≥ 37.8°C rectal or tympanic [00714] Peripheral capillary oxygen saturation (SpO2) ≤ 92% on room air at screening

[00715] Radiographic evidence of pulmonary infiltrates [00716] IND Agent [00717] Zanubrutinib is an irreversible inhibitor of Bruton’s Tyrosine Kinase (BTK) that is approved by the U.S. FDA for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. [00718] Zanubrutinib is a potent, specific, and irreversible BTK inhibitor that was designed to be more specific than ibrutinib; similar to ibrutinib, zanubrutinib potently inhibited BTK kinase in biochemical assays, with a 50% inhibitory concentration (IC₅₀) of 0.3 nM, and in vitro cellular assays also show that zanubrutinib inhibited BTK signaling in mantle cell lymphoma (MCL) cell lines and cellular growth of several MCL cell lines. [00719] Zanubrutinib was more selective than ibrutinib for the inhibition of kinase activity of BTK vs. EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, and TEC. Cellular assays also confirmed that zanubrutinib is significantly less active than ibrutinib in inhibiting ITK (10- fold) and EGFR (> 6-fold). Zanubrutinib was shown to be at least 10-fold weaker than ibrutinib in inhibiting rituximab-induced antibody-dependent cell-mediated cytotoxicity (ADCC). [00720] Eligibility Criteria [00721] Inclusion Criteria [00722] Age > 18 years [00723] Willing and able to provide written informed consent prior to therapy. [00724] Patient requires hospitalization for COVID-19. [00725] Patient has Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection confirmed by polymerase chain reaction (PCR) test before study entry including all three following features: [00726] Currently hospitalized with fever defined as temperature ≥ 36.6°C armpit, ≥ 37.2°C oral, or ≥ 37.8°C rectal or tympanic [00727] Peripheral capillary oxygen saturation (SpO2) ≤ 92% on room air at screening [00728] Radiographic evidence of pulmonary infiltrates [00729] Females of childbearing potential (FCBP) must use one reliable form of contraception or have complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) while participating in the study; and 2) for at least 90 days after discontinuation from the study. FCBP must be referred to a qualified provider of

contraceptive methods if needed. FCBP must have a negative serum pregnancy test as of screening. [00730] Men must agree to use a latex condom during treatment and for up to 90 days after the last dose of zanubrutinib during sexual contact with a FCBP. [00731] Adequate hematologic function defined as: [00732] Absolute neutrophil count (ANC) > 750 cells/mm3 (0.75 x 10⁹/L) [00733] Platelet count > 50,000 cells/mm3 (50 x 10⁹/L) [00734] Adequate hepatic and renal function defined as: [00735] Estimated Creatinine Clearance (CrCl) ≥30 mL/min (Cockcroft-Gault). [00736] Bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non- hepatic origin). [00737] Prothrombin time (PT)/International normal ratio (INR) < 1.5 x (upper limit of normal) ULN and PTT (activated partial thromboplastin time [aPTT]) < 1.5 x ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder). When treated with warfarin or other vitamin K antagonists, then INR ≤ 3.0). [00738] Key Exclusion Criteria [00739] Requiring mechanical ventilation at screening [00740] Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction [00741] Known bleeding disorders (e.g., von Willebrand’s disease or hemophilia) [00742] Patients in whom surgery is anticipated to be necessary within 72 hours. [00743] History of stroke or intracranial hemorrhage within 6 months prior to enrollment. [00744] Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded. [00745] Major surgery within 4 weeks of study entry or in patients for whom surgery is anticipated to be necessary within 72 hours. [00746] Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart

Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization. [00747] Asymptomatic arrythmias (e.g NSVT, bradycardia HR less <50, or AV block, or any other atrial or ventricular arrythmia) and or EF <40% on a baseline echo. [00748] Subjects receiving a moderate or strong cytochrome P450 (CYP) 3A4 inducer. [00749] Subjects receiving a strong cytochrome P450 (CYP) 3A4 inhibitor with the exception of those receiving anti-fungal therapy/prophylaxis. [00750] Subjects with chronic liver disease and hepatic impairment meeting Child Pugh class C. [00751] Female subjects who are pregnant, or breastfeeding, or planning to become pregnant while enrolled in this study or within 1 month of last dose of study drug. Male subjects who plan to father a child while enrolled in this study or within 3 months after the last dose of study drug. [00752] Unwilling or unable to participate in all required study evaluations and procedures [00753] Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations). [00754] Inclusion of Women and Minorities [00755] Both men and women of all races and ethnic groups are eligible for this trial. [00756] REGISTRATION [00757] General Guidelines for DF/HCC Institutions [00758] Institutions will register eligible participants in the Clinical Trials Management System (CTMS) OnCore. Registrations must occur prior to the initiation of any protocol- specific therapy or intervention. Any participant not registered to the protocol before protocol- specific therapy or intervention begins will be considered ineligible and registration will be denied. [00759] An investigator will confirm eligibility criteria and a member of the study team will complete the protocol-specific eligibility checklist. [00760] An email confirmation of the registration will be sent to the study coordinator(s) from the registering site, treating investigator and registering person immediately following the registration and/or randomization. [00761] Following registration, participants may begin protocol-specific therapy and/or intervention. Issues that would cause treatment delays should be discussed with the Principal

Investigator (PI) of the registering site. If the subject does not receive protocol therapy following registration, the subject must be taken off study in the CTMS (OnCore) with an appropriate date and reason entered. [00762] Registration Process for DF/HCC Institutions [00763] Applicable DF/HCC policy (REGIST-101) must be followed. [00764] TREATMENT PLAN [00765] Patients will be enrolled and randomized 3:1 to receive supportive care along with zanubrutinib for 28 days or supportive care alone. For patients randomized to receive zanubrutinib, the dose of zanubrutinib will be 320 mg once daily for 28 days. [00766] Dose-escalation will also be permitted to 320 mg once daily if patients experience symptom recurrence related to COVID-19 following dose de-escalation. Nasogastric tube administration of zanubrutinib is permitted for patients unable to take zanubrutinib orally. Dose-de-escalation for toxicity is permitted (see below). Patients may receive any supportive care treatments and/or interventions, however, infection prophylaxis and dose modifications may be necessary in certain situations (see Table). Administration of zanubrutinib therapy and dosing should be recorded in the patient’s medical record. A diary will be provided for discharged patients to record daily dosing. [00767] Treatment Criteria [00768] Treatment should be withheld for adverse events as outlined below: [00769] Grade 3 or 4 nausea, vomiting, or diarrhea (if persistent despite optimal antiemetic and/or antidiarrheal therapy) related to zanubrutinib. [00770] Grade 4 or unmanageable nonhematologic grade 3 toxicities related to zanubrutinib [00771] Neutrophil count </=500/μL [00772] In subjects without baseline thrombocytopenia: [00773] Platelet count </= 50,000/μL in the presence of bleeding [00774] Platelet count </= 25,000 μL without bleeding [00775] For AEs that are felt to be related to worsening Covid-19 infection, the investigator may continue zanubrutinib, however, in patients with hepatic or cardiac dysfunction, bleeding, or multiple infections related to Covid-19 infection, the risks of continuing zanubrutinib may outweigh the potential benefit of continuing treatment with zanubrutinib. [00776] Agent Administration [00777] Zanubrutinib 320 mg is administered orally once daily. The capsules are to be taken around the same time each day with a glass of water. Zanubrutinib can be taken with or without

food. The capsules should be swallowed intact and subjects should not attempt to open capsules or dissolve them in water. For patients who require NGT placement while on study, zanubrutinib may be administered by opening the capsules, mixing with water, and flushing down the NGT. Though the use of strong CYP3A inhibitors/inducers, and grapefruit and Seville oranges should be avoided for the duration of treatment, treatment with antifungal prophylaxis (e.g. voriconazole, posaconazole) is permitted; however, dose reductions of zanbrutinib are necessary. If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. The subject should not take extra capsules to make up the missed dose. [00778] Dose reductions for toxicity will be permitted (see below). Dose re-escalation to the start dose will also be permitted for patients reduced below 320 mg once daily if toxicities that prompted dose de-escalation have resolved. [00779] For hospitalized patients, zanubrutinib will be administered by nursing staff. For patients discharged from the hospital, zanubrutinib will be self-administered, and participants will be instructed to write in a diary daily, documenting that the drug was taken and adverse events experienced. Patients should be instructed to take the study drug with a glass of water at approximately the same time each day. Patients taking zanubrutinib at home will be instructed on how to complete the diary by study staff prior to discharge. If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. The subject should not take extra capsules to make up the missed dose. The missed dose will not be made up and must be returned at the next scheduled visit. The patient will be instructed to document missed drug doses in the study diary. Furthermore, they will be instructed to call their provider, the principal investigator or research nurse if vomiting occurs or they have recurrence of their COVID-19 symptoms or any other adverse events consistent with the product label. If the pills are vomited, this should be noted on the patient diary, but a replacement dose should not be taken that day. All dosages prescribed and dispensed to the patient, and all dose changes during the study should be recorded. Diaries will be collected at the end of the treatment period. In the event of circumstances that prevent a discharged patient from returning to clinic, a tele-health visit is permitted. Study staff will collect or coordinate with patient in the event of a tele-health visit for the return of any unused drug and the study diary. Unused drug will be counted and returned to the pharmacy to be destroyed. A prescription for dispensing ibrutinib for at home use, as detailed above, will be filled by the study pharmacy. Medication labels will comply with US legal requirements and

be printed in English. The storage conditions for study drug will be described on the medication label. Ibrutinib will be provided by the storage conditions for study drug will be described on the medication label. Zanubrutinib is formulated as capsules for oral administration and will be available for this study in 80 mg capsules. [00780] Overdose [00781] Any dose of study drug in excess of that specified in this protocol is considered to be an overdose. Signs and symptoms of an overdose that meet any Serious Adverse Event criterion must be reported as a Serious Adverse Event in the appropriate time frame and documented as clinical sequelae to an overdose. There is no specific experience in the management of zanubrutinib overdose in patients. There are limited data on the effects of zanubrutinib overdose. No maximum tolerated dose (MTD) was reached in the Phase 1 study in which subjects received up 320 mg daily. [00782] General Concomitant Medication and Supportive Care Guidelines [00783] Supportive care medications and intervention for COVID-19 infection, including use of a ventilator support as clinically indicated is permitted at the treating physician’s discretion. Careful monitoring for signs and symptoms of bleeding are indicated, consistent with the safety profile of zanubrutinib. Anti-emetics are permitted if clinically indicated. All concomitant medications during the treatment period should be recorded. Drug guidance for dose modifications of zanubrutinib related to agents that may be in use to treat COVID-19 infection are also provided below. The following restrictions apply during the entire duration of the study: [00784] For cancer patients, no other anti-neoplastic therapy including radiation therapy should be given to participants during the treatment period. If such agents are required, then the patient must first be withdrawn from receiving zanubrutinib. [00785] The use of concomitant steroids if possible, should be avoided or minimized (if medically possible). If steroids are necessary, strongly consider treatment with an appropriate anti-fungal prophylaxis agent (e.g voriconazole/posaconazole). Consider the addition of anti- bacterial prophylaxis as clinically necessary [00786] Growth factors (i.e. G-CSF, GM-CSF, erythropoietin, platelets growth factors etc.) and transfusion support is permitted. [00787] Concomitant use of anti-platelet agents and anticoagulants should be avoided (if possible) due to the anti-platelet effects of zanubrutinib, however their use may be clinically necessary.

[00788] The use of DVT prophylaxis is permitted. Participants receiving anti-platelet agents in conjunction with zanubrutinib should be observed closely for any signs of bleeding or bruising, and zanubrutinib should be withheld in the event of any grade 2 or higher bleeding events until complete resolution to < grade 1. Participants with any grade CNS bleeding should have treatment discontinued. [00789] Subjects requiring the initiation of therapeutic anticoagulation therapy (eg, atrial fibrillation), consider the risks and benefits of continuing zanubrutinib treatment. Subjects should be observed closely for signs and symptoms of bleeding. No dose reduction is required when study drug is restarted. [00790] Supplements such as fish oils and vitamin E preparations should be avoided. [00791] Use zanubrutinib with caution in subjects requiring other anticoagulants or medications that inhibit platelet function. [00792] Medications to be Used with Caution [00793] CYP3A Enzyme Inhibitors/Inducers [00794] Co-administration of zanubrutinib with moderate and strong CYP3A inducers decreases zanubrutinib C_max and AUC, which may reduce efficacy. Concomitant use of moderate and strong CYP3A inducers is prohibited during trial therapy. [00795] Moderate and strong CYP3A inhibitors should be avoided when clinically feasible during trial therapy. If use is not avoidable, the dose of zanubrutinib should be reduced as below:

[00796] A list of common CYP3A inhibitors and inducers is provided in Example 4. For further information, the current version of the zanubrutinib IB and examples of inhibitors, inducers, and substrates can be found at medicine.iupui.edu/clinpharm/ddis/main-table/. [00797] This website is continually revised and should be checked frequently for updates. [00798] Drugs That May Have Their Plasma Concentrations Altered by Zanubrutinib [00799] Co-administration of multiple doses of zanubrutinib increased digoxin (P-gp substrate) Cmax by 34% and AUC by 11%. No clinically significant differences in the

pharmacokinetics of rosuvastatin (BCRP substrate) were observed when co-administered with zanubrutinib. [00800] Antiplatelet Agents and Anticoagulants [00801] Zanubrutinib may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulation therapies. Use zanubrutinib with caution in subjects requiring anticoagulants or medications that inhibit platelet function. These patients should be monitored closely for signs of bleeding. [00802] Guidelines for Zanubrutinib Management with Surgeries or Procedures [00803] Zanubrutinib may increase the risk of hemorrhage. Treating investigators may elect to hold zanubrutinib for 3 – 7 days pre and post-surgery at their discretion based on the type of surgery and the risk of bleeding. [00804] Duration of Therapy [00805] Duration of therapy will depend on individual response, evidence of pulmonary disease progression and tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue until one of the following criteria applies: [00806] Intercurrent illness that in the medical judgment of the treating physician prevents further administration of treatment [00807] Unacceptable adverse event(s) [00808] Patient demonstrates an inability or unwillingness to comply with the oral medication regimen and/or documentation requirements [00809] Patient decides to withdraw from the protocol therapy [00810] General or specific changes in the participant's condition render the participant unacceptable for further treatment in the judgment of the treating investigator [00811] Patients will be removed from the protocol therapy when any of these criteria apply. The reason for removal from protocol therapy, and the date the participant was removed, must be documented in the medical record. Alternative care options will be discussed with the participant. [00812] When a participant is removed from protocol therapy and/or is off of the study, the participant’s status must be updated in OnCore in accordance with REGIST-OP-1. [00813] Duration of Follow Up [00814] Participants will be followed for 4 weeks after completion of therapy or until death, whichever occurs first. Participants removed from protocol therapy for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.

[00815] Criteria for Taking a Participant Off Study [00816] Participants will be removed from study when any of the following criteria apply: [00817] Lost to follow-up [00818] Withdrawal of consent for data submission [00819] Death [00820] The reason for taking a participant off study, and the date the participant was removed, must be documented in the case report form (CRF). In addition, the study team will ensure the participant’s status is updated in OnCore in accordance with REGIST-OP-1. DOSING DELAYS/DOSE MODIFICATIONS [00821] Dose delays and modifications will be made using above. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose modifications. A copy of the CTCAE version 5.0 can be downloaded from the CTEP website: ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

[00822] Dosing will be held for any of the following conditions: [00823] Grade 4 ANC (< 500/μL). Neutrophil growth factors may be used for ANC recovery. [00824] Grade 3 Platelets (< 50,000/μL) in the presence of clinically significant bleeding events; or [00825] Grade 4 Platelets (< 25,000/μL). Platelet transfusions may be used for platelet recovery. [00826] Grade 3 or 4 nausea, vomiting, or diarrhea (if persistent despite optimal antiemetic and/or antidiarrheal therapy); [00827] Any other zanubrutinib related grade 4 toxicities and any unmanageable non- hematologic Grade 3 or higher toxicities. [00828] For Grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade, consider the risks and benefits of restarting and continuing zanubrutinib treatment. If clinically

indicated, the use of non-warfarin or vitamin k antagonist anticoagulants or antiplatelet agents may be considered for the thromboprophylaxis of atrial fibrillation. [00829] For AEs that are felt to be related to worsening Covid-19 infection, the investigator may continue zanubrutinib, however, in patients with hepatic or cardiac dysfunction, bleeding, or multiple infections related to Covid-19 infection, the risks of continuing zanubrutinib may outweigh the potential benefit of continuing treatment with zanubrutinib. [00830] Dose Modification for Hepatic Impaired Patients [00831] No dosage modification is recommended in patients with mild to moderate hepatic impairment Dosage modification of zanubrutinib is recommended in patients with severe hepatic impairment. The recommended dose of zanubrutinib for patients with severe hepatic impairment is 80 mg orally twice daily. [00832] ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS (Section 7) [00833] Adverse event (AE) deemed at least possibly related to zanubrutinib will be collected. Additionally, lab abnormalities which are clinically significant will be collected. The following list of reported and/or potential AEs and the characteristics of an observed AE will determine whether the event requires expedited reporting in addition to routine reporting. [00834] Adverse Event List for Zanubrutinib [00835] Risks [00836] Hemorrhage [00837] Serious and fatal hemorrhagic events have occurred in patients with hematological malignancies treated with zanubrutinib monotherapy. All hemorrhagic events were reported in 46.3% of patients with hematological malignancies in the combined database of 671 patients who were treated with zanubrutinib monotherapy, with the majority (44.1%) consisting of Grade 1 and 2 events. Petechiae, purpura, and contusion were reported in 28.2% of the patients, and all the petechiae, purpura, and contusion events were Grades 1 and 2, except for one. Grade 3 or higher bleeding events including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 2.2% of these patients. [00838] Infections [00839] Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred in patients with hematological malignancies treated with zanubrutinib monotherapy. Infections have occurred in 66.6% of patients with hematological malignancies in the combined database of 671 patients who were treated with zanubrutinib monotherapy. Grade 3 or higher infections occurred in 21.3% of these patients. The most common Grade 3 or higher infection was

pneumonia. Infections due to hepatitis B virus (HBV) reactivation have occurred. Patients with hematologic malignancies, particularly those having received prior lymphodepleting chemotherapy or having prolonged corticosteroid exposure, are pre-disposed to opportunistic infections as a result of disease and treatment-related factors. In patients with a high risk for opportunistic infections, including Pneumocystis jirovecii pneumonia (PJP), prophylaxis is strongly recommended as per institutional standards. [00840] Cytopenias [00841] Cytopenias including neutropenia, thrombocytopenia, and anemia based on laboratory measurements were reported in 41.1%, 39.3%, and 23.4%, respectively, in patients with hematologic malignancies in the combined database of 671 patients who were treated with zanubrutinib monotherapy. Grade 3 or 4 events occurred in 19.8%, 8.5%, and 6.5% of these patients with neutropenia, thrombocytopenia, and anemia, respectively. [00842] Second Primary Malignancies [00843] Second primary malignancies, including non-skin carcinoma have occurred in 7.9% of patients with hematological malignancies in the combined database of 671 patients who were treated with zanubrutinib monotherapy. The most frequent second primary malignancy was skin cancer (basal cell carcinoma, 3.6%, and squamous cell carcinoma of skin, 1.9%). [00844] Atrial Fibrillation and Flutter [00845] Atrial fibrillation and atrial flutter have occurred in 1.8% of patients with hematological malignancies in the combined database of 671 patients who were treated with zanubrutinib monotherapy, particularly in patients with cardiac risk factors, hypertension, and acute infections. This rate appears to be significantly lower than has been reported with ibrutinib. Adverse Events Considered Possibly Related to Zanubrutinib [00846] Refer to Section 7 for a list of adverse events (AEs) considered expected for zanubrutinib expedited reporting purposes. The list of AEs below represents events experienced by patients that are considered possibly related to zanubrutinib and are continuing to be monitored in ongoing studies:

[00847] Adverse Event Characteristics [00848] CTCAE term (AE description) and grade: The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. [00849] For expedited reporting purposes only: AEs for the agent(s) that are listed above should be reported only if the adverse event varies in nature, intensity or frequency from the expected toxicity information which is provided.

[00850] Other AEs for the protocol that do not require expedited reporting are outlined in the next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol- [00851] Specific Expedited Adverse Event Reporting Exclusions. [00852] Attribution of the AE: [00853] Definite – The AE is clearly related to the study treatment. [00854] Probable – The AE is likely related to the study treatment. [00855] Possible – The AE may be related to the study treatment. [00856] Unlikely – The AE is doubtfully related to the study treatment. [00857] Unrelated – The AE is clearly NOT related to the study treatment. [00858] Expedited Adverse Event Reporting [00859] Investigators must report to the Overall PI any serious adverse event (SAE) that occurs after the initial dose of zanubrutinib, during treatment, or up to 30 days of the last dose of treatment on the local institutional SAE form. [00860] Investigative sites will report SAEs directly to the DFCI Office for Human Research Studies (OHRS) per the DFCI IRB reporting policy. Grade 3 and 4 expected hematologic events that have not induced clinical signs or symptoms do not require separate reporting as serious adverse events. [00861] Expedited Reporting Guidelines [00862] Use the protocol number and the protocol-specific participant ID assigned during trial registration on all reports. Note: A death on study requires both routine and expedited reporting regardless of causality, unless as noted below. Attribution to treatment or other cause must be provided. [00863] Expedited Reporting to FDA

[00864] Expedited Reporting to Hospital Risk Management

[00865] Participating investigators will report to their local Risk Management office any participant safety reports or sentinel events that require reporting according to institutional policy. [00866] Routine Adverse Event Reporting [00867] Information on all Grade 2 or higher adverse events that at least are possibly related to zanubrutinib will be reported in routine study data submissions to the Overall PI on the toxicity case report forms. AEs reported through expedited processes (e.g., reported to the IRB, FDA, etc.) must also be reported in routine study data submissions. [00868] PHARMACEUTICAL INFORMATION [00869] Zanubrutinib (BGB-3111) [00870] Description [00871] Zanubrutinib is a white to off-white powder, with a pH of 7.8 in saturated solution. The aqueous solubility of zanubrutinib is pH dependent, from very slightly soluble to practically insoluble. [00872] Molecular Formula: C27H₂9N5O3 [00873] Molecular Weight: 471.55 Daltons

[00874] Chemical Structure: [00875] Form [00876] Zanubrutinib drug product contains zanubrutinib active pharmaceutical ingredient and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The capsule shell contains edible black ink, gelatin, and titanium dioxide. [00877] Zanubrutinib drug product is supplied as 80 mg strength in capsules (size 0, white opaque capsules). The drug product is designed as an immediate-release dosage form [80% (Q) at 30 minutes]. [00878] Storage

[00879] Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). [00880] Handling [00881] Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the environment, should undertake the preparation, handling, and safe disposal of the chemotherapeutic agent in a self-contained and protective environment. [00882] Accountability [00883] The investigator, or a responsible party designated by the investigator, should maintain a careful record of the inventory and disposition of the agent using the NCI Drug Accountability Record Form (DARF) or another comparable drug accountability form. (See the NCI Investigator’s Handbook for Procedures for Drug Accountability and Storage.) [00884] Destruction and Return [00885] Expired, returned, or unused supplies of zanubrutinib should be destroyed according to local institutional policies. Destruction will be documented in the Drug Accountability Record Form. [00886] STUDY CALENDAR [00887] Screening evaluations for eligibility are to be conducted within 4 days prior to start of zanubrutinib including RT-PCR assay for COVID-19; O2 saturation on room air; and CT scans or Chest X-Rays. Assessments must be performed prior to administration of any study agent. [00888] STUDY CALENDAR

[00889] BIOMARKER/ Pharmacokinetic STUDIES [00890] Two green tops will be collected for cytokine analysis using multiplex quantitative assessment for inflammatory cytokines (Niemann et al., Clin. Cancer Res. 22:1572-1582 (2015); Vos et al., Haematologica 102:e45592017)). Green tops will be collected at screening, and on day 3 + 1 day and day 7 + 1 day. Patients who are medically unstable for additional blood collection will be excluded from biomarker sampling. Samples will be sent to the Treon Laboratory for analysis. Exploratory analysis will be performed to delineate cytokine suppression associated with zanubrutinib activity. Any remainder serum not used for cytokine studies will be banked for future studies for other biomarkers and response. [00891] For patients unable to take zanubrutinib orally, thus requiring nasogastric/feeding tube administration, a sample will be drawn 2 hours after the first dose of zanubrutinib administered via the nasogastric/feeding tube route. Blood samples (2 mL) for PK analysis will be collected into EDTA collection tubes. Details concerning handling of the PK plasma samples, including labeling and shipping instructions will be provided in the Laboratory Manual for this study. Samples will be shipped to the designated bioanalytical laboratory for quantification of plasma zanubrutinib concentrations using a validated method. [00892] DATA REPORTING / REGULATORY REQUIREMENTS [00893] Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse Events: List and Reporting Requirements). [00894] Data Reporting [00895] The DF/HCC Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the data for this study. [00896] Responsibility for Data Submission [00897] Investigative sites are responsible for submitting data and/or data forms to the Office of Data Quality (ODQ) in accordance with DF/HCC policies. [00898] Data Safety Monitoring [00899] A Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and accrual data from this study on an ongoing basis. The DSMC will be composed of physicians with extensive expertise in the administration, efficacy and safety of zanubrutinib as well as expertise in pulmonary/critical care medicine and/or infectious diseases. [00900] The DSMC will meet at least biweekly until the study is fully accrued and all patients have completed 28 day treatment period, and thereafter at a frequency determined by the outcome of previous meetings/reviews. Information to be provided to the committee may

include: up-to-date participant accrual; dosing information; all grade 2 or higher adverse events that have been reported across all sites as well as a summary of all deaths occurring within 30 days of the last day of the treatment period. In addition to safety results, all response/efficacy information (including laboratory results, scans etc) will be reviewed to better assess the risk/benefit of the study intervention. Should any major concerns arise, the DSMC, after meeting in a closed session, will offer recommendations regarding whether or not to suspend or amend the study. [00901] STATISTICAL CONSIDERATIONS [00902] Study Design and Endpoints [00903] As no standard for treatment of COVID-19 currently exists and new treatment options are urgently needed given the high mortality rate associated with COVD-19 infection, this study will be exploratory in nature. Data acquired as part of this study will be used to inform future studies. Up to 40 patients will be enrolled and randomized 3:1 with response assessments for treatment efficacy that include: [00904] Duration of fever in days, i.e until start of normalization of temperature to < 36.6°C armpit, <37.2°C oral, or < 37.8°C rectal for 48 hours [00905] Days until attainment of peripheral capillary oxygen saturation (SpO2) > 92% on room air [00906] Days until supplemental oxygen is no longer required i.e. until start of period in which supplemental oxygen is not required for a duration of at least 24 hours [00907] Improvement or resolution of radiographic evidence of pulmonary infiltrates during treatment follow-up. [00908] Survival [00909] Proportion of patients needing a ventilator based on clinical condition of patient [00910] Ventilator-free survival in days [00911] Duration in days on ventilator [00912] Tolerability of therapy [00913] Cmax achieved in those patients requiring NGT/FT route of administration [00914] These endpoints are in alignment with other ongoing studies in COVID-19 subjects with pulmonary complications (31, 32) [00915] Sample Size, Accrual Rate and Study Duration [00916] Up to 40 patients will be randomized at an allocation of 3:1 to supportive care plus zanubrutinigb or supportive care alone. Enrollment is anticipated to be complete within 3-6

months. The study is expected to be complete in 6-12 months after activation. If the standardized treatment effect is 1.2 at alpha_1-sided=0.025, 28 subjects would need to be treated to maintain a power of 0.863. [00917] The standardized treatment effect allows for sample size to be calculated based on the proportion of the difference in mean days of fever between the treatment group, divided by the standard deviation of fever duration in the population. If the mean duration of fever in the moderate to severe population is 16.5 days, with a standard deviation of 1.25 (in which case fever for most subjects would last between 14 and 19 days), than at a standardized treatment effect of 1.2, than it would be expected that the zanubrutinib plus SOC arm would reduce the mean duration of fever by 1.5 days compared to the SOC, only, arm. [00918] Fever is selected as an important parameter based on the investigators’ experience in a study of Waldenstrom's Macroglobulinemia (WM) patients who held drug and developed constitutional symptoms upon withdrawal, resolution of these withdrawal symptoms including fever occurred within a day of ibrutinib being restarted. WM patients like COVID-19 patients have activated TOLL-receptor/MYD88 signaling; in the case of WM due to MYD88 activating mutations, in the case of COVID-19, activation by virus. Fever is also reasonable corollary to improvement in cytokine release associated with ibrutinib (Castillo et al., Haematologica 103:e307-e310 (2018)). [00919] Of note, as COVID-19 symptom duration is still being characterized, this sample size justification and study design allow for uncertainty in the mean length of symptoms while providing guidance on the minimum improvement detectable between the study arms given population variability. The same sample size would be required if the standard deviation is twice as large, if the effect size is also doubled, i.e. a 3 day difference in fever between arms with a 2.5 standard deviation. A standardized effect size of 1.25 provides sufficient power to detect a moderate improvement in the experimental study arm. [00920] Per FDA guidance on adaptive design, if the pooled standard deviation is greater than 1.25, sample size may increase to maintain study power. The timing of this interim calculation would be once 20 subjects have been randomized and the calculation will be performed without unblinding the datapoints to the statistician of the study. No reduction of sample size will be made, should the actual standard deviation be under 1.25.

[00921] Example 6: Nasogastric/Feeding Tube Administration for Zanubrutinib [00922] The solubility of zanubrutinib in water has been established allowing for the exploration of this route of administration. 1. The zanubrutinib capsule(s) should be opened at the bedside and the contents dissolved in 50 mL of water for injection. 2. The zanubrutinib suspension should be drawn into a syringe and administered via the nasogastric or feeding tube. 3. An additional 50 mL of water for injection should be drawn up and used to flush the syringe and the nasogastric/feeding tube. 4. A PK sample will be drawn two hours after the first dose of zanubrutinib administered via the NG/feeding tube route. The time of zanubrutinib administration and sample collection will be documented. OTHER EMBODIMENTS [00923] While the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. [00924] The patent and scientific literature referred to herein establishes the knowledge that is available to those with skill in the art. All United States patents and published or unpublished United States patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are hereby incorporated by reference. Genbank and NCBI submissions indicated by accession number cited herein are hereby incorporated by reference. All other published references, documents, manuscripts and scientific literature cited herein are hereby incorporated by reference. [00925] While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

What is claimed is: 1. A method of treating coronavirus of 2019 (COVID-19) infection in a patient comprising administering to the patient a therapeutically effective amount of a Bruton’s tyrosine kinase (BTK) inhibitor.

2. The method of claim 1, wherein the BTK inhibitor comprises ibrutinib or an analog thereof.

3. The method of claim 2, wherein ibrutinib is administered orally.

4. The method of claim 3, wherein ibrutinib is administered in a composition further comprising croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauril sulfate.

5. The method of any one of claims 2-4, wherein the effective amount of ibrutinib is about 420 or 560 mg/day.

6. The method of claim 1, wherein the BTK inhibitor is acalabrutinib or an analog thereof.

7. The method of claim 6, wherein acalabrutinib is administered orally.

8. The method of claim 7, wherein acalabrutinib is administered in a composition further comprising silicified microcrystalline cellulose, pregelatinised starch, magnesium stearate, and sodium starch glycollate Type A.

9. The method of any one of claims 6-8, wherein the effective amount of acalabrutinib is about 200 mg/day.

10. The method of claim 1, wherein the BTK inhibitor is zanubrutinib, or an analog thereof.

11. The method of claim 10, wherein zanubrutinib is administered orally.

12. The method of claim 11, wherein zanubrutinib is administered in a composition further comprising colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.

13. The method of any one of claims 10-12, wherein the effective amount of zanubrutinib is about 320 mg/day.

14. The method of claim 1, wherein the BTK inhibitor is LCB 03-0110 dihydrochloride, LFM-A13, PCI 29732, PF 06465469, (-)-Terreic acid, BMX-IN-1, ARQ-531, BI-BTK-1, BMS-986142, CGI-1746, Evobrutinib, Fenebrutinib, GDC-0834, Olmutinib, PLS-123, PRN1008, RN-486, Spebrutinib, Tirabrutinib, or Vecabrutinib.

15. The method of claim 1, wherein the BTK inhibitor is a bispecific compound having a structure represented by formula (VII): or a pharmaceutically acceptable salt or

stereoisomer thereof, wherein: the Targeting Ligand is capable of binding BTK; the Linker is a group that covalently binds to the Targeting Ligand and the Degron; and the Degron is capable of binding to an E3 ubiquitin ligase.

16. The method of claim 15, wherein the bispecific compound is represented by any one of structures:

,

,

,

,

,

,

pharmaceutically acceptable salt or stereoisomer thereof.

17. The method of any one of claims 1-16, wherein the patient is immune-suppressed.

18. The method of claim 17, wherein the patient is suffering from pulmonary or respiratory distress.

19. The method of claim 17, wherein the patient has a pre-existing pulmonary or respiratory condition.

20. The method of claim 17, wherein the patient is diabetic.

21. The method of claim 17, wherein the patient is hypertensive.

22. The method of claim 17, wherein the patient is obese.

23. The method of any one of claims 1-22, wherein the patient is at least 65 years of age.