Compositions and Methods for Inhibiting Reticulon 4

CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 62/454,681, filed February 3, 2017, and U.S. Provisional Application No. 62/471,865, filed March 15, 2017, which are incorporated herein by reference in their entirety and for all purposes.

REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER

PROGRAM LISTING APPENDIX SUBMITTED AS AN ASCII FILE

[0002] The Sequence Listing written in file 052103-503001WO Sequence Listing_ST25.txt, created January 11, 2018, 166,113 bytes, machine format IBM-PC, MS Windows operating system, is hereby incorporated by reference.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0003] This invention was made with government support under CA172667 and GM112948 awarded by the National Institutes of Health and under W81XWH-15-1-0050 awarded by ARMY/MRMC. The government has certain rights in the invention.

BACKGROUND

[0004] In the United States, it is estimated that over 134,000 people will be diagnosed with colorectal cancer and over 49,000 patients will die from colorectal cancer ¹ . Current therapeutic strategies for colorectal cancer include resection and non-specific therapies such as radiation or chemotherapy ² . Unfortunately, these treatment strategies are insufficient for aggressive and metastatic colorectal cancers, and thus better strategies are needed to discover both novel anti- cancer agents and targets for combatting colorectal cancer. Towards this goal, identifying new anti-cancer targets, druggable nodes, and lead small-molecules are critical for combatting colorectal cancer. Disclosed herein, inter alia, are solutions to these and other problems in the art.

BRIEF SUMMARY

[0005] Herein are provided, inter alia, compounds capable of modulating the level of activity of reticulon 4 and methods of using the same. [0006] In an aspect is provided a compound having the formula:

[0007] R ¹ is independently halogen, -CX ¹ ₃ , -CHX ¹ ₂ , -CH ₂ X ¹ , -OCX ¹ ₃ , - OCH ₂ X ¹ , -OCHX ¹ ₂ , -CN, -SO _n1 R ^1D , -SO _v1 NR ^1A R ^1B , -NHC(O)NR ^1A R ^1B , -N(O) _m1 , -NR ^1A R ^1B , -C( O)R ^1C , -C(O)-OR ^1C , -C(O)NR ^1A R ^1B , -OR ^1D , -NR ^1A SO2R ^1D , -NR ^1A C(O)R ^1C , -NR ^1A C(O)OR ^1C , -N R ^1A OR ^1C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The symbol z1 is an integer from 0 to 5. R ² is independently halogen, -CX ² 3, - CHX ² 2, -CH2X ² , -OCX ² 3, - OCH ₂ X ² , -OCHX ² ₂ , -CN, -SO _n2 R ^2D , -SO _v2 NR ^2A R ^2B , -NHC(O)NR ^2A R ^2B , -N(O) _m2 , -NR ^2A R ^2B , -C( O)R ^2C , -C(O)-OR ^2C , -C(O)NR ^2A R ^2B , -OR ^2D , -NR ^2A SO2R ^2D , -NR ^2A C(O)R ^2C , -NR ^2A C(O)OR ^2C , -N R ^2A OR ^2C , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The symbol z2 is an integer from 0 to 4. L ¹ is a

bond, -S(O)2-, -NR ⁴ -, -O-, -S-, -C(O)-, -C(O)NR ⁴ -, -NR ⁴ C(O)-, -NR ⁴ C(O)NH-, -NHC(O)NR ⁴ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted

heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. R ⁴ is hydrogen, -CX ⁴ 3, -CHX ⁴ 2, -CH2X ⁴ , -OCX ⁴ 3, - OCH ₂ X ⁴ , -OCHX ⁴ ₂ , -CN, -C(O)R ^4A , -C(O)-OR ^4A , -C(O)NR ^4A R ^4B , -OR ^4A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. L ² is a

bond, -S(O) ₂ -, -NR ⁵ -, -O-, -S-, -C(O)-, -C(O)NR ⁵ -, -NR ⁵ C(O)-, -NR ⁵ C(O)NH-, -NHC(O)NR ⁵ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. R ⁵ is hydrogen, -CX ⁵ ₃ , -CHX ⁵ ₂ , -CH ₂ X ⁵ , -OCX ⁵ ₃ , - OCH2X ⁵ , -OCHX ⁵ 2, -CN, -C(O)R ^5A , -C(O)-OR ^5A , -C(O)NR ^5A R ^5B , -OR ^5A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. E is an electrophilic moiety. Each R ^1A , R ^1B , R ^1C , R ^1D , R ^2A , R ^2B , R ^2C , R ^2D , R ^4A , R ^4B , R ^5A , and R ^5B is independently

hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R ^2A and R ^2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R ^4A and R ^4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R ^5A and R ^5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. Each X, X ¹ , X ² , X ⁴ , and X ⁵ is independently–F, -Cl, -Br, or–I. The symbols n1, n2, n4, and n5 are independently an integer from 0 to 4. The symbols m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2. [0008] In an aspect is provided a pharmaceutical composition including a Reticulon 4 inhibitor and a pharmaceutically acceptable excipient. [0009] In an aspect is provided a pharmaceutical composition including a compound described herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0010] In an aspect is provided a method of treating cancer, the method including

administering to a subject in need thereof an effective amount of a Reticulon 4 inhibitor. [0011] In an aspect is provided a method of treating cancer including administering to a subject in need thereof an effective amount of a compound described herein. [0012] In an aspect is provided a method of treating a disease associated with reticulon 4 activity including administering to a subject in need thereof an effective amount of a Reticulon 4 inhibitor. [0013] In an aspect is provided a method of inhibiting reticulon 4 activity including contacting the reticulon 4 with a Reticulon 4 inhibitor. [0014] In an aspect is provided a method of inhibiting reticulon 4 activity including contacting the reticulon 4 with a compound described herein. [0015] In an aspect is provided a reticulon 4 protein covalently bonded to a Reticulon 4 inhibitor. [0016] In an aspect is provided a reticulon 4 protein covalently bonded to a compound described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG.1A-1E. Coupling Screening of Cysteine-Reactive Covalent Ligands with isoTOP- ABPP to Identify Anti-Cancer Compounds, Targets, and Druggable Hotspots for Colorectal Cancer. (FIG.1A) We screened a library of cysteine-reactive fragment-based covalent ligands in colorectal cancer cells to identify compounds that impair colorectal cancer pathogenicity and used isoTOP-ABPP platforms to identify the targets and druggable hotspots within these targets. (FIG.1B) The compounds tested, from left to right in the top chart of FIG.1B (i.e. survival), are DKM 3-30, DKM 3-16, DKM 2-40, DKM 2-91, DKM 2-101, DKM 3-10, DKM 2-94, DKM 2- 76, DKM 2-80, TRH 1-55, TRH 1-12, DKM 3-7, DKM 2-95, DKM 3-43, DKM 2-98, DKM 3- 36, TRH 1-32, DKM 3-41, DKM 3-70, DKM 2-37, TRH 1-50, DKM 3-5, DKM 2-108, DKM 3- 31, DKM 2-83, DKM 2-59, TRH 1-53, DKM 3-32, DKM 2-93, DKM 2-84, DKM 2-113, DKM 3-9, DKM 2-114, DKM 3-13, DKM 2-34, DKM 2-47, DKM 3-29, DKM 2-49, DKM 2-71, DKM 2-43, DKM 2-017, DKM 2-67, DKM 2-50, DKM 2-31, DKM 2-48, DKM 2-32, DKM 2- 33, DKM 2-52, DKM 2-39, TRH 1-13, DKM 2-72, DKM 2-58, TRH 1-19, DKM 2-120, DKM 3-42, DKM 2-42, DKM 2-97, DKM 2-60, DKM 2-86, DKM 2-110, TRH 1-20, DKM 2-62, DKM 3-11, DKM 3-4, DKM 2-116, DKM 2-102, DKM 3-12, DKM 2-111, DKM 2-103, DKM 2-100, DKM 2-109, TRH 1-27, DKM 2-106, DKM 3-8, and TRH 1-54. The compounds tested, from left to right in the bottom chart of FIG.1B (i.e. proliferation), are DKM 2-94, DKM 2-71, DKM 2-98, DKM 2-83, DKM 2-80, DKM 2-76, DKM 3-70, DKM 2-52, TRH 1-55, DKM 3-30, DKM 2-93, DKM 2-91, DKM 3-16, TRH 1-53, DKM 2-67, DKM 2-37, DKM 2-59, TRH 1-50, DKM 3-10, DKM 3-5, DKM 2-84, DKM 2-48, DKM 2-95, TRH 1-12, DKM 2-116, DKM 3-41, DKM 3-13, DKM 3-43, DKM 3-32, DKM 2-62, DKM 2-110, DKM 2-108, DKM 2-120, DKM 2-109, DKM 2-97, DKM 2-101, DKM 3-36, DKM 2-40, DKM 2-107, DKM 3-31, DKM 2-100, DKM 3-7, TRH 1-32, DKM 2-72, DKM 3-9, DKM 2-106, DKM 2-60, DKM 2-86, DKM 3-8, DKM 2-34, DKM 2-111, DKM 3-12, DKM 2-49, DKM 2-39, DKM 2-114, DKM 2-47, DKM 2- 103, DKM 3-42, DKM 2-32, DKM 2-33, DKM 2-58, DKM 2-31, DKM 3-11, TRH 1-19, DKM 3-4, DKM 3-29, TRH 1-20, TRH 1-27, DKM 2-43, TRH 1-13, DKM 2-50, DKM 2-102, DKM 2-42, TRH 1-54, and DKM 2-113. Cysteine-reactive covalent ligand screening in SW620 colorectal cancer cells: we screened a cysteine-reactive fragment library consisting of

acrylamides and chloroacetamides in SW620 colorectal cancer cells (50 µM) to identify any leads that significantly impaired SW620 serum-free cell survival and proliferation. Survival and proliferation were assessed after 48 h by Hoescht staining. (FIG.1C, 1D) Shown is the structure of the lead covalent ligand DKM 3-30 (FIG.1C) that significantly (p<0.05) impaired SW620 cell survival and proliferation (FIG.1D). (FIG.1E) SW620 tumor xenograft growth in immune- deficient SCID mice. Mice were subcutaneously injected with SW620 cells to initiate the tumor xenograft study and treatments of mice were initiated with vehicle or DKM 3-30 (50 mg/kg ip, once per day) ten days initiation of the xenograft study. Data in (FIGS.1B, 1D, 1E) are presented as mean ± sem, n=3-8/group. Significance expressed as *p<0.05 compared to vehicle- treated controls. Raw data for screen can be found in Table 1. [0018] FIG.2A-2D. DKM 3-30 Targets C1101 on RTN4. (Fig.2A) IsoTOP-ABPP analysis of DKM 3-30 in SW620 colorectal cancer cells. SW620 proteomes were pre-treated with DMSO or DKM 3-30 (50 µM) prior to labeling proteomes with IAyne and appending a biotin-azide handle bearing a TEV protease recognition site and an isotopically light (for DMSO-treated) and heavy (for DKM 3-30-treated) tag. DMSO and treated proteomes were then mixed in a 1:1 ratio and subsequently avidin-enriched, tryptically digested, and then probe-modified tryptic peptides were released by TEV protease and analyzed using quantitative proteomic approaches. IsoTOP-ABPP data represents mean light to heavy ratios for those probe-modified peptides identified in at least 2 out of 3 biological replicates. A light to heavy ratio of 1 indicates that the probe-labeled cysteine-bearing peptide was not bound by the covalent ligands, whereas a ratio >3 indicates bound sites. Also shown on the right are competition studies of DKM 3-30 against IAyne labeling of pure human RTN4 protein. Pure proteins were pre-incubated with the designated concentrations of ligand, followed by labeling with IAyne and visualization of labeling by subsequent click-chemistry mediated appendage of rhodamine-azide, SDS/PAGE, and in-gel fluorescence detection. (FIG.2B) IsoTOP-ABPP analysis of cysteine-reactivity in pooled primary human colorectal tumors. Nine primary human colorectal tumors were pooled together and labeled with 100 or 10 µM of IAyne followed by subsequent isoTOP-ABPP analysis. Shown are ratios of heavy (100 µM) to light (10 µM) peptides. (FIGS.2C, 2D) Serum-free cell survival and proliferation (48 h) and tumor xenograft growth in immune-deficient SCID mice from transient siRNA or stable shRNA knockdown of RTN4 in SW620 cells. Expression was determined by qPCR. All data shown represents n=3-6/group. Data in (FIGS.2C, 2D) are presented as mean ± sem. Significance is expressed as *p<0.05 compared to vehicle-treated or si or shControls. Raw data for (FIGS.2A, 2B) can be found in Table 2. [0019] FIG.3A-3F. DKM 3-30 disrupts the ER tubular network. (FIG.3A) A schematic illustration depicts the proposed topology of Rtn4 and the position of C1101 modified by DKM 3-30 (indicated by an arrow). A homology model of human Rtn4 illustrates the membrane- associated portion (lower), the cytosolically accessible portion (upper), and the position of C1101 (central dark gray). (FIG.3B) U2OS cells expressing GFP-tagged Sec61β, an ER marker, were treated with DKM 3-30 (50 µM) for 16 hr and the ER (light gray/white) and nucleus (dark gray) of fixed cells visualized by fluorescence microscopy. Scale bar = 10 µm. (FIGS.3C, 3D) U2OS cells expressing GFP-tagged Sec61β were treated with vehicle (DMSO) (FIGS.3C) or DKM 3-30 (50 µM) (FIGS.3D) and ER morphology visualized by time-lapse fluorescence microscopy. Time (min) is indicated on each panel. Bottom panels indicate boxed region. (FIG.3E) U2OS cells were transiently transfected with control or RTN4 siRNA and expression determined by qPCR. Data are presented as mean ± sem, n=3. Significance is expressed as *p<0.05. (FIG.3F) U2OS cells expressing GFP-tagged Sec61β were transfected with siRNAs as in panel (FIG.3D) and the ER (light gray/white) and nucleus (dark gray) of fixed cells visualized by fluorescence microscopy. Scale bar = 10 µm. [0020] FIGS.4A-4C. DKM 3-30 disrupts nuclear envelope morphology during mitosis.

(FIGS.4A-4C) U2OS cells expressing GFP-tagged Sec61β were treated with vehicle (DMSO) or DKM 3-30 (50 µM) and the ER morphology of mitotic cells visualized by time-lapse

fluorescence microscopy. Time (min) is indicated on each panel. Panels (FIGS.4A, 4B) provide examples of mitotic cells. Enlarged images following mitosis show the nuclear envelope. White arrowheads indicate a GFP-Sec61β structure bisecting the nucleus of a cell incubated with DKM 3-30. Panel (FIG.4C) shows alterations in the nuclear envelope structure, followed by cell death at the 800 min time point. Bottom panels indicate boxed region. [0021] FIG.5. Body weight of mice treated with DKM 3-30 in tumor xenograft studies. Mice from tumor xenograft studies shown in FIG.1E were weighed at the end of the study. The mice treated with DKM 3-30 did not show any significant changes in body weight compared to vehicle-treated control mice. Data are presented as mean ± sem, n=8 mice/group. [0022] FIG.6. Sequence alignment of human and xenopus laevis RTN4. The position of the shared cysteine in human RTN4 (C1101) and xenopus laevis RTN4 (C952) is indicated by the red arrow. The shaded amino acids indicate shared sequence identity (black) or similarity (gray). The human RTN4 presenting in FIG.6 corresponds to UniProt ID Q9NQC3, having the full sequence described herein as SEQ ID NO: 331. The xenopus laevis RTN4 presenting in FIG.6 corresponds to UniProt ID Q6JRV0, having the full sequence described herein as SEQ ID NO:332. [0023] FIG.7. Sequence alignment of the reticulon homology domain from human reticulon proteins. The reticulon homology domain consists of the tandem hydrophobic regions and the intervening linker region. C1101 of RTN4 is indicated by the arrow. The shaded amino acids indicate shared sequence identity (black) or similarity (gray). The sequences in FIG.7 include, from top to bottom, UniProt O75298 (RTN2a) SEQ ID NO:333, UniProt O75298-2 (RTN2b) SEQ ID NO:334, UniProt O95197 (RTN3a) SEQ ID NO:335, UniProt O95197-2 (RTN3b) SEQ ID NO:336, UniProt O95197-3 (RTN3c) SEQ ID NO:337, UniProt Q16799 (RTN1a) SEQ ID NO:338, UniProt Q16799-2 (RTN1b) SEQ ID NO:339, UniProt Q16799-3 (RTN1c) SEQ ID NO:340, UniProt Q9NQC3 (RTN4a) SEQ ID NO:331, UniProt Q9NQC3-2 (RTN4b) SEQ ID NO:341, and UniProt Q9NQC3-3 (RTN4c) SEQ ID NO:342. [0024] FIG.8. ER Morphology in SW620 Colorectal Cancer Cells. SW620 cells expressing GFP-tagged Sec61β were treated with DKM 3-30 (50 µM) for the indicated times and the ER (light gray/white) and nuclear (dark gray) morphology visualized by fluorescence microscopy. [0025] FIGS.9A-9B. DKM 3-30 alters ER morphology. (FIGS.9A, 9B) U2OS cells expressing GFP-tagged Sec61β were treated with DKM 3-30 (50 µM) and ER morphology visualized by time-lapse fluorescence microscopy. Time (min) is indicated on each panel.

Bottom panels indicate boxed region. [0026] FIG.10. DKM 3-30 modifies C1101 of Rtn4. C1101 projects into the cytoplasm and laterally towards a prominent groove in the surface of Rtn4. Covalent modification of C1101 with DKM 3-30 may interact with, or modify the location of, surrounding residues that line the groove, including E1105, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098. These interactions or modifications could result in local or global structural

derangements that could influence Rtn4 functions, interactions with lipids, and/or interactions with protein binding partners. [0027] FIGS.11A-11C. DKM 3-30 and analogs. (FIG.11A) Structures of DKM 3-30 and analogs. (FIG.11B) Gel-based ABPP analysis showing competition side-by-side competition studies of DKM 3-30, YP 1-46, and AMR 1-125 against IA-rhodamine labelling of pure human RTN4. Shown are the 50 % inhibitory concentration (IC50) values for each compound. (FIG. 11C) Serum-free cell survival of U2OS (48 h) or SW620 (24 h) cells treated with DMSO vehicle or each compound (50 µM). Data in (C) are presented as mean ± sem. Significance is expressed as *p<0.001 compared to vehicle-treated controls. [0028] FIG.12. Effect of DKM 3-30 in Mouse Embryonic Fibroblast (MEF) cells expressing human RTN4. C1101 in human RTN4 is instead a serine in mouse RTN4. DKM 3-30 does not induce apoptosis in GFP-expressing MEF cells, but induces apoptosis in MEF cells expressing human RTN4-GFP. GFP or RTN4-GFP expressing MEF cells were treated with DKM 3-30 (50 µM) for 0, 8, or 16 h and apoptotic cells (propidium iodine positive and Annexin-V positive) were assessed by flow cytometry. Data are presented as mean ± sem. Significance is expressed as *p<0.05 compared to 0 h time-point. [0029] FIG.13. AMR 1-125, but not YP 146, alters ER morphology. U2OS cells expressing GFP-tagged Sec61β were incubated with control, 1 µM AMR 1-125, or 50 µM YP 146 and the ER morphology was visualized by time-lapse fluorescence microscopy. Time (min) is indicated on each panel. Bottom panels indicate boxed region.

DETAILED DESCRIPTION

I. Definitions

[0030] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. [0031] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH ₂ O- is equivalent to -OCH ₂ -. [0032] The term“alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkyl moiety may be fully saturated. An alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds. An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds. [0033] The term“alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, - CH ₂ CH ₂ CH ₂ CH ₂ -. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A“lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term“alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. [0034] The term“heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, or S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., O, N, P, S, B, As, or Si) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, - CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, - CH=CH-N(CH ₃ )-CH ₃ , -O-CH ₃ , -O-CH ₂ -CH ₃ , and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). [0035] Similarly, the term“heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH ₂ -CH ₂ -S-CH ₂ -CH ₂ - and -CH ₂ -S-CH ₂ -CH ₂ -NH-CH ₂ -. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy,

alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as - C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO ₂ R'. Where“heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term“heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like. [0036] The terms“cycloalkyl” and“heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of“alkyl” and“heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for

heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6- tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1- piperazinyl, 2-piperazinyl, and the like. A“cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and

heterocycloalkyl, respectively. [0037] The terms“halo” or“halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. [0038] The term“acyl” means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0039] The term“aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term“heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non- limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1- naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4- imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2- benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3- quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An“arylene” and a“heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen. [0040] Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different.

Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g. all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different. [0041] The symbol“ ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula. [0042] The term“oxo,” as used herein, means an oxygen that is double bonded to a carbon atom. [0043] The term“alkylarylene” as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula: . [0044] An alkylarylene moiety may be substituted (e.g. with a substituent group) on the alkylene moiety or the arylene linker (e.g. at carbons 2, 3, 4, or 6) with halogen, oxo, -N ₃ , -CF ₃ , - CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3 -SO3H, - OSO3H, -SO2NH2,−NHNH2,−ONH2,−NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted. [0045] Each of the above terms (e.g.,“alkyl,”“heteroalkyl,”“cycloalkyl,”“hete rocycloalkyl,” “aryl,” and“heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below. [0046] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl,

heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, - SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'- C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', - S(O) ₂ NR'R'', -NRSO ₂ R',−NR'NR''R''',−ONR'R'',−NR'C(O)NR''NR'''R'''', -CN, -NO ₂ , - NR'SO ₂ R'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR'', in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term“alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF ₃ and -CH ₂ CF ₃ ) and acyl (e.g., -C(O)CH ₃ , -C(O)CF ₃ , -C(O)CH ₂ OCH ₃ , and the like). [0047] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R'', -SR', -halogen, - SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'- C(O)NR''R''', -NR''C(O) ₂ R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O) ₂ R', - S(O)2NR'R'', -NRSO2R',−NR'NR''R''',−ONR'R'',−NR'C(O)NR''NR'''R'''', -CN, -NO2, -R', -N3, - CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)- OR'', -NR'OR'', in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R'', R''', and R'''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' groups when more than one of these groups is present. [0048] Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency. [0049] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring- forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring- forming substituents are attached to non-adjacent members of the base structure. [0050] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')q-U-, wherein T and U are independently -NR-, -O-, - CRR'-, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O) -, - S(O) ₂ -, -S(O) ₂ NR'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') _s -X'- (C''R''R''') _d -, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O) ₂ -, or -S(O) ₂ NR'-. The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. [0051] As used herein, the terms“heteroatom” or“ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si). [0052] A“substituent group,” as used herein, means a group selected from the following moieties: (A) oxo,

halogen, -CCl ₃ , -CBr ₃ , -CF ₃ , -CI ₃ ,-CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H , -SO2NH2,−NHNH2,−ONH2,−NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H,

-NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3,-OCHCl2, -OCHBr2, -OCHI2 , -OCHF2, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6- C ₁₀ aryl, C ₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: (i) oxo,

halogen, -CCl3, -CBr3, -CF3, -CI3,-CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H , -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC(O)NHNH ₂ ,−NHC(O)NH ₂ , -NHSO ₂ H,

-NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3,-OCHCl2, -OCHBr2, -OCHI2 , -OCHF ₂ , unsubstituted alkyl (e.g., C ₁ -C ₈ alkyl, C ₁ -C ₆ alkyl, or C ₁ -C ₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: (a) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3,-CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC(O)NHNH ₂ ,−NHC(O)NH ₂ ,

-NHSO ₂ H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl ₃ , -OCF ₃ , -OCBr ₃ , -OCI ₃ ,-OCHCl ₂ , -OCH Br2, -OCHI2, -OCHF2, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C ₆ -C ₁₀ aryl, C ₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo, halogen, -CCl3, -CBr3, -CF3, -CI3,-CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC(O)NHNH2,−NHC(O)NH2, -NHSO2H,

-NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3,-OCHCl2, -OCHBr2, -OCHI ₂ , -OCHF ₂ , unsubstituted alkyl (e.g., C ₁ -C ₈ alkyl, C ₁ -C ₆ alkyl, or C ₁ -C ₄ alkyl),

unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C ₅ -C ₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0053] A“size-limited substituent” or“ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C ₆ -C ₁₀ aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. [0054] A“lower substituent” or“ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C ₃ -C ₇ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. [0055] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group. [0056] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C ₁ -C ₂₀ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C ₃ -C ₈ cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C ₆ -C ₁₀ arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene. [0057] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C ₆ -C ₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C ₆ -C ₁₀ arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below. [0058] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different. [0059] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one size-limited substituent group, wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different. [0060] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one lower substituent group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different. [0061] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size- limited substituent group, and/or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group is different. [0062] Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute

stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention. The compounds of the present invention do not include those that are known in art to be too unstable to synthesize and/or isolate. The present invention is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. [0063] As used herein, the term“isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms. [0064] The term“tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. [0065] It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention. [0066] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. [0067] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³ C- or ¹⁴ C-enriched carbon are within the scope of this invention. [0068] Unless otherwise stated, structures depicted herein are also meant to include

compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³ C- or ¹⁴ C-enriched carbon are within the scope of this invention. [0069] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( ³ H), iodine-125 ( ¹²⁵ I), or carbon-14 ( ¹⁴ C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. [0070] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit. [0071] “Analog,” or“analogue” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called“reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound. [0072] The terms "a" or "an," as used in herein means one or more. In addition, the phrase "substituted with a[n]," as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is "substituted with an unsubstituted C ₁ -C ₂₀ alkyl, or unsubstituted 2 to 20 membered heteroalkyl," the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls. [0073] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as“R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R ¹³ substituents are present, each R ¹³ substituent may be distinguished as R ^13A , R ^13B , R ^13C , R ^13D , etc., wherein each of R ^13A , R ^13B , R ^13C , R ^13D , etc. is defined within the scope of the definition of R ¹³ and optionally differently. [0074] A“covalent cysteine modifier moiety” as used herein refers to a substituent that is capable of reacting with the sulfhydryl functional group of a cysteine amino acid (e.g. cysteine corresponding to C1101 of the human reticulon 4) to form a covalent bond. Thus, the covalent cysteine modifier moiety is typically electrophilic. [0075] Description of compounds of the present invention are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds. [0076] The term“pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic,

methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al.,“Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1- 19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. [0077] Thus, the compounds of the present invention may exist as salts, such as with pharmaceutically acceptable acids. The present invention includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates,

methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art. [0078] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. [0079] In addition to salt forms, the present invention provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent. [0080] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention. [0081] “Pharmaceutically acceptable excipient” and“pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other

pharmaceutical excipients are useful in the present invention. [0082] The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.

Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration. [0083] A“Reticulon 4 inhibitor” and“RTN 4 inhibitor” is a substance (e.g., oligonucleotide, protein, composition, or compound) that negatively affects (e.g. decreases) the activity or function of reticulon 4 relative to the activity or function of reticulon 4 in the absence of the inhibitor (e.g., wherein the reticulon 4 inhibitor binds reticulon 4). A“reticulon 4 inhibitor compound” or“RTN 4 inhibitor compound” or“RTN 4 inhibitor compound” refers to a compound (e.g. a compound described herein) that reduces the activity of reticulon 4 when compared to a control, such as absence of the compound or a compound with known inactivity. In embodiments, a Reticulon 4 inhibitor is a compound described herein. [0084] The terms“polypeptide,”“peptide” and“protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may optionally be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer. [0085] A polypeptide, or a cell is“recombinant” when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g. non-natural or not wild type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Likewise, a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is

recombinant. [0086] An amino acid residue in a protein "corresponds" to a given residue when it occupies the same essential structural and/or spatial position within the protein as the given residue in a reference sequence. For example, a selected residue in a selected protein corresponds to Cys1101 when the selected residue occupies the same essential structural and/or spatial position as Cys1101 in SEQ ID NO:331. In some embodiments, where a selected protein is aligned for maximum homology with the human reticulon 4 protein, the position in the aligned selected protein aligning with Cys1101 is said to correspond to Cys1101. Instead of a primary sequence alignment, a three dimensional structural alignment can also be used, e.g., where the three dimensional structure of the selected protein is aligned for maximum correspondence with the human reticulon 4 protein (reference sequence) and the overall structures compared. In this case, the amino acid that occupies the same essential structural position as Cys1101 in the structural model relative to the reference sequence is said to correspond to the Cys1101 residue. [0087] “Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including

biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents that can be produced in the reaction mixture. [0088] The term“contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway. [0089] As defined herein, the term“activation”,“activate”,“activating” and the like in reference to a protein-inhibitor interaction means positively affecting (e.g. increasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the activator. In embodiments activation means positively affecting (e.g. increasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the activator. The terms may reference activation, or activating, sensitizing, or up- regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease. [0090] As defined herein, the term“inhibition”,“inhibitor”,“inhibit”,“inhibi ting” and the like in reference to a protein-inhibitor interaction means negatively affecting (e.g. decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In embodiments inhibition means negatively affecting (e.g. decreasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor. In embodiments inhibition refers to reduction of a disease or symptoms of disease. In embodiments, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. In embodiments, inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g. an inhibitor binds to the target protein). In embodiments, inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g. an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation). [0091] The terms“reticulon 4” and“RTN 4” and“RTN4” refer to a protein (including homologs, isoforms, and functional fragments thereof) with reticulon 4 activity. The term includes any recombinant or naturally-occurring form of reticulon 4 or variants thereof that maintain reticulon 4 activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype reticulon 4). In embodiments, the reticulon 4 protein encoded by the RTN 4 gene has the amino acid sequence set forth in or corresponding to Entrez 57142, UniProt Q9NQC3, or RefSeq (protein) NP_065393. In embodiments, the reticulon 4 gene has the nucleic acid sequence set forth in RefSeq (mRNA) NM_020532. In embodiments, the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application. In embodiments, the sequence corresponds to NP_065393.1. In embodiments, the sequence corresponds to NM_020532.4. In embodiments, the reticulon 4 is a human reticulon 4, such as a human cancer causing reticulon 4. [0092] In embodiments, the RTN4 sequence corresponds to UniProt ID Q9NQC3, and has the sequence:

MEDLDQSPLVSSSDSPPRPQPAFKYQFVREPEDEEEEEEEEEEDEDEDLEELEVLER KPA AGLSAAPVPTAPAAGAPLMDFGNDFVPPAPRGPLPAAPPVAPERQPSWDPSPVSSTVPAP SPLSAAAVSPSKLPEDDEPPARPPPPPPASVSPQAEPVWTPPAPAPAAPPSTPAAPKRRG ^{SSGSVDETLFALPAASEPVIRSSAENMDLKEQPGNTISAGQEDFPSVLLETAASL PSLSP} LSAASFKEHEYLGNLSTVLPTEGTLQENVSEASKEVSEKAKTLLIDRDLTEFSELEYSEM GSSFSVSPKAESAVIVANPREEIIVKNKDEEEKLVSNNILHNQQELPTALTKLVKEDEVV SSEKAKDSFNEKRVAVEAPMREEYADFKPFERVWEVKDSKEDSDMLAAGGKIESNLESKV DKKCFADSLEQTNHEKDSESSNDDTSFPSTPEGIKDRSGAYITCAPFNPAATESIATNIF PLLGDPTSENKTDEKKIEEKKAQIVTEKNTSTKTSNPFLVAAQDSETDYVTTDNLTKVTE EVVANMPEGLTPDLVQEACESELNEVTGTKIAYETKMDLVQTSEVMQESLYPAAQLCPSF EESEATPSPVLPDIVMEAPLNSAVPSAGASVIQPSSSPLEASSVNYESIKHEPENPPPYE EAMSVSLKKVSGIKEEIKEPENINAALQETEAPYISIACDLIKETKLSAEPAPDFSDYSE MAKVEQPVPDHSELVEDSSPDSEPVDLFSDDSIPDVPQKQDETVMLVKESLTETSFESMI EYENKEKLSALPPEGGKPYLESFKLSLDNTKDTLLPDEVSTLSKKEKIPLQMEELSTAVY SNDDLFISKEAQIRETETFSDSSPIEIIDEFPTLISSKTDSFSKLAREYTDLEVSHKSEI ANAPDGAGSLPCTELPHDLSLKNIQPKVEEKISFSDDFSKNGSATSKVLLLPPDVSALAT QAEIESIVKPKVLVKEAEKKLPSDTEKEDRSPSAIFSAELSKTSVVDLLYWRDIKKTGVV FGASLFLLLSLTVFSIVSVTAYIALALLSVTISFRIYKGVIQAIQKSDEGHPFRAYLESE ^{VAISEELVQKYSNSALGHVNCTIKELRRLFLVDDLVDSLKFAVLMWVFTYVGALF NGLTL} LILALISLFSVPVIYERHQAQIDHYLGLANKNVKDAMAKIQAKIPGLKRKAE

(SEQ ID NO: 331) [0093] In embodiments, the RTN4 sequence corresponds to UniProt ID Q6JRV0, and has the following sequence:

MDEQSPDISSSHSGDERREPAQPGERKPWDDLDDVLDLTGGAGQFSQPFSGSHPARD IEE EEEDEEEERGAWKDSLEPSPVEEEPGSIDSISPVSPHSPAVPSAPMEEPERPPAPCTAPS GSVDENLFTLPAASAHLMHASADKIMEPYSTVSTGQEEFASVLLQSTASLSSLPSLSTDS SKEHAETVAFPTGLAATEALQEPTDNMYSVSRITSHLPLSDNLESKALDQVKEEVIFSEK GYVVDHPTSQQETISEEHAKLYSQSAKEMFSGMLQSVAPPHEEFTDIKEVYDPYVDFKPF MSSKSGDVGYEVSDVAEKFQVDVGRLNLESAVKHEEKSSEEMEIDSISDDISPLTPELLP DSTDYDMFATVEQNIPFSFGGGHVAGNKTDEKKIEDIEAQKTSVGFGLKVATVNPFYNES AQESEYVTTHVATHVSTKPEGPTPDIVQEAYESEAYDTGIPKQKYESNIDLVQTAANSVQ EKVSPTAQAPARLEETDSVSSPVLPDIVMEAPLASALETVALKPDISPVGIKPPARVEKT KAEPEKPPSYEEAVTEVLQNQDLAAALGGSKQGAVVEETETPYISIACDLIKGTESVASG ^{FTEFSKLKQNEFESQFMEPSDESSPDSECSEPSYKQWDSEVVQKEAFSIKTESVN AQSII} IPEQKQVFDQKSEESSPSKSYLDSFQPEICVSKATSDLFAKGLTTLLQEKPLQMEELDEG LSLEKIPCTKYSPVSESPEPRPSPVPEDLSSKLGDIQKEVLIAKQPEDKVQKNRSNLDFV PENIEFTPAVQKPDDSGKAVSDTFGGLDTTTKGGSAVHEVKVDKPKPPSKEDDGSKLPKK ESKASTVSSSDFMNSVVDLIYWRDIKRSGVVFGASLFLLLSLSVFSIVSVLAYIALALLS VTISLRIYKGILQAIQKSEEGHPFRSILESNLAVPEDLVQKYCNVALNHVNCTVKELRHL FLVEDLVDSLKFAVLMWVFTYIGALFNGLTLLIVALISLFSIPVIYERHQTQVDHYLALV NKNLKSTSDLILSKVPGLKRKAE

(SEQ ID NO: 332). [0094] As observed in FIG.7, UniProt O75298 (RTN2a) has the following sequence: MGQVLPVFAHCKEAPSTASSTPDSTEGGNDDSDFRELHTAREFSEEDEEETTSQDWGTPR ELTFSYIAFDGVVGSGGRRDSTARRPRPQGRSVSEPRDQHPQPSLGDSLESIPSLSQSPE PGRRGDPDTAPPSERPLEDLRLRLDHLGWVARGTGSGEDSSTSSSTPLEDEEPQEPNRLE TGEAGEELDLRLRLAQPSSPEVLTPQLSPGSGTPQAGTPSPSRSRDSNSGPEEPLLEEEE KQWGPLEREPVRGQCLDSTDQLEFTVEPRLLGTAMEWLKTSLLLAVYKTVPILELSPPLW TAIGWVQRGPTPPTPVLRVLLKWAKSPRSSGVPSLSLGADMGSKVADLLYWKDTRTSGVV FTGLMVSLLCLLHFSIVSVAAHLALLLLCGTISLRVYRKVLQAVHRGDGANPFQAYLDVD LTLTREQTERLSHQITSRVVSAATQLRHFFLVEDLVDSLKLALLFYILTFVGAIFNGLTL LILGVIGLFTIPLLYRQHQAQIDQYVGLVTNQLSHIKAKIRAKIPGTGALASAAAAVSGS ^KAKAE

(SEQ ID NO: 333) [0095] As observed in FIG.7, UniProt O75298-2 (RTN2b) has the following sequence: MGQVLPVFAHCKEAPSTASSTPDSTEGGNDDSDFRELHTAREFSEEDEEETTSQDWGTPR ELTFSYIAFDGVVGSGGRRDSTARRPRPQGRSVSEPRDQHPQPSLGDSLESIPSLSQSPE PGRRGDPDTAPPSERPLEDLRLRLDHLGWVARGTGSGEDSSTSSSTPLEDEEPQEPNRLE TGEAGEELDLRLRLAQPSSPEVLTPQLSPGSGTPQAGTPSPSRSRDSNSGPEEPLLEEEE KQWGPLEREPVRGQCLDSTDQLEFTVEPRLLVADLLYWKDTRTSGVVFTGLMVSLLCLLH FSIVSVAAHLALLLLCGTISLRVYRKVLQAVHRGDGANPFQAYLDVDLTLTREQTERLSH QITSRVVSAATQLRHFFLVEDLVDSLKLALLFYILTFVGAIFNGLTLLILGVIGLFTIPL LYRQHQAQIDQYVGLVTNQLSHIKAKIRAKIPGTGALASAAAAVSGSKAKAE

(SEQ ID NO: 334) [0096] As observed in FIG.7, UniProt O95197 (RTN3a) has the following sequence: MAEPSAATQSHSISSSSFGAEPSAPGGGGSPGACPALGTKSCSSSCADSFVSSSSSQPVS LFSTSQEGLSSLCSDEPSSEIMTSSFLSSSEIHNTGLTILHGEKSHVLGSQPILAKEGKD HLDLLDMKKMEKPQGTSNNVSDSSVSLAAGVHCDRPSIPASFPEHPAFLSKKIGQVEEQI DKETKNPNGVSSREAKTALDADDRFTLLTAQKPPTEYSKVEGIYTYSLSPSKVSGDDVIE KDSPESPFEVIIDKAAFDKEFKDSYKESTDDFGSWSVHTDKESSEDISETNDKLFPLRNK EAGRYPMSALLSRQFSHTNAALEEVSRCVNDMHNFTNEILTWDLVPQVKQQTDKSSDCIT KTTGLDMSEYNSEIPVVNLKTSTHQKTPVCSIDGSTPITKSTGDWAEASLQQENAITGKP ^{VPDSLNSTKEFSIKGVQGNMQKQDDTLAELPGSPPEKCDSLGSGVATVKVVLPDD HLKDE} MDWQSSALGEITEADSSGESDDTVIEDITADTSFENNKIQAEKPVSIPSAVVKTGEREIK EIPSCEREEKTSKNFEELVSDSELHQDQPDILGRSPASEAACSKVPDTNVSLEDVSEVAP EKPITTENPKLPSTVSPNVFNETEFSLNVTTSAYLESLHGKNVKHIDDSSPEDLIAAFTE TRDKGIVDSERNAFKAISEKMTDFKTTPPVEVLHENESGGSEIKDIGSKYSEQSKETNGS EPLGVFPTQGTPVASLDLEQEQLTIKALKELGERQVEKSTSAQRDAELPSEEVLKQTFTF APESWPQRSYDILERNVKNGSDLGISQKPITIRETTRVDAVSSLSKTELVKKHVLARLLT DFSVHDLIFWRDVKKTGFVFGTTLIMLLSLAAFSVISVVSYLILALLSVTISFRIYKSVI QAVQKSEEGHPFKAYLDVDITLSSEAFHNYMNAAMVHINRALKLIIRLFLVEDLVDSLKL AVFMWLMTYVGAVFNGITLLILAELLIFSVPIVYEKYKTQIDHYVGIARDQTKSIVEKIQ AKLPGIAKKKAE

(SEQ ID NO: 335) [0097] As observed in FIG.7, UniProt O95197-2 (RTN3b) has the following sequence: MAEPSAATQSHSISSSSFGAEPSAPGGGGSPGACPALGTKSCSSSCAEGLSSLCSDEPSS EIMTSSFLSSSEIHNTGLTILHGEKSHVLGSQPILAKEGKDHLDLLDMKKMEKPQGTSNN VSDSSVSLAAGVHCDRPSIPASFPEHPAFLSKKIGQVEEQIDKETKNPNGVSSREAKTAL DADDRFTLLTAQKPPTEYSKVEGIYTYSLSPSKVSGDDVIEKDSPESPFEVIIDKAAFDK EFKDSYKESTDDFGSWSVHTDKESSEDISETNDKLFPLRNKEAGRYPMSALLSRQFSHTN AALEEVSRCVNDMHNFTNEILTWDLVPQVKQQTDKSSDCITKTTGLDMSEYNSEIPVVNL KTSTHQKTPVCSIDGSTPITKSTGDWAEASLQQENAITGKPVPDSLNSTKEFSIKGVQGN MQKQDDTLAELPGSPPEKCDSLGSGVATVKVVLPDDHLKDEMDWQSSALGEITEADSSGE SDDTVIEDITADTSFENNKIQAEKPVSIPSAVVKTGEREIKEIPSCEREEKTSKNFEELV SDSELHQDQPDILGRSPASEAACSKVPDTNVSLEDVSEVAPEKPITTENPKLPSTVSPNV FNETEFSLNVTTSAYLESLHGKNVKHIDDSSPEDLIAAFTETRDKGIVDSERNAFKAISE KMTDFKTTPPVEVLHENESGGSEIKDIGSKYSEQSKETNGSEPLGVFPTQGTPVASLDLE QEQLTIKALKELGERQVEKSTSAQRDAELPSEEVLKQTFTFAPESWPQRSYDILERNVKN GSDLGISQKPITIRETTRVDAVSSLSKTELVKKHVLARLLTDFSVHDLIFWRDVKKTGFV FGTTLIMLLSLAAFSVISVVSYLILALLSVTISFRIYKSVIQAVQKSEEGHPFKAYLDVD ITLSSEAFHNYMNAAMVHINRALKLIIRLFLVEDLVDSLKLAVFMWLMTYVGAVFNGITL LILAELLIFSVPIVYEKYKTQIDHYVGIARDQTKSIVEKIQAKLPGIAKKKAE

(SEQ ID NO:336) [0098] As observed in FIG.7, UniProt O95197-3 (RTN3c) has the following sequence: MAEPSAATQSHSISSSSFGAEPSAPGGGGSPGACPALGTKSCSSSCAVHDLIFWRDVKKT GFVFGTTLIMLLSLAAFSVISVVSYLILALLSVTISFRIYKSVIQAVQKSEEGHPFKAYL DVDITLSSEAFHNYMNAAMVHINRALKLIIRLFLVEDLVDSLKLAVFMWLMTYVGAVFNG ITLLILAELLIFSVPIVYEKYKTQIDHYVGIARDQTKSIVEKIQAKLPGIAKKKAE

(SEQ ID NO:337) [0099] As observed in FIG.7, UniProt Q16799 (RTN1a) has the following sequence: MAAPGDPQDELLPLAGPGSQWLRHRGEGENEAVTPKGATPAPQAGEPSPGLGARAREAAS REAGSGPARQSPVAMETASTGVAGVSSAMDHTFSTTSKDGEGSCYTSLISDICYPPQEDS TYFTGILQKENGHVTISESPEELGTPGPSLPDVPGIESRGLFSSDSGIEMTPAESTEVNK ILADPLDQMKAEAYKYIDITRPEEVKHQEQHHPELEDKDLDFKNKDTDISIKPEGVREPD KPAPVEGKIIKDHLLEESTFAPYIDDLSEEQRRAPQITTPVKITLTEIEPSVETTTQEKT PEKQDICLKPSPDTVPTVTVSEPEDDSPGSITPPSSGTEPSAAESQGKGSISEDELITAI KEAKGLSYETAENPRPVGQLADRPEVKARSGPPTIPSPLDHEASSAESGDSEIELVSEDP MAAEDALPSGYVSFGHVGGPPPSPASPSIQYSILREEREAELDSELIIESCDASSASEES PKREQDSPPMKPSALDAIREETGVRAEERAPSRRGLAEPGSFLDYPSTEPQPGPELPPGD GALEPETPMLPRKPEEDSSSNQSPAATKGPGPLGPGAPPPLLFLNKQKAIDLLYWRDIKQ TGIVFGSFLLLLFSLTQFSVVSVVAYLALAALSATISFRIYKSVLQAVQKTDEGHPFKAY LELEITLSQEQIQKYTDCLQFYVNSTLKELRRLFLVQDLVDSLKFAVLMWLLTYVGALFN GLTLLLMAVVSMFTLPVVYVKHQAQIDQYLGLVRTHINAVVAKIQAKIPGAKRHAE

(SEQ ID NO:338) [0100] As observed in FIG.7, UniProt Q16799-2 (RTN1b) has the following sequence: MAAEDALPSGYVSFGHVGGPPPSPASPSIQYSILREEREAELDSELIIESCDASSASEES PKREQDSPPMKPSALDAIREETGVRAEERAPSRRGLAEPGSFLDYPSTEPQPGPELPPGD GALEPETPMLPRKPEEDSSSNQSPAATKGPGPLGPGAPPPLLFLNKQKAIDLLYWRDIKQ TGIVFGSFLLLLFSLTQFSVVSVVAYLALAALSATISFRIYKSVLQAVQKTDEGHPFKAY LELEITLSQEQIQKYTDCLQFYVNSTLKELRRLFLVQDLVDSLKFAVLMWLLTYVGALFN GLTLLLMAVVSMFTLPVVYVKHQAQIDQYLGLVRTHINAVVAKIQAKIPGAKRHAE

(SEQ ID NO:339) [0101] As observed in FIG.7, UniProt Q16799-3 (RTN1c) has the following sequence: MQATADSTKMDCVWSNWKSQAIDLLYWRDIKQTGIVFGSFLLLLFSLTQFSVVSVVAYLA LAALSATISFRIYKSVLQAVQKTDEGHPFKAYLELEITLSQEQIQKYTDCLQFYVNSTLK ELRRLFLVQDLVDSLKFAVLMWLLTYVGALFNGLTLLLMAVVSMFTLPVVYVKHQAQIDQ YLGLVRTHINAVVAKIQAKIPGAKRHAE

(SEQ ID NO:340) [0102] As observed in FIG.7, UniProt Q9NQC3 (RTN4a) has the following sequence: ^{MEDLDQSPLVSSSDSPPRPQPAFKYQFVREPEDEEEEEEEEEEDEDEDLEELEVL ERKPA} AGLSAAPVPTAPAAGAPLMDFGNDFVPPAPRGPLPAAPPVAPERQPSWDPSPVSSTVPAP SPLSAAAVSPSKLPEDDEPPARPPPPPPASVSPQAEPVWTPPAPAPAAPPSTPAAPKRRG

SSGSVDETLFALPAASEPVIRSSAENMDLKEQPGNTISAGQEDFPSVLLETAASLPS LSP LSAASFKEHEYLGNLSTVLPTEGTLQENVSEASKEVSEKAKTLLIDRDLTEFSELEYSEM GSSFSVSPKAESAVIVANPREEIIVKNKDEEEKLVSNNILHNQQELPTALTKLVKEDEVV SSEKAKDSFNEKRVAVEAPMREEYADFKPFERVWEVKDSKEDSDMLAAGGKIESNLESKV DKKCFADSLEQTNHEKDSESSNDDTSFPSTPEGIKDRSGAYITCAPFNPAATESIATNIF PLLGDPTSENKTDEKKIEEKKAQIVTEKNTSTKTSNPFLVAAQDSETDYVTTDNLTKVTE EVVANMPEGLTPDLVQEACESELNEVTGTKIAYETKMDLVQTSEVMQESLYPAAQLCPSF EESEATPSPVLPDIVMEAPLNSAVPSAGASVIQPSSSPLEASSVNYESIKHEPENPPPYE ^{EAMSVSLKKVSGIKEEIKEPENINAALQETEAPYISIACDLIKETKLSAEPAPDF SDYSE} MAKVEQPVPDHSELVEDSSPDSEPVDLFSDDSIPDVPQKQDETVMLVKESLTETSFESMI EYENKEKLSALPPEGGKPYLESFKLSLDNTKDTLLPDEVSTLSKKEKIPLQMEELSTAVY SNDDLFISKEAQIRETETFSDSSPIEIIDEFPTLISSKTDSFSKLAREYTDLEVSHKSEI ANAPDGAGSLPCTELPHDLSLKNIQPKVEEKISFSDDFSKNGSATSKVLLLPPDVSALAT QAEIESIVKPKVLVKEAEKKLPSDTEKEDRSPSAIFSAELSKTSVVDLLYWRDIKKTGVV FGASLFLLLSLTVFSIVSVTAYIALALLSVTISFRIYKGVIQAIQKSDEGHPFRAYLESE VAISEELVQKYSNSALGHVNCTIKELRRLFLVDDLVDSLKFAVLMWVFTYVGALFNGLTL LILALISLFSVPVIYERHQAQIDHYLGLANKNVKDAMAKIQAKIPGLKRKAE

(SEQ ID NO:341) [0103] As observed in FIG.7, UniProt Q9NQC3-2 (RTN4b) has the following sequence: MEDLDQSPLVSSSDSPPRPQPAFKYQFVREPEDEEEEEEEEEEDEDEDLEELEVLERKPA AGLSAAPVPTAPAAGAPLMDFGNDFVPPAPRGPLPAAPPVAPERQPSWDPSPVSSTVPAP SPLSAAAVSPSKLPEDDEPPARPPPPPPASVSPQAEPVWTPPAPAPAAPPSTPAAPKRRG SSGSVVVDLLYWRDIKKTGVVFGASLFLLLSLTVFSIVSVTAYIALALLSVTISFRIYKG VIQAIQKSDEGHPFRAYLESEVAISEELVQKYSNSALGHVNCTIKELRRLFLVDDLVDSL KFAVLMWVFTYVGALFNGLTLLILALISLFSVPVIYERHQAQIDHYLGLANKNVKDAMAK IQAKIPGLKRKAE

(SEQ ID NO:342) [0104] As observed in FIG.7, UniProt Q9NQC3-3 (RTN4c) has the following sequence: ^{MDGQKKNWKDKVVDLLYWRDIKKTGVVFGASLFLLLSLTVFSIVSVTAYIALALL SVTIS} FRIYKGVIQAIQKSDEGHPFRAYLESEVAISEELVQKYSNSALGHVNCTIKELRRLFLVD DLVDSLKFAVLMWVFTYVGALFNGLTLLILALISLFSVPVIYERHQAQIDHYLGLANKNV KDAMAKIQAKIPGLKRKAE

(SEQ ID NO:343) [0105] The term "expression" includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post- translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry,

immunofluorescence, immunohistochemistry, etc.). [0106] The terms“disease” or“condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. The disease may be a cancer. The disease may be stroke. The disease may be an inflammatory disease. In some further instances,“cancer” refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin’s lymphomas (e.g., Burkitt’s, Small Cell, and Large Cell lymphomas), Hodgkin’s lymphoma, leukemia (including AML, ALL, and CML), or multiple myeloma. [0107] As used herein, the term "cancer" refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g. humans), including leukemia, carcinomas and sarcomas.

Exemplary cancers that may be treated with a compound or method provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, lung cancer, and cancer of the head.

Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus,

Medulloblastoma, colorectal cancer, pancreatic cancer. Additional examples include, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary

macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer. [0108] The term "leukemia" refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia,

promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia. [0109] The term "sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma. [0110] The term "melanoma" is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma. [0111] The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma,

encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet- ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum. [0112] As used herein, the term“neurodegenerative disease” refers to a disease or condition in which the function of a subject’s nervous system becomes impaired. Examples of

neurodegenerative diseases that may be treated with a compound, pharmaceutical composition, or method described herein include Alexander's disease, Alper's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease (also known as Spielmeyer- Vogt-Sjogren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Sträussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewy body dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple sclerosis, Multiple System Atrophy,

Narcolepsy, Neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher Disease, Pick's disease, Primary lateral sclerosis, Prion diseases, Refsum's disease, Sandhoff's disease, Schilder's disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia,

Schizophrenia, Spinocerebellar ataxia (multiple types with varying characteristics), Spinal muscular atrophy, Steele-Richardson-Olszewski disease , progressive supranuclear palsy, or Tabes dorsalis. [0113] The terms“treating”, or“treatment” refers to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. The term "treating" and conjugations thereof, may include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. In embodiments, the treating or treatment is no prophylactic treatment. [0114] “Patient” or“subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human. [0115] A“effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). An example of an“effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.” A“reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A“prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A“function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). [0116] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art. [0117] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan. [0118] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state. [0119] As used herein, the term "administering" means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal) compatible with the preparation. Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. In embodiments, the administering does not include administration of any active agent other than the recited active agent. [0120] "Co-administer" it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the

compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation). The compositions of the present invention can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. [0121] A“cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaroytic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization. [0122] “Control” or“control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples). [0123] The term“modulator” refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule. In some embodiments, a reticulon 4 associated disease modulator is a compound that reduces the severity of one or more symptoms of a disease associated with reticulon 4 (e.g. cancer). A reticulon 4 modulator is a compound that increases or decreases the activity or function or level of activity or level of function of reticulon 4. [0124] The term“modulate” is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties.“Modulation” refers to the process of changing or varying one or more properties. For example, as applied to the effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule. [0125] The term“associated” or“associated with” in the context of a substance or substance activity or function associated with a disease (e.g. a protein associated disease, a cancer associated with reticulon 4 activity, reticulon 4 associated cancer, reticulon 4 associated disease) means that the disease (e.g. cancer) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or inpart) the substance or substance activity or function. For example, a cancer associated with reticulon 4 activity or function may be a cancer that results (entirely or partially) from aberrant reticulon 4 function (e.g. enzyme activity, protein-protein interaction, signaling pathway) or a cancer wherein a particular symptom of the disease is caused (entirely or partially) by aberrant reticulon 4 activity or function. As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease. For example, a cancer associated with reticulon 4 activity or function or a reticulon 4 associated cancer, may be treated with a reticulon 4 modulator or reticulon 4 inhibitor, in the instance where reticulon 4 activity or function (e.g. signaling pathway activity) causes the cancer. [0126] The term“aberrant” as used herein refers to different from normal. When used to describe enzymatic activity or protein function, aberrant refers to activity or function that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g. by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms. [0127] The term“signaling pathway” as used herein refers to a series of interactions between cellular and optionally extra-cellular components (e.g. proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propogated to other signaling pathway components. For example, binding of a reticulon 4 protein with a compound as described herein may reduce the interactions between the reticulon 4 protein and downstream effectors or signaling pathway components, resulting in changes in cell growth, proliferation, or survival. [0128] The term“electrophilic chemical moiety” is used in accordance with its plain ordinary chemical meaning and refers to a chemical group (e.g., monovalent chemical group) that is electrophilic. [0129] The term“nucleophilic chemical moiety” is used in accordance with its plain ordinary chemical meaning and refers to a chemical group (e.g., monovalent chemical group) that is nucleophilic. [0130] "Nucleic acid" refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof in either single-, double- or multiple-stranded form, or complements thereof. The terms“polynucleotide,”“oligonucleotide,”“oligo” or the like refer, in the usual and customary sense, to a linear sequence of nucleotides. The term“nucleotide” refers, in the usual and customary sense, to a single unit of a polynucleotide, i.e., a monomer. Nucleotides can be ribonucleotides, deoxyribonucleotides, or modified versions thereof. Examples of

polynucleotides contemplated herein include single and double stranded DNA, single and double stranded RNA, and hybrid molecules having mixtures of single and double stranded DNA and RNA. Examples of nucleic acid, e.g. polynucleotides contemplated herein include any types of RNA, e.g. mRNA, siRNA, miRNA, and guide RNA and any types of DNA, genomic DNA, plasmid DNA, and minicircle DNA, and any fragments thereof. The term“duplex” in the context of polynucleotides refers, in the usual and customary sense, to double strandedness. Nucleic acids can be linear or branched. For example, nucleic acids can be a linear chain of nucleotides or the nucleic acids can be branched, e.g., such that the nucleic acids comprise one or more arms or branches of nucleotides. Optionally, the branched nucleic acids are repetitively branched to form higher ordered structures such as dendrimers and the like. [0131] Nucleic acids, including e.g., nucleic acids with a phosphothioate backbone, can include one or more reactive moieties. As used herein, the term reactive moiety includes any group capable of reacting with another molecule, e.g., a nucleic acid or polypeptide through covalent, non-covalent or other interactions. By way of example, the nucleic acid can include an amino acid reactive moiety that reacts with an amio acid on a protein or polypeptide through a covalent, non-covalent or other interaction. [0132] The terms also encompass nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non- naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, include, without limitation, phosphodiester derivatives including, e.g., phosphoramidate, phosphorodiamidate, phosphorothioate (also known as phosphothioate having double bonded sulfur replacing oxygen in the phosphate), phosphorodithioate,

phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boron phosphonate, or O-methylphosphoroamidite linkages (see Eckstein, OLIGONUCLEOTIDES AND ANALOGUES: A PRACTICAL APPROACH, Oxford University Press) as well as modifications to the nucleotide bases such as in 5-methyl cytidine or pseudouridine.; and peptide nucleic acid backbones and linkages. Other analog nucleic acids include those with positive backbones; non-ionic backbones, modified sugars, and non-ribose backbones (e.g. phosphorodiamidate morpholino oligos or locked nucleic acids (LNA) as known in the art), including those described in U.S. Patent Nos.5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, CARBOHYDRATE MODIFICATIONS IN ANTISENSE

RESEARCH, Sanghui & Cook, eds. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids. Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made. In embodiments, the internucleotide linkages in DNA are phosphodiester, phosphodiester derivatives, or a combination of both. [0133] Nucleic acids can include nonspecific sequences. As used herein, the term "nonspecific sequence" refers to a nucleic acid sequence that contains a series of residues that are not designed to be complementary to or are only partially complementary to any other nucleic acid sequence. By way of example, a nonspecific nucleic acid sequence is a sequence of nucleic acid residues that does not function as an inhibitory nucleic acid when contacted with a cell or organism. [0134] An "antisense nucleic acid" as referred to herein is a nucleic acid (e.g., DNA or RNA molecule) that is complementary to at least a portion of a specific target nucleic acid (e.g., a nucleic acid coding for one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331) and is capable of reducing transcription of the target nucleic acid (e.g. mRNA from DNA), reducing the translation of the target nucleic acid (e.g. mRNA), altering transcript splicing (e.g. single stranded morpholino oligo), or interfering with the endogenous activity of the target nucleic acid. See, e.g., Weintraub, Scientific American, 262:40 (1990). Typically, synthetic antisense nucleic acids (e.g. oligonucleotides) are generally between 15 and 25 bases in length. Thus, antisense nucleic acids are capable of hybridizing to (e.g. selectively hybridizing to) a target nucleic acid (e.g., a nucleic acid coding for one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331). In

embodiments, the antisense nucleic acid hybridizes to the target nucleic acid (e.g. a nucleic acid coding for one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331) in vitro. In embodiments, the antisense nucleic acid hybridizes to the target nucleic acid (e.g. a nucleic acid coding for one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331) in a cell. In embodiments, the antisense nucleic acid hybridizes to the target nucleic acid (e.g. a nucleic acid coding for one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331) in an organism. In embodiments, the antisense nucleic acid hybridizes to the target nucleic acid (e.g. a nucleic acid coding for one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331) under physiological conditions. Antisense nucleic acids may comprise naturally occurring nucleotides or modified nucleotides such as, e.g., phosphorothioate, methylphosphonate, and -anomeric sugar-phosphate, backbonemodified nucleotides. [0046] In the cell, the antisense nucleic acids hybridize to the corresponding RNA (e.g., a nucleic acid coding for one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331) forming a double-stranded molecule. The antisense nucleic acids interfere with the endogenous behavior of the RNA (e.g., a nucleic acid coding for one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331) and inhibit its function relative to the absence of the antisense nucleic

acid. Furthermore, the double-stranded molecule may be degraded via the RNAi pathway. The use of antisense methods to inhibit the in vitro translation of genes is well known in the art (Marcus-Sakura, Anal. Biochem., 172:289, (1988)). Further, antisense molecules which bind directly to the DNA may be used. Antisense nucleic acids may be single or double stranded nucleic acids. Non-limiting examples of antisense nucleic acids include siRNAs (including their derivatives or pre-cursors, such as nucleotide analogs), short hairpin RNAs (shRNA), micro RNAs (miRNA), saRNAs (small activating RNAs) and small nucleolar RNAs (snoRNA) or certain of their derivatives or pre-cursors. [0092] The term“complement,” as used herein, refers to a nucleotide (e.g., RNA or DNA) or a sequence of nucleotides capable of base pairing with a complementary nucleotide or sequence of nucleotides. As described herein and commonly known in the art the complementary (matching) nucleotide of adenosine is thymidine and the complementary (matching) nucleotide of guanidine is cytosine. Thus, a complement may include a sequence of nucleotides that base pair with corresponding complementary nucleotides of a second nucleic acid sequence. The nucleotides of a complement may partially or completely match the nucleotides of the second nucleic acid sequence. Where the nucleotides of the complement completely match each nucleotide of the second nucleic acid sequence, the complement forms base pairs with each nucleotide of the second nucleic acid sequence. Where the nucleotides of the complement partially match the nucleotides of the second nucleic acid sequence only some of the nucleotides of the complement form base pairs with nucleotides of the second nucleic acid sequence. Examples of

complementary sequences include coding and a non-coding sequences, wherein the non-coding sequence contains complementary nucleotides to the coding sequence and thus forms the complement of the coding sequence. A further example of complementary sequences are sense and antisense sequences, wherein the sense sequence contains complementary nucleotides to the antisense sequence and thus forms the complement of the antisense sequence. [0135] As described herein the complementarity of sequences may be partial, in which only some of the nucleic acids match according to base pairing, or complete, where all the nucleic acids match according to base pairing. Thus, two sequences that are complementary to each other, may have a specified percentage of nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region). [0136] The term "antibody" refers to a polypeptide encoded by an immunoglobulin gene or functional fragments thereof that specifically binds and recognizes an antigen. The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively. [0137] An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one“light” (about 25 kDa) and one“heavy” chain (about 50-70 kDa). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms“variable heavy chain,”“VH,” or“VH” refer to the variable region of an immunoglobulin heavy chain, including an Fv, scFv , dsFv or Fab; while the terms“variable light chain,”“VL” or“VL” refer to the variable region of an immunoglobulin light chain, including of an Fv, scFv , dsFv or Fab. [0138] Examples of antibody functional fragments include, but are not limited to, complete antibody molecules, antibody fragments, such as Fv, single chain Fv (scFv), complementarity determining regions (CDRs), VL (light chain variable region), VH (heavy chain variable region), Fab, F(ab)2' and any combination of those or any other functional portion of an immunoglobulin peptide capable of binding to target antigen (see, e.g., FUNDAMENTAL IMMUNOLOGY (Paul ed., 4th ed.2001). As appreciated by one of skill in the art, various antibody fragments can be obtained by a variety of methods, for example, digestion of an intact antibody with an enzyme, such as pepsin; or de novo synthesis. Antibody fragments are often synthesized de novo either chemically or by using recombinant DNA methodology. Thus, the term antibody, as used herein, includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv) or those identified using phage display libraries (see, e.g., McCafferty et al., (1990) Nature

348:552). The term "antibody" also includes bivalent or bispecific molecules, diabodies, triabodies, and tetrabodies. Bivalent and bispecific molecules are described in, e.g., Kostelny et al. (1992) J. Immunol.148:1547, Pack and Pluckthun (1992) Biochemistry 31:1579, Hollinger et al.( 1993), PNAS. USA 90:6444, Gruber et al. (1994) J Immunol.152:5368, Zhu et al. (1997) Protein Sci.6:781, Hu et al. (1996) Cancer Res.56:3055, Adams et al. (1993) Cancer Res. 53:4026, and McCartney, et al. (1995) Protein Eng.8:301. [0139] "Percentage of sequence identity" is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity. [0140] The terms "identical" or percent "identity," in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site

http://www.ncbi.nlm.nih.gov/BLAST/ or the like). Such sequences are then said to be

"substantially identical." This definition also refers to, or may be applied to, the compliment of a test sequence. The definition also includes sequences that have deletions and/or additions, as well as those that have substitutions. As described below, the preferred algorithms can account for gaps and the like. Preferably, identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length. [0141] The term“irreversible covalent bond” is used in accordance with its plain ordinary meaning in the art and refers to the resulting association between atoms or molecules of (e.g., electrophilic chemical moiety and nucleophilic moiety) wherein the probability of dissociation is low. In embodiments, the irreversible covalent bond does not easily dissociate under normal biological conditions. In embodiments, the irreversible covalent bond is formed through a chemical reaction between two species (e.g., electrophilic chemical moiety and nucleophilic moiety). [0142] “Anti-cancer agent” and“anticancer agent” are used in accordance with their plain ordinary meaning and refers to a composition (e.g. compound, drug, antagonist, inhibitor, modulator) having antineoplastic properties or the ability to inhibit the growth or proliferation of cells. In some embodiments, an anti-cancer agent is a chemotherapeutic. In some embodiments, an anti-cancer agent is an agent identified herein having utility in methods of treating cancer. In some embodiments, an anti-cancer agent is an agent approved by the FDA or similar regulatory agency of a country other than the USA, for treating cancer. Examples of anti-cancer agents include, but are not limited to, MEK (e.g. MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g. XL518, CI-1040, PD035901, selumetinib/ AZD6244, GSK1120212/ trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin), triazenes (decarbazine)), anti- metabolites (e.g., 5- azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin), etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g. cisplatin, oxaloplatin, carboplatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors of mitogen- activated protein kinase signaling (e.g. U0126, PD98059, PD184352, PD0325901, ARRY- 142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., rituxan), gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec.RTM.), geldanamycin, 17-N-Allylamino-17- Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352, 20-epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide;

anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen;

antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;

atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;

azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A;

bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole;

carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole;

collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin;

crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;

cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;

cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone;

dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron;

doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine;

edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane;

fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors;

gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide;

hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;

imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;

kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate;

leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon;

leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;

meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim;

monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1- based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract;

myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;

naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene;

parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate;

phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum- triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone;

prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide;

roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin;

spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide;

stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist;

suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;

thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer, Adriamycin,

Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole

hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;

cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine;

dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;

edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole

hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil;

fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride;

hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin I1 (including recombinant interleukin II, or rlL.sub.2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-1a; interferon gamma-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine

hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin;

mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone

hydrochloride; mycophenolic acid; nocodazoie; nogalamycin; ormaplatin; oxisuran;

pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman;

piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium;

porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine;

thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;

vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride, agents that arrest cells in the G2-M phases and/or modulate the formation or stability of microtubules, (e.g. Taxol.TM (i.e. paclitaxel), Taxotere.TM, compounds comprising the taxane skeleton, Erbulozole (i.e. R-55104), Dolastatin 10 (i.e. DLS-10 and NSC-376128), Mivobulin isethionate (i.e. as CI-980), Vincristine, NSC-639829, Discodermolide (i.e. as NVP-XX-A-296), ABT-751 (Abbott, i.e. E-7010), Altorhyrtins (e.g. Altorhyrtin A and Altorhyrtin C),

Spongistatins (e.g. Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (i.e. LU-103793 and NSC-D-669356), Epothilones (e.g. Epothilone A, Epothilone B, Epothilone C (i.e. desoxyepothilone A or dEpoA), Epothilone D (i.e. KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (i.e. BMS-310705), 21-hydroxyepothilone D (i.e. Desoxyepothilone F and dEpoF), 26-fluoroepothilone, Auristatin PE (i.e. NSC-654663), Soblidotin (i.e. TZT-1027), LS-4559-P (Pharmacia, i.e. LS-4577), LS-4578 (Pharmacia, i.e. LS- 477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, i.e. WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, i.e. ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (i.e. LY-355703), AC-7739 (Ajinomoto, i.e. AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, i.e. AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (i.e. NSC-106969), T-138067 (Tularik, i.e. T-67, TL-138067 and TI- 138067), COBRA-1 (Parker Hughes Institute, i.e. DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (i.e. BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, i.e. SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of

Medicine, i.e. MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, i.e. MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T- 138026 (Tularik), Monsatrol, lnanocine (i.e. NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, i.e. T-900607), RPR-115781

(Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, lsoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D- 68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (i.e. NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, i.e. D- 81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e. SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi)), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guérin (BCG), levamisole, interleukin-2, alpha- interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody- calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹ In, ⁹⁰ Y, or ¹³¹ I, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapy or therapeutic (e.g. gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib/BIBW2992, CI-1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethyl erlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, or the like. [0143] The term“reticulon 4 activity” as used herein refers to the biological activity of the protein. In embodiments, reticulon 4 activity includes endoplasmic reticulum (ER) tubule formation. Reticulon 4 activity may be quantified by measuring tubular ER network formation, ER morphology, mitosis rate, nuclear envelope assembly, nuclear envelope disassembly, or cell death. [0144] The term“reticulon 4 protein-reticulon 4 inhibitor complex” as used herein refers to a reticulon 4 protein bonded (e.g., covalently bonded) to a Reticulon 4 inhibitor (e.g., a compound described herein). II. Compounds

[0145] In an aspect is provided a compound having the formula:

[0146] R ¹ is independently halogen, -CX ¹ ₃ , -CHX ¹ ₂ , -CH ₂ X ¹ , -OCX ¹ ₃ , - OCH2X ¹ , -OCHX ¹ 2, -CN, -SOn1R ^1D , -SOv1NR ^1A R ^1B , -NHC(O)NR ^1A R ^1B , -N(O)m1, -NR ^1A R ^1B , -C( O)R ^1C , -C(O)-OR ^1C , -C(O)NR ^1A R ^1B , -OR ^1D , -NR ^1A SO2R ^1D , -NR ^1A C(O)R ^1C , -NR ^1A C(O)OR ^1C , -N R ^1A OR ^1C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0147] Two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0148] The symbol z1 is an integer from 0 to 5. [0149] R ² is independently halogen, -CX ² ₃ , -CHX ² ₂ , -CH ₂ X ² , -OCX ² ₃ , - OCH2X ² , -OCHX ² 2, -CN, -SOn2R ^2D , -SOv2NR ^2A R ^2B , -NHC(O)NR ^2A R ^2B , -N(O)m2, -NR ^2A R ^2B , -C( O)R ^2C , -C(O)-OR ^2C , -C(O)NR ^2A R ^2B , -OR ^2D , -NR ^2A SO2R ^2D , -NR ^2A C(O)R ^2C , -NR ^2A C(O)OR ^2C , -N R ^2A OR ^2C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0150] Two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0151] The symbol z2 is an integer from 0 to 4. [0152] L ¹ is a

bond, -S(O)2-, -NR ⁴ -, -O-, -S-, -C(O)-, -C(O)NR ⁴ -, -NR ⁴ C(O)-, -NR ⁴ C(O)NH-, -NHC(O)NR ⁴ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted

heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. [0153] R ⁴ is hydrogen, -CX ⁴ ₃ , -CHX ⁴ ₂ , -CH ₂ X ⁴ , -OCX ⁴ ₃ , - OCH2X ⁴ , -OCHX ⁴ 2, -CN, -C(O)R ^4A , -C(O)-OR ^4A , -C(O)NR ^4A R ^4B , -OR ^4A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0154] L ² is a

bond, -S(O) ₂ -, -NR ⁵ -, -O-, -S-, -C(O)-, -C(O)NR ⁵ -, -NR ⁵ C(O)-, -NR ⁵ C(O)NH-, -NHC(O)NR ⁵ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. [0155] R ⁵ is hydrogen, -CX ⁵ 3, -CHX ⁵ 2, -CH2X ⁵ , -OCX ⁵ 3, - OCH2X ⁵ , -OCHX ⁵ 2, -CN, -C(O)R ^5A , -C(O)-OR ^5A , -C(O)NR ^5A R ^5B , -OR ^5A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0156] E is an electrophilic moiety. [0157] Each R ^1A , R ^1B , R ^1C , R ^1D , R ^2A , R ^2B , R ^2C , R ^2D , R ^4A , R ^4B , R ^5A , and R ^5B is independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0158] R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R ^2A and R ^2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R ^4A and R ^4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R ^5A and R ^5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. [0159] Each X, X ¹ , X ² , X ⁴ , and X ⁵ is independently–F, -Cl, -Br, or–I. [0160] The symbols n1, n2, n4, and n5 are independently an integer from 0 to 4. [0161] The symbols m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2. [0162] In embodiments, the compound has the formula: (Ia). R ¹ , R ² , L ¹ , L ² , E, z1 and z2 are as described herein. [0163] In embodiments, the compound has the formula:

(Ib). R ¹ , R ² , L ¹ , L ² , and E are as described herein. [0164] In embodiments, the compound has the formula: (II). R ¹ , L ¹ , L ² , and E are as described herein. [0165] In embodiments, the compound has the formula: (IIa). R ¹ , L ¹ , L ² , and E are as described herein. [0166] In embodiments, the compound has the formula:

(IIb). R ¹ , R ⁴ , L ² , and E are as described herein. [0167] In embodiments, the compound has the formula:

(IIc). R ⁴ , L ² , and E are as described herein. [0168] In embodiments, the compound has the formula:

(IId). R ¹ , R ⁴ , L ² , and E are as described herein. [0169] In embodiments, the compound has the formula: (IIe). R ¹ , R ⁵ , L ¹ , and E are as described herein. [0170] In embodiments, the compound has the formula:

L ¹ , and E are as described herein. [0171] In embodiments, the compound has the formula: (IIg). R ¹ , L ² , and E are as described herein. [0172] In embodiments, the compound has the formula:

(III), wherein R ²⁰ , L ¹ , L ² , and E are as described herein; two adjacent R ¹ substituents form Ring A, wherein Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. The symbol z20 is an integer from 0 to 8. [0173] In embodiments, the compound has the formula:

(IIIa), wherein R ²⁰ , z20, L ¹ , L ² , and E are as described herein. [0174] In embodiments, the compound has the formula:

(IIIb), wherein R ²⁰ , z20, L ¹ , L ² , and E are as described herein. [0175] In embodiments, the compound has the formula: (IIIb), wherein R ²⁰ , z20, L ¹ , L ² , and E are as described herein. [0176] In embodiments, the compound has the formula:

. L ¹ , L ² , and E are as described herein. [0177] In embodiments, R ¹ is independently halogen, -CX ¹ ₃ , -CHX ¹ ₂ , -CH ₂ X ¹ , -OCX ¹ ₃ , - OCH2X ¹ , -OCHX ¹ 2, -CN, -SR ^1D , -NR ^1A R ^1B , -C(O)R ^1C , -C(O)OR ^1C , -C(O)NR ^1A R ^1B , -OR ^1D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0178] In embodiments, R ¹ is independently halogen, -CX ¹ 3, -CHX ¹ 2, -CH2X ¹ , -OCX ¹ 3, - OCH ₂ X ¹ , -OCHX ¹ ₂ , -CN, -SH, -NH ₂ , -C(O)OH, -C(O)NH ₂ , -OH, substituted or unsubstituted C1-C8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₂ aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl. [0179] In embodiments, R ¹ is independently halogen, -CX ¹ 3, -CHX ¹ 2, -CH2X ¹ , -OCX ¹ 3, - OCH ₂ X ¹ , -OCHX ¹ ₂ , -CN, -SH, -NH ₂ , -C(O)OH, -C(O)NH ₂ , -OH, substituted or unsubstituted C ₁ -C ₈ alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. [0180] In embodiments, two adjacent R ¹ substituents are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, two adjacent R ¹ substituents are joined to form an unsubstituted cycloalkyl. In embodiments, two adjacent R ¹ substituents are joined to form an unsubstituted C ₃ -C ₆ cycloalkyl. [0181] In embodiments, R ¹ is independently–Cl. In embodiments, R ¹ is independently halogen. In embodiments, R ¹ is independently unsubstituted methyl. In embodiments, R ¹ is independently unsubstituted ethyl. In embodiments, R ¹ is independently unsubstituted propyl. In embodiments, R ¹ is independently unsubstituted isopropyl. In embodiments, R ¹ is independently unsubstituted n-propyl. In embodiments, R ¹ is independently unsubstituted butyl. In embodiments, R ¹ is independently unsubstituted n-butyl. In embodiments, R ¹ is

independently unsubstituted t-butyl. In embodiments, R ¹ is independently unsubstituted pentyl. In embodiments, R ¹ is independently unsubstituted n-pentyl. In embodiments, R ¹ is

independently unsubstituted hexyl. In embodiments, R ¹ is independently unsubstituted n-hexyl. In embodiments, R ¹ is independently unsubstituted heptyl. In embodiments, R ¹ is independently unsubstituted n-heptyl. In embodiments, R ¹ is independently unsubstituted octyl. In

embodiments, R ¹ is independently unsubstituted n-octyl. In embodiments, R ¹ is independently unsubstituted benzyl. In embodiments, R ¹ is independently unsubstituted C ₁ -C ₈ alkyl. In embodiments, R ¹ is independently halo-substituted methyl. In embodiments, R ¹ is independently halo-substituted ethyl. In embodiments, R ¹ is independently halo-substituted isopropyl. In embodiments, R ¹ is independently halo-substituted n-propyl. In embodiments, R ¹ is

independently halo-substituted n-butyl. In embodiments, R ¹ is independently halo-substituted t- butyl. In embodiments, R ¹ is independently halo-substituted n-pentyl. In embodiments, R ¹ is independently halo-substituted benzyl. In embodiments, R ¹ is independently halo-substituted C ₁ -C ₈ alkyl. In embodiments, R ¹ is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R ¹ is independently unsubstituted 2 to 7 membered heteroalkyl. In

embodiments, R ¹ is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R ¹ is independently unsubstituted 2 to 9 membered heteroalkyl. In embodiments, R ¹ is independently unsubstituted 2 to 10 membered heteroalkyl. In embodiments, R ¹ is

independently unsubstituted 3 to 10 membered heteroalkyl. In embodiments, R ¹ is

independently unsubstituted 4 to 10 membered heteroalkyl. In embodiments, R ¹ is

independently unsubstituted 5 to 10 membered heteroalkyl. In embodiments, R ¹ is

independently unsubstituted 6 to 10 membered heteroalkyl. In embodiments, R ¹ is

independently unsubstituted 7 to 10 membered heteroalkyl. In embodiments, R ¹ is

independently unsubstituted 8 to 10 membered heteroalkyl. In embodiments, R ¹ is

independently unsubstituted 6 to 10 membered heteroalkyl. In embodiments, R ¹ is

independently unsubstituted 7 to 9 membered heteroalkyl. [0182] In embodiments, two adjacent R ¹ substituents are joined to form an unsubstituted C3-C6 cycloalkyl. In embodiments, two adjacent R ¹ substituents are joined to form an unsubstituted C ₄ -C ₆ cycloalkyl. In embodiments, two adjacent R ¹ substituents are joined to form an unsubstituted C3-C5 cycloalkyl. In embodiments, two adjacent R ¹ substituents are joined to form an unsubstituted C5-C6 cycloalkyl. In embodiments, two adjacent R ¹ substituents are joined to form an unsubstituted C ₄ cycloalkyl. [0183] In embodiments, R ¹ is independently unsubstituted 5 membered heteroaryl. In embodiments, R ¹ is independently unsubstituted 6 membered heteroaryl. In embodiments, R ¹ is independently unsubstituted pyridyl. In embodiments, R ¹ is independently unsubstituted 2- pyridyl. In embodiments, R ¹ is independently unsubstituted 3-pyridyl. In embodiments, R ¹ is independently unsubstituted 4-pyridyl. In embodiments, R ¹ is independently unsubstituted pyridazinyl. In embodiments, R ¹ is independently unsubstituted pyrimidinyl. In embodiments, R ¹ is independently unsubstituted pyrazinyl. In embodiments, R ¹ is independently unsubstituted triazinyl. In embodiments, R ¹ is independently unsubstituted pyrrolyl. In embodiments, R ¹ is independently unsubstituted 2-pyrrolyl. In embodiments, R ¹ is independently unsubstituted 3- pyrrolyl. In embodiments, R ¹ is independently unsubstituted furanyl. In embodiments, R ¹ is independently unsubstituted 2-furanyl. In embodiments, R ¹ is independently unsubstituted 3- furanyl. In embodiments, R ¹ is independently unsubstituted thienyl. In embodiments, R ¹ is independently unsubstituted 2-thienyl. In embodiments, R ¹ is independently unsubstituted 3- thienyl. In embodiments, R ¹ is independently unsubstituted pyrazolyl. In embodiments, R ¹ is independently unsubstituted isoxazolyl. In embodiments, R ¹ is independently unsubstituted isothiazolyl. In embodiments, R ¹ is independently unsubstituted imidazolyl. In embodiments, R ¹ is independently unsubstituted oxazolyl. In embodiments, R ¹ is independently unsubstituted thiazolyl. In embodiments, R ¹ is independently unsubstituted phenyl. In embodiments, R ¹ is independently unsubstituted biphenyl. In embodiments, R ¹ is independently unsubstituted 2- biphenyl. In embodiments, R ¹ is independently unsubstituted 3-biphenyl. In embodiments, R ¹ is independently unsubstituted 4-biphenyl. [0184] In embodiments, R ¹ is independently -CX ¹ 3. In embodiments, R ¹ is independently - CHX ¹ ₂ . In embodiments, R ¹ is independently -CH ₂ X ¹ . In embodiments, R ¹ is

independently -OCX ¹ ₃ . In embodiments, R ¹ is independently -OCH ₂ X ¹ . In embodiments, R ¹ is independently -OCHX ¹ 2. In embodiments, R ¹ is independently -CN. In embodiments, R ¹ is independently -SOn1R ^1D . In embodiments, R ¹ is independently -SOv1NR ^1A R ^1B . In embodiments, R ¹ is independently -NHC(O)NR ^1A R ^1B . In embodiments, R ¹ is independently -N(O) _m1 . In embodiments, R ¹ is independently -NR ^1A R ^1B . In embodiments, R ¹ is independently -C(O)R ^1C . In embodiments, R ¹ is independently -C(O)-OR ^1C . In embodiments, R ¹ is

independently -C(O)NR ^1A R ^1B . In embodiments, R ¹ is independently -OR ^1D . In embodiments, R ¹ is independently -NR ^1A SO2R ^1D . In embodiments, R ¹ is independently -NR ^1A C(O)R ^1C . In embodiments, R ¹ is independently -NR ^1A C(O)OR ^1C . In embodiments, R ¹ is

independently -NR ^1A OR ^1C . In embodiments, R ¹ is independently -OH. In embodiments, R ¹ is independently -NH ₂ . In embodiments, R ¹ is independently -COOH. In embodiments, R ¹ is independently -CONH2. In embodiments, R ¹ is independently -NO2. In embodiments, R ¹ is independently -SH. In embodiments, R ¹ is independently halogen. In embodiments, R ¹ is independently–F. In embodiments, R ¹ is independently–Cl. In embodiments, R ¹ is

independently–Br. In embodiments, R ¹ is independently–I. In embodiments, R ¹ is

independently -CF3. In embodiments, R ¹ is independently -CHF2. In embodiments, R ¹ is independently -CH ₂ F. In embodiments, R ¹ is independently -OCF ₃ . In embodiments, R ¹ is independently -OCH2F. In embodiments, R ¹ is independently -OCHF2. In embodiments, R ¹ is independently–OCH3. In embodiments, R ¹ is independently–OCH2CH3. In embodiments, R ¹ is independently–OCH ₂ CH ₂ CH ₃ . In embodiments, R ¹ is independently–OCH(CH ₃ ) ₂ . In embodiments, R ¹ is independently–OC(CH ₃ ) ₃ . In embodiments, R ¹ is independently–SCH ₃ . In embodiments, R ¹ is independently–SCH2CH3. In embodiments, R ¹ is independently–

SCH2CH2CH3. In embodiments, R ¹ is independently–SCH(CH3)2. In embodiments, R ¹ is independently–SC(CH ₃ ) ₃ . In embodiments, R ¹ is independently–CH ₃ . In embodiments, R ¹ is independently–CH2CH3. In embodiments, R ¹ is independently–CH2CH2CH3. In embodiments, R ¹ is independently–CH(CH3)2. In embodiments, R ¹ is independently–C(CH3)3. [0185] In embodiments, R ¹ is independently halogen, -CX ¹ ₃ , -CHX ¹ ₂ , -CH ₂ X ¹ , -OCX ¹ ₃ , - OCH2X ¹ , -OCHX ¹ 2, -CN, -SOn1R ^1D , -SOv1NR ^1A R ^1B , -NHC(O)NR ^1A R ^1B , -N(O)m1, -NR ^1A R ^1B , -C( O)R ^1C , -C(O)-OR ^1C , -C(O)NR ^1A R ^1B , -OR ^1D , -NR ^1A SO2R ^1D , -NR ^1A C(O)R ^1C , -NR ^1A C(O)OR ^1C , -N R ^1A OR ^1C , -N ₃ , substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4- C ₆ , or C ₅ -C ₆ ), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ¹ is independently halogen, -CX ¹ ₃ , -CHX ¹ ₂ , -CH ₂ X ¹ , -OCX ¹ ₃ , - OCH2X ¹ , -OCHX ¹ 2, -CN, -SOn1R ^1D , -SOv1NR ^1A R ^1B , -NHC(O)NR ^1A R ^1B , -N(O)m1, -NR ^1A R ^1B , -C( O)R ^1C , -C(O)-OR ^1C , -C(O)NR ^1A R ^1B , -OR ^1D , -NR ^1A SO2R ^1D , -NR ^1A C(O)R ^1C , -NR ^1A C(O)OR ^1C , -N R ^1A OR ^1C , -N ₃ , substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4- C ₆ , or C ₅ -C ₆ ), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0186] In embodiments, R ¹ is independently substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ - C6, C1-C4, or C1-C2). In embodiments, R ¹ is independently substituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R ¹ is independently unsubstituted alkyl (e.g., C1-C8, C1-C6, C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ¹ is independently unsubstituted methyl. In embodiments, R ¹ is independently unsubstituted ethyl. In embodiments, R ¹ is independently unsubstituted propyl. In embodiments, R ¹ is independently unsubstituted isopropyl. In embodiments, R ¹ is independently unsubstituted tert-butyl. In embodiments, R ¹ is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ¹ is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ¹ is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ¹ is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4- C ₆ , or C ₅ -C ₆ ). In embodiments, R ¹ is independently substituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C4-C6, or C5-C6). In embodiments, R ¹ is independently unsubstituted cycloalkyl (e.g., C3-C8, C3- C6, C4-C6, or C5-C6). In embodiments, R ¹ is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ¹ is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ¹ is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ¹ is independently substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl). In

embodiments, R ¹ is independently substituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, R ¹ is independently unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, R ¹ is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ¹ is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ¹ is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0187] In embodiments, two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, two adjacent R ¹ substituents may optionally be joined to form a substituted cycloalkyl (e.g., C3- C8, C3-C6, C4-C6, or C5-C6). In embodiments, two adjacent R ¹ substituents may optionally be joined to form an unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In

embodiments, two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R ¹ substituents may optionally be joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R ¹ substituents may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, two adjacent R ¹ substituents may optionally be joined to form a substituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, two adjacent R ¹ substituents may optionally be joined to form an unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R ¹ substituents may optionally be joined to form a substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R ¹ substituents may optionally be joined to form an unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0188] In embodiments, R ^1A is independently hydrogen. In embodiments, R ^1A is

independently -CX ^1A ₃ . In embodiments, R ^1A is independently -CHX ^1A ₂ . In embodiments, R ^1A is independently -CH2X ^1A . In embodiments, R ^1A is independently -CN. In embodiments, R ^1A is independently -COOH. In embodiments, R ^1A is independently -CONH2. In embodiments, X ^1A is independently–F, -Cl, -Br, or -I. [0189] In embodiments, R ^1A is independently substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R ^1A is independently substituted alkyl (e.g., C1-C8, C1- C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ^1A is independently unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ - C6, C1-C4, or C1-C2). In embodiments, R ^1A is independently unsubstituted methyl. In

embodiments, R ^1A is independently unsubstituted ethyl. In embodiments, R ^1A is independently unsubstituted propyl. In embodiments, R ^1A is independently unsubstituted isopropyl. In embodiments, R ^1A is independently unsubstituted tert-butyl. In embodiments, R ^1A is

independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^1A is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^1A is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^1A is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R ^1A is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R ^1A is independently unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ^1A is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^1A is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^1A is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^1A is independently substituted or unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, R ^1A is independently substituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, R ^1A is independently unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, R ^1A is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^1A is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^1A is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0190] In embodiments, R ^1B is independently hydrogen. In embodiments, R ^1B is

independently -CX ^1B 3. In embodiments, R ^1B is independently -CHX ^1B 2. In embodiments, R ^1B is independently -CH ₂ X ^1B . In embodiments, R ^1B is independently -CN. In embodiments, R ^1B is independently -COOH. In embodiments, R ^1B is independently -CONH2. In embodiments, X ^1B is independently–F, -Cl, -Br, or -I. [0191] In embodiments, R ^1B is independently substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C1-C6, C1-C4, or C1-C2). In embodiments, R ^1B is independently substituted alkyl (e.g., C1-C8, C1- C6, C1-C4, or C1-C2). In embodiments, R ^1B is independently unsubstituted alkyl (e.g., C1-C8, C1- C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ^1B is independently unsubstituted methyl. In

embodiments, R ^1B is independently unsubstituted ethyl. In embodiments, R ^1B is independently unsubstituted propyl. In embodiments, R ^1B is independently unsubstituted isopropyl. In embodiments, R ^1B is independently unsubstituted tert-butyl. In embodiments, R ^1B is

independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^1B is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^1B is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^1B is independently substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ^1B is independently substituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ^1B is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R ^1B is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^1B is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^1B is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^1B is independently substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, R ^1B is independently substituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, R ^1B is independently unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, R ^1B is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^1B is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^1B is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0192] In embodiments, R ^1A and R ^1B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^1A and R ^1B substituents bonded to the same nitrogen atom may be joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^1A and R ^1B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). [0193] In embodiments, R ^1A and R ^1B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^1A and R ^1B substituents bonded to the same nitrogen atom may be joined to form a substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^1A and R ^1B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0194] In embodiments, R ^1C is independently hydrogen. In embodiments, R ^1C is

independently -CX ^1C ₃ . In embodiments, R ^1C is independently -CHX ^1C ₂ . In embodiments, R ^1C is independently -CH2X ^1C . In embodiments, R ^1C is independently -CN. In embodiments, R ^1C is independently -COOH. In embodiments, R ^1C is independently -CONH ₂ . In embodiments, X ^1C is independently–F, -Cl, -Br, or -I. [0195] In embodiments, R ^1C is independently substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R ^1C is independently substituted alkyl (e.g., C1-C8, C1- C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ^1C is independently unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ - C6, C1-C4, or C1-C2). In embodiments, R ^1C is independently unsubstituted methyl. In

embodiments, R ^1C is independently unsubstituted ethyl. In embodiments, R ^1C is independently unsubstituted propyl. In embodiments, R ^1C is independently unsubstituted isopropyl. In embodiments, R ^1C is independently unsubstituted tert-butyl. In embodiments, R ^1C is

independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^1C is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^1C is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^1C is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R ^1C is independently substituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ^1C is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R ^1C is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^1C is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^1C is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^1C is independently substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, R ^1C is independently substituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, R ^1C is independently unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, R ^1C is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^1C is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^1C is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0196] In embodiments, R ^1D is independently hydrogen. In embodiments, R ^1D is

independently -CX ^1D ₃ . In embodiments, R ^1D is independently -CHX ^1D ₂ . In embodiments, R ^1D is independently -CH2X ^1D . In embodiments, R ^1D is independently -CN. In embodiments, R ^1D is independently -COOH. In embodiments, R ^1D is independently -CONH2. In embodiments, X ^1D is independently–F, -Cl, -Br, or -I. [0197] In embodiments, R ^1D is independently substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R ^1D is independently substituted alkyl (e.g., C1-C8, C1- C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ^1D is independently unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ - C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ^1D is independently unsubstituted methyl. In

embodiments, R ^1D is independently unsubstituted ethyl. In embodiments, R ^1D is independently unsubstituted propyl. In embodiments, R ^1D is independently unsubstituted isopropyl. In embodiments, R ^1D is independently unsubstituted tert-butyl. In embodiments, R ^1D is

independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^1D is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^1D is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^1D is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R ^1D is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R ^1D is independently unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ^1D is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^1D is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^1D is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^1D is independently substituted or unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, R ^1D is independently substituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, R ^1D is independently unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, R ^1D is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^1D is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^1D is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0198] In embodiments, R ¹ is independently

halogen, -CX ¹ 3, -CHX ¹ 2, -CH2X ¹ , -OCX ¹ 3, -OCH2X ¹ , -OCHX ¹ 2, -CN, -OH, -NH2, -COOH, -CO NH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,

−NHC=(O)NH ₂ , -NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, R ²⁰ -substituted or

unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ²⁰ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ²⁰ -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ²⁰ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ²⁰ -substituted or unsubstituted aryl (e.g., C ₆ - C12, C6-C10, or phenyl), or R ²⁰ -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ¹ is independently halogen, -CX ¹ ₃ , -CHX ¹ ₂ , -CH ₂ X ¹ , -OCX ¹ ₃ , -OCH ₂ X ¹ , -OCHX ¹ ₂ , -CN, -OH, -NH ₂ , -COOH, -CO NH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ¹ is independently–F, -Cl, -Br, or–I. In embodiments, R ¹ is independently hydrogen. In embodiments, R ¹ is independently unsubstituted methyl. In embodiments, R ¹ is independently unsubstituted ethyl. In embodiments, R ¹ is independently halogen, -CX ¹ 3, -CHX ¹ 2, -CH2X ¹ , -OCX ¹ 3, -OCH2X ¹ , -OCHX ¹ 2, -CN, -OH, -NH2, -COOH, -CO NH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,

−NHC=(O)NH ₂ , -NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, R ²⁰ -substituted or

unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ²⁰ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ²⁰ -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ²⁰ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ²⁰ -substituted or unsubstituted aryl (e.g., C ₆ - C12, C6-C10, or phenyl), or R ²⁰ -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ¹ is independently halogen, -CX ¹ ₃ , -CHX ¹ ₂ , -CH ₂ X ¹ , -OCX ¹ ₃ , -OCH ₂ X ¹ , -OCHX ¹ ₂ , -CN, -OH, -NH ₂ , -COOH, -CO NH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,

−NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0199] In embodiments, two adjacent R ¹ substituents may optionally be joined to form a R ²⁰ - substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, two adjacent R ¹ substituents may optionally be joined to form a R ²⁰ -substituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, two adjacent R ¹ substituents may optionally be joined to form an unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, two adjacent R ¹ substituents may optionally be joined to form a R ²⁰ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R ¹ substituents may optionally be joined to form a R ²⁰ -substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R ¹ substituents may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R ¹ substituents may optionally be joined to form a R ²⁰ -substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, two adjacent R ¹ substituents may optionally be joined to form a R ²⁰ -substituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, two adjacent R ¹ substituents may optionally be joined to form an unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, two adjacent R ¹ substituents may optionally be joined to form a R ²⁰ -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R ¹ substituents may optionally be joined to form a R ²⁰ -substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R ¹ substituents may optionally be joined to form an unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0200] R ²⁰ is independently oxo,

halogen, -CX ²⁰ ₃ , -CHX ²⁰ ₂ , -CH ₂ X ²⁰ , -OCX ²⁰ ₃ , -OCH ₂ X ²⁰ , -OCHX ²⁰ ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, R ²¹ -substituted or

unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ²¹ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ²¹ -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ²¹ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ²¹ -substituted or unsubstituted aryl (e.g., C6- C ₁₂ , C ₆ -C ₁₀ , or phenyl), or R ²¹ -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ²⁰ is independently oxo,

halogen, -CX ²⁰ 3, -CHX ²⁰ 2, -CH2X ²⁰ , -OCX ²⁰ 3, -OCH2X ²⁰ , -OCHX ²⁰ 2, -CN, -OH, -NH2, -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ²⁰ is independently–F, -Cl, -Br, or–I. In embodiments, R ²⁰ is independently unsubstituted methyl. In embodiments, R ²⁰ is independently unsubstituted ethyl. [0201] R ²¹ is independently oxo,

halogen, -CX ²¹ ₃ , -CHX ²¹ ₂ , -CH ₂ X ²¹ , -OCX ²¹ ₃ , -OCH ₂ X ²¹ , -OCHX ²¹ ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ²² -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ²² -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ²² -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ²² -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ²² -substituted or unsubstituted aryl (e.g., C6- C ₁₂ , C ₆ -C ₁₀ , or phenyl), or R ²² -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ²¹ is independently oxo,

halogen, -CX ²¹ 3, -CHX ²¹ 2, -CH2X ²¹ , -OCX ²¹ 3, -OCH2X ²¹ , -OCHX ²¹ 2, -CN, -OH, -NH2, -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ²¹ is independently–F, -Cl, -Br, or–I. In embodiments, R ²¹ is independently unsubstituted methyl. In embodiments, R ²¹ is independently unsubstituted ethyl. [0202] R ²² is independently oxo,

halogen, -CX ²² 3, -CHX ²² 2, -CH2X ²² , -OCX ²² 3, -OCH2X ²² , -OCHX ²² 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ²² is independently–F, -Cl, -Br, or–I. In embodiments, R ²² is independently unsubstituted methyl. In embodiments, R ²² is independently unsubstituted ethyl. [0203] In embodiments, R ^1A is independently

hydrogen, -CX ^1A ₃ , -CHX ^1A ₂ , -CH ₂ X ^1A , -CN, -COOH, -CONH ₂ , R ^20A -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ^20A -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^20A -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ^20A - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^20A -substituted or unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or R ^20A -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^1A is independently hydrogen, -CX ^1A 3, -CHX ^1A 2, -CH2X ^1A , -CN, -COOH, -CONH2, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^1A is independently–F, -Cl, -Br, or–I. In embodiments, R ^1A is independently hydrogen. In embodiments, R ^1A is independently

unsubstituted methyl. In embodiments, R ^1A is independently unsubstituted ethyl. [0204] In embodiments, R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a R ^20A -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or R ^20A - substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a R ^20A -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). [0205] R ^20A is independently oxo,

halogen, -CX ^20A 3, -CHX ^20A 2, -CH2X ^20A , -OCX ^20A 3, -OCH2X ^20A , -OCHX ^20A 2, -CN, -OH, -NH2, - COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^21A -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ^21A -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^21A -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ^21A -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^21A -substituted or unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or R ^21A -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^20A is independently oxo,

halogen, -CX ^20A ₃ , -CHX ^20A ₂ , -CH ₂ X ^20A , -OCX ^20A ₃ , -OCH ₂ X ^20A , -OCHX ^20A ₂ , -CN, -OH, -NH ₂ , - COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^20A is independently–F, -Cl, -Br, or–I. In embodiments, R ^20A is independently unsubstituted methyl. In embodiments, R ^20A is independently

unsubstituted ethyl. [0206] R ^21A is independently oxo,

halogen, -CX ^21A 3, -CHX ^21A 2, -CH2X ^21A , -OCX ^21A 3, -OCH2X ^21A , -OCHX ^21A 2, -CN, -OH, -NH2, - COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^22A -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ^22A -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^22A -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^22A -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^22A -substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or R ^22A -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^21A is independently oxo,

halogen, -CX ^21A 3, -CHX ^21A 2, -CH2X ^21A , -OCX ^21A 3, -OCH2X ^21A , -OCHX ^21A 2, -CN, -OH, -NH2, - COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^21A is independently–F, -Cl, -Br, or–I. In embodiments, R ^21A is independently unsubstituted methyl. In embodiments, R ^21A is independently

unsubstituted ethyl. [0207] R ^22A is independently oxo,

halogen, -CX ^22A ₃ , -CHX ^22A ₂ , -CH ₂ X ^22A , -OCX ^22A ₃ , -OCH ₂ X ^22A , -OCHX ^22A ₂ , -CN, -OH, -NH ₂ , - COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^22A is independently–F, -Cl, -Br, or–I. In embodiments, R ^22A is independently unsubstituted methyl. In embodiments, R ^22A is independently unsubstituted ethyl. [0208] In embodiments, R ^1B is independently

hydrogen, -CX ^1B 3, -CHX ^1B 2, -CH2X ^1B , -CN, -COOH, -CONH2, R ^20B -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ^20B -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^20B -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ^20B - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^20B -substituted or unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or R ^20B -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^1B is independently hydrogen, -CX ^1B 3, -CHX ^1B 2, -CH2X ^1B , -CN, -COOH, -CONH2, unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^1B is independently–F, -Cl, -Br, or–I. In embodiments, R ^1B is independently hydrogen. In embodiments, R ^1B is independently unsubstituted methyl. In embodiments, R ^1B is independently unsubstituted ethyl. [0209] In embodiments, R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a R ^20B -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or R ^20B - substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a R ^20B -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). [0210] R ^20B is independently oxo,

halogen, -CX ^20B 3, -CHX ^20B 2, -CH2X ^20B , -OCX ^20B 3, -OCH2X ^20B , -OCHX ^20B 2, -CN, -OH, -NH2, - COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^21B -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ^21B -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^21B -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ^21B -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^21B -substituted or unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or R ^21B -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^20B is independently oxo,

halogen, -CX ^20B ₃ , -CHX ^20B ₂ , -CH ₂ X ^20B , -OCX ^20B ₃ , -OCH ₂ X ^20B , -OCHX ^20B ₂ , -CN, -OH, -NH ₂ , -C OOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^20B is independently–F, -Cl, -Br, or–I. In embodiments, R ^20B is independently unsubstituted methyl. In embodiments, R ^20B is independently

unsubstituted ethyl. [0211] R ^21B is independently oxo,

halogen, -CX ^21B ₃ , -CHX ^21B ₂ , -CH ₂ X ^21B , -OCX ^21B ₃ , -OCH ₂ X ^21B , -OCHX ^21B ₂ , -CN, -OH, -NH ₂ , -C OOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^22B -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ^22B -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^22B -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^22B -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^22B -substituted or unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or R ^22B -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^21B is independently oxo,

halogen, -CX ^21B ₃ , -CHX ^21B ₂ , -CH ₂ X ^21B , -OCX ^21B ₃ , -OCH ₂ X ^21B , -OCHX ^21B ₂ , -CN, -OH, -NH ₂ , -C OOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^21B is independently–F, -Cl, -Br, or–I. In embodiments, R ^21B is independently unsubstituted methyl. In embodiments, R ^21B is independently

unsubstituted ethyl. [0212] R ^22B is independently oxo,

halogen, -CX ^22B ₃ , -CHX ^22B ₂ , -CH ₂ X ^22B , -OCX ^22B ₃ , -OCH ₂ X ^22B , -OCHX ^22B ₂ , -CN, -OH, -NH ₂ , -C OOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O)NH ₂ , -NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^22B is independently–F, -Cl, -Br, or–I. In embodiments, R ^22B is independently unsubstituted methyl. In embodiments, R ^22B is independently

unsubstituted ethyl. [0213] In embodiments, R ^1C is independently

hydrogen, -CX ^1C 3, -CHX ^1C 2, -CH2X ^1C , -CN, -COOH, -CONH2, R ^20C -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ^20C -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^20C -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^20C - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^20C -substituted or unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or R ^20C -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^1C is independently hydrogen, -CX ^1C 3, -CHX ^1C 2, -CH2X ^1C , -CN, -COOH, -CONH2, unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^1C is independently–F, -Cl, -Br, or–I. In embodiments, R ^1C is independently hydrogen. In embodiments, R ^1C is independently

unsubstituted methyl. In embodiments, R ^1C is independently unsubstituted ethyl. [0214] R ^20C is independently oxo,

halogen, -CX ^20C 3, -CHX ^20C 2, -CH2X ^20C , -OCX ^20C 3, -OCH2X ^20C , -OCHX ^20C 2, -CN, -OH, -NH2, - COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^21C -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ^21C -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^21C -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^21C -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^21C -substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or R ^21C -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^20C is independently oxo,

halogen, -CX ^20C ₃ , -CHX ^20C ₂ , -CH ₂ X ^20C , -OCX ^20C ₃ , -OCH ₂ X ^20C , -OCHX ^20C ₂ , -CN, -OH, -NH ₂ , -C OOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^20C is independently–F, -Cl, -Br, or–I. In embodiments, R ^20C is independently unsubstituted methyl. In embodiments, R ^20C is independently

unsubstituted ethyl. [0215] R ^21C is independently oxo,

halogen, -CX ^21C 3, -CHX ^21C 2, -CH2X ^21C , -OCX ^21C 3, -OCH2X ^21C , -OCHX ^21C 2, -CN, -OH, -NH2, -C OOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^22C -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ^22C -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^22C -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^22C -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^22C -substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or R ^22C -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^21C is independently oxo,

halogen, -CX ^21C ₃ , -CHX ^21C ₂ , -CH ₂ X ^21C , -OCX ^21C ₃ , -OCH ₂ X ^21C , -OCHX ^21C ₂ , -CN, -OH, -NH ₂ , -C OOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^21C is independently–F, -Cl, -Br, or–I. In embodiments, R ^21C is independently unsubstituted methyl. In embodiments, R ^21C is independently

unsubstituted ethyl. [0216] R ^22C is independently oxo,

halogen, -CX ^22C ₃ , -CHX ^22C ₂ , -CH ₂ X ^22C , -OCX ^22C ₃ , -OCH ₂ X ^22C , -OCHX ^22C ₂ , -CN, -OH, -NH ₂ , -C OOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^22C is independently–F, -Cl, -Br, or–I. In embodiments, R ^22C is independently unsubstituted methyl. In embodiments, R ^22C is independently

unsubstituted ethyl. [0217] In embodiments, R ^1D is independently

hydrogen, -CX ^1D 3, -CHX ^1D 2, -CH2X ^1D , -CN, -COOH, -CONH2, R ^20D -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ^20D -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^20D -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^20D - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^20D -substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or R ^20D -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^1D is independently hydrogen, -CX ^1D ₃ , -CHX ^1D ₂ , -CH ₂ X ^1D , -CN, -COOH, -CONH ₂ , unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^1D is independently–F, -Cl, -Br, or–I. In embodiments, R ^1D is independently hydrogen. In embodiments, R ^1D is independently

unsubstituted methyl. In embodiments, R ^1D is independently unsubstituted ethyl. [0218] R ^20D is independently oxo,

halogen, -CX ^20D ₃ , -CHX ^20D ₂ , -CH ₂ X ^20D , -OCX ^20D ₃ , -OCH ₂ X ^20D , -OCHX ^20D ₂ , -CN, -OH, -NH ₂ , - COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^21D -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ^21D -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^21D -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^21D -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^21D -substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or R ^21D -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^20D is independently oxo,

halogen, -CX ^20D 3, -CHX ^20D 2, -CH2X ^20D , -OCX ^20D 3, -OCH2X ^20D , -OCHX ^20D 2, -CN, -OH, -NH2, - COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^20D is independently–F, -Cl, -Br, or–I. In embodiments, R ^20D is independently unsubstituted methyl. In embodiments, R ^20D is independently

unsubstituted ethyl. [0219] R ^21D is independently oxo,

halogen, -CX ^21D ₃ , -CHX ^21D ₂ , -CH ₂ X ^21D , -OCX ^21D ₃ , -OCH ₂ X ^21D , -OCHX ^21D ₂ , -CN, -OH, -NH ₂ , - COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^22D -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ^22D -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^22D -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ^22D -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^22D -substituted or unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or R ^22D -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^21D is independently oxo,

halogen, -CX ^21D ₃ , -CHX ^21D ₂ , -CH ₂ X ^21D , -OCX ^21D ₃ , -OCH ₂ X ^21D , -OCHX ^21D ₂ , -CN, -OH, -NH ₂ , - COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^21D is independently–F, -Cl, -Br, or–I. In embodiments, R ^21D is independently unsubstituted methyl. In embodiments, R ^21D is independently

unsubstituted ethyl. [0220] R ^22D is independently oxo,

halogen, -CX ^22D ₃ , -CHX ^22D ₂ , -CH ₂ X ^22D , -OCX ^22D ₃ , -OCH ₂ X ^22D , -OCHX ^22D ₂ , -CN, -OH, -NH ₂ , - COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O)NH ₂ , -NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^22D is independently–F, -Cl, -Br, or–I. In embodiments, R ^22D is independently unsubstituted methyl. In embodiments, R ^22D is independently

unsubstituted ethyl. [0221] In embodiments, z1 is 0. In embodiments, z1 is 1. In embodiments, z1 is 2. In embodiments, z1 is 3. In embodiments, z1 is 4. In embodiments, z1 is 5. [0222] In embodiments, R ² is independently halogen, -CX ² ₃ , -CHX ² ₂ , -CH ₂ X ² , -OCX ² ₃ , - OCH2X ² , -OCHX ² 2, -CN, -SR ^2D , -NR ^2A R ^2B , -C(O)R ^2C , -C(O)OR ^2C , -C(O)NR ^2A R ^2B , -OR ^2D , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0223] In embodiments, R ² is independently halogen, -CX ² 3, -CHX ² 2, -CH2X ² , -OCX ² 3, - OCH ₂ X ² , -OCHX ² ₂ , -CN, -SH, -NH ₂ , -C(O)OH, -C(O)NH ₂ , -OH, substituted or unsubstituted C ₁ -C ₈ alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₂ aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl. [0224] In embodiments, R ² is independently halogen, -CX ² 3, -CHX ² 2, -CH2X ² , -OCX ² 3, - OCH2X ² , -OCHX ² 2, -CN, -SH, -NH2, -C(O)OH, -C(O)NH2, -OH, substituted or unsubstituted C1-C8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. [0225] In embodiments, two adjacent R ² substituents are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, two adjacent R ² substituents are joined to form an unsubstituted cycloalkyl. In embodiments, two adjacent R ² substituents are joined to form an unsubstituted C3-C6 cycloalkyl. [0226] In embodiments, R ² is independently -CX ² ₃ . In embodiments, R ² is independently - CHX ² ₂ . In embodiments, R ² is independently -CH ₂ X ² . In embodiments, R ² is

independently -OCX ² 3. In embodiments, R ² is independently -OCH2X ² . In embodiments, R ² is independently -OCHX ² 2. In embodiments, R ² is independently -CN. In embodiments, R ² is independently -SO _n2 R ^2D . In embodiments, R ² is independently -SO _v2 NR ^2A R ^2B . In embodiments, R ² is independently -NHC(O)NR ^2A R ^2B . In embodiments, R ² is independently -N(O) _m2 . In embodiments, R ² is independently -NR ^2A R ^2B . In embodiments, R ² is independently -C(O)R ^2C . In embodiments, R ² is independently -C(O)-OR ^2C . In embodiments, R ² is

independently -C(O)NR ^2A R ^2B . In embodiments, R ² is independently -OR ^2D . In embodiments, R ² is independently -NR ^2A SO2R ^2D . In embodiments, R ² is independently -NR ^2A C(O)R ^2C . In embodiments, R ² is independently -NR ^2A C(O)OR ^2C . In embodiments, R ² is

independently -NR ^2A OR ^2C . In embodiments, R ² is independently -OH. In embodiments, R ² is independently -NH2. In embodiments, R ² is independently -COOH. In embodiments, R ² is independently -CONH2. In embodiments, R ² is independently -NO2. In embodiments, R ² is independently -SH. In embodiments, R ² is independently halogen. In embodiments, R ² is independently–F. In embodiments, R ² is independently–Cl. In embodiments, R ² is

independently–Br. In embodiments, R ² is independently–I. In embodiments, R ² is

independently -CF ₃ . In embodiments, R ² is independently -CHF ₂ . In embodiments, R ² is independently -CH ₂ F. In embodiments, R ² is independently -OCF ₃ . In embodiments, R ² is independently -OCH2F. In embodiments, R ² is independently -OCHF2. In embodiments, R ² is independently–OCH ₃ . In embodiments, R ² is independently–OCH ₂ CH ₃ . In embodiments, R ² is independently–OCH ₂ CH ₂ CH ₃ . In embodiments, R ² is independently–OCH(CH ₃ ) ₂ . In embodiments, R ² is independently–OC(CH3)3. In embodiments, R ² is independently–SCH3. In embodiments, R ² is independently–SCH2CH3. In embodiments, R ² is independently–

SCH ₂ CH ₂ CH ₃ . In embodiments, R ² is independently–SCH(CH ₃ ) ₂ . In embodiments, R ² is independently–SC(CH3)3. In embodiments, R ² is independently–CH3. In embodiments, R ² is independently–CH2CH3. In embodiments, R ² is independently–CH2CH2CH3. In embodiments, R ² is independently–CH(CH ₃ ) ₂ . In embodiments, R ² is independently–C(CH ₃ ) ₃ . [0227] In embodiments, R ² is independently halogen, -CX ² 3, -CHX ² 2, -CH2X ² , -OCX ² 3, - OCH2X ² , -OCHX ² 2, -CN, -SOn2R ^2D , -SOv2NR ^2A R ^2B , -NHC(O)NR ^2A R ^2B , -N(O)m2, -NR ^2A R ^2B , -C( O)R ^2C , -C(O)-OR ^2C , -C(O)NR ^2A R ^2B , -OR ^2D , -NR ^2A SO ₂ R ^2D , -NR ^2A C(O)R ^2C , -NR ^2A C(O)OR ^2C , -N R ^2A OR ^2C , -N ₃ , substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4- C ₆ , or C ₅ -C ₆ ), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ² is independently halogen, -CX ² 3, -CHX ² 2, -CH2X ² , -OCX ² 3, - OCH2X ² , -OCHX ² 2, -CN, -SOn2R ^2D , -SOv2NR ^2A R ^2B , -NHC(O)NR ^2A R ^2B , -N(O)m2, -NR ^2A R ^2B , -C( O)R ^2C , -C(O)-OR ^2C , -C(O)NR ^2A R ^2B , -OR ^2D , -NR ^2A SO ₂ R ^2D , -NR ^2A C(O)R ^2C , -NR ^2A C(O)OR ^2C , -N R ^2A OR ^2C , -N ₃ , substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ - C ₆ , or C ₅ -C ₆ ), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0228] In embodiments, R ² is independently substituted or unsubstituted alkyl (e.g., C1-C8, C1- C6, C1-C4, or C1-C2). In embodiments, R ² is independently substituted alkyl (e.g., C1-C8, C1-C6, C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ² is independently unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ² is independently unsubstituted methyl. In embodiments, R ² is independently unsubstituted ethyl. In embodiments, R ² is independently unsubstituted propyl. In embodiments, R ² is independently unsubstituted isopropyl. In embodiments, R ² is independently unsubstituted tert-butyl. In embodiments, R ² is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ² is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ² is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ² is independently substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ - C6, or C5-C6). In embodiments, R ² is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R ² is independently unsubstituted cycloalkyl (e.g., C3-C8, C3- C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ² is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ² is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ² is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ² is independently substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl). In

embodiments, R ² is independently substituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, R ² is independently unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, R ² is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ² is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ² is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0229] In embodiments, two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, two adjacent R ² substituents may optionally be joined to form a substituted cycloalkyl (e.g., C3- C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, two adjacent R ² substituents may optionally be joined to form an unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In

embodiments, two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R ² substituents may optionally be joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R ² substituents may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, two adjacent R ² substituents may optionally be joined to form a substituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, two adjacent R ² substituents may optionally be joined to form an unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R ² substituents may optionally be joined to form a substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R ² substituents may optionally be joined to form an unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0230] In embodiments, R ^2A is independently hydrogen. In embodiments, R ^2A is

independently -CX ^2A 3. In embodiments, R ^2A is independently -CHX ^2A 2. In embodiments, R ^2A is independently -CH2X ^2A . In embodiments, R ^2A is independently -CN. In embodiments, R ^2A is independently -COOH. In embodiments, R ^2A is independently -CONH ₂ . In embodiments, X ^2A is independently–F, -Cl, -Br, or -I. [0231] In embodiments, R ^2A is independently substituted or unsubstituted alkyl (e.g., C1-C8, C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ^2A is independently substituted alkyl (e.g., C ₁ -C ₈ , C ₁ - C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ^2A is independently unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ - C6, C1-C4, or C1-C2). In embodiments, R ^2A is independently unsubstituted methyl. In

embodiments, R ^2A is independently unsubstituted ethyl. In embodiments, R ^2A is independently unsubstituted propyl. In embodiments, R ^2A is independently unsubstituted isopropyl. In embodiments, R ^2A is independently unsubstituted tert-butyl. In embodiments, R ^2A is

independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^2A is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^2A is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^2A is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R ^2A is independently substituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ^2A is independently unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ^2A is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^2A is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^2A is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^2A is independently substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, R ^2A is independently substituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, R ^2A is independently unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, R ^2A is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^2A is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^2A is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0232] In embodiments, R ^2B is independently hydrogen. In embodiments, R ^2B is

independently -CX ^2B ₃ . In embodiments, R ^2B is independently -CHX ^2B ₂ . In embodiments, R ^2B is independently -CH2X ^2B . In embodiments, R ^2B is independently -CN. In embodiments, R ^2B is independently -COOH. In embodiments, R ^2B is independently -CONH2. In embodiments, X ^2B is independently–F, -Cl, -Br, or -I. [0233] In embodiments, R ^2B is independently substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C1-C6, C1-C4, or C1-C2). In embodiments, R ^2B is independently substituted alkyl (e.g., C1-C8, C1- C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ^2B is independently unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ - C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ^2B is independently unsubstituted methyl. In

embodiments, R ^2B is independently unsubstituted ethyl. In embodiments, R ^2B is independently unsubstituted propyl. In embodiments, R ^2B is independently unsubstituted isopropyl. In embodiments, R ^2B is independently unsubstituted tert-butyl. In embodiments, R ^2B is

independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^2B is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^2B is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^2B is independently substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ^2B is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R ^2B is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R ^2B is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^2B is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^2B is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^2B is independently substituted or unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, R ^2B is independently substituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, R ^2B is independently unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, R ^2B is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^2B is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^2B is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0234] In embodiments, R ^2A and R ^2B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^2A and R ^2B substituents bonded to the same nitrogen atom may be joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^2A and R ^2B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). [0235] In embodiments, R ^2A and R ^2B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^2A and R ^2B substituents bonded to the same nitrogen atom may be joined to form a substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^2A and R ^2B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0236] In embodiments, R ^2C is independently hydrogen. In embodiments, R ^2C is

independently -CX ^2C ₃ . In embodiments, R ^2C is independently -CHX ^2C ₂ . In embodiments, R ^2C is independently -CH2X ^2C . In embodiments, R ^2C is independently -CN. In embodiments, R ^2C is independently -COOH. In embodiments, R ^2C is independently -CONH2. In embodiments, X ^2C is independently–F, -Cl, -Br, or -I. [0237] In embodiments, R ^2C is independently substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C1-C6, C1-C4, or C1-C2). In embodiments, R ^2C is independently substituted alkyl (e.g., C1-C8, C1- C6, C1-C4, or C1-C2). In embodiments, R ^2C is independently unsubstituted alkyl (e.g., C1-C8, C1- C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ^2C is independently unsubstituted methyl. In

embodiments, R ^2C is independently unsubstituted ethyl. In embodiments, R ^2C is independently unsubstituted propyl. In embodiments, R ^2C is independently unsubstituted isopropyl. In embodiments, R ^2C is independently unsubstituted tert-butyl. In embodiments, R ^2C is

independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^2C is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^2C is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^2C is independently substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ^2C is independently substituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ^2C is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R ^2C is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^2C is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^2C is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^2C is independently substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, R ^2C is independently substituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, R ^2C is independently unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, R ^2C is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^2C is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^2C is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0238] In embodiments, R ^2D is independently hydrogen. In embodiments, R ^2D is independently -CX ^2D 3. In embodiments, R ^2D is independently -CHX ^2D 2. In embodiments, R ^2D is independently -CH ₂ X ^2D . In embodiments, R ^2D is independently -CN. In embodiments, R ^2D is independently -COOH. In embodiments, R ^2D is independently -CONH2. In embodiments, X ^2D is independently–F, -Cl, -Br, or -I. [0239] In embodiments, R ^2D is independently substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ^2D is independently substituted alkyl (e.g., C ₁ -C ₈ , C ₁ - C6, C1-C4, or C1-C2). In embodiments, R ^2D is independently unsubstituted alkyl (e.g., C1-C8, C1- C6, C1-C4, or C1-C2). In embodiments, R ^2D is independently unsubstituted methyl. In

embodiments, R ^2D is independently unsubstituted ethyl. In embodiments, R ^2D is independently unsubstituted propyl. In embodiments, R ^2D is independently unsubstituted isopropyl. In embodiments, R ^2D is independently unsubstituted tert-butyl. In embodiments, R ^2D is

independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^2D is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^2D is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^2D is independently substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ^2D is independently substituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ^2D is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R ^2D is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^2D is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^2D is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^2D is independently substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, R ^2D is independently substituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, R ^2D is independently unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, R ^2D is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^2D is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^2D is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0240] In embodiments, R ² is independently

halogen, -CX ² 3, -CHX ² 2, -CH2X ² , -OCX ² 3, -OCH2X ² , -OCHX ² 2, -CN, -OH, -NH2, -COOH, -CO NH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,

−NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, R ²³ -substituted or

unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ²³ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ²³ -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ²³ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ²³ -substituted or unsubstituted aryl (e.g., C6- C ₁₂ , C ₆ -C ₁₀ , or phenyl), or R ²³ -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ² is independently halogen, -CX ² 3, -CHX ² 2, -CH2X ² , -OCX ² 3, -OCH2X ² , -OCHX ² 2, -CN, -OH, -NH2, -COOH, -CO NH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,

−NHC=(O)NH ₂ , -NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ² is independently–F, -Cl, -Br, or–I. In embodiments, R ² is independently unsubstituted methyl. In embodiments, R ² is independently unsubstituted ethyl. In embodiments, R ² is independently

halogen, -CX ² ₃ , -CHX ² ₂ , -CH ₂ X ² , -OCX ² ₃ , -OCH ₂ X ² , -OCHX ² ₂ , -CN, -OH, -NH ₂ , -COOH, -CO NH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,

−NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, R ²³ -substituted or

unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ²³ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ²³ -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ²³ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ²³ -substituted or unsubstituted aryl (e.g., C6- C ₁₂ , C ₆ -C ₁₀ , or phenyl), or R ²³ -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ² is independently halogen, -CX ² 3, -CHX ² 2, -CH2X ² , -OCX ² 3, -OCH2X ² , -OCHX ² 2, -CN, -OH, -NH2, -COOH, -CO NH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,

−NHC=(O)NH ₂ , -NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0241] In embodiments, two adjacent R ² substituents may optionally be joined to form a R ²³ - substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, two adjacent R ² substituents may optionally be joined to form a R ²³ -substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, two adjacent R ² substituents may optionally be joined to form an unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In

embodiments, two adjacent R ² substituents may optionally be joined to form a R ²³ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R ² substituents may optionally be joined to form a R ²³ -substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R ² substituents may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R ² substituents may optionally be joined to form a R ²³ -substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, two adjacent R ²

substituents may optionally be joined to form a R ²³ -substituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl). In embodiments, two adjacent R ² substituents may optionally be joined to form an unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl). In embodiments, two adjacent R ²

substituents may optionally be joined to form a R ²³ -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R ² substituents may optionally be joined to form a R ²³ -substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R ² substituents may optionally be joined to form an unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0242] R ²³ is independently oxo,

halogen, -CX ²³ 3, -CHX ²³ 2, -CH2X ²³ , -OCX ²³ 3, -OCH2X ²³ , -OCHX ²³ 2, -CN, -OH, -NH2, -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O)NH ₂ , -NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, R ²⁴ -substituted or

unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ²⁴ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ²⁴ -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ²⁴ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ²⁴ -substituted or unsubstituted aryl (e.g., C ₆ - C12, C6-C10, or phenyl), or R ²⁴ -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ²³ is independently oxo,

halogen, -CX ²³ 3, -CHX ²³ 2, -CH2X ²³ , -OCX ²³ 3, -OCH2X ²³ , -OCHX ²³ 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ²³ is independently–F, -Cl, -Br, or–I. In embodiments, R ²³ is independently unsubstituted methyl. In embodiments, R ²³ is independently unsubstituted ethyl. [0243] R ²⁴ is independently oxo,

halogen, -CX ²⁴ ₃ , -CHX ²⁴ ₂ , -CH ₂ X ²⁴ , -OCX ²⁴ ₃ , -OCH ₂ X ²⁴ , -OCHX ²⁴ ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ²⁵ -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ²⁵ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ²⁵ -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ²⁵ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ²⁵ -substituted or unsubstituted aryl (e.g., C6- C ₁₂ , C ₆ -C ₁₀ , or phenyl), or R ²⁵ -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ²⁴ is independently oxo,

halogen, -CX ²⁴ ₃ , -CHX ²⁴ ₂ , -CH ₂ X ²⁴ , -OCX ²⁴ ₃ , -OCH ₂ X ²⁴ , -OCHX ²⁴ ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ²⁴ is independently–F, -Cl, -Br, or–I. In embodiments, R ²⁴ is independently unsubstituted methyl. In embodiments, R ²⁴ is independently unsubstituted ethyl. [0244] R ²⁵ is independently oxo,

halogen, -CX ²⁵ ₃ , -CHX ²⁵ ₂ , -CH ₂ X ²⁵ , -OCX ²⁵ ₃ , -OCH ₂ X ²⁵ , -OCHX ²⁵ ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O)NH ₂ , -NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ²⁵ is independently–F, -Cl, -Br, or–I. In embodiments, R ²⁵ is independently unsubstituted methyl. In embodiments, R ²⁵ is independently unsubstituted ethyl. [0245] In embodiments, R ^2A is independently

hydrogen, -CX ^2A ₃ , -CHX ^2A ₂ , -CH ₂ X ^2A , -CN, -COOH, -CONH ₂ , R ^23A -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ^23A -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^23A -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^23A - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^23A -substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or R ^23A -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^2A is independently hydrogen, -CX ^2A 3, -CHX ^2A 2, -CH2X ^2A , -CN, -COOH, -CONH2, unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^2A is independently–F, -Cl, -Br, or–I. In embodiments, R ^2A is independently hydrogen. In embodiments, R ^2A is independently unsubstituted methyl. In embodiments, R ^2A is independently unsubstituted ethyl. [0246] In embodiments, R ^2A and R ^2B substituents bonded to the same nitrogen atom may optionally be joined to form a R ^23A -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or R ^23A - substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^2A and R ^2B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^2A and R ^2B substituents bonded to the same nitrogen atom may optionally be joined to form a R ^23A -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^2A and R ^2B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). [0247] R ^23A is independently oxo,

halogen, -CX ^23A ₃ , -CHX ^23A ₂ , -CH ₂ X ^23A , -OCX ^23A ₃ , -OCH ₂ X ^23A , -OCHX ^23A ₂ , -CN, -OH, -NH ₂ , - COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^24A -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ^24A -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^24A -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^24A -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^24A -substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or R ^24A -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^23A is independently oxo,

halogen, -CX ^23A 3, -CHX ^23A 2, -CH2X ^23A , -OCX ^23A 3, -OCH2X ^23A , -OCHX ^23A 2, -CN, -OH, -NH2, - COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^23A is independently–F, -Cl, -Br, or–I. In embodiments, R ^23A is independently unsubstituted methyl. In embodiments, R ^23A is independently

unsubstituted ethyl. [0248] R ^24A is independently oxo,

halogen, -CX ^24A ₃ , -CHX ^24A ₂ , -CH ₂ X ^24A , -OCX ^24A ₃ , -OCH ₂ X ^24A , -OCHX ^24A ₂ , -CN, -OH, -NH ₂ , - COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^25A -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ^25A -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^25A -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ^25A -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^25A -substituted or unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or R ^25A -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^24A is independently oxo,

halogen, -CX ^24A ₃ , -CHX ^24A ₂ , -CH ₂ X ^24A , -OCX ^24A ₃ , -OCH ₂ X ^24A , -OCHX ^24A ₂ , -CN, -OH, -NH ₂ , - COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^24A is independently–F, -Cl, -Br, or–I. In embodiments, R ^24A is independently unsubstituted methyl. In embodiments, R ^24A is independently

unsubstituted ethyl. [0249] R ^25A is independently oxo,

halogen, -CX ^25A ₃ , -CHX ^25A ₂ , -CH ₂ X ^25A , -OCX ^25A ₃ , -OCH ₂ X ^25A , -OCHX ^25A ₂ , -CN, -OH, -NH ₂ , - COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O)NH ₂ , -NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^25A is independently–F, -Cl, -Br, or–I. In embodiments, R ^25A is independently unsubstituted methyl. In embodiments, R ^25A is independently

unsubstituted ethyl. [0250] In embodiments, R ^2B is independently

hydrogen, -CX ^2B ₃ , -CHX ^2B ₂ , -CH ₂ X ^2B , -CN, -COOH, -CONH ₂ , R ^23B -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ^23B -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^23B -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^23B - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^23B -substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or R ^23B -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^2B is independently hydrogen, -CX ^2B ₃ , -CHX ^2B ₂ , -CH ₂ X ^2B , -CN, -COOH, -CONH ₂ , unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^2B is independently–F, -Cl, -Br, or–I. In embodiments, R ^2B is independently hydrogen. In embodiments, R ^2B is independently unsubstituted methyl. In embodiments, R ^2B is independently unsubstituted ethyl. [0251] In embodiments, R ^2A and R ^2B substituents bonded to the same nitrogen atom may optionally be joined to form a R ^23B -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or R ^23B - substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^2A and R ^2B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^2A and R ^2B substituents bonded to the same nitrogen atom may optionally be joined to form a R ^23B -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^2A and R ^2B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). [0252] R ^23B is independently oxo,

halogen, -CX ^23B 3, -CHX ^23B 2, -CH2X ^23B , -OCX ^23B 3, -OCH2X ^23B , -OCHX ^23B 2, -CN, -OH, -NH2, - COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^24B -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ^24B -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^24B -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ^24B -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^24B -substituted or unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or R ^24B -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^23B is independently oxo,

halogen, -CX ^23B ₃ , -CHX ^23B ₂ , -CH ₂ X ^23B , -OCX ^23B ₃ , -OCH ₂ X ^23B , -OCHX ^23B ₂ , -CN, -OH, -NH ₂ , -C OOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^23B is independently–F, -Cl, -Br, or–I. In embodiments, R ^23B is independently unsubstituted methyl. In embodiments, R ^23B is independently

unsubstituted ethyl. [0253] R ^24B is independently oxo,

halogen, -CX ^24B 3, -CHX ^24B 2, -CH2X ^24B , -OCX ^24B 3, -OCH2X ^24B , -OCHX ^24B 2, -CN, -OH, -NH2, -C OOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^25B -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ^25B -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^25B -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^25B -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^25B -substituted or unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or R ^25B -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^24B is independently oxo,

halogen, -CX ^24B ₃ , -CHX ^24B ₂ , -CH ₂ X ^24B , -OCX ^24B ₃ , -OCH ₂ X ^24B , -OCHX ^24B ₂ , -CN, -OH, -NH ₂ , -C OOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^24B is independently–F, -Cl, -Br, or–I. In embodiments, R ^24B is independently unsubstituted methyl. In embodiments, R ^24B is independently

unsubstituted ethyl. [0254] R ^25B is independently oxo,

halogen, -CX ^25B ₃ , -CHX ^25B ₂ , -CH ₂ X ^25B , -OCX ^25B ₃ , -OCH ₂ X ^25B , -OCHX ^25B ₂ , -CN, -OH, -NH ₂ , -C OOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^25B is independently–F, -Cl, -Br, or–I. In embodiments, R ^25B is independently unsubstituted methyl. In embodiments, R ^25B is independently

unsubstituted ethyl. [0255] In embodiments, R ^2C is independently

hydrogen, -CX ^2C ₃ , -CHX ^2C ₂ , -CH ₂ X ^2C , -CN, -COOH, -CONH ₂ , R ^23C -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ^23C -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^23C -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ^23C - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^23C -substituted or unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or R ^23C -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^2C is independently hydrogen, -CX ^2C 3, -CHX ^2C 2, -CH2X ^2C , -CN, -COOH, -CONH2, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^2C is independently–F, -Cl, -Br, or–I. In embodiments, R ^2C is independently hydrogen. In embodiments, R ^2C is independently

unsubstituted methyl. In embodiments, R ^2C is independently unsubstituted ethyl. [0256] R ^23C is independently oxo,

halogen, -CX ^23C 3, -CHX ^23C 2, -CH2X ^23C , -OCX ^23C 3, -OCH2X ^23C , -OCHX ^23C 2, -CN, -OH, -NH2, - COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^24C -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ^24C -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^24C -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^24C -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^24C -substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or R ^24C -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^23C is independently oxo,

halogen, -CX ^23C ₃ , -CHX ^23C ₂ , -CH ₂ X ^23C , -OCX ^23C ₃ , -OCH ₂ X ^23C , -OCHX ^23C ₂ , -CN, -OH, -NH ₂ , -C OOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^23C is independently–F, -Cl, -Br, or–I. In embodiments, R ^23C is independently unsubstituted methyl. In embodiments, R ^23C is independently

unsubstituted ethyl. [0257] R ^24C is independently oxo,

halogen, -CX ^24C ₃ , -CHX ^24C ₂ , -CH ₂ X ^24C , -OCX ^24C ₃ , -OCH ₂ X ^24C , -OCHX ^24C ₂ , -CN, -OH, -NH ₂ , -C OOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^25C -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ^25C -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^25C -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ^25C -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^25C -substituted or unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or R ^25C -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^24C is independently oxo,

halogen, -CX ^24C 3, -CHX ^24C 2, -CH2X ^24C , -OCX ^24C 3, -OCH2X ^24C , -OCHX ^24C 2, -CN, -OH, -NH2, -C OOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^24C is independently–F, -Cl, -Br, or–I. In embodiments, R ^24C is independently unsubstituted methyl. In embodiments, R ^24C is independently

unsubstituted ethyl. [0258] R ^25C is independently oxo,

halogen, -CX ^25C 3, -CHX ^25C 2, -CH2X ^25C , -OCX ^25C 3, -OCH2X ^25C , -OCHX ^25C 2, -CN, -OH, -NH2, -C OOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O)NH ₂ , -NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₂ , C ₆ -C ₁₀ , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^25C is independently–F, -Cl, -Br, or–I. In embodiments, R ^25C is independently unsubstituted methyl. In embodiments, R ^25C is independently

unsubstituted ethyl. [0259] In embodiments, R ^2D is independently

hydrogen, -CX ^2D 3, -CHX ^2D 2, -CH2X ^2D , -CN, -COOH, -CONH2, R ^23D -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ^23D -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^23D -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^23D - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^23D -substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or R ^23D -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^2D is independently hydrogen, -CX ^2D ₃ , -CHX ^2D ₂ , -CH ₂ X ^2D , -CN, -COOH, -CONH ₂ , unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^2D is independently–F, -Cl, -Br, or–I. In embodiments, R ^2D is independently hydrogen. In embodiments, R ^2D is independently

unsubstituted methyl. In embodiments, R ^2D is independently unsubstituted ethyl. [0260] R ^23D is independently oxo,

halogen, -CX ^23D ₃ , -CHX ^23D ₂ , -CH ₂ X ^23D , -OCX ^23D ₃ , -OCH ₂ X ^23D , -OCHX ^23D ₂ , -CN, -OH, -NH ₂ , - COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^24D -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ^24D -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^24D -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^24D -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^24D -substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or R ^24D -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^23D is independently oxo,

halogen, -CX ^23D 3, -CHX ^23D 2, -CH2X ^23D , -OCX ^23D 3, -OCH2X ^23D , -OCHX ^23D 2, -CN, -OH, -NH2, - COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^23D is independently–F, -Cl, -Br, or–I. In embodiments, R ^23D is independently unsubstituted methyl. In embodiments, R ^23D is independently

unsubstituted ethyl. [0261] R ^24D is independently oxo,

halogen, -CX ^24D 3, -CHX ^24D 2, -CH2X ^24D , -OCX ^24D 3, -OCH2X ^24D , -OCHX ^24D 2, -CN, -OH, -NH2, - COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^25D -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ^25D -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^25D -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^25D -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^25D -substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or R ^25D -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^24D is independently oxo,

halogen, -CX ^24D 3, -CHX ^24D 2, -CH2X ^24D , -OCX ^24D 3, -OCH2X ^24D , -OCHX ^24D 2, -CN, -OH, -NH2, - COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^24D is independently–F, -Cl, -Br, or–I. In embodiments, R ^24D is independently unsubstituted methyl. In embodiments, R ^24D is independently

unsubstituted ethyl. [0262] R ^25D is independently oxo,

halogen, -CX ^25D 3, -CHX ^25D 2, -CH2X ^25D , -OCX ^25D 3, -OCH2X ^25D , -OCHX ^25D 2, -CN, -OH, -NH2, - COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^25D is independently–F, -Cl, -Br, or–I. In embodiments, R ^25D is independently unsubstituted methyl. In embodiments, R ^25D is independently

unsubstituted ethyl. [0263] In embodiments, z2 is 0. In embodiments, z2 is 1. In embodiments, z2 is 2. In embodiments, z2 is 3. In embodiments, z2 is 4. [0264] In embodiments, L ¹ is a bond, substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8

cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene. In embodiments, L ¹ is a bond. [0265] In embodiments, L ¹ is a bond. In embodiments, L ¹ is -S(O) ₂ -. In embodiments, L ¹ is– NR ⁴ -. In embodiments, L ¹ is -O-. In embodiments, L ¹ is -S-. In embodiments, L ¹ is -C(O)- . In embodiments, L ¹ is -C(O)NR ⁴ -. In embodiments, L ¹ is–NR ⁴ C(O)- . In embodiments, L ¹ is– NR ⁴ C(O)NH-. In embodiments, L ¹ is -NHC(O)NR ⁴ -. In embodiments, L ¹ is -C(O)O-. In embodiments, L ¹ is -OC(O)-. In embodiments, L ¹ is -NH-. In embodiments, L ¹ is -C(O)NH-. In embodiments, L ¹ is -NHC(O)- . In embodiments, L ¹ is -NHC(O)NH-. In embodiments, L ¹ is– CH2-. In embodiments, L ¹ is–OCH2-. In embodiments, L ¹ is–CH2O-. In embodiments, L ¹ is– CH ₂ CH ₂ -. In embodiments, L ¹ is–NHCH ₂ -. In embodiments, L ¹ is–CH ₂ NH-. In embodiments, L ¹ is a bond. [0266] In embodiments, L ¹ is a

bond, -S(O) ₂ -, -NR ⁴ -, -O-, -S-, -C(O)-, -C(O)NR ⁴ -, -NR ⁴ C(O)-, -NR ⁴ C(O)NH-, -NHC(O)NR ⁴ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0267] In embodiments, L ¹ is independently substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L ¹ is independently substituted alkylene (e.g., C1-C8, C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, L ¹ is independently unsubstituted alkylene (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, L ¹ is independently unsubstituted methylene. In embodiments, L ¹ is independently unsubstituted ethylene. In embodiments, L ¹ is independently unsubstituted propylene. In embodiments, L ¹ is independently unsubstituted isopropylene. In embodiments, L ¹ is independently unsubstituted tert-butylene. In embodiments, L ¹ is

independently substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L ¹ is independently substituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L ¹ is independently unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L ¹ is independently substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, L ¹ is independently substituted cycloalkylene (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, L ¹ is independently unsubstituted cycloalkylene (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, L ¹ is independently substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, L ¹ is independently substituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, L ¹ is independently unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, L ¹ is independently substituted or unsubstituted arylene (e.g., C6-C10 or phenylene). In embodiments, L ¹ is independently substituted arylene (e.g., C6-C10 or phenylene). In embodiments, L ¹ is independently unsubstituted arylene (e.g., C ₆ -C ₁₀ or phenylene). In embodiments, L ¹ is independently substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L ¹ is independently substituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L ¹ is independently unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0268] In embodiments, L ¹ is independently

bond, -S(O) ₂ -, -N(R ⁴ )-, -O-, -S-, -C(O)-, -C(O)N(R ⁴ )-, -N(R ⁴ )C(O)-, -N(R ⁴ )C(O)NH-, -NHC(O) N(R ⁴ )-, -C(O)O-, -OC(O)-, R ³⁵ -substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ³⁵ -substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ³⁵ -substituted or unsubstituted cycloalkylene (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ³⁵ -substituted or

unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ³⁵ -substituted or unsubstituted arylene (e.g., C ₆ -C ₁₀ or phenylene), or R ³⁵ -substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L ¹ is independently

bond, -S(O)2-, -N(R ⁴ )-, -O-, -S-, -C(O)-, -C(O)N(R ⁴ )-, -N(R ⁴ )C(O)-, -N(R ⁴ )C(O)NH-, -NHC(O) N(R ⁴ )-, -C(O)O-, -OC(O)-, unsubstituted alkylene (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5- C ₆ ), unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted arylene (e.g., C6-C10 or phenylene), or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L ¹ is independently unsubstituted methylene. In embodiments, L ¹ is independently unsubstituted ethylene. In embodiments, L ¹ is independently methyl- substituted methylene. [0269] R ³⁵ is independently oxo,

halogen, -CX ³⁵ ₃ , -CHX ³⁵ ₂ , -CH ₂ X ³⁵ , -OCX ³⁵ ₃ , -OCH ₂ X ³⁵ , -OCHX ³⁵ ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ³⁶ -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ³⁶ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ³⁶ -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ³⁶ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ³⁶ -substituted or unsubstituted aryl (e.g., C6- C ₁₀ or phenyl), or R ³⁶ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ³⁵ is independently oxo,

halogen, -CX ³⁵ 3, -CHX ³⁵ 2, -CH2X ³⁵ , -OCX ³⁵ 3, -OCH2X ³⁵ , -OCHX ³⁵ 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ³⁵ is independently–F, -Cl, -Br, or–I. In embodiments, R ³⁵ is independently unsubstituted methyl. In embodiments, R ³⁵ is independently unsubstituted ethyl. [0270] R ³⁶ is independently oxo,

halogen, -CX ³⁶ ₃ , -CHX ³⁶ ₂ , -CH ₂ X ³⁶ , -OCX ³⁶ ₃ , -OCH ₂ X ³⁶ , -OCHX ³⁶ ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ³⁷ -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ³⁷ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ³⁷ -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ³⁷ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ³⁷ -substituted or unsubstituted aryl (e.g., C6- C ₁₀ or phenyl), or R ³⁷ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ³⁶ is independently oxo,

halogen, -CX ³⁶ 3, -CHX ³⁶ 2, -CH2X ³⁶ , -OCX ³⁶ 3, -OCH2X ³⁶ , -OCHX ³⁶ 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ³⁶ is independently–F, -Cl, -Br, or–I. In embodiments, R ³⁶ is independently unsubstituted methyl. In embodiments, R ³⁶ is independently unsubstituted ethyl. [0271] R ³⁷ is independently oxo,

halogen, -CX ³⁷ ₃ , -CHX ³⁷ ₂ , -CH ₂ X ³⁷ , -OCX ³⁷ ₃ , -OCH ₂ X ³⁷ , -OCHX ³⁷ ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ³⁷ is independently–F, -Cl, -Br, or–I. In embodiments, R ³⁷ is independently unsubstituted methyl. In embodiments, R ³⁷ is independently unsubstituted ethyl. [0272] In embodiments, R ⁴ is independently hydrogen, -CX ⁴ 3, -CHX ⁴ 2, -CH2X ⁴ , -OCX ⁴ 3, - OCH2X ⁴ , -OCHX ⁴ 2, -CN, -C(O)R ^4A , -C(O)OR ^4A , -C(O)NR ^4A R ^4B , -OR ^4A , substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0273] In embodiments, R ⁴ is independently hydrogen. In embodiments, R ⁴ is

independently -CX ⁴ 3. In embodiments, R ⁴ is independently -CHX ⁴ 2. In embodiments, R ⁴ is independently -CH2X ⁴ . In embodiments, R ⁴ is independently -CN. In embodiments, R ⁴ is independently -C(O)R ^4A . In embodiments, R ⁴ is independently -C(O)-OR ^4A . In embodiments, R ⁴ is independently -C(O)NR ^4A R ^4B . In embodiments, R ⁴ is independently -COOH. In embodiments, R ⁴ is independently -CONH2. In embodiments, R ⁴ is independently -CF3. In embodiments, R ⁴ is independently -CHF ₂ . In embodiments, R ⁴ is independently -CH ₂ F. In embodiments, R ⁴ is independently–CH3. In embodiments, R ⁴ is independently–CH2CH3. In embodiments, R ⁴ is independently–CH2CH2CH3. In embodiments, R ⁴ is independently– CH(CH ₃ ) ₂ . In embodiments, R ⁴ is independently–C(CH ₃ ) ₃ . [0274] In embodiments, R ⁴ is independently unsubstituted methyl. In embodiments, R ⁴ is independently unsubstituted ethyl. In embodiments, R ⁴ is independently unsubstituted propyl. In embodiments, R ⁴ is independently unsubstituted isopropyl. In embodiments, R ⁴ is independently unsubstituted n-propyl. In embodiments, R ⁴ is independently unsubstituted butyl. In embodiments, R ⁴ is independently unsubstituted n-butyl. In embodiments, R ⁴ is

independently unsubstituted t-butyl. In embodiments, R ⁴ is independently unsubstituted pentyl. In embodiments, R ⁴ is independently unsubstituted n-pentyl. In embodiments, R ⁴ is

independently unsubstituted hexyl. In embodiments, R ⁴ is independently unsubstituted n-hexyl. In embodiments, R ⁴ is independently unsubstituted heptyl. In embodiments, R ⁴ is independently unsubstituted n-heptyl. In embodiments, R ⁴ is independently unsubstituted octyl. In

embodiments, R ⁴ is independently unsubstituted n-octyl. In embodiments, R ⁴ is independently unsubstituted benzyl. In embodiments, R ⁴ is independently unsubstituted C1-C8 alkyl. In embodiments, R ⁴ is independently halo-substituted methyl. In embodiments, R ⁴ is independently halo-substituted ethyl. In embodiments, R ⁴ is independently halo-substituted isopropyl. In embodiments, R ⁴ is independently halo-substituted n-propyl. In embodiments, R ⁴ is

independently halo-substituted n-butyl. In embodiments, R ⁴ is independently halo-substituted t- butyl. In embodiments, R ¹ is independently halo-substituted n-pentyl. In embodiments, R ⁴ is independently halo-substituted benzyl. In embodiments, R ⁴ is independently halo-substituted C1-C8 alkyl. In embodiments, R ⁴ is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R ⁴ is independently unsubstituted 2 to 7 membered heteroalkyl. In

embodiments, R ⁴ is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R ⁴ is independently unsubstituted 2 to 9 membered heteroalkyl. In embodiments, R ⁴ is independently unsubstituted 2 to 10 membered heteroalkyl. In embodiments, R ⁴ is

independently unsubstituted 3 to 10 membered heteroalkyl. In embodiments, R ⁴ is

independently unsubstituted 4 to 10 membered heteroalkyl. In embodiments, R ⁴ is

independently unsubstituted 5 to 10 membered heteroalkyl. In embodiments, R ⁴ is

independently unsubstituted 6 to 10 membered heteroalkyl. In embodiments, R ⁴ is

independently unsubstituted 7 to 10 membered heteroalkyl. In embodiments, R ⁴ is

independently unsubstituted 8 to 10 membered heteroalkyl. In embodiments, R ⁴ is

independently unsubstituted 6 to 10 membered heteroalkyl. In embodiments, R ⁴ is

independently unsubstituted 7 to 9 membered heteroalkyl. [0275] In embodiments, R ⁴ is independently substituted or unsubstituted alkyl (e.g., C1-C8, C1- C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ⁴ is independently substituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ⁴ is independently unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C1-C4, or C1-C2). In embodiments, R ⁴ is independently unsubstituted methyl. In embodiments, R ⁴ is independently unsubstituted ethyl. In embodiments, R ⁴ is independently unsubstituted propyl. In embodiments, R ⁴ is independently unsubstituted isopropyl. In embodiments, R ⁴ is independently unsubstituted tert-butyl. In embodiments, R ⁴ is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ⁴ is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ⁴ is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ⁴ is independently substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ - C6, or C5-C6). In embodiments, R ⁴ is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ⁴ is independently unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ - C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ⁴ is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ⁴ is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ⁴ is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ⁴ is independently substituted or unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl). In embodiments, R ⁴ is independently substituted aryl (e.g., C6-C10 or phenyl). In embodiments, R ⁴ is independently unsubstituted aryl (e.g., C6-C10 or phenyl). In embodiments, R ⁴ is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ⁴ is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ⁴ is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0276] In embodiments, R ^4A is independently hydrogen. In embodiments, R ^4A is

independently -CX ^4A 3. In embodiments, R ^4A is independently -CHX ^4A 2. In embodiments, R ^4A is independently -CH2X ^4A . In embodiments, R ^4A is independently -CN. In embodiments, R ^4A is independently -COOH. In embodiments, R ^4A is independently -CONH ₂ . In embodiments, X ^4A is independently–F, -Cl, -Br, or -I. [0277] In embodiments, R ^4A is independently substituted or unsubstituted alkyl (e.g., C1-C8, C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ^4A is independently substituted alkyl (e.g., C ₁ -C ₈ , C ₁ - C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ^4A is independently unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ - C6, C1-C4, or C1-C2). In embodiments, R ^4A is independently unsubstituted methyl. In

embodiments, R ^4A is independently unsubstituted ethyl. In embodiments, R ^4A is independently unsubstituted propyl. In embodiments, R ^4A is independently unsubstituted isopropyl. In embodiments, R ^4A is independently unsubstituted tert-butyl. In embodiments, R ^4A is

independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^4A is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^4A is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^4A is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R ^4A is independently substituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ^4A is independently unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ^4A is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^4A is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^4A is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^4A is independently substituted or unsubstituted aryl (e.g., C6-C10 or phenyl). In embodiments, R ^4A is independently substituted aryl (e.g., C6-C10 or phenyl). In embodiments, R ^4A is independently unsubstituted aryl (e.g., C6- C ₁₀ or phenyl). In embodiments, R ^4A is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^4A is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^4A is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0278] In embodiments, R ^4B is independently hydrogen. In embodiments, R ^4B is

independently -CX ^4B 3. In embodiments, R ^4B is independently -CHX ^4B 2. In embodiments, R ^4B is independently -CH ₂ X ^4B . In embodiments, R ^4B is independently -CN. In embodiments, R ^4B is independently -COOH. In embodiments, R ^4B is independently -CONH2. In embodiments, X ^4B is independently–F, -Cl, -Br, or -I. [0279] In embodiments, R ^4B is independently substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ^4B is independently substituted alkyl (e.g., C ₁ -C ₈ , C ₁ - C6, C1-C4, or C1-C2). In embodiments, R ^4B is independently unsubstituted alkyl (e.g., C1-C8, C1- C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ^4B is independently unsubstituted methyl. In

embodiments, R ^4B is independently unsubstituted ethyl. In embodiments, R ^4B is independently unsubstituted propyl. In embodiments, R ^4B is independently unsubstituted isopropyl. In embodiments, R ^4B is independently unsubstituted tert-butyl. In embodiments, R ^4B is

independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^4B is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^4B is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^4B is independently substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ^4B is independently substituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ^4B is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R ^4B is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^4B is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^4B is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^4B is independently substituted or unsubstituted aryl (e.g., C6-C10 or phenyl). In embodiments, R ^4B is independently substituted aryl (e.g., C ₆ -C ₁₀ or phenyl). In embodiments, R ^4B is independently unsubstituted aryl (e.g., C ₆ - C ₁₀ or phenyl). In embodiments, R ^4B is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^4B is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^4B is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0280] In embodiments, R ^4A and R ^4B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^4A and R ^4B substituents bonded to the same nitrogen atom may be joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^4A and R ^4B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). [0281] In embodiments, R ^4A and R ^4B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^4A and R ^4B substituents bonded to the same nitrogen atom may be joined to form a substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^4A and R ^4B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0282] In embodiments, R ⁴ is independently

hydrogen, -CX ⁴ 3, -CHX ⁴ 2, -CH2X ⁴ , -CN, -COOH, -CONH2, R ²⁹ -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ²⁹ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ²⁹ - substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ²⁹ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ²⁹ -substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or R ²⁹ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ⁴ is independently

hydrogen, -CX ⁴ 3, -CHX ⁴ 2, -CH2X ⁴ , -CN, -COOH, -CONH2, unsubstituted alkyl (e.g., C1-C8, C1- C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ⁴ is independently–F, -Cl, -Br, or–I. In embodiments, R ⁴ is independently hydrogen. In

embodiments, R ⁴ is independently unsubstituted methyl. In embodiments, R ⁴ is independently unsubstituted ethyl. [0283] R ²⁹ is independently oxo,

halogen, -CX ²⁹ 3, -CHX ²⁹ 2, -CH2X ²⁹ , -OCX ²⁹ 3, -OCH2X ²⁹ , -OCHX ²⁹ 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ³⁰ -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ³⁰ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ³⁰ -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ³⁰ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ³⁰ -substituted or unsubstituted aryl (e.g., C6- C ₁₀ or phenyl), or R ³⁰ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ²⁹ is independently oxo,

halogen, -CX ²⁹ 3, -CHX ²⁹ 2, -CH2X ²⁹ , -OCX ²⁹ 3, -OCH2X ²⁹ , -OCHX ²⁹ 2, -CN, -OH, -NH2, -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ²⁹ is independently–F, -Cl, -Br, or–I. In embodiments, R ²⁹ is independently unsubstituted methyl. In embodiments, R ²⁹ is independently unsubstituted ethyl. [0284] R ³⁰ is independently oxo,

halogen, -CX ³⁰ 3, -CHX ³⁰ 2, -CH2X ³⁰ , -OCX ³⁰ 3, -OCH2X ³⁰ , -OCHX ³⁰ 2, -CN, -OH, -NH2, -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ³¹ -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ³¹ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ³¹ -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ³¹ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ³¹ -substituted or unsubstituted aryl (e.g., C ₆ - C10 or phenyl), or R ³¹ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ³⁰ is independently oxo,

halogen, -CX ³⁰ ₃ , -CHX ³⁰ ₂ , -CH ₂ X ³⁰ , -OCX ³⁰ ₃ , -OCH ₂ X ³⁰ , -OCHX ³⁰ ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ³⁰ is independently–F, -Cl, -Br, or–I. In embodiments, R ³⁰ is independently unsubstituted methyl. In embodiments, R ³⁰ is independently unsubstituted ethyl. [0285] R ³¹ is independently oxo,

halogen, -CX ³¹ 3, -CHX ³¹ 2, -CH2X ³¹ , -OCX ³¹ 3, -OCH2X ³¹ , -OCHX ³¹ 2, -CN, -OH, -NH2, -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O)NH ₂ , -NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ³¹ is independently–F, -Cl, -Br, or–I. In embodiments, R ³¹ is independently unsubstituted methyl. In embodiments, R ³¹ is independently unsubstituted ethyl. [0286] In embodiments, R ^4A is independently

hydrogen, -CX ^4A 3, -CHX ^4A 2, -CH2X ^4A , -CN, -COOH, -CONH2, R ^29A -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ^29A -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^29A -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^29A - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^29A -substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or R ^29A -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^4A is independently

hydrogen, -CX ^4A ₃ , -CHX ^4A ₂ , -CH ₂ X ^4A , -CN, -COOH, -CONH ₂ , unsubstituted alkyl (e.g., C ₁ -C ₈ , C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3- C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^4A is independently–F, -Cl, -Br, or–I. In embodiments, R ^4A is independently hydrogen. In embodiments, R ^4A is independently unsubstituted methyl. In embodiments, R ^4A is independently unsubstituted ethyl. [0287] In embodiments, R ^4A and R ^4B substituents bonded to the same nitrogen atom may optionally be joined to form a R ^29A -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or R ^29A - substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^4A and R ^4B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^4A and R ^4B substituents bonded to the same nitrogen atom may optionally be joined to form a R ^29A - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^4A and R ^4B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted

heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). [0288] R ^29A is independently oxo,

halogen, -CX ^29A 3, -CHX ^29A 2, -CH2X ^29A , -OCX ^29A 3, -OCH2X ^29A , -OCHX ^29A 2, -CN, -OH, -NH2, - COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^30A -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ^30A -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^30A -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^30A -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^30A -substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or R ^30A -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^29A is independently oxo,

halogen, -CX ^29A ₃ , -CHX ^29A ₂ , -CH ₂ X ^29A , -OCX ^29A ₃ , -OCH ₂ X ^29A , -OCHX ^29A ₂ , -CN, -OH, -NH ₂ , - COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^29A is independently–F, -Cl, -Br, or–I. In embodiments, R ^29A is independently unsubstituted methyl. In embodiments, R ^29A is independently unsubstituted ethyl. [0289] R ^30A is independently oxo,

halogen, -CX ^30A 3, -CHX ^30A 2, -CH2X ^30A , -OCX ^30A 3, -OCH2X ^30A , -OCHX ^30A 2, -CN, -OH, -NH2, - COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^31A -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ^31A -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^31A -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^31A -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^31A -substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or R ^31A -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^30A is independently oxo,

halogen, -CX ^30A ₃ , -CHX ^30A ₂ , -CH ₂ X ^30A , -OCX ^30A ₃ , -OCH ₂ X ^30A , -OCHX ^30A ₂ , -CN, -OH, -NH ₂ , - COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^30A is independently–F, -Cl, -Br, or–I. In embodiments, R ^30A is independently unsubstituted methyl. In embodiments, R ^30A is independently unsubstituted ethyl. [0290] R ^31A is independently oxo,

halogen, -CX ^31A 3, -CHX ^31A 2, -CH2X ^31A , -OCX ^31A 3, -OCH2X ^31A , -OCHX ^31A 2, -CN, -OH, -NH2, - COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O)NH ₂ , -NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^31A is independently–F, -Cl, -Br, or–I. In embodiments, R ^31A is independently unsubstituted methyl. In embodiments, R ^31A is independently unsubstituted ethyl. [0291] In embodiments, R ^4B is independently

hydrogen, -CX ^4B ₃ , -CHX ^4B ₂ , -CH ₂ X ^4B , -CN, -COOH, -CONH ₂ , R ^29B -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ^29B -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^29B -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ^29B - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^29B -substituted or unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl), or R ^29B -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^4B is independently

hydrogen, -CX ^4B 3, -CHX ^4B 2, -CH2X ^4B , -CN, -COOH, -CONH2, unsubstituted alkyl (e.g., C1-C8, C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3- C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^4B is independently–F, -Cl, -Br, or–I. In embodiments, R ^4B is independently hydrogen. In embodiments, R ^4B is independently unsubstituted methyl. In embodiments, R ^4B is independently unsubstituted ethyl. [0292] In embodiments, R ^4A and R ^4B substituents bonded to the same nitrogen atom may optionally be joined to form a R ^29B -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or R ^29B - substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^4A and R ^4B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^4A and R ^4B substituents bonded to the same nitrogen atom may optionally be joined to form a R ^29B - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^4A and R ^4B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted

heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). [0293] R ^29B is independently oxo,

halogen, -CX ^29B 3, -CHX ^29B 2, -CH2X ^29B , -OCX ^29B 3, -OCH2X ^29B , -OCHX ^29B 2, -CN, -OH, -NH2, - COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^30B -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ^30B -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^30B -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ^30B -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^30B -substituted or unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl), or R ^30B -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^29B is independently oxo,

halogen, -CX ^29B 3, -CHX ^29B 2, -CH2X ^29B , -OCX ^29B 3, -OCH2X ^29B , -OCHX ^29B 2, -CN, -OH, -NH2, -C OOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^29B is independently–F, -Cl, -Br, or–I. In embodiments, R ^29B is independently unsubstituted methyl. In embodiments, R ^29B is independently unsubstituted ethyl. [0294] R ^30B is independently oxo,

halogen, -CX ^30B 3, -CHX ^30B 2, -CH2X ^30B , -OCX ^30B 3, -OCH2X ^30B , -OCHX ^30B 2, -CN, -OH, -NH2, -C OOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^31B -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ^31B -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^31B -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^31B -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^31B -substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or R ^31B -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^30B is independently oxo,

halogen, -CX ^30B ₃ , -CHX ^30B ₂ , -CH ₂ X ^30B , -OCX ^30B ₃ , -OCH ₂ X ^30B , -OCHX ^30B ₂ , -CN, -OH, -NH ₂ , -C OOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^30B is independently–F, -Cl, -Br, or–I. In embodiments, R ^30B is independently unsubstituted methyl. In embodiments, R ^30B is independently unsubstituted ethyl. [0295] R ^31B is independently oxo,

halogen, -CX ^31B 3, -CHX ^31B 2, -CH2X ^31B , -OCX ^31B 3, -OCH2X ^31B , -OCHX ^31B 2, -CN, -OH, -NH2, -C OOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O)NH ₂ , -NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^31B is independently–F, -Cl, -Br, or–I. In embodiments, R ^31B is independently unsubstituted methyl. In embodiments, R ^31B is independently unsubstituted ethyl. [0296] In embodiments, L ² is–NR ⁵ - or substituted or unsubstituted heterocycloalkylene including a ring nitrogen bonded directly to E. In embodiments, L ² is–NR ⁵ -. [0297] In embodiments, L ² is a bond. In embodiments, L ² is -S(O) ₂ -. In embodiments, L ² is– NR ⁵ -. In embodiments, L ² is -O-. In embodiments, L ² is -S-. In embodiments, L ² is -C(O)- . In embodiments, L ² is -C(O)NR ⁵ -. In embodiments, L ² is–NR ⁵ C(O)- . In embodiments, L ² is– NR ⁵ C(O)NH-. In embodiments, L ² is -NHC(O)NR ⁵ -. In embodiments, L ² is -C(O)O-. In embodiments, L ² is -OC(O)-. In embodiments, L ² is -NH-. In embodiments, L ² is -C(O)NH-. In embodiments, L ² is -NHC(O)- . In embodiments, L ² is -NHC(O)NH-. In embodiments, L ² is– CH ₂ -. In embodiments, L ² is–OCH ₂ -. In embodiments, L ² is–CH ₂ O-. In embodiments, L ² is– NHCH ₂ -. In embodiments, L ² is–CH ₂ NH-. [0298] In embodiments, L ² is a

bond, -S(O)2-, -NR ⁵ -, -O-, -S-, -C(O)-, -C(O)NR ⁵ -, -NR ⁴ C(O)-, -NR ⁵ C(O)NH-, -NHC(O)NR ⁵ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0299] In embodiments, L ² is independently substituted or unsubstituted alkylene (e.g., C ₁ -C ₈ , C1-C6, C1-C4, or C1-C2). In embodiments, L ² is independently substituted alkylene (e.g., C1-C8, C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, L ² is independently unsubstituted alkylene (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, L ² is independently unsubstituted methylene. In embodiments, L ² is independently unsubstituted ethylene. In embodiments, L ² is independently unsubstituted propylene. In embodiments, L ² is independently unsubstituted isopropylene. In embodiments, L ² is independently unsubstituted tert-butylene. In embodiments, L ² is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L ² is independently substituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L ² is independently unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L ² is independently substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, L ² is independently substituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, L ² is independently unsubstituted cycloalkylene (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, L ² is independently substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, L ² is independently substituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, L ² is independently unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, L ² is independently substituted or unsubstituted arylene (e.g., C ₆ -C ₁₀ or phenylene). In embodiments, L ² is independently substituted arylene (e.g., C6-C10 or phenylene). In embodiments, L ² is independently unsubstituted arylene (e.g., C6-C10 or phenylene). In embodiments, L ² is independently substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L ² is independently substituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L ² is independently unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0300] In embodiments, L ² is independently

bond, -S(O) ₂ -, -N(R ⁵ )-, -O-, -S-, -C(O)-, -C(O)N(R ⁵ )-, -N(R ⁵ )C(O)-, -N(R ⁵ )C(O)NH-, -NHC(O) N(R ⁵ )-, -C(O)O-, -OC(O)-, R ³⁸ -substituted or unsubstituted alkylene (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C1-C2), R ³⁸ -substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ³⁸ -substituted or unsubstituted cycloalkylene (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ³⁸ -substituted or

unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ³⁸ -substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or R ³⁸ -substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L ² is independently

bond, -S(O)2-, -N(R ⁵ )-, -O-, -S-, -C(O)-, -C(O)N(R ⁵ )-, -N(R ⁵ )C(O)-, -N(R ⁵ )C(O)NH-, -NHC(O) N(R ⁵ )-, -C(O)O-, -OC(O)-, unsubstituted alkylene (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5- C ₆ ), unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted arylene (e.g., C ₆ -C ₁₀ or phenylene), or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L ² is independently unsubstituted methylene. In embodiments, L ² is independently unsubstituted ethylene. In embodiments, L ² is independently methyl- substituted methylene. [0301] R ³⁸ is independently oxo,

halogen, -CX ³⁸ ₃ , -CHX ³⁸ ₂ , -CH ₂ X ³⁸ , -OCX ³⁸ ₃ , -OCH ₂ X ³⁸ , -OCHX ³⁸ ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ³⁹ -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ³⁹ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ³⁹ -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ³⁹ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ³⁹ -substituted or unsubstituted aryl (e.g., C6- C10 or phenyl), or R ³⁹ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ³⁸ is independently oxo,

halogen, -CX ³⁸ 3, -CHX ³⁸ 2, -CH2X ³⁸ , -OCX ³⁸ 3, -OCH2X ³⁸ , -OCHX ³⁸ 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ³⁸ is independently–F, -Cl, -Br, or–I. In embodiments, R ³⁸ is independently unsubstituted methyl. In embodiments, R ³⁸ is independently unsubstituted ethyl. [0302] R ³⁹ is independently oxo,

halogen, -CX ³⁹ 3, -CHX ³⁹ 2, -CH2X ³⁹ , -OCX ³⁹ 3, -OCH2X ³⁹ , -OCHX ³⁹ 2, -CN, -OH, -NH2, -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ⁴⁰ -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ⁴⁰ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ⁴⁰ -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ⁴⁰ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ⁴⁰ -substituted or unsubstituted aryl (e.g., C ₆ - C10 or phenyl), or R ⁴⁰ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ³⁹ is independently oxo,

halogen, -CX ³⁹ ₃ , -CHX ³⁹ ₂ , -CH ₂ X ³⁹ , -OCX ³⁹ ₃ , -OCH ₂ X ³⁹ , -OCHX ³⁹ ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ³⁹ is independently–F, -Cl, -Br, or–I. In embodiments, R ³⁹ is independently unsubstituted methyl. In embodiments, R ³⁹ is independently unsubstituted ethyl. [0303] R ⁴⁰ is independently oxo,

halogen, -CX ⁴⁰ 3, -CHX ⁴⁰ 2, -CH2X ⁴⁰ , -OCX ⁴⁰ 3, -OCH2X ⁴⁰ , -OCHX ⁴⁰ 2, -CN, -OH, -NH2, -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O)NH ₂ , -NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ⁴⁰ is independently–F, -Cl, -Br, or–I. In embodiments, R ⁴⁰ is independently unsubstituted methyl. In embodiments, R ⁴⁰ is independently unsubstituted ethyl. [0304] In embodiments, R ⁵ is hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R ⁵ is hydrogen or unsubstituted C ₁ -C ₃ alkyl. In embodiments, R ⁵ is hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted hexyl, or unsubstituted benzyl. In embodiments, R ⁵ is hydrogen. [0305] In embodiments, R ⁵ is independently unsubstituted methyl. In embodiments, R ⁵ is independently unsubstituted ethyl. In embodiments, R ⁵ is independently unsubstituted propyl. In embodiments, R ⁵ is independently unsubstituted isopropyl. In embodiments, R ⁵ is independently unsubstituted n-propyl. In embodiments, R ⁵ is independently unsubstituted butyl. In embodiments, R ⁵ is independently unsubstituted n-butyl. In embodiments, R ⁵ is

independently unsubstituted t-butyl. In embodiments, R ⁵ is independently unsubstituted pentyl. In embodiments, R ⁵ is independently unsubstituted n-pentyl. In embodiments, R ⁵ is

independently unsubstituted hexyl. In embodiments, R ⁵ is independently unsubstituted n-hexyl. In embodiments, R ⁵ is independently unsubstituted heptyl. In embodiments, R ⁵ is independently unsubstituted n-heptyl. In embodiments, R ⁵ is independently unsubstituted octyl. In

embodiments, R ⁵ is independently unsubstituted n-octyl. In embodiments, R ⁵ is independently unsubstituted benzyl. In embodiments, R ⁵ is independently unsubstituted C ₁ -C ₈ alkyl. In embodiments, R ⁵ is independently halo-substituted methyl. In embodiments, R ⁵ is independently halo-substituted ethyl. In embodiments, R ⁵ is independently halo-substituted isopropyl. In embodiments, R ⁵ is independently halo-substituted n-propyl. In embodiments, R ⁵ is

independently halo-substituted n-butyl. In embodiments, R ⁵ is independently halo-substituted t- butyl. In embodiments, R ¹ is independently halo-substituted n-pentyl. In embodiments, R ⁵ is independently halo-substituted benzyl. In embodiments, R ⁵ is independently halo-substituted C ₁ -C ₈ alkyl. In embodiments, R ⁵ is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R ⁵ is independently unsubstituted 2 to 7 membered heteroalkyl. In

embodiments, R ⁵ is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R ⁵ is independently unsubstituted 2 to 9 membered heteroalkyl. In embodiments, R ⁵ is independently unsubstituted 2 to 10 membered heteroalkyl. In embodiments, R ⁵ is

independently unsubstituted 3 to 10 membered heteroalkyl. In embodiments, R ⁵ is

independently unsubstituted 4 to 10 membered heteroalkyl. In embodiments, R ⁵ is

independently unsubstituted 5 to 10 membered heteroalkyl. In embodiments, R ⁵ is

independently unsubstituted 6 to 10 membered heteroalkyl. In embodiments, R ⁵ is

independently unsubstituted 7 to 10 membered heteroalkyl. In embodiments, R ⁵ is

independently unsubstituted 8 to 10 membered heteroalkyl. In embodiments, R ⁵ is independently unsubstituted 6 to 10 membered heteroalkyl. In embodiments, R ⁵ is independently unsubstituted 7 to 9 membered heteroalkyl. [0306] In embodiments, R ⁵ is independently hydrogen, -CX ⁵ ₃ , -CHX ⁵ ₂ , -CH ₂ X ⁵ , -OCX ⁵ ₃ , - OCH2X ⁵ , -OCHX ⁵ 2, -CN, -C(O)R ^5A , -C(O)OR ^5A , -C(O)NR ^5A R ^5B , -OR ^5A , substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0307] In embodiments, R ⁵ is independently hydrogen. In embodiments, R ⁵ is

independently -CX ⁵ ₃ . In embodiments, R ⁵ is independently -CHX ⁵ ₂ . In embodiments, R ⁵ is independently -CH ₂ X ⁵ . In embodiments, R ⁵ is independently -CN. In embodiments, R ⁵ is independently -C(O)R ^5A . In embodiments, R ⁵ is independently -C(O)-OR ^5A . In embodiments, R ⁵ is independently -C(O)NR ^5A R ^5B . In embodiments, R ⁵ is independently -COOH. In embodiments, R ⁵ is independently -CONH ₂ . In embodiments, R ⁵ is independently -CF ₃ . In embodiments, R ⁵ is independently -CHF2. In embodiments, R ⁵ is independently -CH2F. In embodiments, R ⁵ is independently–CH ₃ . In embodiments, R ⁵ is independently–CH ₂ CH ₃ . In embodiments, R ⁵ is independently–CH ₂ CH ₂ CH ₃ . In embodiments, R ⁵ is independently– CH(CH3)2. In embodiments, R ⁵ is independently–C(CH3)3. [0308] In embodiments, R ⁵ is independently substituted or unsubstituted alkyl (e.g., C1-C8, C1- C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ⁵ is independently substituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C1-C4, or C1-C2). In embodiments, R ⁵ is independently unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R ⁵ is independently unsubstituted methyl. In embodiments, R ⁵ is independently unsubstituted ethyl. In embodiments, R ⁵ is independently unsubstituted propyl. In embodiments, R ⁵ is independently unsubstituted isopropyl. In embodiments, R ⁵ is independently unsubstituted tert-butyl. In embodiments, R ⁵ is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ⁵ is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ⁵ is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ⁵ is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4- C ₆ , or C ₅ -C ₆ ). In embodiments, R ⁵ is independently substituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C4-C6, or C5-C6). In embodiments, R ⁵ is independently unsubstituted cycloalkyl (e.g., C3-C8, C3- C6, C4-C6, or C5-C6). In embodiments, R ⁵ is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ⁵ is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ⁵ is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ⁵ is independently substituted or unsubstituted aryl (e.g., C6-C10 or phenyl). In embodiments, R ⁵ is independently substituted aryl (e.g., C6-C10 or phenyl). In embodiments, R ⁵ is independently unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl). In embodiments, R ⁵ is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ⁵ is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ⁵ is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0309] In embodiments, R ^5A is independently hydrogen. In embodiments, R ^5A is

independently -CX ^5A ₃ . In embodiments, R ^5A is independently -CHX ^5A ₂ . In embodiments, R ^5A is independently -CH ₂ X ^5A . In embodiments, R ^5A is independently -CN. In embodiments, R ^5A is independently -COOH. In embodiments, R ^5A is independently -CONH2. In embodiments, X ^5A is independently–F, -Cl, -Br, or -I. [0310] In embodiments, R ^5A is independently substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C1-C6, C1-C4, or C1-C2). In embodiments, R ^5A is independently substituted alkyl (e.g., C1-C8, C1- C6, C1-C4, or C1-C2). In embodiments, R ^5A is independently unsubstituted alkyl (e.g., C1-C8, C1- C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ^5A is independently unsubstituted methyl. In

embodiments, R ^5A is independently unsubstituted ethyl. In embodiments, R ^5A is independently unsubstituted propyl. In embodiments, R ^5A is independently unsubstituted isopropyl. In embodiments, R ^5A is independently unsubstituted tert-butyl. In embodiments, R ^5A is

independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^5A is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^5A is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^5A is independently substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ^5A is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R ^5A is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R ^5A is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^5A is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^5A is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^5A is independently substituted or unsubstituted aryl (e.g., C6-C10 or phenyl). In embodiments, R ^5A is independently substituted aryl (e.g., C ₆ -C ₁₀ or phenyl). In embodiments, R ^5A is independently unsubstituted aryl (e.g., C ₆ - C10 or phenyl). In embodiments, R ^5A is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^5A is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^5A is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0311] In embodiments, R ^5B is independently hydrogen. In embodiments, R ^5B is

independently -CX ^5B ₃ . In embodiments, R ^5B is independently -CHX ^5B ₂ . In embodiments, R ^5B is independently -CH2X ^5B . In embodiments, R ^5B is independently -CN. In embodiments, R ^5B is independently -COOH. In embodiments, R ^5B is independently -CONH2. In embodiments, X ^5B is independently–F, -Cl, -Br, or -I. [0312] In embodiments, R ^5B is independently substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R ^5B is independently substituted alkyl (e.g., C1-C8, C1- C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ^5B is independently unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ - C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ). In embodiments, R ^5B is independently unsubstituted methyl. In

embodiments, R ^5B is independently unsubstituted ethyl. In embodiments, R ^5B is independently unsubstituted propyl. In embodiments, R ^5B is independently unsubstituted isopropyl. In embodiments, R ^5B is independently unsubstituted tert-butyl. In embodiments, R ^5B is

independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^5B is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^5B is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R ^5B is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R ^5B is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R ^5B is independently unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ). In embodiments, R ^5B is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^5B is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^5B is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^5B is independently substituted or unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl). In embodiments, R ^5B is independently substituted aryl (e.g., C6-C10 or phenyl). In embodiments, R ^5B is independently unsubstituted aryl (e.g., C6- C10 or phenyl). In embodiments, R ^5B is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^5B is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^5B is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0313] In embodiments, R ^5A and R ^5B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^5A and R ^5B substituents bonded to the same nitrogen atom may be joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^5A and R ^5B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). [0314] In embodiments, R ^5A and R ^5B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^5A and R ^5B substituents bonded to the same nitrogen atom may be joined to form a substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^5A and R ^5B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0315] In embodiments, R ⁵ is independently

hydrogen, -CX ⁵ 3, -CHX ⁵ 2, -CH2X ⁵ , -CN, -COOH, -CONH2, R ³² -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ³² -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ³² - substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ³² -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ³² -substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or R ³² -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ⁵ is independently

hydrogen, -CX ⁵ 3, -CHX ⁵ 2, -CH2X ⁵ , -CN, -COOH, -CONH2, unsubstituted alkyl (e.g., C1-C8, C1- C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ⁵ is independently–F, -Cl, -Br, or–I. In embodiments, R ⁵ is independently hydrogen. In

embodiments, R ⁵ is independently unsubstituted methyl. In embodiments, R ⁵ is independently unsubstituted ethyl. [0316] R ³² is independently oxo,

halogen, -CX ³² 3, -CHX ³² 2, -CH2X ³² , -OCX ³² 3, -OCH2X ³² , -OCHX ³² 2, -CN, -OH, -NH2, -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ³³ -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ³³ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ³³ -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ³³ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ³³ -substituted or unsubstituted aryl (e.g., C ₆ - C10 or phenyl), or R ³³ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ³² is independently oxo,

halogen, -CX ³² ₃ , -CHX ³² ₂ , -CH ₂ X ³² , -OCX ³² ₃ , -OCH ₂ X ³² , -OCHX ³² ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ³² is independently–F, -Cl, -Br, or–I. In embodiments, R ³² is independently unsubstituted methyl. In embodiments, R ³² is independently unsubstituted ethyl. [0317] R ³³ is independently oxo,

halogen, -CX ³³ 3, -CHX ³³ 2, -CH2X ³³ , -OCX ³³ 3, -OCH2X ³³ , -OCHX ³³ 2, -CN, -OH, -NH2, -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ³⁴ -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ³⁴ -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ³⁴ -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ³⁴ -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ³⁴ -substituted or unsubstituted aryl (e.g., C ₆ - C10 or phenyl), or R ³⁴ -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ³³ is independently oxo,

halogen, -CX ³³ ₃ , -CHX ³³ ₂ , -CH ₂ X ³³ , -OCX ³³ ₃ , -OCH ₂ X ³³ , -OCHX ³³ ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ³³ is independently–F, -Cl, -Br, or–I. In embodiments, R ³³ is independently unsubstituted methyl. In embodiments, R ³³ is independently unsubstituted ethyl. [0318] R ³⁴ is independently oxo,

halogen, -CX ³⁴ 3, -CHX ³⁴ 2, -CH2X ³⁴ , -OCX ³⁴ 3, -OCH2X ³⁴ , -OCHX ³⁴ 2, -CN, -OH, -NH2, -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ³⁴ is independently–F, -Cl, -Br, or–I. In embodiments, R ³⁴ is independently unsubstituted methyl. In embodiments, R ³⁴ is independently unsubstituted ethyl. [0319] In embodiments, R ^5A is independently

hydrogen, -CX ^5A 3, -CHX ^5A 2, -CH2X ^5A , -CN, -COOH, -CONH2, R ^32A -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ^32A -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^32A -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^32A - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^32A -substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or R ^32A -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^5A is independently

hydrogen, -CX ^5A ₃ , -CHX ^5A ₂ , -CH ₂ X ^5A , -CN, -COOH, -CONH ₂ , unsubstituted alkyl (e.g., C ₁ -C ₈ , C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3- C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^5A is independently–F, -Cl, -Br, or–I. In embodiments, R ^5A is independently hydrogen. In embodiments, R ^5A is independently unsubstituted methyl. In embodiments, R ^5A is independently unsubstituted ethyl. [0320] In embodiments, R ^5A and R ^5B substituents bonded to the same nitrogen atom may optionally be joined to form a R ^32A -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or R ^32A - substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^5A and R ^5B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^5A and R ^5B substituents bonded to the same nitrogen atom may optionally be joined to form a R ^32A - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^5A and R ^5B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted

heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). [0321] R ^32A is independently oxo,

halogen, -CX ^32A 3, -CHX ^32A 2, -CH2X ^32A , -OCX ^32A 3, -OCH2X ^32A , -OCHX ^32A 2, -CN, -OH, -NH2, - COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^33A -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ^33A -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^33A -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^33A -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^33A -substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or R ^33A -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^32A is independently oxo,

halogen, -CX ^32A ₃ , -CHX ^32A ₂ , -CH ₂ X ^32A , -OCX ^32A ₃ , -OCH ₂ X ^32A , -OCHX ^32A ₂ , -CN, -OH, -NH ₂ , - COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^32A is independently–F, -Cl, -Br, or–I. In embodiments, R ^32A is independently unsubstituted methyl. In embodiments, R ^32A is independently unsubstituted ethyl. [0322] R ^33A is independently oxo,

halogen, -CX ^33A 3, -CHX ^33A 2, -CH2X ^33A , -OCX ^33A 3, -OCH2X ^33A , -OCHX ^33A 2, -CN, -OH, -NH2, - COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^34A -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ^34A -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^34A -substituted or unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), R ^34A -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^34A -substituted or unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl), or R ^34A -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^33A is independently oxo,

halogen, -CX ^33A 3, -CHX ^33A 2, -CH2X ^33A , -OCX ^33A 3, -OCH2X ^33A , -OCHX ^33A 2, -CN, -OH, -NH2, - COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^33A is independently–F, -Cl, -Br, or–I. In embodiments, R ^33A is independently unsubstituted methyl. In embodiments, R ^33A is independently unsubstituted ethyl. [0323] R ^34A is independently oxo,

halogen, -CX ^34A ₃ , -CHX ^34A ₂ , -CH ₂ X ^34A , -OCX ^34A ₃ , -OCH ₂ X ^34A , -OCHX ^34A ₂ , -CN, -OH, -NH ₂ , - COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2, −NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C ₃ -C ₆ , C ₄ -C ₆ , or C ₅ -C ₆ ), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^34A is independently–F, -Cl, -Br, or–I. In embodiments, R ^34A is independently unsubstituted methyl. In embodiments, R ^34A is independently unsubstituted ethyl. [0324] In embodiments, R ^5B is independently

hydrogen, -CX ^5B 3, -CHX ^5B 2, -CH2X ^5B , -CN, -COOH, -CONH2, R ^32B -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ^32B -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^32B -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^32B - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^32B -substituted or unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl), or R ^32B -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^5B is independently

hydrogen, -CX ^5B 3, -CHX ^5B 2, -CH2X ^5B , -CN, -COOH, -CONH2, unsubstituted alkyl (e.g., C1-C8, C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C ₃ - C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^5B is independently–F, -Cl, -Br, or–I. In embodiments, R ^5B is independently hydrogen. In embodiments, R ^5B is independently unsubstituted methyl. In embodiments, R ^5B is independently unsubstituted ethyl. [0325] In embodiments, R ^5A and R ^5B substituents bonded to the same nitrogen atom may optionally be joined to form a R ^32B -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or R ^32B - substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^5A and R ^5B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^5A and R ^5B substituents bonded to the same nitrogen atom may optionally be joined to form a R ^32B - substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ^5A and R ^5B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted

heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). [0326] R ^32B is independently oxo,

halogen, -CX ^32B ₃ , -CHX ^32B ₂ , -CH ₂ X ^32B , -OCX ^32B ₃ , -OCH ₂ X ^32B , -OCHX ^32B ₂ , -CN, -OH, -NH ₂ , - COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^33B -substituted or unsubstituted alkyl (e.g., C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), R ^33B -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^33B -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^33B -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^33B -substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or R ^33B -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^32B is independently oxo,

halogen, -CX ^32B ₃ , -CHX ^32B ₂ , -CH ₂ X ^32B , -OCX ^32B ₃ , -OCH ₂ X ^32B , -OCHX ^32B ₂ , -CN, -OH, -NH ₂ , -C OOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^32B is independently–F, -Cl, -Br, or–I. In embodiments, R ^32B is independently unsubstituted methyl. In embodiments, R ^32B is independently unsubstituted ethyl. [0327] R ^33B is independently oxo,

halogen, -CX ^33B 3, -CHX ^33B 2, -CH2X ^33B , -OCX ^33B 3, -OCH2X ^33B , -OCHX ^33B 2, -CN, -OH, -NH2, -C OOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, R ^34B -substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R ^34B -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R ^34B -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R ^34B -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R ^34B -substituted or unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl), or R ^34B -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ^33B is independently oxo,

halogen, -CX ^33B ₃ , -CHX ^33B ₂ , -CH ₂ X ^33B , -OCX ^33B ₃ , -OCH ₂ X ^33B , -OCHX ^33B ₂ , -CN, -OH, -NH ₂ , -C OOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O) NH ₂ , -NHSO ₂ H, -NHC= (O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₂ ), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C ₆ -C ₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^33B is independently–F, -Cl, -Br, or–I. In embodiments, R ^33B is independently unsubstituted methyl. In embodiments, R ^33B is independently unsubstituted ethyl. [0328] R ^34B is independently oxo,

halogen, -CX ^34B 3, -CHX ^34B 2, -CH2X ^34B , -OCX ^34B 3, -OCH2X ^34B , -OCHX ^34B 2, -CN, -OH, -NH2, -C OOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ , −NHC=(O)NH ₂ , -NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C ₁ - C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C ₃ -C ₈ , C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X ^34B is independently–F, -Cl, -Br, or–I. In embodiments, R ^34B is independently unsubstituted methyl. In embodiments, R ^34B is independently unsubstituted ethyl. [0329] In embodiments, X is–F. In embodiments, X is–Cl. In embodiments, X is–Br. In embodiments, X is–I. In embodiments, X ¹ is–F. In embodiments, X ¹ is–Cl. In embodiments, X ¹ is–Br. In embodiments, X ¹ is–I. In embodiments, X ² is–F. In embodiments, X ² is–Cl. In embodiments, X ² is–Br. In embodiments, X ² is–I. In embodiments, X ⁴ is–F. In embodiments, X ⁴ is–Cl. In embodiments, X ⁴ is–Br. In embodiments, X ⁴ is–I. In embodiments, X ⁵ is–F. In embodiments, X ⁵ is–Cl. In embodiments, X ⁵ is–Br. In embodiments, X ⁵ is–I. [0330] In embodiments, n1 is 0. In embodiments, n1 is 1. In embodiments, n1 is 2. In embodiments, n1 is 3. In embodiments, n1 is 4. In embodiments, n2 is 0. In embodiments, n2 is 1. In embodiments, n2 is 2. In embodiments, n2 is 3. In embodiments, n2 is 4. In

embodiments, n4 is 0. In embodiments, n4 is 1. In embodiments, n4 is 2. In embodiments, n4 is 3. In embodiments, n4 is 4. In embodiments, n5 is 0. In embodiments, n5 is 1. In

embodiments, n5 is 2. In embodiments, n5 is 3. In embodiments, n5 is 4. [0331] In embodiments, m1 is 1. In embodiments, m1 is 2. In embodiments, m2 is 1. In embodiments, m2 is 2. In embodiments, m4 is 1. In embodiments, m4 is 2. In embodiments, m5 is 1. In embodiments, m5 is 2. [0332] In embodiments, v1 is 1. In embodiments, v1 is 2. In embodiments, v2 is 1. In embodiments, v2 is 2. In embodiments, v4 is 1. In embodiments, v4 is 2. In embodiments, v5 is 1. In embodiments, v5 is 2. [0333] In embodiments, E is a covalent cysteine modifier moiety.

[0334] In embodiments, E

. [0335] R ¹⁵ is independently hydrogen, halogen, CX ¹⁵ ₃ , -CHX ¹⁵ ₂ , - CH2X ¹⁵ , -CN, -SOn15R ^15D , -SOv15NR ^15A R ^15B ,−NHNR ^15A R ^15B ,−ONR ^15A R ^15B ,

−NHC=(O)NHNR ^15A R ^15B ,−NHC(O)NR ^15A R ^15B , -N(O)m15, -NR ^15A R ^15B , -C(O)R ^15C ,

-C(O)-OR ^15C , -C(O)NR ^15A R ^15B , -OR ^15D , -NR ^15A SO2R ^15D , -NR ^15A C(O)R ^15C , - NR ^15A C(O)OR ^15C , -NR ^15A OR ^15C , -OCX ¹⁵ 3, -OCHX ¹⁵ 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. R ¹⁶ is independently hydrogen, halogen, CX ¹⁶ 3, -CHX ¹⁶ 2, - CH ₂ X ¹⁶ , -CN, -SO _n16 R ^16D , -SO _v16 NR ^16A R ^16B ,−NHNR ^16A R ^16B ,−ONR ^16A R ^16B ,

−NHC=(O)NHNR ^16A R ^16B ,−NHC(O)NR ^16A R ^16B , -N(O) _m16 , -NR ^16A R ^16B , -C(O)R ^16C ,

-C(O)-OR ^16C , -C(O)NR ^16A R ^16B , -OR ^16D , -NR ^16A SO ₂ R ^16D , -NR ^16A C(O)R ^16C , - NR ^16A C(O)OR ^16C , -NR ^16A OR ^16C , -OCX ¹⁶ ₃ , -OCHX ¹⁶ ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. R ¹⁷ is independently hydrogen, halogen, CX ¹⁷ ₃ , -CHX ¹⁷ ₂ , - CH2X ¹⁷ , -CN, -SOn17R ^17D , -SOv17NR ^17A R ^17B ,−NHNR ^17A R ^17B ,−ONR ^17A R ^17B ,

−NHC=(O)NHNR ^17A R ^17B ,−NHC(O)NR ^17A R ^17B , -N(O) _m17 , -NR ^17A R ^17B , -C(O)R ^17C ,

-C(O)-OR ^17C , -C(O)NR ^17A R ^17B , -OR ^17D , -NR ^17A SO ₂ R ^17D , -NR ^17A C(O)R ^17C , - NR ^17A C(O)OR ^17C , -NR ^17A OR ^17C , -OCX ¹⁷ 3, -OCHX ¹⁷ 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. R ¹⁸ is independently hydrogen, -CX ¹⁸ 3, -CHX ¹⁸ 2, -CH2X ¹⁸ ,

-C(O)R ^18C , -C(O)OR ^18C , -C(O)NR ^18A R ^18B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. [0336] Each R ^15A , R ^15B , R ^15C , R ^15D , R ^16A , R ^16B , R ^16C , R ^16D , R ^17A , R ^17B , R ^17C , R ^17D , R ^18A , R ^18B , R ^18C , R ^18D , is independently hydrogen, -CX ₃ , -CN, -COOH, -CONH ₂ , -CHX ₂ , -CH ₂ X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^15A and R ^15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^16A and R ^16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^17A and R ^17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^18A and R ^18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. Each X, X ¹⁵ , X ¹⁶ , X ¹⁷ and X ¹⁸ is independently–F, -Cl, -Br, or–I. The symbols n15, n16, n17, v15, v16, and v17, are independently and integer from 0 to 4. The symbols m15, m16, and m17 are independently and integer between 1 and 2.

[0337] In embodiments, E is: and X ¹⁷ is -Cl. In embodiments, E is: . In embodiments, X ¹⁷ is -Cl.

[0338] In embodiments, E is: d R ¹⁵ , R ¹⁶ , and R ¹⁷ are independently

hydrogen. In embodiments, E i . In embodiments, R ¹⁵ , R ¹⁶ , and R ¹⁷ are independently hydrogen. [0339] In embodiments, E is: ; R ¹⁵ is independently hydrogen; R ¹⁶ is independently hydrogen or−CH2NR ^16A R ^16B ; R ¹⁷ is independently hydrogen; and R ^16A and R ^16B

are independently hydrogen or unsubstituted alkyl. In embodiments, E is: . In embodiments, R ¹⁵ is independently hydrogen. In embodiments, R ¹⁶ is independently hydrogen or−CH2NR ^16A R ^16B . In embodiments, R ¹⁷ is independently hydrogen. In embodiments, R ^16A and R ^16B are independently hydrogen or unsubstituted alkyl. In embodiments, R ^16A and R ^16B are independently unsubstituted methyl.

[0341] X may independently be–F. X may independently be–Cl. X may independently be– Br. X may independently be–I. X ¹⁵ may independently be–F. X ¹⁵ may independently be–Cl. X ¹⁵ may independently be–Br. X ¹⁵ may independently be–I. X ¹⁶ may independently be–F. X ¹⁶ may independently be–Cl. X ¹⁶ may independently be–Br. X ¹⁶ may independently be–I. X ¹⁷ may independently be–F. X ¹⁷ may independently be–Cl. X ¹⁷ may independently be–Br. X ¹⁷ may independently be–I. X ¹⁸ may independently be–F. X ¹⁸ may independently be–Cl. X ¹⁸ may independently be–Br. X ¹⁸ may independently be–I. n15 may independently be 0. n15 may independently be 1. n15 may independently be 2. n15 may independently be 3. n15 may independently be 4. n16 may independently be 0. n16 may independently be 1. n16 may independently be 2. n16 may independently be 3. n16 may independently be 4. n17 may independently be 0. n17 may independently be 1. n17 may independently be 2. n17 may independently be 3. n17 may independently be 4. v15 may independently be 0. v15 may independently be 1. v15 may independently be 2. v15 may independently be 3. v15 may independently be 4. v16 may independently be 0. v16 may independently be 1. v16 may independently be 2. v16 may independently be 3. v16 may independently be 4. v17 may independently be 0. v17 may independently be 1. v17 may independently be 2. v17 may independently be 3. v17 may independently be 4. m15 may independently be 1. m15 may independently be 2. m16 may independently be 1. m16 may independently be 2. m17 may independently be 1. m17 may independently be 2. [0342] In embodiments, R ¹⁵ is hydrogen. In embodiments, R ¹⁵ is halogen. In embodiments, R ¹⁵ is CX ¹⁵ ₃ . In embodiments, R ¹⁵ is -CHX ¹⁵ ₂ . In embodiments, R ¹⁵ is -CH ₂ X ¹⁵ . In

embodiments, R ¹⁵ is–CN. In embodiments, R ¹⁵ is -SO _n15 R ^15D . In embodiments, R ¹⁵ is -SOv15NR ^15A R ^15B . In embodiments, R ¹⁵ is−NHNR ^15A R ^15B . In embodiments, R ¹⁵ is −ONR ^15A R ^15B . In embodiments, R ¹⁵ is−NHC=(O)NHNR ^15A R ^15B . In embodiments, R ¹⁵ is −NHC(O)NR ^15A R ^15B . In embodiments, R ¹⁵ is -N(O)m15. In embodiments, R ¹⁵ is -NR ^15A R ^15B . In embodiments, R ¹⁵ is -C(O)R ^15C . In embodiments, R ¹⁵ is -C(O)-OR ^15C . In embodiments, R ¹⁵ is -C(O)NR ^15A R ^15B . In embodiments, R ¹⁵ is -OR ^15D . In embodiments, R ¹⁵ is -NR ^15A SO2R ^15D . In embodiments, R ¹⁵ is -NR ^15A C(O)R ^15C . In embodiments, R ¹⁵ is -NR ^15A C(O)OR ^15C . In embodiments, R ¹⁵ is -NR ^15A OR ^15C . In embodiments, R ¹⁵ is -OCX ¹⁵ ₃ . In embodiments, R ¹⁵ is -OCHX ¹⁵ 2. In embodiments, R ¹⁵ is substituted or unsubstituted alkyl. In embodiments, R ¹⁵ is substituted or unsubstituted heteroalkyl. In embodiments, R ¹⁵ is substituted or unsubstituted cycloalkyl. In embodiments, R ¹⁵ is substituted or unsubstituted heterocycloalkyl. In

embodiments, R ¹⁵ is substituted or unsubstituted aryl. In embodiments, R ¹⁵ is substituted or unsubstituted heteroaryl. In embodiments, R ¹⁵ is substituted alkyl. In embodiments, R ¹⁵ is substituted heteroalkyl. In embodiments, R ¹⁵ is substituted cycloalkyl. In embodiments, R ¹⁵ is substituted heterocycloalkyl. In embodiments, R ¹⁵ is substituted aryl. In embodiments, R ¹⁵ is substituted heteroaryl. In embodiments, R ¹⁵ is unsubstituted alkyl. In embodiments, R ¹⁵ is unsubstituted heteroalkyl. In embodiments, R ¹⁵ is unsubstituted cycloalkyl. In embodiments, R ¹⁵ is unsubstituted heterocycloalkyl. In embodiments, R ¹⁵ is unsubstituted aryl. In embodiments, R ¹⁵ is unsubstituted heteroaryl. In embodiments, R ¹⁵ is unsubstituted methyl. In embodiments, R ¹⁵ is unsubstituted ethyl. In embodiments, R ¹⁵ is unsubstituted propyl. In embodiments, R ¹⁵ is unsubstituted isopropyl. In embodiments, R ¹⁵ is unsubstituted butyl. In embodiments, R ¹⁵ is unsubstituted tert-butyl. [0343] In embodiments, R ^15A is hydrogen. In embodiments, R ^15A is -CX ₃ . In embodiments, R ^15A is -CN. In embodiments, R ^15A is -COOH. In embodiments, R ^15A is -CONH ₂ . In embodiments, R ^15A is -CHX2. In embodiments, R ^15A is -CH2X. In embodiments, R ^15A is unsubstituted methyl. In embodiments, R ^15A is unsubstituted ethyl. In embodiments, R ^15A is unsubstituted propyl. In embodiments, R ^15A is unsubstituted isopropyl. In embodiments, R ^15A is unsubstituted butyl. In embodiments, R ^15A is unsubstituted tert-butyl. [0344] In embodiments, R ^15B is hydrogen. In embodiments, R ^15B is -CX3. In embodiments, R ^15B is -CN. In embodiments, R ^15B is -COOH. In embodiments, R ^15B is -CONH ₂ . In embodiments, R ^15B is -CHX ₂ . In embodiments, R ^15B is -CH ₂ X. In embodiments, R ^15B is unsubstituted methyl. In embodiments, R ^15B is unsubstituted ethyl. In embodiments, R ^15B is unsubstituted propyl. In embodiments, R ^15B is unsubstituted isopropyl. In embodiments, R ^15B is unsubstituted butyl. In embodiments, R ^15B is unsubstituted tert-butyl. [0345] In embodiments, R ^15C is hydrogen. In embodiments, R ^15C is -CX3. In embodiments, R ^15C is -CN. In embodiments, R ^15C is -COOH. In embodiments, R ^15C is -CONH2. In embodiments, R ^15C is -CHX ₂ . In embodiments, R ^15C is -CH ₂ X. In embodiments, R ^15C is unsubstituted methyl. In embodiments, R ^15C is unsubstituted ethyl. In embodiments, R ^15C is unsubstituted propyl. In embodiments, R ^15C is unsubstituted isopropyl. In embodiments, R ^15C is unsubstituted butyl. In embodiments, R ^15C is unsubstituted tert-butyl. [0346] In embodiments, R ^15D is hydrogen. In embodiments, R ^15D is -CX3. In embodiments, R ^15D is -CN. In embodiments, R ^15D is -COOH. In embodiments, R ^15D is -CONH2. In embodiments, R ^15D is -CHX ₂ . In embodiments, R ^15D is -CH ₂ X. In embodiments, R ^15D is unsubstituted methyl. In embodiments, R ^15D is unsubstituted ethyl. In embodiments, R ^15D is unsubstituted propyl. In embodiments, R ^15D is unsubstituted isopropyl. In embodiments, R ^15D is unsubstituted butyl. In embodiments, R ^15D is unsubstituted tert-butyl. [0347] In embodiments, R ¹⁵ is independently hydrogen, oxo,

halogen, -CX ¹⁵ 3, -CHX ¹⁵ 2, -OCH2X ¹⁵ , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, - SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ¹⁵ 3, -OCHX ¹⁵ 2, R ⁷² -substituted or unsubstituted alkyl, R ⁷² -substituted or unsubstituted heteroalkyl, R ⁷² -substituted or unsubstituted cycloalkyl, R ⁷² - substituted or unsubstituted heterocycloalkyl, R ⁷² -substituted or unsubstituted aryl, or R ⁷² - substituted or unsubstituted heteroaryl. X ¹⁵ is halogen. In embodiments, X ¹⁵ is F. [0348] R ⁷² is independently oxo,

halogen, -CX ⁷² ₃ , -CHX ⁷² ₂ , -OCH ₂ X ⁷² , -OCHX ⁷² ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -S H, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , - NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ⁷² ₃ , -OCHX ⁷² ₂ , R ⁷³ -substituted or unsubstituted alkyl, R ⁷³ -substituted or unsubstituted heteroalkyl, R ⁷³ -substituted or unsubstituted cycloalkyl, R ⁷³ -substituted or unsubstituted heterocycloalkyl, R ⁷³ -substituted or unsubstituted aryl, or R ⁷³ -substituted or unsubstituted heteroaryl. X ⁷² is halogen. In embodiments, X ⁷² is F. [0349] R ⁷³ is independently oxo,

halogen, -CX ⁷³ 3, -CHX ⁷³ 2, -OCH2X ⁷³ , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, - SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ⁷³ ₃ , -OCHX ⁷³ ₂ , R ⁷⁴ -substituted or unsubstituted alkyl, R ⁷⁴ -substituted or unsubstituted heteroalkyl, R ⁷⁴ -substituted or unsubstituted cycloalkyl, R ⁷⁴ - substituted or unsubstituted heterocycloalkyl, R ⁷⁴ -substituted or unsubstituted aryl, or R ⁷⁴ - substituted or unsubstituted heteroaryl. X ⁷³ is halogen. In embodiments, X ⁷³ is F. [0350] In embodiments, R ^15A is independently hydrogen, oxo,

halogen, -CX ^15A 3, -CHX ^15A 2, -OCH2X ^15A , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, -NHSO2H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^15A 3, -OCHX ^15A 2, R ^72A -substituted or unsubstituted alkyl, R ^72A -substituted or unsubstituted heteroalkyl, R ^72A -substituted or unsubstituted cycloalkyl, R ^72A -substituted or unsubstituted heterocycloalkyl, R ^72A -substituted or unsubstituted aryl, or R ^72A -substituted or unsubstituted heteroaryl. X ^15A is halogen. In embodiments, X ^15A is F. [0351] R ^72A is independently oxo,

halogen, -CX ^72A ₃ , -CHX ^72A ₂ , -OCH ₂ X ^72A , -OCHX ^72A ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, - NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^72A 3, -OCHX ^72A 2, R ^73A -substituted or unsubstituted alkyl, R ^73A -substituted or unsubstituted heteroalkyl, R ^73A -substituted or

unsubstituted cycloalkyl, R ^73A -substituted or unsubstituted heterocycloalkyl, R ^73A -substituted or unsubstituted aryl, or R ^73A -substituted or unsubstituted heteroaryl. X ^72A is halogen. In embodiments, X ^72A is F. [0352] R ^73A is independently oxo,

halogen, -CX ^73A 3, -CHX ^73A 2, -OCH2X ^73A , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, -NHSO2H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^73A 3, -OCHX ^73A 2, R ^74A -substituted or unsubstituted alkyl, R ^74A -substituted or unsubstituted heteroalkyl, R ^74A -substituted or unsubstituted cycloalkyl, R ^74A -substituted or unsubstituted heterocycloalkyl, R ^74A -substituted or unsubstituted aryl, or R ^74A -substituted or unsubstituted heteroaryl. X ^73A is halogen. In embodiments, X ^73A is F. [0353] In embodiments, R ^15B is independently hydrogen, oxo,

halogen, -CX ^15B ₃ , -CHX ^15B ₂ , -OCH ₂ X ^15B , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, - SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, -NHSO2H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^15B ₃ , -OCHX ^15B ₂ , R ^72B -substituted or unsubstituted alkyl, R ^72B -substituted or unsubstituted heteroalkyl, R ^72B -substituted or unsubstituted cycloalkyl, R ^72B -substituted or unsubstituted heterocycloalkyl, R ^72B -substituted or unsubstituted aryl, or R ^72B -substituted or unsubstituted heteroaryl. X ^15B is halogen. In embodiments, X ^15B is F. [0354] R ^72B is independently oxo,

halogen, -CX ^72B 3, -CHX ^72B 2, -OCH2X ^72B , -OCHX ^72B 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2 , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , - NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^72B ₃ , -OCHX ^72B ₂ , R ^73B -substituted or unsubstituted alkyl, R ^73B -substituted or unsubstituted heteroalkyl, R ^73B -substituted or

unsubstituted cycloalkyl, R ^73B -substituted or unsubstituted heterocycloalkyl, R ^73B -substituted or unsubstituted aryl, or R ^73B -substituted or unsubstituted heteroaryl. X ^72B is halogen. In embodiments, X ^72B is F. [0355] R ^73B is independently oxo,

halogen, -CX ^73B ₃ , -CHX ^73B ₂ , -OCH ₂ X ^73B , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, - SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^73B ₃ , -OCHX ^73B ₂ , R ^74B -substituted or unsubstituted alkyl, R ^74B -substituted or unsubstituted heteroalkyl, R ^74B -substituted or unsubstituted cycloalkyl, R ^74B -substituted or unsubstituted heterocycloalkyl, R ^74B -substituted or unsubstituted aryl, or R ^74B -substituted or unsubstituted heteroaryl. X ^73B is halogen. In embodiments, X ^73B is F. [0356] In embodiments, R ^15C is independently hydrogen, oxo,

halogen, -CX ^15C 3, -CHX ^15C 2, -OCH2X ^15C , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^15C ₃ , -OCHX ^15C ₂ , R ^72C -substituted or unsubstituted alkyl, R ^72C -substituted or unsubstituted heteroalkyl, R ^72C -substituted or unsubstituted cycloalkyl, R ^72C -substituted or unsubstituted heterocycloalkyl, R ^72C -substituted or unsubstituted aryl, or R ^72C -substituted or unsubstituted heteroaryl. X ^15C is halogen. In embodiments, X ^15C is F. [0357] R ^72C is independently oxo,

halogen, -CX ^72C 3, -CHX ^72C 2, -OCH2X ^72C , -OCHX ^72C 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2 , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , - NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^72C 3, -OCHX ^72C 2, R ^73C -substituted or unsubstituted alkyl, R ^73C -substituted or unsubstituted heteroalkyl, R ^73C -substituted or

unsubstituted cycloalkyl, R ^73C -substituted or unsubstituted heterocycloalkyl, R ^73C -substituted or unsubstituted aryl, or R ^73C -substituted or unsubstituted heteroaryl. X ^72C is halogen. In embodiments, X ^72C is F. [0358] R ^73C is independently oxo,

halogen, -CX ^73C 3, -CHX ^73C 2, -OCH2X ^73C , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^73C 3, -OCHX ^73C 2, R ^74C -substituted or unsubstituted alkyl, R ^74C -substituted or unsubstituted heteroalkyl, R ^74C -substituted or unsubstituted cycloalkyl, R ^74C -substituted or unsubstituted heterocycloalkyl, R ^74C -substituted or unsubstituted aryl, or R ^74C -substituted or unsubstituted heteroaryl. X ^73C is halogen. In embodiments, X ^73C is F. [0359] In embodiments, R ^15D is independently hydrogen, oxo,

halogen, -CX ^15D ₃ , -CHX ^15D ₂ , -OCH ₂ X ^15D , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, - SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, -NHSO2H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^15D 3, -OCHX ^15D 2, R ^72D -substituted or unsubstituted alkyl, R ^72D -substituted or unsubstituted heteroalkyl, R ^72D -substituted or unsubstituted cycloalkyl, R ^72D -substituted or unsubstituted heterocycloalkyl, R ^72D -substituted or unsubstituted aryl, or R ^72D -substituted or unsubstituted heteroaryl. X ^15D is halogen. In embodiments, X ^15D is F. [0360] R ^72D is independently oxo,

halogen, -CX ^72D ₃ , -CHX ^72D ₂ , -OCH ₂ X ^72D , -OCHX ^72D ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, - NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^72D 3, -OCHX ^72D 2, R ^73D -substituted or unsubstituted alkyl, R ^73D -substituted or unsubstituted heteroalkyl, R ^73D -substituted or unsubstituted cycloalkyl, R ^73D -substituted or unsubstituted heterocycloalkyl, R ^73D -substituted or unsubstituted aryl, or R ^73D -substituted or unsubstituted heteroaryl. X ^72D is halogen. In embodiments, X ^72D is F. [0361] R ^73D is independently oxo,

halogen, -CX ^73D ₃ , -CHX ^73D ₂ , -OCH ₂ X ^73D , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, - SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, -NHSO2H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^73D 3, -OCHX ^73D 2, R ^74D -substituted or unsubstituted alkyl, R ^74D -substituted or unsubstituted heteroalkyl, R ^74D -substituted or unsubstituted cycloalkyl, R ^74D -substituted or unsubstituted heterocycloalkyl, R ^74D -substituted or unsubstituted aryl, or R ^74D -substituted or unsubstituted heteroaryl. X ^73D is halogen. In embodiments, X ^73D is F. [0362] In embodiments, R ¹⁶ is hydrogen. In embodiments, R ¹⁶ is halogen. In embodiments, R ¹⁶ is CX ¹⁶ ₃ . In embodiments, R ¹⁶ is -CHX ¹⁶ ₂ . In embodiments, R ¹⁶ is -CH ₂ X ¹⁶ . In

embodiments, R ¹⁶ is–CN. In embodiments, R ¹⁶ is -SOn16R ^16D . In embodiments, R ¹⁶ is -SOv16NR ^16A R ^16B . In embodiments, R ¹⁶ is−NHNR ^16A R ^16B . In embodiments, R ¹⁶ is −ONR ^16A R ^16B . In embodiments, R ¹⁶ is−NHC=(O)NHNR ^16A R ^16B . In embodiments, R ¹⁶ is −NHC(O)NR ^16A R ^16B . In embodiments, R ¹⁶ is -N(O)m16. In embodiments, R ¹⁶ is -NR ^16A R ^16B . In embodiments, R ¹⁶ is -C(O)R ^16C . In embodiments, R ¹⁶ is -C(O)-OR ^16C . In embodiments, R ¹⁶ is -C(O)NR ^16A R ^16B . In embodiments, R ¹⁶ is -OR ^16D . In embodiments, R ¹⁶ is -NR ^16A SO2R ^16D . In embodiments, R ¹⁶ is -NR ^16A C(O)R ^16C . In embodiments, R ¹⁶ is -NR ^16A C(O)OR ^16C . In embodiments, R ¹⁶ is -NR ^16A OR ^16C . In embodiments, R ¹⁶ is -OCX ¹⁶ ₃ . In embodiments, R ¹⁶ is -OCHX ¹⁶ 2. In embodiments, R ¹⁶ is substituted or unsubstituted alkyl. In embodiments, R ¹⁶ is substituted or unsubstituted heteroalkyl. In embodiments, R ¹⁶ is substituted or unsubstituted cycloalkyl. In embodiments, R ¹⁶ is substituted or unsubstituted heterocycloalkyl. In

embodiments, R ¹⁶ is substituted or unsubstituted aryl. In embodiments, R ¹⁶ is substituted or unsubstituted heteroaryl. In embodiments, R ¹⁶ is substituted alkyl. In embodiments, R ¹⁶ is substituted heteroalkyl. In embodiments, R ¹⁶ is substituted cycloalkyl. In embodiments, R ¹⁶ is substituted heterocycloalkyl. In embodiments, R ¹⁶ is substituted aryl. In embodiments, R ¹⁶ is substituted heteroaryl. In embodiments, R ¹⁶ is unsubstituted alkyl. In embodiments, R ¹⁶ is unsubstituted heteroalkyl. In embodiments, R ¹⁶ is unsubstituted cycloalkyl. In embodiments, R ¹⁶ is unsubstituted heterocycloalkyl. In embodiments, R ¹⁶ is unsubstituted aryl. In

embodiments, R ¹⁶ is unsubstituted heteroaryl. In embodiments, R ¹⁶ is unsubstituted methyl. In embodiments, R ¹⁶ is unsubstituted ethyl. In embodiments, R ¹⁶ is unsubstituted propyl. In embodiments, R ¹⁶ is unsubstituted isopropyl. In embodiments, R ¹⁶ is unsubstituted butyl. In embodiments, R ¹⁶ is unsubstituted tert-butyl. [0363] In embodiments, R ^16A is hydrogen. In embodiments, R ^16A is -CX3. In embodiments, R ^16A is -CN. In embodiments, R ^16A is -COOH. In embodiments, R ^16A is -CONH2. In embodiments, R ^16A is -CHX ₂ . In embodiments, R ^16A is -CH ₂ X. In embodiments, R ^16A is unsubstituted methyl. In embodiments, R ^16A is unsubstituted ethyl. In embodiments, R ^16A is unsubstituted propyl. In embodiments, R ^16A is unsubstituted isopropyl. In embodiments, R ^16A is unsubstituted butyl. In embodiments, R ^16A is unsubstituted tert-butyl. [0364] In embodiments, R ^16B is hydrogen. In embodiments, R ^16B is -CX ₃ . In embodiments, R ^16B is -CN. In embodiments, R ^16B is -COOH. In embodiments, R ^16B is -CONH2. In

embodiments, R ^16B is -CHX2. In embodiments, R ^16B is -CH2X. In embodiments, R ^16B is unsubstituted methyl. In embodiments, R ^16B is unsubstituted ethyl. In embodiments, R ^16B is unsubstituted propyl. In embodiments, R ^16B is unsubstituted isopropyl. In embodiments, R ^16B is unsubstituted butyl. In embodiments, R ^16B is unsubstituted tert-butyl. [0365] In embodiments, R ^16C is hydrogen. In embodiments, R ^16C is -CX ₃ . In embodiments, R ^16C is -CN. In embodiments, R ^16C is -COOH. In embodiments, R ^16C is -CONH ₂ . In

embodiments, R ^16C is -CHX2. In embodiments, R ^16C is -CH2X. In embodiments, R ^16C is unsubstituted methyl. In embodiments, R ^16C is unsubstituted ethyl. In embodiments, R ^16C is unsubstituted propyl. In embodiments, R ^16C is unsubstituted isopropyl. In embodiments, R ^16C is unsubstituted butyl. In embodiments, R ^16C is unsubstituted tert-butyl. [0366] In embodiments, R ^16D is hydrogen. In embodiments, R ^16D is -CX3. In embodiments, R ^16D is -CN. In embodiments, R ^16D is -COOH. In embodiments, R ^16D is -CONH ₂ . In embodiments, R ^16D is -CHX2. In embodiments, R ^16D is -CH2X. In embodiments, R ^16D is unsubstituted methyl. In embodiments, R ^16D is unsubstituted ethyl. In embodiments, R ^16D is unsubstituted propyl. In embodiments, R ^16D is unsubstituted isopropyl. In embodiments, R ^16D is unsubstituted butyl. In embodiments, R ^16D is unsubstituted tert-butyl. [0367] In embodiments, R ¹⁶ is independently hydrogen, oxo,

halogen, -CX ¹⁶ ₃ , -CHX ¹⁶ ₂ , -OCH ₂ X ¹⁶ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, - SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ¹⁶ ₃ , -OCHX ¹⁶ ₂ , R ⁷⁵ -substituted or unsubstituted alkyl, R ⁷⁵ -substituted or unsubstituted heteroalkyl, R ⁷⁵ -substituted or unsubstituted cycloalkyl, R ⁷⁵ - substituted or unsubstituted heterocycloalkyl, R ⁷⁵ -substituted or unsubstituted aryl, or R ⁷⁵ - substituted or unsubstituted heteroaryl. X ¹⁶ is halogen. In embodiments, X ¹⁶ is F. [0368] R ⁷⁵ is independently oxo,

halogen, -CX ⁷⁵ 3, -CHX ⁷⁵ 2, -OCH2X ⁷⁵ , -OCHX ⁷⁵ 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -S H, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, - NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ⁷⁵ 3, -OCHX ⁷⁵ 2, R ⁷⁶ -substituted or unsubstituted alkyl, R ⁷⁶ -substituted or unsubstituted heteroalkyl, R ⁷⁶ -substituted or unsubstituted cycloalkyl, R ⁷⁶ -substituted or unsubstituted heterocycloalkyl, R ⁷⁶ -substituted or unsubstituted aryl, or R ⁷⁶ -substituted or unsubstituted heteroaryl. X ⁷⁵ is halogen. In embodiments, X ⁷⁵ is F. [0369] R ⁷⁶ is independently oxo,

halogen, -CX ⁷⁶ ₃ , -CHX ⁷⁶ ₂ , -OCH ₂ X ⁷⁶ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, - SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, -NHSO2H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ⁷⁶ ₃ , -OCHX ⁷⁶ ₂ , R ⁷⁷ -substituted or unsubstituted alkyl, R ⁷⁷ -substituted or unsubstituted heteroalkyl, R ⁷⁷ -substituted or unsubstituted cycloalkyl, R ⁷⁷ - substituted or unsubstituted heterocycloalkyl, R ⁷⁷ -substituted or unsubstituted aryl, or R ⁷⁷ - substituted or unsubstituted heteroaryl. X ⁷⁶ is halogen. In embodiments, X ⁷⁶ is F. [0370] In embodiments, R ^16A is independently hydrogen, oxo,

halogen, -CX ^16A 3, -CHX ^16A 2, -OCH2X ^16A , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^16A ₃ , -OCHX ^16A ₂ , R ^75A -substituted or unsubstituted alkyl, R ^75A -substituted or unsubstituted heteroalkyl, R ^75A -substituted or unsubstituted cycloalkyl, R ^75A -substituted or unsubstituted heterocycloalkyl, R ^75A -substituted or unsubstituted aryl, or R ^75A -substituted or unsubstituted heteroaryl. X ^16A is halogen. In embodiments, X ^16A is F. [0371] R ^75A is independently oxo,

halogen, -CX ^75A 3, -CHX ^75A 2, -OCH2X ^75A , -OCHX ^75A 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2 , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , - NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^75A ₃ , -OCHX ^75A ₂ , R ^76A -substituted or unsubstituted alkyl, R ^76A -substituted or unsubstituted heteroalkyl, R ^76A -substituted or

unsubstituted cycloalkyl, R ^76A -substituted or unsubstituted heterocycloalkyl, R ^76A -substituted or unsubstituted aryl, or R ^76A -substituted or unsubstituted heteroaryl. X ^75A is halogen. In embodiments, X ^75A is F. [0372] R ^76A is independently oxo,

halogen, -CX ^76A 3, -CHX ^76A 2, -OCH2X ^76A , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^76A ₃ , -OCHX ^76A ₂ , R ^77A -substituted or unsubstituted alkyl, R ^77A -substituted or unsubstituted heteroalkyl, R ^77A -substituted or unsubstituted cycloalkyl, R ^77A -substituted or unsubstituted heterocycloalkyl, R ^77A -substituted or unsubstituted aryl, or R ^77A -substituted or unsubstituted heteroaryl. X ^76A is halogen. In embodiments, X ^76A is F. [0373] In embodiments, R ^16B is independently hydrogen, oxo,

halogen, -CX ^16B 3, -CHX ^16B 2, -OCH2X ^16B , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^16B 3, -OCHX ^16B 2, R ^75B -substituted or unsubstituted alkyl, R ^75B -substituted or unsubstituted heteroalkyl, R ^75B -substituted or unsubstituted cycloalkyl, R ^75B -substituted or unsubstituted heterocycloalkyl, R ^75B -substituted or unsubstituted aryl, or R ^75B -substituted or unsubstituted heteroaryl. X ^16B is halogen. In embodiments, X ^16B is F. [0374] R ^75B is independently oxo,

halogen, -CX ^75B ₃ , -CHX ^75B ₂ , -OCH ₂ X ^75B , -OCHX ^75B ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, - NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^75B 3, -OCHX ^75B 2, R ^76B -substituted or unsubstituted alkyl, R ^76B -substituted or unsubstituted heteroalkyl, R ^76B -substituted or

unsubstituted cycloalkyl, R ^76B -substituted or unsubstituted heterocycloalkyl, R ^76B -substituted or unsubstituted aryl, or R ^76B -substituted or unsubstituted heteroaryl. X ^75B is halogen. In embodiments, X ^75B is F. [0375] R ^76B is independently oxo,

halogen, -CX ^76B ₃ , -CHX ^76B ₂ , -OCH ₂ X ^76B , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, - SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, -NHSO2H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^76B 3, -OCHX ^76B 2, R ^77B -substituted or unsubstituted alkyl, R ^77B -substituted or unsubstituted heteroalkyl, R ^77B -substituted or unsubstituted cycloalkyl, R ^77B -substituted or unsubstituted heterocycloalkyl, R ^77B -substituted or unsubstituted aryl, or R ^77B -substituted or unsubstituted heteroaryl. X ^76B is halogen. In embodiments, X ^76B is F. [0376] In embodiments, R ^16C is independently hydrogen, oxo,

halogen, -CX ^16C ₃ , -CHX ^16C ₂ , -OCH ₂ X ^16C , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, - SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, -NHSO2H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^16C 3, -OCHX ^16C 2, R ^75C -substituted or unsubstituted alkyl, R ^75C -substituted or unsubstituted heteroalkyl, R ^75C -substituted or unsubstituted cycloalkyl, R ^75C -substituted or unsubstituted heterocycloalkyl, R ^75C -substituted or unsubstituted aryl, or R ^75C -substituted or unsubstituted heteroaryl. X ^16C is halogen. In embodiments, X ^16C is F. [0377] R ^75C is independently oxo,

halogen, -CX ^75C ₃ , -CHX ^75C ₂ , -OCH ₂ X ^75C , -OCHX ^75C ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , - NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^75C ₃ , -OCHX ^75C ₂ , R ^76C -substituted or unsubstituted alkyl, R ^76C -substituted or unsubstituted heteroalkyl, R ^76C -substituted or

unsubstituted cycloalkyl, R ^76C -substituted or unsubstituted heterocycloalkyl, R ^76C -substituted or unsubstituted aryl, or R ^76C -substituted or unsubstituted heteroaryl. X ^75C is halogen. In embodiments, X ^75C is F. [0378] R ^76C is independently oxo,

halogen, -CX ^76C ₃ , -CHX ^76C ₂ , -OCH ₂ X ^76C , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, - SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, -NHSO2H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^76C ₃ , -OCHX ^76C ₂ , R ^77C -substituted or unsubstituted alkyl, R ^77C -substituted or unsubstituted heteroalkyl, R ^77C -substituted or unsubstituted cycloalkyl, R ^77C -substituted or unsubstituted heterocycloalkyl, R ^77C -substituted or unsubstituted aryl, or R ^77C -substituted or unsubstituted heteroaryl. X ^76C is halogen. In embodiments, X ^76C is F. [0379] In embodiments, R ^16D is independently hydrogen, oxo,

halogen, -CX ^16D 3, -CHX ^16D 2, -OCH2X ^16D , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^16D ₃ , -OCHX ^16D ₂ , R ^75D -substituted or unsubstituted alkyl, R ^75D -substituted or unsubstituted heteroalkyl, R ^75D -substituted or unsubstituted cycloalkyl, R ^75D -substituted or unsubstituted heterocycloalkyl, R ^75D -substituted or unsubstituted aryl, or R ^75D -substituted or unsubstituted heteroaryl. X ^16D is halogen. In embodiments, X ^16D is F. [0380] R ^75D is independently oxo,

halogen, -CX ^75D 3, -CHX ^75D 2, -OCH2X ^75D , -OCHX ^75D 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2 , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , - NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^75D 3, -OCHX ^75D 2, R ^76D -substituted or unsubstituted alkyl, R ^76D -substituted or unsubstituted heteroalkyl, R ^76D -substituted or

unsubstituted cycloalkyl, R ^76D -substituted or unsubstituted heterocycloalkyl, R ^76D -substituted or unsubstituted aryl, or R ^76D -substituted or unsubstituted heteroaryl. X ^75D is halogen. In embodiments, X ^75D is F. [0381] R ^76D is independently oxo,

halogen, -CX ^76D 3, -CHX ^76D 2, -OCH2X ^76D , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, -NHSO2H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^76D 3, -OCHX ^76D 2, R ^77D -substituted or unsubstituted alkyl, R ^77D -substituted or unsubstituted heteroalkyl, R ^77D -substituted or unsubstituted cycloalkyl, R ^77D -substituted or unsubstituted heterocycloalkyl, R ^77D -substituted or unsubstituted aryl, or R ^77D -substituted or unsubstituted heteroaryl. X ^76D is halogen. In embodiments, X ^76D is F. [0382] In embodiments, R ¹⁷ is hydrogen. In embodiments, R ¹⁷ is halogen. In embodiments, R ¹⁷ is CX ¹⁷ ₃ . In embodiments, R ¹⁷ is -CHX ¹⁷ ₂ . In embodiments, R ¹⁷ is -CH ₂ X ¹⁷ . In

embodiments, R ¹⁷ is–CN. In embodiments, R ¹⁷ is -SOn17R ^17D . In embodiments, R ¹⁷ is -SOv17NR ^17A R ^17B . In embodiments, R ¹⁷ is−NHNR ^17A R ^17B . In embodiments, R ¹⁷ is −ONR ^17A R ^17B . In embodiments, R ¹⁷ is−NHC=(O)NHNR ^17A R ^17B . In embodiments, R ¹⁷ is −NHC(O)NR ^17A R ^17B . In embodiments, R ¹⁷ is -N(O)m17. In embodiments, R ¹⁷ is -NR ^17A R ^17B . In embodiments, R ¹⁷ is -C(O)R ^17C . In embodiments, R ¹⁷ is -C(O)-OR ^17C . In embodiments, R ¹⁷ is -C(O)NR ^17A R ^17B . In embodiments, R ¹⁷ is -OR ^17D . In embodiments, R ¹⁷ is -NR ^17A SO ₂ R ^17D . In embodiments, R ¹⁷ is -NR ^17A C(O)R ^17C . In embodiments, R ¹⁷ is -NR ^17A C(O)OR ^17C . In embodiments, R ¹⁷ is -NR ^17A OR ^17C . In embodiments, R ¹⁷ is -OCX ¹⁷ 3. In embodiments, R ¹⁷ is -OCHX ¹⁷ 2. In embodiments, R ¹⁷ is substituted or unsubstituted alkyl. In embodiments, R ¹⁷ is substituted or unsubstituted heteroalkyl. In embodiments, R ¹⁷ is substituted or unsubstituted cycloalkyl. In embodiments, R ¹⁷ is substituted or unsubstituted heterocycloalkyl. In

embodiments, R ¹⁷ is substituted or unsubstituted aryl. In embodiments, R ¹⁷ is substituted or unsubstituted heteroaryl. In embodiments, R ¹⁷ is substituted alkyl. In embodiments, R ¹⁷ is substituted heteroalkyl. In embodiments, R ¹⁷ is substituted cycloalkyl. In embodiments, R ¹⁷ is substituted heterocycloalkyl. In embodiments, R ¹⁷ is substituted aryl. In embodiments, R ¹⁷ is substituted heteroaryl. In embodiments, R ¹⁷ is unsubstituted alkyl. In embodiments, R ¹⁷ is unsubstituted heteroalkyl. In embodiments, R ¹⁷ is unsubstituted cycloalkyl. In embodiments, R ¹⁷ is unsubstituted heterocycloalkyl. In embodiments, R ¹⁷ is unsubstituted aryl. In

embodiments, R ¹⁷ is unsubstituted heteroaryl. In embodiments, R ¹⁷ is unsubstituted methyl. In embodiments, R ¹⁷ is unsubstituted ethyl. In embodiments, R ¹⁷ is unsubstituted propyl. In embodiments, R ¹⁷ is unsubstituted isopropyl. In embodiments, R ¹⁷ is unsubstituted butyl. In embodiments, R ¹⁷ is unsubstituted tert-butyl. [0383] In embodiments, R ^17A is hydrogen. In embodiments, R ^17A is -CX3. In embodiments, R ^17A is -CN. In embodiments, R ^17A is -COOH. In embodiments, R ^17A is -CONH2. In embodiments, R ^17A is -CHX ₂ . In embodiments, R ^17A is -CH ₂ X. In embodiments, R ^17A is unsubstituted methyl. In embodiments, R ^17A is unsubstituted ethyl. In embodiments, R ^17A is unsubstituted propyl. In embodiments, R ^17A is unsubstituted isopropyl. In embodiments, R ^17A is unsubstituted butyl. In embodiments, R ^17A is unsubstituted tert-butyl. [0384] In embodiments, R ^17B is hydrogen. In embodiments, R ^17B is -CX ₃ . In embodiments, R ^17B is -CN. In embodiments, R ^17B is -COOH. In embodiments, R ^17B is -CONH2. In

embodiments, R ^17B is -CHX2. In embodiments, R ^17B is -CH2X. In embodiments, R ^17B is unsubstituted methyl. In embodiments, R ^17B is unsubstituted ethyl. In embodiments, R ^17B is unsubstituted propyl. In embodiments, R ^17B is unsubstituted isopropyl. In embodiments, R ^17B is unsubstituted butyl. In embodiments, R ^17B is unsubstituted tert-butyl. [0385] In embodiments, R ^17C is hydrogen. In embodiments, R ^17C is -CX ₃ . In embodiments, R ^17C is -CN. In embodiments, R ^17C is -COOH. In embodiments, R ^17C is -CONH ₂ . In

embodiments, R ^17C is -CHX2. In embodiments, R ^17C is -CH2X. In embodiments, R ^17C is unsubstituted methyl. In embodiments, R ^17C is unsubstituted ethyl. In embodiments, R ^17C is unsubstituted propyl. In embodiments, R ^17C is unsubstituted isopropyl. In embodiments, R ^17C is unsubstituted butyl. In embodiments, R ^17C is unsubstituted tert-butyl. [0386] In embodiments, R ^17D is hydrogen. In embodiments, R ^17D is -CX3. In embodiments, R ^17D is -CN. In embodiments, R ^17D is -COOH. In embodiments, R ^17D is -CONH ₂ . In embodiments, R ^17D is -CHX2. In embodiments, R ^17D is -CH2X. In embodiments, R ^17D is unsubstituted methyl. In embodiments, R ^17D is unsubstituted ethyl. In embodiments, R ^17D is unsubstituted propyl. In embodiments, R ^17D is unsubstituted isopropyl. In embodiments, R ^17D is unsubstituted butyl. In embodiments, R ^17D is unsubstituted tert-butyl. [0387] In embodiments, R ¹⁷ is independently hydrogen, oxo,

halogen, -CX ¹⁷ ₃ , -CHX ¹⁷ ₂ , -OCH ₂ X ¹⁷ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, - SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, -NHSO2H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ¹⁷ ₃ , -OCHX ¹⁷ ₂ , R ⁷⁸ -substituted or unsubstituted alkyl, R ⁷⁸ -substituted or unsubstituted heteroalkyl, R ⁷⁸ -substituted or unsubstituted cycloalkyl, R ⁷⁸ - substituted or unsubstituted heterocycloalkyl, R ⁷⁸ -substituted or unsubstituted aryl, or R ⁷⁸ - substituted or unsubstituted heteroaryl. X ¹⁷ is halogen. In embodiments, X ¹⁷ is F. [0388] R ⁷⁸ is independently oxo,

halogen, -CX ⁷⁸ 3, -CHX ⁷⁸ 2, -OCH2X ⁷⁸ , -OCHX ⁷⁸ 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -S H, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , - NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ⁷⁸ ₃ , -OCHX ⁷⁸ ₂ , R ⁷⁹ -substituted or unsubstituted alkyl, R ⁷⁹ -substituted or unsubstituted heteroalkyl, R ⁷⁹ -substituted or unsubstituted cycloalkyl, R ⁷⁹ -substituted or unsubstituted heterocycloalkyl, R ⁷⁹ -substituted or unsubstituted aryl, or R ⁷⁹ -substituted or unsubstituted heteroaryl. X ⁷⁸ is halogen. In embodiments, X ⁷⁸ is F. [0389] R ⁷⁹ is independently oxo,

halogen, -CX ⁷⁹ 3, -CHX ⁷⁹ 2, -OCH2X ⁷⁹ , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, - SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ⁷⁹ 3, -OCHX ⁷⁹ 2, R ⁸⁰ -substituted or unsubstituted alkyl, R ⁸⁰ -substituted or unsubstituted heteroalkyl, R ⁸⁰ -substituted or unsubstituted cycloalkyl, R ⁸⁰ - substituted or unsubstituted heterocycloalkyl, R ⁸⁰ -substituted or unsubstituted aryl, or R ⁸⁰ - substituted or unsubstituted heteroaryl. X ⁷⁹ is halogen. In embodiments, X ⁷⁹ is F. [0390] In embodiments, R ^17A is independently hydrogen, oxo,

halogen, -CX ^17A ₃ , -CHX ^17A ₂ , -OCH ₂ X ^17A , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, - SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, -NHSO2H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^17A 3, -OCHX ^17A 2, R ^78A -substituted or unsubstituted alkyl, R ^78A -substituted or unsubstituted heteroalkyl, R ^78A -substituted or unsubstituted cycloalkyl, R ^78A -substituted or unsubstituted heterocycloalkyl, R ^78A -substituted or unsubstituted aryl, or R ^78A -substituted or unsubstituted heteroaryl. X ^17A is halogen. In embodiments, X ^17A is F. [0391] R ^78A is independently oxo,

halogen, -CX ^78A ₃ , -CHX ^78A ₂ , -OCH ₂ X ^78A , -OCHX ^78A ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, - NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^78A ₃ , -OCHX ^78A ₂ , R ^79A -substituted or unsubstituted alkyl, R ^79A -substituted or unsubstituted heteroalkyl, R ^79A -substituted or

unsubstituted cycloalkyl, R ^79A -substituted or unsubstituted heterocycloalkyl, R ^79A -substituted or unsubstituted aryl, or R ^79A -substituted or unsubstituted heteroaryl. X ^78A is halogen. In embodiments, X ^78A is F. [0392] R ^79A is independently oxo,

halogen, -CX ^79A ₃ , -CHX ^79A ₂ , -OCH ₂ X ^79A , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, - SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, -NHSO2H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^79A 3, -OCHX ^79A 2, R ^80A -substituted or unsubstituted alkyl, R ^80A -substituted or unsubstituted heteroalkyl, R ^80A -substituted or unsubstituted cycloalkyl, R ^80A -substituted or unsubstituted heterocycloalkyl, R ^80A -substituted or unsubstituted aryl, or R ^80A -substituted or unsubstituted heteroaryl. X ^79A is halogen. In embodiments, X ^79A is F. [0393] In embodiments, R ^17B is independently hydrogen, oxo,

halogen, -CX ^17B ₃ , -CHX ^17B ₂ , -OCH ₂ X ^17B , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, - SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^17B ₃ , -OCHX ^17B ₂ , R ^78B -substituted or unsubstituted alkyl, R ^78B -substituted or unsubstituted heteroalkyl, R ^78B -substituted or unsubstituted cycloalkyl, R ^78B -substituted or unsubstituted heterocycloalkyl, R ^78B -substituted or unsubstituted aryl, or R ^78B -substituted or unsubstituted heteroaryl. X ^17B is halogen. In embodiments, X ^17B is F. [0394] R ^78B is independently oxo,

halogen, -CX ^78B 3, -CHX ^78B 2, -OCH2X ^78B , -OCHX ^78B 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2 , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , - NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^78B ₃ , -OCHX ^78B ₂ , R ^79B -substituted or unsubstituted alkyl, R ^79B -substituted or unsubstituted heteroalkyl, R ^79B -substituted or

unsubstituted cycloalkyl, R ^79B -substituted or unsubstituted heterocycloalkyl, R ^79B -substituted or unsubstituted aryl, or R ^79B -substituted or unsubstituted heteroaryl. X ^78B is halogen. In embodiments, X ^78B is F. [0395] R ^79B is independently oxo,

halogen, -CX ^79B 3, -CHX ^79B 2, -OCH2X ^79B , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^79B ₃ , -OCHX ^79B ₂ , R ^80B -substituted or unsubstituted alkyl, R ^80B -substituted or unsubstituted heteroalkyl, R ^80B -substituted or unsubstituted cycloalkyl, R ^80B -substituted or unsubstituted heterocycloalkyl, R ^80B -substituted or unsubstituted aryl, or R ^80B -substituted or unsubstituted heteroaryl. X ^79B is halogen. In embodiments, X ^79B is F. [0396] In embodiments, R ^17C is independently hydrogen, oxo,

halogen, -CX ^17C 3, -CHX ^17C 2, -OCH2X ^17C , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^17C 3, -OCHX ^17C 2, R ^78C -substituted or unsubstituted alkyl, R ^78C -substituted or unsubstituted heteroalkyl, R ^78C -substituted or unsubstituted cycloalkyl, R ^78C -substituted or unsubstituted heterocycloalkyl, R ^78C -substituted or unsubstituted aryl, or R ^78C -substituted or unsubstituted heteroaryl. X ^17C is halogen. In embodiments, X ^17C is F. [0397] R ^78C is independently oxo,

halogen, -CX ^78C 3, -CHX ^78C 2, -OCH2X ^78C , -OCHX ^78C 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2 , -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, - NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^78C 3, -OCHX ^78C 2, R ^79C -substituted or unsubstituted alkyl, R ^79C -substituted or unsubstituted heteroalkyl, R ^79C -substituted or

unsubstituted cycloalkyl, R ^79C -substituted or unsubstituted heterocycloalkyl, R ^79C -substituted or unsubstituted aryl, or R ^79C -substituted or unsubstituted heteroaryl. X ^78C is halogen. In embodiments, X ^78C is F. [0398] R ^79C is independently oxo,

halogen, -CX ^79C 3, -CHX ^79C 2, -OCH2X ^79C , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, -NHSO2H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^79C 3, -OCHX ^79C 2, R ^80C -substituted or unsubstituted alkyl, R ^80C -substituted or unsubstituted heteroalkyl, R ^80C -substituted or unsubstituted cycloalkyl, R ^80C -substituted or unsubstituted heterocycloalkyl, R ^80C -substituted or unsubstituted aryl, or R ^80C -substituted or unsubstituted heteroaryl. X ^79C is halogen. In embodiments, X ^79C is F. [0399] In embodiments, R ^17D is independently hydrogen, oxo,

halogen, -CX ^17D ₃ , -CHX ^17D ₂ , -OCH ₂ X ^17D , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, - SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, -NHSO2H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^17D 3, -OCHX ^17D 2, R ^78D -substituted or unsubstituted alkyl, R ^78D -substituted or unsubstituted heteroalkyl, R ^78D -substituted or unsubstituted cycloalkyl, R ^78D -substituted or unsubstituted heterocycloalkyl, R ^78D -substituted or unsubstituted aryl, or R ^78D -substituted or unsubstituted heteroaryl. X ^17D is halogen. In embodiments, X ^17D is F. [0400] R ^78D is independently oxo,

halogen, -CX ^78D ₃ , -CHX ^78D ₂ , -OCH ₂ X ^78D , -OCHX ^78D ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , - NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^78D ₃ , -OCHX ^78D ₂ , R ^79D -substituted or unsubstituted alkyl, R ^79D -substituted or unsubstituted heteroalkyl, R ^79D -substituted or

unsubstituted cycloalkyl, R ^79D -substituted or unsubstituted heterocycloalkyl, R ^79D -substituted or unsubstituted aryl, or R ^79D -substituted or unsubstituted heteroaryl. X ^78D is halogen. In embodiments, X ^78D is F. [0401] R ^79D is independently oxo,

halogen, -CX ^79D 3, -CHX ^79D 2, -OCH2X ^79D , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^79D ₃ , -OCHX ^79D ₂ , R ^80D -substituted or unsubstituted alkyl, R ^80D -substituted or unsubstituted heteroalkyl, R ^80D -substituted or unsubstituted cycloalkyl, R ^80D -substituted or unsubstituted heterocycloalkyl, R ^80D -substituted or unsubstituted aryl, or R ^80D -substituted or unsubstituted heteroaryl. X ^79D is halogen. In embodiments, X ^79D is F. [0402] In embodiments, R ¹⁸ is hydrogen. In embodiments, R ¹⁸ is halogen. In embodiments, R ¹⁸ is CX ¹⁸ 3. In embodiments, R ¹⁸ is -CHX ¹⁸ 2. In embodiments, R ¹⁸ is -CH2X ¹⁸ . In

embodiments, R ¹⁸ is–CN. In embodiments, R ¹⁸ is -SOn18R ^18D . In embodiments, R ¹⁸ is -SO _v18 NR ^18A R ^18B . In embodiments, R ¹⁸ is−NHNR ^18A R ^18B . In embodiments, R ¹⁸ is −ONR ^18A R ^18B . In embodiments, R ¹⁸ is−NHC=(O)NHNR ^18A R ^18B . In embodiments, R ¹⁸ is −NHC(O)NR ^18A R ^18B . In embodiments, R ¹⁸ is -N(O) _m18 . In embodiments, R ¹⁸ is -NR ^18A R ^18B . In embodiments, R ¹⁸ is -C(O)R ^18C . In embodiments, R ¹⁸ is -C(O)-OR ^18C . In embodiments, R ¹⁸ is -C(O)NR ^18A R ^18B . In embodiments, R ¹⁸ is -OR ^18D . In embodiments, R ¹⁸ is -NR ^18A SO ₂ R ^18D . In embodiments, R ¹⁸ is -NR ^18A C(O)R ^18C . In embodiments, R ¹⁸ is -NR ^18A C(O)OR ^18C . In embodiments, R ¹⁸ is -NR ^18A OR ^18C . In embodiments, R ¹⁸ is -OCX ¹⁸ 3. In embodiments, R ¹⁸ is -OCHX ¹⁸ ₂ . In embodiments, R ¹⁸ is substituted or unsubstituted alkyl. In embodiments, R ¹⁸ is substituted or unsubstituted heteroalkyl. In embodiments, R ¹⁸ is substituted or unsubstituted cycloalkyl. In embodiments, R ¹⁸ is substituted or unsubstituted heterocycloalkyl. In

embodiments, R ¹⁸ is substituted or unsubstituted aryl. In embodiments, R ¹⁸ is substituted or unsubstituted heteroaryl. In embodiments, R ¹⁸ is substituted alkyl. In embodiments, R ¹⁸ is substituted heteroalkyl. In embodiments, R ¹⁸ is substituted cycloalkyl. In embodiments, R ¹⁸ is substituted heterocycloalkyl. In embodiments, R ¹⁸ is substituted aryl. In embodiments, R ¹⁸ is substituted heteroaryl. In embodiments, R ¹⁸ is unsubstituted alkyl. In embodiments, R ¹⁸ is unsubstituted heteroalkyl. In embodiments, R ¹⁸ is unsubstituted cycloalkyl. In embodiments, R ¹⁸ is unsubstituted heterocycloalkyl. In embodiments, R ¹⁸ is unsubstituted aryl. In

embodiments, R ¹⁸ is unsubstituted heteroaryl. In embodiments, R ¹⁸ is unsubstituted methyl. In embodiments, R ¹⁸ is unsubstituted ethyl. In embodiments, R ¹⁸ is unsubstituted propyl. In embodiments, R ¹⁸ is unsubstituted isopropyl. In embodiments, R ¹⁸ is unsubstituted butyl. In embodiments, R ¹⁸ is unsubstituted tert-butyl. [0403] In embodiments, R ^18A is hydrogen. In embodiments, R ^18A is -CX3. In embodiments, R ^18A is -CN. In embodiments, R ^18A is -COOH. In embodiments, R ^18A is -CONH2. In embodiments, R ^18A is -CHX2. In embodiments, R ^18A is -CH2X. In embodiments, R ^18A is unsubstituted methyl. In embodiments, R ^18A is unsubstituted ethyl. In embodiments, R ^18A is unsubstituted propyl. In embodiments, R ^18A is unsubstituted isopropyl. In embodiments, R ^18A is unsubstituted butyl. In embodiments, R ^18A is unsubstituted tert-butyl. [0404] In embodiments, R ^18B is hydrogen. In embodiments, R ^18B is -CX3. In embodiments, R ^18B is -CN. In embodiments, R ^18B is -COOH. In embodiments, R ^18B is -CONH ₂ . In

embodiments, R ^18B is -CHX ₂ . In embodiments, R ^18B is -CH ₂ X. In embodiments, R ^18B is unsubstituted methyl. In embodiments, R ^18B is unsubstituted ethyl. In embodiments, R ^18B is unsubstituted propyl. In embodiments, R ^18B is unsubstituted isopropyl. In embodiments, R ^18B is unsubstituted butyl. In embodiments, R ^18B is unsubstituted tert-butyl. [0405] In embodiments, R ^18C is hydrogen. In embodiments, R ^18C is -CX3. In embodiments, R ^18C is -CN. In embodiments, R ^18C is -COOH. In embodiments, R ^18C is -CONH2. In

embodiments, R ^18C is -CHX ₂ . In embodiments, R ^18C is -CH ₂ X. In embodiments, R ^18C is unsubstituted methyl. In embodiments, R ^18C is unsubstituted ethyl. In embodiments, R ^18C is unsubstituted propyl. In embodiments, R ^18C is unsubstituted isopropyl. In embodiments, R ^18C is unsubstituted butyl. In embodiments, R ^18C is unsubstituted tert-butyl. [0406] In embodiments, R ^18D is hydrogen. In embodiments, R ^18D is -CX ₃ . In embodiments, R ^18D is -CN. In embodiments, R ^18D is -COOH. In embodiments, R ^18D is -CONH2. In embodiments, R ^18D is -CHX2. In embodiments, R ^18D is -CH2X. In embodiments, R ^18D is unsubstituted methyl. In embodiments, R ^18D is unsubstituted ethyl. In embodiments, R ^18D is unsubstituted propyl. In embodiments, R ^18D is unsubstituted isopropyl. In embodiments, R ^18D is unsubstituted butyl. In embodiments, R ^18D is unsubstituted tert-butyl. [0407] In embodiments, R ¹⁸ is independently hydrogen, oxo,

halogen, -CX ¹⁸ 3, -CHX ¹⁸ 2, -OCH2X ¹⁸ , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, - SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, -NHSO2H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ¹⁸ 3, -OCHX ¹⁸ 2, R ⁸¹ -substituted or unsubstituted alkyl, R ⁸¹ -substituted or unsubstituted heteroalkyl, R ⁸¹ -substituted or unsubstituted cycloalkyl, R ⁸¹ - substituted or unsubstituted heterocycloalkyl, R ⁸¹ -substituted or unsubstituted aryl, or R ⁸¹ - substituted or unsubstituted heteroaryl. X ¹⁸ is halogen. In embodiments, X ¹⁸ is F. [0408] R ⁸¹ is independently oxo,

halogen, -CX ⁸¹ ₃ , -CHX ⁸¹ ₂ , -OCH ₂ X ⁸¹ , -OCHX ⁸¹ ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -S H, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, - NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ⁸¹ 3, -OCHX ⁸¹ 2, R ⁸² -substituted or unsubstituted alkyl, R ⁸² -substituted or unsubstituted heteroalkyl, R ⁸² -substituted or unsubstituted cycloalkyl, R ⁸² -substituted or unsubstituted heterocycloalkyl, R ⁸² -substituted or unsubstituted aryl, or R ⁸² -substituted or unsubstituted heteroaryl. X ⁸¹ is halogen. In embodiments, X ⁸¹ is F. [0409] R ⁸² is independently oxo,

halogen, -CX ⁸² ₃ , -CHX ⁸² ₂ , -OCH ₂ X ⁸² , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, - SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ⁸² ₃ , -OCHX ⁸² ₂ , R ⁸³ -substituted or unsubstituted alkyl, R ⁸³ -substituted or unsubstituted heteroalkyl, R ⁸³ -substituted or unsubstituted cycloalkyl, R ⁸³ - substituted or unsubstituted heterocycloalkyl, R ⁸³ -substituted or unsubstituted aryl, or R ⁸³ - substituted or unsubstituted heteroaryl. X ⁸² is halogen. In embodiments, X ⁸² is F. [0410] In embodiments, R ^18A is independently hydrogen, oxo,

halogen, -CX ^18A 3, -CHX ^18A 2, -OCH2X ^18A , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^18A ₃ , -OCHX ^18A ₂ , R ^81A -substituted or unsubstituted alkyl, R ^81A -substituted or unsubstituted heteroalkyl, R ^81A -substituted or unsubstituted cycloalkyl, R ^81A -substituted or unsubstituted heterocycloalkyl, R ^81A -substituted or unsubstituted aryl, or R ^81A -substituted or unsubstituted heteroaryl. X ^18A is halogen. In embodiments, X ^18A is F. [0411] R ^81A is independently oxo,

halogen, -CX ^81A 3, -CHX ^81A 2, -OCH2X ^81A , -OCHX ^81A 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2 , -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, - NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^81A 3, -OCHX ^81A 2, R ^82A -substituted or unsubstituted alkyl, R ^82A -substituted or unsubstituted heteroalkyl, R ^82A -substituted or

unsubstituted cycloalkyl, R ^82A -substituted or unsubstituted heterocycloalkyl, R ^82A -substituted or unsubstituted aryl, or R ^82A -substituted or unsubstituted heteroaryl. X ^81A is halogen. In embodiments, X ^81A is F. [0412] R ^82A is independently oxo,

halogen, -CX ^82A 3, -CHX ^82A 2, -OCH2X ^82A , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^82A 3, -OCHX ^82A 2, R ^83A -substituted or unsubstituted alkyl, R ^83A -substituted or unsubstituted heteroalkyl, R ^83A -substituted or unsubstituted cycloalkyl, R ^83A -substituted or unsubstituted heterocycloalkyl, R ^83A -substituted or unsubstituted aryl, or R ^83A -substituted or unsubstituted heteroaryl. X ^82A is halogen. In embodiments, X ^82A is F. [0413] In embodiments, R ^18B is independently hydrogen, oxo,

halogen, -CX ^18B 3, -CHX ^18B 2, -OCH2X ^18B , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, -NHSO2H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^18B 3, -OCHX ^18B 2, R ^81B -substituted or unsubstituted alkyl, R ^81B -substituted or unsubstituted heteroalkyl, R ^81B -substituted or unsubstituted cycloalkyl, R ^81B -substituted or unsubstituted heterocycloalkyl, R ^81B -substituted or unsubstituted aryl, or R ^81B -substituted or unsubstituted heteroaryl. X ^18B is halogen. In embodiments, X ^18B is F. [0414] R ^81B is independently oxo,

halogen, -CX ^81B ₃ , -CHX ^81B ₂ , -OCH ₂ X ^81B , -OCHX ^81B ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, - NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^81B ₃ , -OCHX ^81B ₂ , R ^82B -substituted or unsubstituted alkyl, R ^82B -substituted or unsubstituted heteroalkyl, R ^82B -substituted or

unsubstituted cycloalkyl, R ^82B -substituted or unsubstituted heterocycloalkyl, R ^82B -substituted or unsubstituted aryl, or R ^82B -substituted or unsubstituted heteroaryl. X ^81B is halogen. In embodiments, X ^81B is F. [0415] R ^82B is independently oxo,

halogen, -CX ^82B ₃ , -CHX ^82B ₂ , -OCH ₂ X ^82B , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, - SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, -NHSO2H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^82B 3, -OCHX ^82B 2, R ^83B -substituted or unsubstituted alkyl, R ^83B -substituted or unsubstituted heteroalkyl, R ^83B -substituted or unsubstituted cycloalkyl, R ^83B -substituted or unsubstituted heterocycloalkyl, R ^83B -substituted or unsubstituted aryl, or R ^83B -substituted or unsubstituted heteroaryl. X ^82B is halogen. In embodiments, X ^82B is F. [0416] In embodiments, R ^18C is independently hydrogen, oxo,

halogen, -CX ^18C ₃ , -CHX ^18C ₂ , -OCH ₂ X ^18C , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, - SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^18C ₃ , -OCHX ^18C ₂ , R ^81C -substituted or unsubstituted alkyl, R ^81C -substituted or unsubstituted heteroalkyl, R ^81C -substituted or unsubstituted cycloalkyl, R ^81C -substituted or unsubstituted heterocycloalkyl, R ^81C -substituted or unsubstituted aryl, or R ^81C -substituted or unsubstituted heteroaryl. X ^18C is halogen. In embodiments, X ^18C is F. [0417] R ^81C is independently oxo,

halogen, -CX ^81C 3, -CHX ^81C 2, -OCH2X ^81C , -OCHX ^81C 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2 , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , - NHSO ₂ H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^81C ₃ , -OCHX ^81C ₂ , R ^82C -substituted or unsubstituted alkyl, R ^82C -substituted or unsubstituted heteroalkyl, R ^82C -substituted or

unsubstituted cycloalkyl, R ^82C -substituted or unsubstituted heterocycloalkyl, R ^82C -substituted or unsubstituted aryl, or R ^82C -substituted or unsubstituted heteroaryl. X ^81C is halogen. In embodiments, X ^81C is F. [0418] R ^82C is independently oxo,

halogen, -CX ^82C 3, -CHX ^82C 2, -OCH2X ^82C , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^82C ₃ , -OCHX ^82C ₂ , R ^83C -substituted or unsubstituted alkyl, R ^83C -substituted or unsubstituted heteroalkyl, R ^83C -substituted or unsubstituted cycloalkyl, R ^83C -substituted or unsubstituted heterocycloalkyl, R ^83C -substituted or unsubstituted aryl, or R ^83C -substituted or unsubstituted heteroaryl. X ^82C is halogen. In embodiments, X ^82C is F. [0419] In embodiments, R ^18D is independently hydrogen, oxo,

halogen, -CX ^18D 3, -CHX ^18D 2, -OCH2X ^18D , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ ,−NHNH ₂ ,−ONH ₂ ,−NHC=(O)NHNH ₂ ,−NHC=(O)NH ₂ , -NHSO ₂ H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^18D 3, -OCHX ^18D 2, R ^81D -substituted or unsubstituted alkyl, R ^81D -substituted or unsubstituted heteroalkyl, R ^81D -substituted or unsubstituted cycloalkyl, R ^81D -substituted or unsubstituted heterocycloalkyl, R ^81D -substituted or unsubstituted aryl, or R ^81D -substituted or unsubstituted heteroaryl. X ^18D is halogen. In embodiments, X ^18D is F. [0420] R ^81D is independently oxo,

halogen, -CX ^81D ₃ , -CHX ^81D ₂ , -OCH ₂ X ^81D , -OCHX ^81D ₂ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, - NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^81D 3, -OCHX ^81D 2, R ^82D -substituted or unsubstituted alkyl, R ^82D -substituted or unsubstituted heteroalkyl, R ^82D -substituted or

unsubstituted cycloalkyl, R ^82D -substituted or unsubstituted heterocycloalkyl, R ^82D -substituted or unsubstituted aryl, or R ^82D -substituted or unsubstituted heteroaryl. X ^81D is halogen. In embodiments, X ^81D is F. [0421] R ^82D is independently oxo,

halogen, -CX ^82D 3, -CHX ^82D 2, -OCH2X ^82D , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - SO3H, -SO4H, -SO2NH2,−NHNH2,−ONH2,−NHC=(O)NHNH2,−NHC=(O)NH2, -NHSO2H, - NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX ^82D 3, -OCHX ^82D 2, R ^83D -substituted or unsubstituted alkyl, R ^83D -substituted or unsubstituted heteroalkyl, R ^83D -substituted or unsubstituted cycloalkyl, R ^83D -substituted or unsubstituted heterocycloalkyl, R ^83D -substituted or unsubstituted aryl, or R ^83D -substituted or unsubstituted heteroaryl. X ^82D is halogen. In embodiments, X ^82D is F. [0422] R ⁷⁴ , R ⁷⁷ , R ⁸⁰ , R ⁸³ , R ^74A , R ^77A , R ^80A , R ^83A , R ^74B , R ^77B , R ^80B , R ^83B , R ^74C , R ^77C , R ^80C , R ^83C , R ^74D , R ^77D , R ^80D , R ^83D , R ⁸⁶ , R ⁸⁹ , R ⁹² , and R ⁹⁸ are independently hydrogen, oxo,

halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ , −NHNH2,−ONH2,−NHC(O)NHNH2,−NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R ⁷⁴ , R ⁷⁷ , R ⁸⁰ , R ⁸³ , R ^74A , R ^77A , R ^80A , R ^83A , R ^74B , R ^77B , R ^80B , R ^83B , R ^74C , R ^77C , R ^80C , R ^83C , R ^74D , R ^77D , R ^80D , R ^83D , R ⁸⁶ , R ⁸⁹ , R ⁹² , and R ⁹⁸ are independently oxo,

halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, −NHNH ₂ ,−ONH ₂ ,−NHC(O)NHNH ₂ ,−NHC(O)NH ₂ , -NHSO ₂ H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R ⁷⁴ , R ⁷⁷ , R ⁸⁰ , R ⁸³ , R ^74A , R ^77A , R ^80A , R ^83A , R ^74B , R ^77B , R ^80B , R ^83B , R ^74C , R ^77C , R ^80C , R ^83C , R ^74D , R ^77D , R ^80D , R ^83D , R ⁸⁶ , R ⁸⁹ , R ⁹² , and R ⁹⁸ are independently oxo,

halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -SO ₃ H, -SO ₄ H, -SO ₂ NH ₂ , −NHNH2,−ONH2,−NHC(O)NHNH2,−NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF3, -OCHF2, unsubstituted C1-C8 alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C3-C8 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. [0423] In embodiments, R ¹⁵ , R ¹⁶ , R ¹⁷ , and R ¹⁸ are hydrogen.

[0425] In some embodiments, a compound as described herein may include multiple instances of R ¹ or R ² , and/or other variables. In such embodiments, each variable may optional be different and be appropriately labeled to distinguish each group for greater clarity. For example, where each R ¹ and/or R ² , is different, they may be referred to, for example, as R ^1.1 , R ^1.2 , R ^1.3 , R ^1.4 , R ^1.5 , R ^2.1 , R ^2.2 , R ^2.3 , or R ^2.4 , respectively, wherein the definition of R ¹ is assumed by R ^1.1 , R ^1.2 , R ^1.3 , R ^1.4 , R ^1.5 ; and/or R ² is assumed by R ^2.1 , R ^2.2 , R ^2.3 , R ^2.4 . The variables used within a definition of R ¹ and/or R ² , and/or other variables that appear at multiple instances and are different may similarly be appropriately labeled to distinguish each group for greater clarity. In some embodiments, the compound is a compound described herein (e.g., in an aspect, embodiment, example, claim, table, scheme, drawing, or figure). [0426] In embodiments, unless otherwise indicated, a compound described herein is a racemic mixture of all stereoisomers. In embodiments, unless otherwise indicated, a compound described herein is a racemic mixture of all enantiomers. In embodiments, unless otherwise indicated, a compound described herein is a racemic mixture of two opposite stereoisomers. In

embodiments, unless otherwise indicated, a compound described herein is a racemic mixture of two opposite enantiomers. In embodiments, unless otherwise indicated, a compound described herein is a single stereoisomer. In embodiments, unless otherwise indicated, a compound described herein is a single enantiomer. In embodiments, the compound is a compound described herein (e.g., in an aspect, embodiment, example, figure, table, scheme, or claim). [0427] In an aspect is provided a Reticulon 4 inhibitor. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, shRNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein). In embodiments, the Reticulon 4 inhibitor contacts one or more amino acids

corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor covalently binds an amino acid corresponding to C1101 in human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1105 of human reticulon 4. In

embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to C1101 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1078 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to S1079 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to A1082 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to I1083 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to K1090 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to Y1091 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to S1094 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to G1097of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to H1098 of human reticulon 4. [0428] In an aspect is provided a Reticulon 4 inhibitor. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, shRNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein). In embodiments, the Reticulon 4 inhibitor contacts one or more amino acids

corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor covalently binds an amino acid corresponding to C1101 in of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of of SEQ ID NO:331. In embodiments, the

Reticulon 4 inhibitor contacts an amino acids corresponding to E1105 of of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to C1101 of of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids

corresponding to E1078 of of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to S1079 of of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to A1082 of of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to I1083 of of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to K1090 of of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to Y1091 of of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to S1094 of of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to G1097of of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids

corresponding to H1098 of of SEQ ID NO:331.

[0429] In embodiments, the compound has the formula:

wherein R ¹ , L ² , and E are as described herein, including embodiments. In embodiments, the , wherein R ¹ , L ¹ , and E are as described herein, including embodiments. In embodiments, R ¹ is independently

halogen, -CX ¹ 3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCX ¹ 3, -OCHX ¹ 2, -OCH2X ¹ , - CHX ¹ 2, -CH2X ¹ , substituted or unsubstituted C1-C8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹ is independently

halogen, -CX ¹ ₃ , -CN, unsubstituted C ₁ -C ₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹ is independently unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, or unsubstituted tert-butyl. In embodiments, R ¹ is independently unsubstituted methyl. In embodiments, R ¹ is independently unsubstituted ethyl. In embodiments, R ¹ is independently unsubstituted propyl. In embodiments, R ¹ is independently unsubstituted n- propyl. In embodiments, R ¹ is independently unsubstituted isopropyl. In embodiments, R ¹ is independently unsubstituted butyl. In embodiments, R ¹ is independently unsubstituted n-butyl. In embodiments, R ¹ is independently unsubstituted isobutyl. In embodiments, R ¹ is

independently unsubstituted tert-butyl. In embodiments, R ¹ is independently unsubstituted pentyl. In embodiments, R ¹ is independently unsubstituted hexyl. In embodiments, R ¹ is independently unsubstituted heptyl. In embodiments, R ¹ is independently unsubstituted octyl. In embodiments, R ¹ is independently -CF3. In embodiments, R ¹ is independently -CCl3. In embodiments, R ¹ is independently unsubstituted phenyl. In embodiments, R ¹ is independently unsubstituted pyridyl. In embodiments, R ¹ is independently halogen. In embodiments, R ¹ is independently -CN. In embodiments, R ¹ is independently -OH. In embodiments, R ¹ is independently -NH ₂ . In embodiments, R ¹ is independently -COOH. In embodiments, R ¹ is independently -CONH2. In embodiments, R ¹ is independently -NO2. In embodiments, R ¹ is independently -SH. In embodiments, R ¹ is independently -SO3H. In embodiments, R ¹ is independently -SO ₄ H. In embodiments, R ¹ is independently -SO ₂ NH ₂ . In embodiments, R ¹ is independently−NHNH ₂ . In embodiments, R ¹ is independently−ONH ₂ . In embodiments, R ¹ is independently−NHC(O)NHNH ₂ . In embodiments, R ¹ is independently−NHC(O)NH ₂ . In embodiments, R ¹ is independently -NHSO ₂ H. In embodiments, R ¹ is independently -NHC(O)H. In embodiments, R ¹ is independently -NHC(O)OH. In embodiments, R ¹ is

independently -NHOH. In embodiments, R ¹ is independently substituted or unsubstituted alkyl. In embodiments, R ¹ is independently substituted or unsubstituted heteroalkyl. In embodiments, R ¹ is independently substituted or unsubstituted cycloalkyl. In embodiments, R ¹ is

independently substituted or unsubstituted heterocycloalkyl. In embodiments, R ¹ is

independently substituted or unsubstituted aryl. In embodiments, R ¹ is independently substituted or unsubstituted heteroaryl. In embodiments, R ¹ is independently substituted alkyl. In embodiments, R ¹ is independently substituted heteroalkyl. In embodiments, R ¹ is independently substituted cycloalkyl. In embodiments, R ¹ is independently substituted heterocycloalkyl. In embodiments, R ¹ is independently substituted aryl. In embodiments, R ¹ is independently substituted heteroaryl. In embodiments, R ¹ is independently unsubstituted alkyl. In

embodiments, R ¹ is independently unsubstituted heteroalkyl. In embodiments, R ¹ is

independently unsubstituted cycloalkyl. In embodiments, R ¹ is independently unsubstituted heterocycloalkyl. In embodiments, R ¹ is independently unsubstituted aryl. In embodiments, R ¹ is independently unsubstituted heteroaryl. In embodiments, R ¹ is independently substituted or unsubstituted C ₁ -C ₈ alkyl. In embodiments, R ¹ is independently substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R ¹ is independently substituted or unsubstituted C ₃ - C8 cycloalkyl. In embodiments, R ¹ is independently substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R ¹ is independently substituted or unsubstituted C ₆ -C ₁₀ aryl. In embodiments, R ¹ is independently substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R ¹ is independently substituted C1-C8 alkyl. In embodiments, R ¹ is independently substituted 2 to 8 membered heteroalkyl. In embodiments, R ¹ is independently substituted C ₃ -C ₈ cycloalkyl. In embodiments, R ¹ is independently substituted 3 to 8 membered heterocycloalkyl. In embodiments, R ¹ is independently substituted C6-C10 aryl. In embodiments, R ¹ is independently substituted 5 to 10 membered heteroaryl. In embodiments, R ¹ is independently unsubstituted C1-C8 alkyl. In embodiments, R ¹ is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R ¹ is independently unsubstituted C ₃ -C ₈ cycloalkyl. In embodiments, R ¹ is independently unsubstituted 3 to 8 membered

heterocycloalkyl. In embodiments, R ¹ is independently unsubstituted C6-C10 aryl. In

embodiments, R ¹ is independently unsubstituted 5 to 10 membered heteroaryl. In embodiments, R ¹ is independently substituted or unsubstituted C ₁ -C ₄ alkyl. In embodiments, R ¹ is

independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹ is independently substituted or unsubstituted C3-C6 cycloalkyl. In embodiments, R ¹ is

independently substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R ¹ is independently substituted or unsubstituted phenyl. In embodiments, R ¹ is independently substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹ is independently substituted C ₁ -C ₄ alkyl. In embodiments, R ¹ is independently substituted 2 to 4 membered heteroalkyl. In embodiments, R ¹ is independently substituted C3-C6 cycloalkyl. In

embodiments, R ¹ is independently substituted 3 to 6 membered heterocycloalkyl. In

embodiments, R ¹ is independently substituted phenyl. In embodiments, R ¹ is independently substituted 5 to 6 membered heteroaryl. In embodiments, R ¹ is independently unsubstituted C ₁ - C4 alkyl. In embodiments, R ¹ is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ¹ is independently unsubstituted C3-C6 cycloalkyl. In embodiments, R ¹ is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R ¹ is independently unsubstituted phenyl. In embodiments, R ¹ is independently unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ¹ is independently -OH. In embodiments, R ¹ is independently -NH ₂ . In embodiments, R ¹ is independently -COOH. In embodiments, R ¹ is independently -CONH2. In embodiments, R ¹ is independently -NO2. In embodiments, R ¹ is independently -SH. In embodiments, R ¹ is independently -CF3. In embodiments, R ¹ is independently -CHF ₂ . In embodiments, R ¹ is independently -CH ₂ F. In embodiments, R ¹ is independently -OCF ₃ . In embodiments, R ¹ is independently -OCH ₂ F. In embodiments, R ¹ is independently -OCHF2. In embodiments, R ¹ is independently–OCH3. In embodiments, R ¹ is independently–OCH2CH3. In embodiments, R ¹ is independently–OCH2CH2CH3. In embodiments, R ¹ is independently–OCH(CH ₃ ) ₂ . In embodiments, R ¹ is independently– OC(CH3)3. In embodiments, R ¹ is independently–SCH3. In embodiments, R ¹ is independently –SCH2CH3. In embodiments, R ¹ is independently–SCH2CH2CH3. In embodiments, R ¹ is independently–SCH(CH ₃ ) ₂ . In embodiments, R ¹ is independently–SC(CH ₃ ) ₃ . In embodiments, R ¹ is independently–CH3. In embodiments, R ¹ is independently–CH2CH3. In embodiments, R ¹ is independently–CH2CH2CH3. In embodiments, R ¹ is independently–CH(CH3)2. In embodiments, R ¹ is independently–C(CH3)3. In embodiments, R ¹ is independently–F. In embodiments, R ¹ is independently–Cl. In embodiments, R ¹ is independently–Br. In embodiments, R ¹ is independently–I. [0430] In embodiments, R ¹ is R ²⁰ -substituted or unsubstituted methyl. In embodiments, R ¹ is R ²⁰ -substituted or unsubstituted C ₂ alkyl. In embodiments, R ¹ is R ²⁰ -substituted or unsubstituted C ₃ alkyl. In embodiments, R ¹ is R ²⁰ -substituted or unsubstituted C ₄ alkyl. In embodiments, R ¹ is R ²⁰ -substituted or unsubstituted C5 alkyl. In embodiments, R ¹ is R ²⁰ -substituted or unsubstituted C6 alkyl. In embodiments, R ¹ is R ²⁰ -substituted or unsubstituted C7 alkyl. In embodiments, R ¹ is R ²⁰ -substituted or unsubstituted C ₈ alkyl. In embodiments, R ¹ is R ²⁰ -substituted methyl. In embodiments, R ¹ is R ²⁰ -substituted C2 alkyl. In embodiments, R ¹ is R ²⁰ -substituted C3 alkyl. In embodiments, R ¹ is R ²⁰ -substituted C4 alkyl. In embodiments, R ¹ is R ²⁰ -substituted C5 alkyl. In embodiments, R ¹ is R ²⁰ -substituted C ₆ alkyl. In embodiments, R ¹ is R ²⁰ -substituted C ₇ alkyl. In embodiments, R ¹ is R ²⁰ -substituted C8 alkyl. In embodiments, R ¹ is an unsubstituted methyl. In embodiments, R ¹ is an unsubstituted C2 alkyl. In embodiments, R ¹ is an unsubstituted C3 alkyl. In embodiments, R ¹ is an unsubstituted C ₄ alkyl. In embodiments, R ¹ is an unsubstituted C ₅ alkyl. In embodiments, R ¹ is an unsubstituted C ₆ alkyl. In embodiments, R ¹ is an unsubstituted C7 alkyl. In embodiments, R ¹ is an unsubstituted C8 alkyl. [0431] In embodiments, the compound has the formula: . X ¹ , L ¹ , L ² , and E are as described herein. [0432] In embodiments, the compound has the formula:

. R ¹ and R ⁴ are as described herein. [0433] In embodiments, the compound has the formula: . R ⁴ is as described herein. [0434] In embodiments, the compound has the formula: . R ¹ , R ⁵ , and L ¹ are as described herein. [0435] In embodiments, the compound has the formula: . L ¹ and R ⁵ are as described herein. [0436] In embodiments, R ⁴ is independently substituted or unsubstituted alkyl. In

embodiments, R ⁴ is independently substituted or unsubstituted heteroalkyl. In embodiments, R ⁴ is independently substituted or unsubstituted cycloalkyl. In embodiments, R ⁴ is independently substituted or unsubstituted heterocycloalkyl. In embodiments, R ⁴ is independently substituted or unsubstituted aryl. In embodiments, R ⁴ is independently substituted or unsubstituted heteroaryl. In embodiments, R ⁴ is independently substituted alkyl. In embodiments, R ⁴ is independently substituted heteroalkyl. In embodiments, R ⁴ is independently substituted cycloalkyl. In embodiments, R ⁴ is independently substituted heterocycloalkyl. In embodiments, R ⁴ is independently substituted aryl. In embodiments, R ⁴ is independently substituted heteroaryl. In embodiments, R ⁴ is independently unsubstituted alkyl. In embodiments, R ⁴ is independently unsubstituted heteroalkyl. In embodiments, R ⁴ is independently unsubstituted cycloalkyl. In embodiments, R ⁴ is independently unsubstituted heterocycloalkyl. In embodiments, R ⁴ is independently unsubstituted aryl. In embodiments, R ⁴ is independently unsubstituted heteroaryl. In embodiments, R ⁴ is independently substituted or unsubstituted C ₁ -C ₈ alkyl. In embodiments, R ⁴ is independently substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R ⁴ is independently substituted or unsubstituted C3-C8 cycloalkyl. In embodiments, R ⁴ is independently substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R ⁴ is independently substituted or unsubstituted C ₆ -C ₁₀ aryl. In embodiments, R ⁴ is

independently substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R ⁴ is independently substituted C ₁ -C ₈ alkyl. In embodiments, R ⁴ is independently substituted 2 to 8 membered heteroalkyl. In embodiments, R ⁴ is independently substituted C3-C8 cycloalkyl. In embodiments, R ⁴ is independently substituted 3 to 8 membered heterocycloalkyl. In

embodiments, R ⁴ is independently substituted C ₆ -C ₁₀ aryl. In embodiments, R ⁴ is independently substituted 5 to 10 membered heteroaryl. In embodiments, R ⁴ is independently unsubstituted C1- C8 alkyl. In embodiments, R ⁴ is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R ⁴ is independently unsubstituted C ₃ -C ₈ cycloalkyl. In embodiments, R ⁴ is independently unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R ⁴ is independently unsubstituted C6-C10 aryl. In embodiments, R ⁴ is independently unsubstituted 5 to 10 membered heteroaryl. In embodiments, R ⁴ is independently substituted or unsubstituted C1- C ₄ alkyl. In embodiments, R ⁴ is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ⁴ is independently substituted or unsubstituted C3-C6 cycloalkyl. In embodiments, R ⁴ is independently substituted or unsubstituted 3 to 6 membered

heterocycloalkyl. In embodiments, R ⁴ is independently substituted or unsubstituted phenyl. In embodiments, R ⁴ is independently substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R ⁴ is independently substituted C1-C4 alkyl. In embodiments, R ⁴ is independently substituted 2 to 4 membered heteroalkyl. In embodiments, R ⁴ is independently substituted C ₃ -C ₆ cycloalkyl. In embodiments, R ⁴ is independently substituted 3 to 6 membered heterocycloalkyl. In embodiments, R ⁴ is independently substituted phenyl. In embodiments, R ⁴ is independently substituted 5 to 6 membered heteroaryl. In embodiments, R ⁴ is independently unsubstituted C1- C ₄ alkyl. In embodiments, R ⁴ is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R ⁴ is independently unsubstituted C3-C6 cycloalkyl. In embodiments, R ⁴ is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R ⁴ is independently unsubstituted phenyl. In embodiments, R ⁴ is independently unsubstituted 5 to 6 membered heteroaryl. [0437] In embodiments, R ⁴ is R ²⁹ -substituted or unsubstituted methyl. In embodiments, R ⁴ is R ²⁹ -substituted or unsubstituted C ₂ alkyl. In embodiments, R ⁴ is R ²⁹ -substituted or unsubstituted C ₃ alkyl. In embodiments, R ⁴ is R ²⁹ -substituted or unsubstituted C ₄ alkyl. In embodiments, R ⁴ is R ²⁹ -substituted or unsubstituted C5 alkyl. In embodiments, R ⁴ is R ²⁹ -substituted or unsubstituted C ₆ alkyl. In embodiments, R ⁴ is R ²⁹ -substituted or unsubstituted C ₇ alkyl. In embodiments, R ⁴ is R ²⁹ -substituted or unsubstituted C ₈ alkyl. In embodiments, R ⁴ is R ²⁹ -substituted methyl. In embodiments, R ⁴ is R ²⁹ -substituted C2 alkyl. In embodiments, R ⁴ is R ²⁹ -substituted C3 alkyl. In embodiments, R ⁴ is R ²⁹ -substituted C4 alkyl. In embodiments, R ⁴ is R ²⁹ -substituted C5 alkyl. In embodiments, R ⁴ is R ²⁹ -substituted C ₆ alkyl. In embodiments, R ⁴ is R ²⁹ -substituted C ₇ alkyl. In embodiments, R ⁴ is R ²⁹ -substituted C8 alkyl. In embodiments, R ⁴ is an unsubstituted methyl. In embodiments, R ⁴ is an unsubstituted C2 alkyl. In embodiments, R ⁴ is an unsubstituted C3 alkyl. In embodiments, R ⁴ is an unsubstituted C ₄ alkyl. In embodiments, R ⁴ is an unsubstituted C ₅ alkyl. In embodiments, R ⁴ is an unsubstituted C6 alkyl. In embodiments, R ⁴ is an unsubstituted C7 alkyl. In embodiments, R ⁴ is an unsubstituted C8 alkyl. [0438] In embodiments, R ⁴ is independently -OH. In embodiments, R ⁴ is independently -NH ₂ . In embodiments, R ⁴ is independently -COOH. In embodiments, R ⁴ is independently -CONH ₂ . In embodiments, R ⁴ is independently -CF3. In embodiments, R ⁴ is independently -CHF2. In embodiments, R ⁴ is independently -CH2F. In embodiments, R ⁴ is independently -OCF3. In embodiments, R ⁴ is independently -OCH ₂ F. In embodiments, R ⁴ is independently -OCHF ₂ . In embodiments, R ⁴ is independently–OCH3. In embodiments, R ⁴ is independently–OCH2CH3. In embodiments, R ⁴ is independently–OCH2CH2CH3. In embodiments, R ⁴ is independently– OCH(CH ₃ ) ₂ . In embodiments, R ⁴ is independently–OC(CH ₃ ) ₃ . In embodiments, R ⁴ is independently–SCH3. In embodiments, R ⁴ is independently–SCH2CH3. In embodiments, R ⁴ is independently–SCH2CH2CH3. In embodiments, R ⁴ is independently–SCH(CH3)2. In embodiments, R ⁴ is independently–SC(CH ₃ ) ₃ . In embodiments, R ⁴ is independently–CH ₃ . In embodiments, R ⁴ is independently–CH ₂ CH ₃ . In embodiments, R ⁴ is independently–

CH2CH2CH3. In embodiments, R ⁴ is independently–CH(CH3)2. In embodiments, R ⁴ is independently–C(CH ₃ ) ₃ . In embodiments, R ⁴ is independently hydrogen. [0439] In an aspect is provided a compound having the formula:

R ¹ , R ² , L ¹ , L ² , E, z1 and z2 are as described herein.

[0440] In embodiments, the compound has the formula:

(IIIa). R ¹ , R ² , z1 and z2 are as described herein.

[0441] In embodiments, the compound has the formula:

[0442] In embodiments, the compound is a compound described herein, including in an aspect, embodiment, claim, figure, table, example, or scheme. [0443] In embodiments, the compound has the formula: [0444] In embodiments, the compound has the formula:

.

[0445] In embodiments, the compound has the formula: .

[0450] In embodiments, the compound has the formula:

.

[0453] In embodiments, the compound has the formula:

III. Pharmaceutical compositions

[0456] In an aspect is provided a pharmaceutical composition including a Reticulon 4 inhibitor and a pharmaceutically acceptable excipient. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein). In embodiments, the Reticulon 4 inhibitor is included in a therapeutically effective amount. [0457] In an aspect is provided a pharmaceutical composition including a compound described herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0458] In embodiments of the pharmaceutical compositions, the compound, or

pharmaceutically acceptable salt thereof, is included in a therapeutically effective amount. [0459] In embodiments of the pharmaceutical compositions, the pharmaceutical composition includes a second agent (e.g. therapeutic agent). In embodiments of the pharmaceutical compositions, the pharmaceutical composition includes a second agent (e.g. therapeutic agent) in a therapeutically effective amount. In embodiments of the pharmaceutical compositions, the second agent is an agent for treating cancer. In embodiments, the second agent is an anti-cancer agent. In embodiments, the second agent is a chemotherapeutic. In embodiments, the second agent is an anti-inflammatory agent. IV. Methods of Treatment

[0460] In an aspect is provided a method of treating cancer, the method including

administering to a subject in need thereof an effective amount of a Reticulon 4 inhibitor. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein). In embodiments, the Reticulon 4 inhibitor is included in a therapeutically effective amount. In embodiments, the Reticulon 4 inhibitor is an antisense nucleic acid. [0461] In an aspect is provided a method of treating cancer including administering to a subject in need thereof an effective amount of a compound described herein. In embodiments, the cancer is colorectal cancer. In embodiments, the cancer is liver cancer. In embodiments, the cancer is hepatocellular cancer. In embodiments, the cancer is breast cancer. In embodiments, the cancer is estrogen receptor positive breast cancer. In embodiments, the cancer is estrogen receptor (ER) negative breast cancer. In embodiments, the cancer is tamoxifen resistant breast cancer. In embodiments, the cancer is HER2 negative breast cancer. In embodiments, the cancer is HER2 positive breast cancer. In embodiments, the cancer is low grade (well differentiated) breast cancer. In embodiments, the cancer is intermediate grade (moderately differentiated) breast cancer. In embodiments, the cancer is high grade (poorly differentiated) breast cancer. In embodiments, the cancer is stage 0 breast cancer. In embodiments, the cancer is stage I breast cancer. In embodiments, the cancer is stage II breast cancer. In embodiments, the cancer is stage III breast cancer. In embodiments, the cancer is stage IV breast cancer. In embodiments, the cancer is triple negative breast cancer. [0462] In an aspect is provided a method of treating a neurodegenerative disease, the method including administering to a subject in need thereof an effective amount of a Reticulon 4 inhibitor. In an aspect is provided a method of treating nerve damage, the method including administering to a subject in need thereof an effective amount of a Reticulon 4 inhibitor. In an aspect is provided a method of treating a traumatic brain injury, the method including

administering to a subject in need thereof an effective amount of a Reticulon 4 inhibitor. In an aspect is provided a method of treating a spinal cord injury, the method including administering to a subject in need thereof an effective amount of a Reticulon 4 inhibitor. In an aspect is provided a method of treating stroke, the method including administering to a subject in need thereof an effective amount of a Reticulon 4 inhibitor. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein). In embodiments, the Reticulon 4 inhibitor is included in a therapeutically effective amount. In embodiments, the neurodegenerative disease is ALS. In embodiments, the neurodegenerative disease is multiple sclerosis. [0463] In an aspect is provided a method of treating neurodegenerative disease including administering to a subject in need thereof an effective amount of a compound described herein. In an aspect is provided a method of treating nerve damage including administering to a subject in need thereof an effective amount of a compound described herein. In an aspect is provided a method of treating traumatic brain injury including administering to a subject in need thereof an effective amount of a compound described herein. In an aspect is provided a method of treating spinal cord injury including administering to a subject in need thereof an effective amount of a compound described herein. In an aspect is provided a method of treating stroke including administering to a subject in need thereof an effective amount of a compound described herein. In embodiments, the neurodegenerative disease is ALS. In embodiments, the neurodegenerative disease is multiple sclerosis. [0464] In an aspect is provided a method of treating a disease associated with reticulon 4 activity including administering to a subject in need thereof an effective amount of a Reticulon 4 inhibitor. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein). In embodiments, the disease is associated with aberrant reticulon 4 activity. [0465] In an aspect is provided a method of increasing nerve growth (e.g., neurite growth, neuron growth), the method including administering to a subject (e.g., contacting the nerve or neurite) in need thereof an effective amount of a Reticulon 4 inhibitor. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein). In embodiments, the Reticulon 4 inhibitor is included in a therapeutically effective amount. [0466] In an aspect is provided a method of increasing nerve growth (e.g., neurite growth, neuron growth) including administering to a subject (e.g., contacting the nerve or neurite) in need thereof an effective amount of a compound described herein. [0467] In embodiments, the method includes administering a second agent (e.g. therapeutic agent). In embodiments, the method includes administering a second agent (e.g. therapeutic agent) in a therapeutically effective amount. In embodiments, the second agent is an agent for treating cancer. In embodiments, the second agent is an anti-cancer agent. In embodiments, the second agent is a chemotherapeutic. In embodiments, the second agent is an agent for treating a neurodegenerative disease. In embodiments, the second agent is an agent for promoting nerve growth. In embodiments, the second agent is an agent for treating traumatic brain injury. In embodiments, the second agent is an agent for treating nerve damage. In embodiments, the second agent is an agent for treating spinal cord injury. In embodiments, the second agent is an agent for treating stroke. V. Methods of Inhibition

[0468] In an aspect is provided a method of inhibiting reticulon 4 activity including contacting the reticulon 4 with a Reticulon 4 inhibitor. In embodiments, the reticulon 4 is a human reticulon 4. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein). In embodiments, the Reticulon 4 inhibitor is provided in a therapeutically effective amount. [0469] In embodiments, the reticulon 4 is SEQ ID NO:333, SEQ ID NO:334, SEQ ID NO:335, SEQ ID NO:336, SEQ ID NO:337, SEQ ID NO:338, SEQ ID NO:339, SEQ ID NO:340, SEQ ID NO:331, SEQ ID NO:341, or SEQ ID NO:342. In embodiments, the reticulon 4 is SEQ ID NO:333. In embodiments, the reticulon 4 is SEQ ID NO:334. In embodiments, the reticulon 4 is SEQ ID NO:335. In embodiments, the reticulon 4 is SEQ ID NO:336. In embodiments, the reticulon 4 is SEQ ID NO:337. In embodiments, the reticulon 4 is SEQ ID NO:338. In embodiments, the reticulon 4 is SEQ ID NO:339. In embodiments, the reticulon 4 is SEQ ID NO:340. In embodiments, the reticulon 4 is SEQ ID NO:331. In embodiments, the reticulon 4 is SEQ ID NO:341. In embodiments, the reticulon 4 is SEQ ID NO:342. [0470] In embodiments, the Reticulon 4 inhibitor contacts one or more amino acids

corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of human reticulon 4 (e.g., SEQ ID NO:331). In embodiments, the Reticulon 4 inhibitor contacts one or more amino acids corresponding to E1105, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts one or more amino acids corresponding to E1105, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor covalently binds an amino acid corresponding to C1101 of SEQ ID NO:331 in human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1105, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. [0471] In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1105 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to C1101 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1078 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to S1079 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to A1082 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to I1083 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids

corresponding to K1090 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to Y1091 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to S1094 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to G1097of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to H1098 of SEQ ID NO:331. [0472] In an aspect is provided a method of inhibiting reticulon 4 activity including contacting the reticulon 4 with a compound described herein. In embodiments, the reticulon 4 is a human reticulon 4. In embodiments, the compound is provided in an effective amount. In

embodiments, the compound is provided in a therapeutically effective amount. In embodiments, the method includes contacting the reticulon 4 protein with an effective amount of a compound described herein. In embodiments, compound is covalently bonded to the amino acid

corresponding to C1101 of SEQ ID NO:331. In embodiments, the compound contacts one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the compound contacts one or more amino acids corresponding to E1105, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the compound covalently binds an amino acid corresponding to C1101 in SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to E1105, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to E1105 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to C1101 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to E1078 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to S1079 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to A1082 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to I1083 of SEQ ID

NO:331. In embodiments, the compound contacts an amino acids corresponding to K1090 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to Y1091 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids

corresponding to S1094 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to G1097of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to H1098 of SEQ ID NO:331. [0473] In embodiments, the compound contacts a cysteine in a sequence described herein. In embodiments, the sequence is (SEQ ID NO:1). In embodiments, the sequence is (SEQ ID NO:2). In embodiments, the sequence is (SEQ ID NO:3). In embodiments, the sequence is (SEQ ID NO:4). In embodiments, the sequence is (SEQ ID NO:5). In embodiments, the sequence is (SEQ ID NO:6). In embodiments, the sequence is (SEQ ID NO:7). In embodiments, the sequence is (SEQ ID NO:8). In embodiments, the sequence is (SEQ ID NO:9). In embodiments, the sequence is (SEQ ID NO:10). In embodiments, the sequence is (SEQ ID NO:11). In

embodiments, the sequence is (SEQ ID NO:12). In embodiments, the sequence is (SEQ ID NO:13). In embodiments, the sequence is (SEQ ID NO:14). In embodiments, the sequence is (SEQ ID NO:15). In embodiments, the sequence is (SEQ ID NO:16). In embodiments, the sequence is (SEQ ID NO:17). In embodiments, the sequence is (SEQ ID NO:18). In

embodiments, the sequence is (SEQ ID NO:19). In embodiments, the sequence is (SEQ ID NO:20). In embodiments, the sequence is (SEQ ID NO:21). In embodiments, the sequence is (SEQ ID NO:22). In embodiments, the sequence is (SEQ ID NO:23). In embodiments, the sequence is (SEQ ID NO:24). In embodiments, the sequence is (SEQ ID NO:25). In

embodiments, the sequence is (SEQ ID NO:26). In embodiments, the sequence is (SEQ ID NO:27). In embodiments, the sequence is (SEQ ID NO:28). In embodiments, the sequence is (SEQ ID NO:29). In embodiments, the sequence is (SEQ ID NO:30). In embodiments, the sequence is (SEQ ID NO:31). In embodiments, the sequence is (SEQ ID NO:32). In

embodiments, the sequence is (SEQ ID NO:33). In embodiments, the sequence is (SEQ ID NO:34). In embodiments, the sequence is (SEQ ID NO:35). In embodiments, the sequence is (SEQ ID NO:36). In embodiments, the sequence is (SEQ ID NO:37). In embodiments, the sequence is (SEQ ID NO:38). In embodiments, the sequence is (SEQ ID NO:39). In

embodiments, the sequence is (SEQ ID NO:40). In embodiments, the sequence is (SEQ ID NO:41). In embodiments, the sequence is (SEQ ID NO:42). In embodiments, the sequence is (SEQ ID NO:43). In embodiments, the sequence is (SEQ ID NO:44). In embodiments, the sequence is (SEQ ID NO:45). In embodiments, the sequence is (SEQ ID NO:46). In embodiments, the sequence is (SEQ ID NO:47). In embodiments, the sequence is (SEQ ID NO:48). In embodiments, the sequence is (SEQ ID NO:49). In embodiments, the sequence is (SEQ ID NO:50). In embodiments, the sequence is (SEQ ID NO:51). In embodiments, the sequence is (SEQ ID NO:52). In embodiments, the sequence is (SEQ ID NO:53). In embodiments, the sequence is (SEQ ID NO:54). In embodiments, the sequence is (SEQ ID NO:55). In embodiments, the sequence is (SEQ ID NO:56). In embodiments, the sequence is (SEQ ID NO:57). In embodiments, the sequence is (SEQ ID NO:58). In embodiments, the sequence is (SEQ ID NO:59). In embodiments, the sequence is (SEQ ID NO:60). In embodiments, the sequence is (SEQ ID NO:61). In embodiments, the sequence is (SEQ ID NO:62). In embodiments, the sequence is (SEQ ID NO:63). In embodiments, the sequence is (SEQ ID NO:64). In embodiments, the sequence is (SEQ ID NO:65). In embodiments, the sequence is (SEQ ID NO:66). In embodiments, the sequence is (SEQ ID NO:67). In embodiments, the sequence is (SEQ ID NO:68). In embodiments, the sequence is (SEQ ID NO:69). In embodiments, the sequence is (SEQ ID NO:70). In embodiments, the sequence is (SEQ ID NO:71). In embodiments, the sequence is (SEQ ID NO:72). In embodiments, the sequence is (SEQ ID NO:73). In embodiments, the sequence is (SEQ ID NO:74). In embodiments, the sequence is (SEQ ID NO:75). In embodiments, the sequence is (SEQ ID NO:76). In embodiments, the sequence is (SEQ ID NO:77). In embodiments, the sequence is (SEQ ID NO:78). In embodiments, the sequence is (SEQ ID NO:79). In embodiments, the sequence is (SEQ ID NO:80). In embodiments, the sequence is (SEQ ID NO:81). In embodiments, the sequence is (SEQ ID NO:82). In embodiments, the sequence is (SEQ ID NO:83). In embodiments, the sequence is (SEQ ID NO:84). In embodiments, the sequence is (SEQ ID NO:85). In embodiments, the sequence is (SEQ ID NO:86). In embodiments, the sequence is (SEQ ID NO:87). In embodiments, the sequence is (SEQ ID NO:88). In embodiments, the sequence is (SEQ ID NO:89). In embodiments, the sequence is (SEQ ID NO:90). In embodiments, the sequence is (SEQ ID NO:91). In embodiments, the sequence is (SEQ ID NO:92). In embodiments, the sequence is (SEQ ID NO:93). In embodiments, the sequence is (SEQ ID NO:94). In embodiments, the sequence is (SEQ ID NO:95). In embodiments, the sequence is (SEQ ID NO:96). In embodiments, the sequence is (SEQ ID NO:97). In embodiments, the sequence is (SEQ ID NO:98). In embodiments, the sequence is (SEQ ID NO:99). In embodiments, the sequence is (SEQ ID NO:100). In embodiments, the sequence is (SEQ ID NO:101). In embodiments, the sequence is (SEQ ID NO:102). In embodiments, the sequence is (SEQ ID NO:103). In embodiments, the sequence is (SEQ ID NO:104). In embodiments, the sequence is (SEQ ID NO:105). In embodiments, the sequence is (SEQ ID NO:106). In embodiments, the sequence is (SEQ ID NO:107). In embodiments, the sequence is (SEQ ID NO:108). In embodiments, the sequence is (SEQ ID NO:109). In embodiments, the sequence is (SEQ ID NO:110). In embodiments, the sequence is (SEQ ID NO:111). In embodiments, the sequence is (SEQ ID NO:112). In embodiments, the sequence is (SEQ ID NO:113). In embodiments, the sequence is (SEQ ID NO:114). In embodiments, the sequence is (SEQ ID NO:115). In embodiments, the sequence is (SEQ ID NO:116). In embodiments, the sequence is (SEQ ID NO:117). In embodiments, the sequence is (SEQ ID NO:118). In embodiments, the sequence is (SEQ ID NO:119). In embodiments, the sequence is (SEQ ID NO:120). In embodiments, the sequence is (SEQ ID NO:121). In embodiments, the sequence is (SEQ ID NO:122). In embodiments, the sequence is (SEQ ID NO:123). In embodiments, the sequence is (SEQ ID NO:124). In embodiments, the sequence is (SEQ ID NO:125). In embodiments, the sequence is (SEQ ID NO:126). In embodiments, the sequence is (SEQ ID NO:127). In embodiments, the sequence is (SEQ ID NO:128). In embodiments, the sequence is (SEQ ID NO:129). In embodiments, the sequence is (SEQ ID NO:130). In embodiments, the sequence is (SEQ ID NO:131). In embodiments, the sequence is (SEQ ID NO:132). In embodiments, the sequence is (SEQ ID NO:133). In embodiments, the sequence is (SEQ ID NO:134). In embodiments, the sequence is (SEQ ID NO:135). In embodiments, the sequence is (SEQ ID NO:136). In embodiments, the sequence is (SEQ ID NO:137). In embodiments, the sequence is (SEQ ID NO:138). In embodiments, the sequence is (SEQ ID NO:139). In embodiments, the sequence is (SEQ ID NO:140). In embodiments, the sequence is (SEQ ID NO:141). In embodiments, the sequence is (SEQ ID NO:142). In embodiments, the sequence is (SEQ ID NO:143). In embodiments, the sequence is (SEQ ID NO:144). In embodiments, the sequence is (SEQ ID NO:145). In embodiments, the sequence is (SEQ ID NO:146). In embodiments, the sequence is (SEQ ID NO:147). In embodiments, the sequence is (SEQ ID NO:148). In embodiments, the sequence is (SEQ ID NO:149). In embodiments, the sequence is (SEQ ID NO:150). In embodiments, the sequence is (SEQ ID NO:151). In embodiments, the sequence is (SEQ ID NO:152). In embodiments, the sequence is (SEQ ID NO:153). In embodiments, the sequence is (SEQ ID NO:154). In embodiments, the sequence is (SEQ ID NO:155). In embodiments, the sequence is (SEQ ID NO:156). In embodiments, the sequence is (SEQ ID NO:157). In embodiments, the sequence is (SEQ ID NO:158). In embodiments, the sequence is (SEQ ID NO:159). In embodiments, the sequence is (SEQ ID NO:160). In embodiments, the sequence is (SEQ ID NO:161). In embodiments, the sequence is (SEQ ID NO:162). In embodiments, the sequence is (SEQ ID NO:163). In embodiments, the sequence is (SEQ ID NO:164). In embodiments, the sequence is (SEQ ID NO:165). In embodiments, the sequence is (SEQ ID NO:166). In embodiments, the sequence is (SEQ ID NO:167). In embodiments, the sequence is (SEQ ID NO:168). In embodiments, the sequence is (SEQ ID NO:169). In embodiments, the sequence is (SEQ ID NO:170). In embodiments, the sequence is (SEQ ID NO:171). In embodiments, the sequence is (SEQ ID NO:172). In embodiments, the sequence is (SEQ ID NO:173). In embodiments, the sequence is (SEQ ID NO:174). In embodiments, the sequence is (SEQ ID NO:175). In embodiments, the sequence is (SEQ ID NO:176). In embodiments, the sequence is (SEQ ID NO:177). In embodiments, the sequence is (SEQ ID NO:178). In embodiments, the sequence is (SEQ ID NO:179). In embodiments, the sequence is (SEQ ID NO:180). In embodiments, the sequence is (SEQ ID NO:181). In embodiments, the sequence is (SEQ ID NO:182). In embodiments, the sequence is (SEQ ID NO:183). In embodiments, the sequence is (SEQ ID NO:184). In embodiments, the sequence is (SEQ ID NO:185). In embodiments, the sequence is (SEQ ID NO:186). In embodiments, the sequence is (SEQ ID NO:187). In embodiments, the sequence is (SEQ ID NO:188). In embodiments, the sequence is (SEQ ID NO:189). In embodiments, the sequence is (SEQ ID NO:190). In embodiments, the sequence is (SEQ ID NO:191). In embodiments, the sequence is (SEQ ID NO:192). In embodiments, the sequence is (SEQ ID NO:193). In embodiments, the sequence is (SEQ ID NO:194). In embodiments, the sequence is (SEQ ID NO:195). In embodiments, the sequence is (SEQ ID NO:196). In embodiments, the sequence is (SEQ ID NO:197). In embodiments, the sequence is (SEQ ID NO:198). In embodiments, the sequence is (SEQ ID NO:199). In embodiments, the sequence is (SEQ ID NO:200). In embodiments, the sequence is (SEQ ID NO:201). In embodiments, the sequence is (SEQ ID NO:202). In embodiments, the sequence is (SEQ ID NO:203). In embodiments, the sequence is (SEQ ID NO:204). In embodiments, the sequence is (SEQ ID NO:205). In embodiments, the sequence is (SEQ ID NO:206). In embodiments, the sequence is (SEQ ID NO:207). In embodiments, the sequence is (SEQ ID NO:208). In embodiments, the sequence is (SEQ ID NO:209). In embodiments, the sequence is (SEQ ID NO:210). In embodiments, the sequence is (SEQ ID NO:211). In embodiments, the sequence is (SEQ ID NO:212). In embodiments, the sequence is (SEQ ID NO:213). In embodiments, the sequence is (SEQ ID NO:214). In embodiments, the sequence is (SEQ ID NO:215). In embodiments, the sequence is (SEQ ID NO:216). In embodiments, the sequence is (SEQ ID NO:217). In embodiments, the sequence is (SEQ ID NO:218). In embodiments, the sequence is (SEQ ID NO:219). In embodiments, the sequence is (SEQ ID NO:220). In embodiments, the sequence is (SEQ ID NO:221). In embodiments, the sequence is (SEQ ID NO:222). In embodiments, the sequence is (SEQ ID NO:223). In embodiments, the sequence is (SEQ ID NO:224). In embodiments, the sequence is (SEQ ID NO:225). In embodiments, the sequence is (SEQ ID NO:226). In embodiments, the sequence is (SEQ ID NO:227). In embodiments, the sequence is (SEQ ID NO:228). In embodiments, the sequence is (SEQ ID NO:229). In embodiments, the sequence is (SEQ ID NO:230). In embodiments, the sequence is (SEQ ID NO:231). In embodiments, the sequence is (SEQ ID NO:232). In embodiments, the sequence is (SEQ ID NO:233). In embodiments, the sequence is (SEQ ID NO:234). In embodiments, the sequence is (SEQ ID NO:235). In embodiments, the sequence is (SEQ ID NO:236). In embodiments, the sequence is (SEQ ID NO:237). In embodiments, the sequence is (SEQ ID NO:238). In embodiments, the sequence is (SEQ ID NO:239). In embodiments, the sequence is (SEQ ID NO:240). In embodiments, the sequence is (SEQ ID NO:241). In embodiments, the sequence is (SEQ ID NO:242). In embodiments, the sequence is (SEQ ID NO:243). In embodiments, the sequence is (SEQ ID NO:244). In embodiments, the sequence is (SEQ ID NO:245). In embodiments, the sequence is (SEQ ID NO:246). In embodiments, the sequence is (SEQ ID NO:247). In embodiments, the sequence is (SEQ ID NO:248). In embodiments, the sequence is (SEQ ID NO:249). In embodiments, the sequence is (SEQ ID NO:250). In embodiments, the sequence is (SEQ ID NO:251). In embodiments, the sequence is (SEQ ID NO:252). In embodiments, the sequence is (SEQ ID NO:253). In embodiments, the sequence is (SEQ ID NO:254). In embodiments, the sequence is (SEQ ID NO:255). In embodiments, the sequence is (SEQ ID NO:256). In embodiments, the sequence is (SEQ ID NO:257). In embodiments, the sequence is (SEQ ID NO:258). In embodiments, the sequence is (SEQ ID NO:259). In embodiments, the sequence is (SEQ ID NO:260). In embodiments, the sequence is (SEQ ID NO:261). In embodiments, the sequence is (SEQ ID NO:262). In embodiments, the sequence is (SEQ ID NO:263). In embodiments, the sequence is (SEQ ID NO:264). In embodiments, the sequence is (SEQ ID NO:265). In embodiments, the sequence is (SEQ ID NO:266). In embodiments, the sequence is (SEQ ID NO:267). In embodiments, the sequence is (SEQ ID NO:268). In embodiments, the sequence is (SEQ ID NO:269). In embodiments, the sequence is (SEQ ID NO:270). In embodiments, the sequence is (SEQ ID NO:271). In embodiments, the sequence is (SEQ ID NO:272). In embodiments, the sequence is (SEQ ID NO:273). In embodiments, the sequence is (SEQ ID NO:274). In embodiments, the sequence is (SEQ ID NO:275). In embodiments, the sequence is (SEQ ID NO:276). In embodiments, the sequence is (SEQ ID NO:277). In embodiments, the sequence is (SEQ ID NO:278). In embodiments, the sequence is (SEQ ID NO:279). In embodiments, the sequence is (SEQ ID NO:280). In embodiments, the sequence is (SEQ ID NO:281). In embodiments, the sequence is (SEQ ID NO:282). In embodiments, the sequence is (SEQ ID NO:283). In embodiments, the sequence is (SEQ ID NO:284). In embodiments, the sequence is (SEQ ID NO:285). In embodiments, the sequence is (SEQ ID NO:286). In embodiments, the sequence is (SEQ ID NO:287). In embodiments, the sequence is (SEQ ID NO:288). In embodiments, the sequence is (SEQ ID NO:289). In embodiments, the sequence is (SEQ ID NO:290). In embodiments, the sequence is (SEQ ID NO:291). In embodiments, the sequence is (SEQ ID NO:292). In embodiments, the sequence is (SEQ ID NO:293). In embodiments, the sequence is (SEQ ID NO:294). In embodiments, the sequence is (SEQ ID NO:295). In embodiments, the sequence is (SEQ ID NO:296). In embodiments, the sequence is (SEQ ID NO:297). In embodiments, the sequence is (SEQ ID NO:298). In embodiments, the sequence is (SEQ ID NO:299). In embodiments, the sequence is (SEQ ID NO:300). In embodiments, the sequence is (SEQ ID NO:301). In embodiments, the sequence is (SEQ ID NO:302). In embodiments, the sequence is (SEQ ID NO:303). In embodiments, the sequence is (SEQ ID NO:304). In embodiments, the sequence is (SEQ ID NO:305). In embodiments, the sequence is (SEQ ID NO:306). In embodiments, the sequence is (SEQ ID NO:307). In embodiments, the sequence is (SEQ ID NO:308). In embodiments, the sequence is (SEQ ID NO:309). In embodiments, the sequence is (SEQ ID NO:310). In embodiments, the sequence is (SEQ ID NO:311). In embodiments, the sequence is (SEQ ID NO:312). In embodiments, the sequence is (SEQ ID NO:313). In embodiments, the sequence is (SEQ ID NO:314). In embodiments, the sequence is (SEQ ID NO:315). In embodiments, the sequence is (SEQ ID NO:316). In embodiments, the sequence is (SEQ ID NO:317). In embodiments, the sequence is (SEQ ID NO:318). In embodiments, the sequence is (SEQ ID NO:319). In embodiments, the sequence is (SEQ ID NO:320). In embodiments, the sequence is (SEQ ID NO:321). In embodiments, the sequence is (SEQ ID NO:322). In embodiments, the sequence is (SEQ ID NO:323). In embodiments, the sequence is (SEQ ID NO:324). In embodiments, the sequence is (SEQ ID NO:325). In embodiments, the sequence is (SEQ ID NO:326). In embodiments, the sequence is (SEQ ID NO:327). In embodiments, the sequence is (SEQ ID NO:328). In embodiments, the sequence is (SEQ ID NO:329). In embodiments, the sequence is (SEQ ID NO:330). In embodiments, the sequence is (SEQ ID NO:331). In embodiments, the sequence is (SEQ ID NO:332). In embodiments, the sequence is (SEQ ID NO:333). In embodiments, the sequence is (SEQ ID NO:334). In embodiments, the sequence is (SEQ ID NO:335). In embodiments, the sequence is (SEQ ID NO:336). In embodiments, the sequence is (SEQ ID NO:337). In embodiments, the sequence is (SEQ ID NO:338). In embodiments, the sequence is (SEQ ID NO:339). In embodiments, the sequence is (SEQ ID NO:340). In embodiments, the sequence is (SEQ ID NO:341). In embodiments, the sequence is (SEQ ID NO:342). In embodiments, the sequence is (SEQ ID NO:343). [0474] In embodiments, the inhibition is competitive inhibition. In embodiments, the inhibition is irreversible. In embodiments, the inhibition is reversible. In embodiments, the compound covalently binds to the reticulon 4 protein. [0475] Where the compound covalently binds to the reticulon 4 a reticulon 4 protein (e.g., human reticulon 4) covalently bonded to a reticulon 4 inhibitor is formed (also referred to herein as a“reticulon 4 -compound adduct”), as described below. In embodiments, the resulting covalent bond is reversible. Where the resulting covalent bond is reversible, the bonding reverses upon denaturation of the protein. Thus, in embodiments, the reversibility of a covalent bond between the compound and the reticulon 4 upon denaturation of the reticulon 4 avoids or decreases autoimmune response in a subject subsequent to administration of the compound (relative to irreversibility). Moreover, in embodiments, the reversibility of a covalent bond between the compound and the reticulon 4 upon denaturation of the reticulon 4 avoids or decreases the toxicity (e.g. liver toxicity) of the compound in a subject (relative to

irreversibility). [0476] In embodiments, the reticulon 4 activity is endoplasmic reticulum (ER) tubule formation. In embodiments, the reticulon 4 activity is an increase in endoplasmic reticulum (ER) tubule formation. In embodiments, the reticulon 4 activity is RTN 4 membrane associate. In embodiments, the reticulon 4 activity is RTN 4 membrane contact. In embodiments, the reticulon 4 activity is increasing ER tubule networks. In embodiments, the reticulon 4 activity is nuclear envelope assembly (e.g., during mitosis). In embodiments, the reticulon 4 activity is nuclear envelope formation (e.g., during mitosis). In embodiments, the reticulon 4 activity is nuclear envelope disassembly (e.g., during mitosis). In embodiments, the reticulon 4 activity is increasing cell division. In embodiments, the reticulon 4 activity is increasing the rate of cell divisional. In embodiments, the reticulon 4 activity is promoting cell division. In embodiments, the reticulon 4 activity is completing cell division. In embodiments, the reticulon 4 activity is maintaining natural nuclear envelope morphology (e.g., during mitosis). In embodiments, the reticulon 4 activity is maintaining natural interphase nuclear envelope morphology. In embodiments, the reticulon 4 activity is nuclear envelope remodeling (e.g., during mitosis). In embodiments, the reticulon 4 activity is inhibition of neurite cell growth. In embodiments, the reticulon 4 activity is neuron growth. In embodiments, the reticulon 4 activity is neuron survival. In embodiments, the reticulon 4 activity is neuron proliferation. In embodiments, the reticulon 4 activity is completing mitosis. In embodiments, the reticulon 4 activity is increasing the rate of mitosis (e.g, compared to lack of RTN 4 activity). [0477] In an aspect is provided a method of inhibiting cell divisional (e.g., cancer cell division, cancer proliferation), the method including contacting a cell (e.g., cancer cell) with an effective amount of a Reticulon 4 inhibitor. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein). [0478] In an aspect is provided a method of inhibiting cell divisional (e.g., cancer cell division, cancer proliferation) including contacting a cell (e.g., cancer cell) with an effective amount of a compound described herein. VI. Reticulon 4 protein

[0479] In an aspect is provided a reticulon 4 protein covalently bonded to a Reticulon 4 inhibitor (a reticulon 4 protein-reticulon 4 inhibitor complex). In embodiments, the reticulon 4 is a human reticulon 4. In embodiments, the reticulon 4 is has the sequence SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein). In embodiments, the Reticulon 4 inhibitor is provided in a therapeutically effective amount. In embodiments, the Reticulon 4 inhibitor contacts one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor covalently binds an amino acid corresponding to C1101 in SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1105 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to C1101 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1078 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to S1079 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to A1082 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to I1083 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to K1090 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to Y1091 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to S1094 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to G1097of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to H1098 of SEQ ID NO:331. [0480] In an aspect is provided a reticulon 4 protein covalently bonded to a compound described herein. In embodiments, compound is covalently bonded to the amino acid corresponding to C1101 of SEQ ID NO:331. In embodiments, the compound contacts one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the compound covalently binds an amino acid corresponding to C1101 in SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to E1105 of SEQ ID NO:331. In

embodiments, the compound contacts an amino acids corresponding to C1101 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to E1078 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to S1079 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids

corresponding to A1082 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to I1083 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to K1090 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to Y1091 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to S1094 of SEQ ID NO:331. In

embodiments, the compound contacts an amino acids corresponding to G1097of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to H1098 of SEQ ID NO:331. [0481] In embodiments, the compound is bonded to a cysteine residue of the reticulon 4 protein. In embodiments, the compound is covalently bonded to a cysteine residue of the reticulon 4 protein. In embodiments, the compound is reversibly covalently bonded to a cysteine residue of the reticulon 4 protein. In embodiments, the compound is irreversibly covalently bonded to a cysteine residue of the reticulon 4 protein. In embodiments, the cysteine residue corresponds to C1101 of SEQ ID NO:331. [0482] In an embodiment, the reticulon 4 protein is covalently bonded (e.g., reversibly or irreversibly) to a portion of a compound described herein (e.g., portion of a reticulon 4 inhibitor or portion of a compound described herein). [0483] In an aspect is provided a reticulon 4 protein (e.g., human reticulon 4) covalently bonded to a reticulon 4 inhibitor (e.g., reticulon 4 inhibitor, compound described herein, or a portion of a compound described herein). [0484] In embodiments, the reticulon 4 protein (e.g., human reticulon 4) is covalently bonded to a reticulon 4 inhibitor (e.g., compound described herein or a portion of a compound described herein). In embodiments, the reticulon 4 protein (e.g., human reticulon 4) is irreversibly covalently bonded to a reticulon 4 inhibitor (e.g., compound described herein or a portion of a compound described herein). In embodiments, the reticulon 4 protein (e.g., human reticulon 4) is reversibly covalently bonded to a reticulon 4 inhibitor (e.g., compound described herein or a portion of a compound described herein). In embodiments, the reticulon 4 protein (e.g., human reticulon 4) is covalently bonded to a portion of a reticulon 4 inhibitor (e.g., compound described herein). In embodiments, the reticulon 4 protein (e.g., human reticulon 4) is irreversibly covalently bonded to a portion of a reticulon 4 inhibitor (e.g., compound described herein). In embodiments, the reticulon 4 protein (e.g., human reticulon 4) is reversibly covalently bonded to a portion of a reticulon 4 inhibitor (e.g., compound described herein). In embodiments, the reticulon 4 inhibitor (e.g., compound described herein) is bonded to a cysteine residue (e.g., Cys1101 of human reticulon 4 or cysteine corresponding to Cys1101 of human reticulon 4) of the reticulon 4 protein (e.g., human reticulon 4). In embodiments, the portion of a reticulon 4 inhibitor (e.g., compound described herein) is bonded to a cysteine residue (e.g., Cys1101 of SEQ ID NO:331 or cysteine corresponding to Cys1101 of SEQ ID NO:331) of the reticulon 4 protein (e.g., human reticulon 4). [0485] In embodiments, the RTN4 protein covalently bonded to a RTN4 inhibitor or compound described herein is the product of a reaction between the RTN4 protein and a RTN4 inhibitor or compound described herein. It will be understood that the covalently bonded RTN4 protein and RTN4 inhibitor (e.g., compound described herein) are the remnants of the reactant RTN4 protein and RTN4 inhibitor or compound, wherein each reactant now participates in the covalent bond between the RTN4 protein and RTN4 inhibitor or compound. In embodiments of the covalently bonded RTN4 protein and compound described herein, the remnant of the E substitutent is a linker including a covalent bond between the RTN4 protein and the remainder of the compound described herein. It will be understood by a person of ordinary skill in the art that when a RTN4 protein is covalently bonded to a RTN4 inhibitor (e.g., compound described herein), the RTN4 inhibitor (e.g., compound described herein) forms a remnant of the pre- reacted RTN4 inhibitor (e.g., compound described herein) wherein a bond connects the remnant of the RTN4 inhibitor (e.g., compound described herein) to the remnant of the RTN4 protein (e.g., cysteine sulfur, sulfur of amino acid corresponding to C1101 of human RTN4, sulfur of C1101 of human RTN4). The remnant of the RTN4 inhibitor (compound described herein) may also be called a portion of the RTN4 inhibitor. In embodiments, the remnant of the E substituent is a linker selected from a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-,

-NHC(O)NH-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -CH2NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted

heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene (e.g., C ₆ -C ₁₀ or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). As a non-limiting example, the RTN4 protein covalently bonded to a RTN4 inhibitor may have the formula: , wherein S is the sulfur of a reticulon 4 protein cysteine (e.g., corresponding to C1101 of human reticulon 4), which is bonded to the remainder of the reticulon 4 protein and wherein R ¹ , R ² , L ¹ , L ² , z1, and z2 are as described herein. As a non-limiting example, the RTN4 protein covalently bonded to a RTN4 inhibitor may have the formula: , wherein S is the sulfur of a reticulon 4 protein cysteine (e.g., corresponding to C1101 of human reticulon 4), which is bonded to the remainder of the reticulon 4 protein and wherein R ¹ , R ² , R ¹⁵ , R ¹⁷ , L ¹ , L ² , z1, and z2 are as described herein. As a non-limiting example, the RTN4 protein covalently bonded to a RTN4 inhibitor may have the formula:

, wherein S is the sulfur of a reticulon 4 protein cysteine (e.g., corresponding to C1101 of human reticulon 4), which is bonded to the remainder of the reticulon 4 protein and wherein R ¹ , R ² , R ¹⁶ , R ¹⁷ , L ¹ , L ² , z1, and z2 are as described herein. VII. Embodiments

[0486] Embodiment P1. A compound having the formula:

wherein, R ¹ is independently halogen, -CX ¹ 3, -CHX ¹ 2, -CH2X ¹ , -OCX ¹ 3, - OCH ₂ X ¹ , -OCHX ¹ ₂ , -CN, -SO _n1 R ^1D , -SO _v1 NR ^1A R ^1B , -NHC(O)NR ^1A R ^1B , -N(O) _m1 , -NR ^1A R ^1B , -C( O)R ^1C , -C(O)-OR ^1C , -C(O)NR ^1A R ^1B , -OR ^1D , -NR ^1A SO2R ^1D , -NR ^1A C(O)R ^1C , -NR ^1A C(O)OR ^1C , -N R ^1A OR ^1C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or

unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z1 is an integer from 0 to 5;

R ² is independently halogen, -CX ² 3, -CHX ² 2, -CH2X ² , -OCX ² 3, - OCH2X ² , -OCHX ² 2, -CN, -SOn2R ^2D , -SOv2NR ^2A R ^2B , -NHC(O)NR ^2A R ^2B , -N(O)m2, -NR ^2A R ^2B , -C( O)R ^2C , -C(O)-OR ^2C , -C(O)NR ^2A R ^2B , -OR ^2D , -NR ^2A SO ₂ R ^2D , -NR ^2A C(O)R ^2C , -NR ^2A C(O)OR ^2C , -N R ^2A OR ^2C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or

unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z2 is an integer from 0 to 4; L ¹ is a

bond, -S(O)2-, -NR ⁴ -, -O-, -S-, -C(O)-, -C(O)NR ⁴ -, -NR ⁴ C(O)-, -NR ⁴ C(O)NH-, -NHC(O)NR ⁴ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted

heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R ⁴ is hydrogen, -CX ⁴ 3, -CHX ⁴ 2, -CH2X ⁴ , -OCX ⁴ 3, - OCH ₂ X ⁴ , -OCHX ⁴ ₂ , -CN, - -C(O)R ^4A , -C(O)-OR ^4A , -C(O)NR ^4A R ^4B , -OR ^4A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L ² is a

bond, -S(O)2-, -NR ⁵ -, -O-, -S-, -C(O)-, -C(O)NR ⁵ -, -NR ⁵ C(O)-, -NR ⁵ C(O)NH-, -NHC(O)NR ⁵ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted

heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R ⁵ is hydrogen, -CX ⁵ 3, -CHX ⁵ 2, -CH2X ⁵ , -OCX ⁵ 3, - OCH2X ⁵ , -OCHX ⁵ 2, -CN, -C(O)R ^5A , -C(O)-OR ^5A , -C(O)NR ^5A R ^5B , -OR ^5A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; E is an electrophilic moiety; Each R ^1A , R ^1B , R ^1C , R ^1D , R ^2A , R ^2B , R ^2C , R ^2D , R ^4A , R ^4B , R ^5A , and R ^5B is independently

hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^2A and R ^2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^4A and R ^4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^5A and R ^5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X, X ¹ , X ² , X ⁴ , and X ⁵ is independently–F, -Cl, -Br, or–I; n1, n2, n4, and n5 are independently an integer from 0 to 4; and m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2.

[0487] Embodiment P2. The compound of embodiment P1 having the formula:

[0488] Embodiment P3. The compound of embodiment P1 having the formula:

[0489] Embodiment P4. The compound of embodiment P1 having the formula:

[0490] Embodiment P5. The compound of embodiment P1 having the formula:

[0491] Embodiment P6. The compound of one of embodiments P1 to P5, wherein R ¹ is independently halogen, -CX ¹ ₃ , -CHX ¹ ₂ , -CH ₂ X ¹ , -OCX ¹ ₃ , - OCH ₂ X ¹ , -OCHX ¹ ₂ , -CN, -SR ^1D , -NR ^1A R ^1B , -C(O)R ^1C , -C(O)OR ^1C , -C(O)NR ^1A R ^1B , -OR ^1D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0492] Embodiment P7. The compound of one of embodiments P1 to P5, wherein R ¹ is independently halogen, -CX ¹ 3, -CHX ¹ 2, -CH2X ¹ , -OCX ¹ 3, - OCH ₂ X ¹ , -OCHX ¹ ₂ , -CN, -SH, -NH ₂ , -C(O)OH, -C(O)NH ₂ , -OH, substituted or unsubstituted C ₁ -C ₈ alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl. [0493] Embodiment P8. The compound of one of embodiments P1 to P5, wherein R ¹ is independently halogen, -CX ¹ 3, -CHX ¹ 2, -CH2X ¹ , -OCX ¹ 3, - OCH ₂ X ¹ , -OCHX ¹ ₂ , -CN, -SH, -NH ₂ , -C(O)OH, -C(O)NH ₂ , -OH, substituted or unsubstituted C1-C8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. [0494] Embodiment P9. The compound of one of embodiments P1 to P5, wherein R ¹ is independently–Cl. [0495] Embodiment P10. The compound of embodiment P1, wherein two adjacent R ¹ substituents are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0496] Embodiment P11. The compound of embodiment P1, wherein two adjacent R ¹ substituents are joined to form an unsubstituted cycloalkyl. [0497] Embodiment P12. The compound of embodiment P1, wherein two adjacent R ¹ substituents are joined to form an unsubstituted C ₃ -C ₆ cycloalkyl. [0498] Embodiment P13. The compound of one of embodiments P1 to P12, wherein L ¹ is a bond, substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C ₃ -C ₈ cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene. [0499] Embodiment P14. The compound of one of embodiments P1 to P12, wherein L ¹ is a bond. [0500] Embodiment P15. The compound of one of embodiments P1 to P14, wherein L ² is– NR ⁵ - or substituted or unsubstituted heterocycloalkylene comprising a ring nitrogen bonded directly to E. [0501] Embodiment P16. The compound of one of embodiments P1 to P14, wherein L ² is– NR ⁵ -. [0502] Embodiment P17. The compound of embodiment P16, wherein R ⁵ is hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. [0503] Embodiment P18. The compound of embodiment P16, wherein R ⁵ is hydrogen or unsubstituted C1-C3 alkyl. [0504] Embodiment P19. The compound of embodiment P16, wherein R ⁵ is hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted hexyl, or unsubstituted benzyl. [0505] Embodiment P20. The compound of embodiment P16, wherein R ⁵ is hydrogen. [0506] Embodiment P21. The compound of one of embodiments P1 to P20, wherein E is a covalent cysteine modifier moiety. [0507] Embodiment P22. The compound of one of embodiments P1 to P20, wherein E is:

R ¹⁵ is independently hydrogen, halogen, CX ¹⁵ 3, -CHX ¹⁵ 2, - CH ₂ X ¹⁵ , -CN, -SO _n15 R ^15D , -SO _v15 NR ^15A R ^15B ,−NHNR ^15A R ^15B ,−ONR ^15A R ^15B ,

−NHC=(O)NHNR ^15A R ^15B ,

−NHC(O)NR ^15A R ^15B , -N(O) _m15 , -NR ^15A R ^15B , -C(O)R ^15C , -C(O)-OR ^15C , -C(O)NR ^15A R ^15B , -OR ^15D , -NR ^15A SO ₂ R ^15D , -NR ^15A C(O)R ^15C , -NR ^15A C(O)OR ^15C , -NR ^15A OR ^15C , -OCX ¹⁵ ₃ , -OCHX ¹⁵ ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ¹⁶ is independently hydrogen, halogen, CX ¹⁶ ₃ , -CHX ¹⁶ ₂ , - CH2X ¹⁶ , -CN, -SOn16R ^16D , -SOv16NR ^16A R ^16B ,−NHNR ^16A R ^16B ,−ONR ^16A R ^16B ,

−NHC=(O)NHNR ^16A R ^16B ,

−NHC(O)NR ^16A R ^16B , -N(O)m16, -NR ^16A R ^16B , -C(O)R ^16C , -C(O)-OR ^16C , -C(O)NR ^16A R ^16B , -OR ^16D , -NR ^16A SO ₂ R ^16D , -NR ^16A C(O)R ^16C , -NR ^16A C(O)OR ^16C , -NR ^16A OR ^16C , -OCX ¹⁶ ₃ , -OCHX ¹⁶ ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ¹⁷ is independently hydrogen, halogen, CX ¹⁷ 3, -CHX ¹⁷ 2, - CH2X ¹⁷ , -CN, -SOn17R ^17D , -SOv17NR ^17A R ^17B ,−NHNR ^17A R ^17B ,−ONR ^17A R ^17B ,

−NHC=(O)NHNR ^17A R ^17B ,

−NHC(O)NR ^17A R ^17B , -N(O)m17, -NR ^17A R ^17B , -C(O)R ^17C , -C(O)-OR ^17C , -C(O)NR ^17A R ^17B , -OR ^17D , -NR ^17A SO2R ^17D , -NR ^17A C(O)R ^17C , -NR ^17A C(O)OR ^17C , -NR ^17A OR ^17C , -OCX ¹⁷ 3,

-OCHX ¹⁷ 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ¹⁸ is independently hydrogen, -CX ¹⁸ 3, -CHX ¹⁸ 2, - CH ₂ X ¹⁸ , -C(O)R ^18C , -C(O)OR ^18C , -C(O)NR ^18A R ^18B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ^15A , R ^15B , R ^15C , R ^15D , R ^16A , R ^16B , R ^16C , R ^16D , R ^17A , R ^17B , R ^17C , R ^17D , R ^18A , R ^18B , R ^18C , R ^18D , are independently hydrogen, -CX ₃ , -CN, -COOH, -CONH ₂ , -CHX ₂ , -CH ₂ X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^15A and R ^15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^16A and R ^16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^17A and R ^17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^18A and R ^18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X ¹⁵ , X ¹⁶ , X ¹⁷ and X ¹⁸ is independently–F, -Cl, -Br, or–I; n15, n16, n17, v15, v16, and v17, are independently an integer from 0 to 4; and m15, m16, and m17 are independently and integer from 1 to 2.

[0508] Embodiment P23. The compound of embodiment P22, wherein R ¹⁵ , R ¹⁶ , R ¹⁷ , and R ¹⁸ are hydrogen. [0509] Embodiment P24. The compound of one of embodiments P22 to P23, wherein E is:

.

[0510] Embodiment P25. A pharmaceutical composition comprising a Reticulon 4 inhibitor and a pharmaceutically acceptable excipient. [0511] Embodiment P26. A pharmaceutical composition comprising the compound of any one of embodiments P1 to P24 and a pharmaceutically acceptable excipient. [0512] Embodiment P27. A method of inhibiting reticulon 4 protein activity, said method comprising contacting the reticulon 4 protein with a Reticulon 4 inhibitor. [0513] Embodiment P28. The method of embodiment P27, wherein the Reticulon 4 inhibitor is an siRNA, antibody, or compound. [0514] Embodiment P29. The method of embodiment P30, wherein the Reticulon 4 inhibitor contacts one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of human reticulon 4. [0515] Embodiment P30. A method of inhibiting reticulon 4 protein activity, said method comprising contacting the reticulon 4 protein with an effective amount of a compound of one of embodiments P1 to P24. [0516] Embodiment P31. The method of embodiment P30, wherein the compound is covalently bonded to the amino acid corresponding to C1101 of human reticulon 4. [0517] Embodiment P32. The method of embodiment P30, wherein the compound contacts one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of human reticulon 4. [0518] Embodiment P33. A method of treating cancer, said method comprising

administering to a subject in need thereof an effective amount of a Reticulon 4 inhibitor. [0519] Embodiment P34. A method of treating cancer, said method comprising

administering to a subject in need thereof an effective amount of a compound of one of embodiments P1 to P24. [0520] Embodiment P35. The method of one of embodiments P33 to P34, wherein the cancer is colorectal cancer. [0521] Embodiment P36. A reticulon 4 protein covalently bonded to a compound of one of embodiments P1 to P24. [0522] Embodiment P37. The Reticulon 4 protein of embodiment P36, wherein the compound is bonded to a cysteine residue of the protein. [0523] Embodiment P38. The reticulon 4 protein of embodiment P36, covalently bonded to a portion of a compound of one of embodiments 1 to 24. [0524] Embodiment P39. The reticulon 4 protein of embodiment P36, irreversibly covalently bonded to a portion of a compound of one of embodiments 1 to 24. [0525] Embodiment P40. The reticulon 4 protein of one of embodiments P36 to P39, wherein the compound or porteion of the compound is covalently bonded to an amino acid corresponding to C1101 of human reticulon 4. VIII. Additional Embodiments

[0526] Embodiment 1. A method of treating cancer, said method comprising

administering to a subject in need thereof an effective amount of a compound having the

wherein,

R ¹ is independently halogen, -CX ¹ 3, -CHX ¹ 2, -CH2X ¹ , -OCX ¹ 3, - OCH2X ¹ , -OCHX ¹ 2, -CN, -SOn1R ^1D , -SOv1NR ^1A R ^1B , -NHC(O)NR ^1A R ^1B , -N(O)m1, -NR ^1A R ^1B , -C( O)R ^1C , -C(O)-OR ^1C , -C(O)NR ^1A R ^1B , -OR ^1D , -NR ^1A SO ₂ R ^1D , -NR ^1A C(O)R ^1C , -NR ^1A C(O)OR ^1C , -N R ^1A OR ^1C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or

unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z1 is an integer from 0 to 5; R ² is independently halogen, -CX ² 3, -CHX ² 2, -CH2X ² , -OCX ² 3, - OCH2X ² , -OCHX ² 2, -CN, -SOn2R ^2D , -SOv2NR ^2A R ^2B , -NHC(O)NR ^2A R ^2B , -N(O)m2, -NR ^2A R ^2B , -C( O)R ^2C , -C(O)-OR ^2C , -C(O)NR ^2A R ^2B , -OR ^2D , -NR ^2A SO ₂ R ^2D , -NR ^2A C(O)R ^2C , -NR ^2A C(O)OR ^2C , -N R ^2A OR ^2C , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or

unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z2 is an integer from 0 to 4;

L ¹ is a

bond, -S(O)2-, -NR ⁴ -, -O-, -S-, -C(O)-, -C(O)NR ⁴ -, -NR ⁴ C(O)-, -NR ⁴ C(O)NH-, -NHC(O)NR ⁴ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted

heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁴ is hydrogen, -CX ⁴ ₃ , -CHX ⁴ ₂ , -CH ₂ X ⁴ , -OCX ⁴ ₃ , - OCH2X ⁴ , -OCHX ⁴ 2, -CN, -C(O)R ^4A , -C(O)-OR ^4A , -C(O)NR ^4A R ^4B , -OR ^4A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

L ² is a

bond, -S(O) ₂ -, -NR ⁵ -, -O-, -S-, -C(O)-, -C(O)NR ⁵ -, -NR ⁵ C(O)-, -NR ⁵ C(O)NH-, -NHC(O)NR ⁵ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted

heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁵ is hydrogen, -CX ⁵ 3, -CHX ⁵ 2, -CH2X ⁵ , -OCX ⁵ 3, - OCH2X ⁵ , -OCHX ⁵ 2, -CN, -C(O)R ^5A , -C(O)-OR ^5A , -C(O)NR ^5A R ^5B , -OR ^5A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

E is an electrophilic moiety; Each R ^1A , R ^1B , R ^1C , R ^1D , R ^2A , R ^2B , R ^2C , R ^2D , R ^4A , R ^4B , R ^5A , and R ^5B is independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^2A and R ^2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^4A and R ^4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^5A and R ^5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X ¹ , X ² , X ⁴ , and X ⁵ is independently–F, -Cl, -Br, or–I; n1, n2, n4, and n5 are independently an integer from 0 to 4; and m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2.

[0527] Embodiment 2. The method of embodiment 1, wherein the compound has the

formula:

[0528] Embodiment 3. The method of embodiment 1, wherein the compound has the

formula:

[0529] Embodiment 4. The method of embodiment 1, wherein the compound has the

formula:

[0530] Embodiment 5. The method of embodiment 1, wherein the compound has the

formula: (IIa). [0531] Embodiment 6. The method of one of embodiments 1 to 5, wherein R ¹ is independently halogen, -CX ¹ 3, -CHX ¹ 2, -CH2X ¹ , -OCX ¹ 3, - OCH ₂ X ¹ , -OCHX ¹ ₂ , -CN, -SR ^1D , -NR ^1A R ^1B , -C(O)R ^1C , -C(O)OR ^1C , -C(O)NR ^1A R ^1B , -OR ^1D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0532] Embodiment 7. The method of one of embodiments 1 to 5, wherein R ¹ is independently halogen, -CX ¹ 3, -CHX ¹ 2, -CH2X ¹ , -OCX ¹ 3, - OCH2X ¹ , -OCHX ¹ 2, -CN, -SH, -NH2, -C(O)OH, -C(O)NH2, -OH, substituted or unsubstituted C ₁ -C ₈ alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl. [0533] Embodiment 8. The method of one of embodiments 1 to 5, wherein R ¹ is independently halogen, -CX ¹ 3, -CHX ¹ 2, -CH2X ¹ , -OCX ¹ 3, - OCH ₂ X ¹ , -OCHX ¹ ₂ , -CN, -SH, -NH ₂ , -C(O)OH, -C(O)NH ₂ , -OH, substituted or unsubstituted C ₁ -C ₈ alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. [0534] Embodiment 9. The method of one of embodiments 1 to 5, wherein R ¹ is independently–Cl. [0535] Embodiment 10. The method of embodiment 1, wherein two adjacent R ¹ substituents are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0536] Embodiment 11. The method of embodiment 1, wherein two adjacent R ¹ substituents are joined to form an unsubstituted cycloalkyl. [0537] Embodiment 12. The method of embodiment 1, wherein two adjacent R ¹ substituents are joined to form an unsubstituted C3-C6 cycloalkyl. [0538] Embodiment 13. The method of one of embodiments 1 to 12, wherein L ¹ is a bond, substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene. [0539] Embodiment 14. The method of one of embodiments 1 to 12, wherein L ¹ is a bond. [0540] Embodiment 15. The method of one of embodiments 1 to 14, wherein L ² is– NR ⁵ - or substituted or unsubstituted heterocycloalkylene comprising a ring nitrogen bonded directly to E. [0541] Embodiment 16. The method of one of embodiments 1 to 14, wherein L ² is–NR ⁵ -. [0542] Embodiment 17. The method of embodiment 16, wherein R ⁵ is hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. [0543] Embodiment 18. The method of embodiment 16, wherein R ⁵ is hydrogen or unsubstituted C ₁ -C ₃ alkyl. [0544] Embodiment 19. The method of embodiment 16, wherein R ⁵ is hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted hexyl, or unsubstituted benzyl. [0545] Embodiment 20. The method of embodiment 16, wherein R ⁵ is hydrogen. [0546] Embodiment 21. The method of one of embodiments 1 to 20, wherein E is a covalent cysteine modifier moiety. [0547] Embodiment 22. The method of one of embodiments 1 to 20, wherein E is:

,

R ¹⁵ is independently hydrogen, halogen, CX ¹⁵ 3, -CHX ¹⁵ 2, - CH ₂ X ¹⁵ , -CN, -SO _n15 R ^15D , -SO _v15 NR ^15A R ^15B ,−NHNR ^15A R ^15B ,−ONR ^15A R ^15B ,

−NHC=(O)NHNR ^15A R ^15B , −NHC(O)NR ^15A R ^15B , -N(O)m15, -NR ^15A R ^15B , -C(O)R ^15C , -C(O)-OR ^15C , -C(O)NR ^15A R ^15B , -OR ^15D , -NR ^15A SO2R ^15D , -NR ^15A C(O)R ^15C , -NR ^15A C(O)OR ^15C , -NR ^15A OR ^15C , -OCX ¹⁵ 3, -OCHX ¹⁵ 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ¹⁶ is independently hydrogen, halogen, CX ¹⁶ 3, -CHX ¹⁶ 2, - CH ₂ X ¹⁶ , -CN, -SO _n16 R ^16D , -SO _v16 NR ^16A R ^16B ,−NHNR ^16A R ^16B ,−ONR ^16A R ^16B ,

−NHC=(O)NHNR ^16A R ^16B ,

−NHC(O)NR ^16A R ^16B , -N(O)m16, -NR ^16A R ^16B , -C(O)R ^16C , -C(O)-OR ^16C , -C(O)NR ^16A R ^16B , -OR ^16D , -NR ^16A SO2R ^16D , -NR ^16A C(O)R ^16C , -NR ^16A C(O)OR ^16C , -NR ^16A OR ^16C , -OCX ¹⁶ 3, -OCHX ¹⁶ 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ¹⁷ is independently hydrogen, halogen, CX ¹⁷ ₃ , -CHX ¹⁷ ₂ , - CH ₂ X ¹⁷ , -CN, -SO _n17 R ^17D , -SO _v17 NR ^17A R ^17B ,−NHNR ^17A R ^17B ,−ONR ^17A R ^17B ,

−NHC=(O)NHNR ^17A R ^17B ,

−NHC(O)NR ^17A R ^17B , -N(O) _m17 , -NR ^17A R ^17B , -C(O)R ^17C , -C(O)-OR ^17C , -C(O)NR ^17A R ^17B , -OR ^17D , -NR ^17A SO ₂ R ^17D , -NR ^17A C(O)R ^17C , -NR ^17A C(O)OR ^17C , -NR ^17A OR ^17C , -OCX ¹⁷ ₃ ,

-OCHX ¹⁷ 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ¹⁸ is independently hydrogen, -CX ¹⁸ ₃ , -CHX ¹⁸ ₂ , - CH2X ¹⁸ , -C(O)R ^18C , -C(O)OR ^18C , -C(O)NR ^18A R ^18B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ^15A , R ^15B , R ^15C , R ^15D , R ^16A , R ^16B , R ^16C , R ^16D , R ^17A , R ^17B , R ^17C , R ^17D , R ^18A , R ^18B , R ^18C , R ^18D , are independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^15A and R ^15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^16A and R ^16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^17A and R ^17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^18A and R ^18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X ¹⁵ , X ¹⁶ , X ¹⁷ and X ¹⁸ is independently–F, -Cl, -Br, or–I; n15, n16, n17, v15, v16, and v17, are independently an integer from 0 to 4; and m15, m16, and m17 are independently and integer from 1 to 2.

[0548] Embodiment 23. The method of embodiment 22, wherein R ¹⁵ , R ¹⁶ , R ¹⁷ , and R ¹⁸ are hydrogen. [0549] Embodiment 24. The method of one of embodiments 22 to 23, wherein E is: . [0550] Embodiment 25. The method of embodiment 1, having the formula: . [0551] Embodiment 26. The method of one of embodiments 1 to 25, wherein the cancer is colorectal cancer. [0552] Embodiment 27. The use of a compound for the preparation of a medicament for the treatment of cancer, wherein the compound has the formula:

wherein,

R ¹ is independently halogen, -CX ¹ 3, -CHX ¹ 2, -CH2X ¹ , -OCX ¹ 3, - OCH ₂ X ¹ , -OCHX ¹ ₂ , -CN, -SO _n1 R ^1D , -SO _v1 NR ^1A R ^1B , -NHC(O)NR ^1A R ^1B , -N(O) _m1 , -NR ^1A R ^1B , -C( O)R ^1C , -C(O)-OR ^1C , -C(O)NR ^1A R ^1B , -OR ^1D , -NR ^1A SO ₂ R ^1D , -NR ^1A C(O)R ^1C , -NR ^1A C(O)OR ^1C , -N R ^1A OR ^1C , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or

unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z1 is an integer from 0 to 5;

R ² is independently halogen, -CX ² ₃ , -CHX ² ₂ , -CH ₂ X ² , -OCX ² ₃ , - OCH ₂ X ² , -OCHX ² ₂ , -CN, -SO _n2 R ^2D , -SO _v2 NR ^2A R ^2B , -NHC(O)NR ^2A R ^2B , -N(O) _m2 , -NR ^2A R ^2B , -C( O)R ^2C , -C(O)-OR ^2C , -C(O)NR ^2A R ^2B , -OR ^2D , -NR ^2A SO2R ^2D , -NR ^2A C(O)R ^2C , -NR ^2A C(O)OR ^2C , -N R ^2A OR ^2C , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or

unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z2 is an integer from 0 to 4;

L ¹ is a

bond, -S(O) ₂ -, -NR ⁴ -, -O-, -S-, -C(O)-, -C(O)NR ⁴ -, -NR ⁴ C(O)-, -NR ⁴ C(O)NH-, -NHC(O)NR ⁴ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted

heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁴ is hydrogen, -CX ⁴ 3, -CHX ⁴ 2, -CH2X ⁴ , -OCX ⁴ 3, - OCH ₂ X ⁴ , -OCHX ⁴ ₂ , -CN, -C(O)R ^4A , -C(O)-OR ^4A , -C(O)NR ^4A R ^4B , -OR ^4A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

L ² is a

bond, -S(O)2-, -NR ⁵ -, -O-, -S-, -C(O)-, -C(O)NR ⁵ -, -NR ⁵ C(O)-, -NR ⁵ C(O)NH-, -NHC(O)NR ⁵ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted

heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁵ is hydrogen, -CX ⁵ ₃ , -CHX ⁵ ₂ , -CH ₂ X ⁵ , -OCX ⁵ ₃ , - OCH2X ⁵ , -OCHX ⁵ 2, -CN, -C(O)R ^5A , -C(O)-OR ^5A , -C(O)NR ^5A R ^5B , -OR ^5A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

E is an electrophilic moiety;

Each R ^1A , R ^1B , R ^1C , R ^1D , R ^2A , R ^2B , R ^2C , R ^2D , R ^4A , R ^4B , R ^5A , and R ^5B is independently hydrogen, -CX ₃ , -CN, -COOH, -CONH ₂ , -CHX ₂ , -CH ₂ X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^2A and R ^2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^4A and R ^4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^5A and R ^5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X ¹ , X ² , X ⁴ , and X ⁵ is independently–F, -Cl, -Br, or–I; n1, n2, n4, and n5 are independently an integer from 0 to 4; and m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2.

[0553] Embodiment 28. The compound of embodiment 27, wherein the compound has the

[0554] Embodiment 29. The compound of embodiment 27, wherein the compound has the

[0555] Embodiment 30. The compound of embodiment 27, wherein the compound has the

formula: [0556] Embodiment 31. The compound of embodiment 27, wherein the compound has the

[0557] Embodiment 32. The compound of embodiment 27, wherein the compound has the . [0558] Embodiment 33. The compound of one of embodiments 27 to 32, wherein R ¹ is independently halogen, -CX ¹ 3, -CHX ¹ 2, -CH2X ¹ , -OCX ¹ 3, - OCH2X ¹ , -OCHX ¹ 2, -CN, -SR ^1D , -NR ^1A R ^1B , -C(O)R ^1C , -C(O)OR ^1C , -C(O)NR ^1A R ^1B , -OR ^1D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0559] Embodiment 34. The compound of one of embodiments 27 to 32, wherein R ¹ is independently halogen, -CX ¹ ₃ , -CHX ¹ ₂ , -CH ₂ X ¹ , -OCX ¹ ₃ , - OCH2X ¹ , -OCHX ¹ 2, -CN, -SH, -NH2, -C(O)OH, -C(O)NH2, -OH, substituted or unsubstituted C1-C8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₂ aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl. [0560] Embodiment 35. The compound of one of embodiments 27 to 32, wherein R ¹ is independently halogen, -CX ¹ ₃ , -CHX ¹ ₂ , -CH ₂ X ¹ , -OCX ¹ ₃ , - OCH2X ¹ , -OCHX ¹ 2, -CN, -SH, -NH2, -C(O)OH, -C(O)NH2, -OH, substituted or unsubstituted C1-C8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. [0561] Embodiment 36. The compound of one of embodiments 27 to 32, wherein R ¹ is independently–Cl. [0562] Embodiment 37. The compound of embodiment 27, wherein two adjacent R ¹ substituents are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0563] Embodiment 38. The compound of embodiment 27, wherein two adjacent R ¹ substituents are joined to form an unsubstituted cycloalkyl. [0564] Embodiment 39. The compound of embodiment 27, wherein two adjacent R ¹ substituents are joined to form an unsubstituted C ₃ -C ₆ cycloalkyl. [0565] Embodiment 40. The compound of one of embodiments 27 to 39, wherein L ¹ is a bond, substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene. [0566] Embodiment 41. The compound of one of embodiments 27 to 39, wherein L ¹ is a bond. [0567] Embodiment 42. The compound of one of embodiments 27 to 41, wherein L ² is– NR ⁵ - or substituted or unsubstituted heterocycloalkylene comprising a ring nitrogen bonded directly to E. [0568] Embodiment 43. The compound of one of embodiments 27 to 41, wherein L ² is– NR ⁵ -. [0569] Embodiment 44. The compound of embodiment 43, wherein R ⁵ is hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. [0570] Embodiment 45. The compound of embodiment 43, wherein R ⁵ is hydrogen or unsubstituted C ₁ -C ₃ alkyl. [0571] Embodiment 46. The compound of embodiment 43, wherein R ⁵ is hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted hexyl, or unsubstituted benzyl. [0572] Embodiment 47. The compound of embodiment 43, wherein R ⁵ is hydrogen. [0573] Embodiment 48. The compound of one of embodiments 27 to 47, wherein E is a covalent cysteine modifier moiety. [0574] Embodiment 49. The compound of one of embodiments 27 to 47, wherein E is: ,

R ¹⁵ is independently hydrogen, halogen, CX ¹⁵ ₃ , -CHX ¹⁵ ₂ , - CH ₂ X ¹⁵ , -CN, -SO _n15 R ^15D , -SO _v15 NR ^15A R ^15B ,−NHNR ^15A R ^15B ,−ONR ^15A R ^15B ,

−NHC=(O)NHNR ^15A R ^15B ,

−NHC(O)NR ^15A R ^15B , -N(O) _m15 , -NR ^15A R ^15B , -C(O)R ^15C , -C(O)-OR ^15C , -C(O)NR ^15A R ^15B , -OR ^15D , -NR ^15A SO ₂ R ^15D , -NR ^15A C(O)R ^15C , -NR ^15A C(O)OR ^15C , -NR ^15A OR ^15C , -OCX ¹⁵ ₃ , -OCHX ¹⁵ ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ¹⁶ is independently hydrogen, halogen, CX ¹⁶ 3, -CHX ¹⁶ 2, - CH2X ¹⁶ , -CN, -SOn16R ^16D , -SOv16NR ^16A R ^16B ,−NHNR ^16A R ^16B ,−ONR ^16A R ^16B ,

−NHC=(O)NHNR ^16A R ^16B ,

−NHC(O)NR ^16A R ^16B , -N(O)m16, -NR ^16A R ^16B , -C(O)R ^16C , -C(O)-OR ^16C , -C(O)NR ^16A R ^16B , -OR ^16D , -NR ^16A SO2R ^16D , -NR ^16A C(O)R ^16C , -NR ^16A C(O)OR ^16C , -NR ^16A OR ^16C , -OCX ¹⁶ 3, -OCHX ¹⁶ 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ¹⁷ is independently hydrogen, halogen, CX ¹⁷ 3, -CHX ¹⁷ 2, - CH ₂ X ¹⁷ , -CN, -SO _n17 R ^17D , -SO _v17 NR ^17A R ^17B ,−NHNR ^17A R ^17B ,−ONR ^17A R ^17B ,

−NHC=(O)NHNR ^17A R ^17B ,

−NHC(O)NR ^17A R ^17B , -N(O) _m17 , -NR ^17A R ^17B , -C(O)R ^17C , -C(O)-OR ^17C , -C(O)NR ^17A R ^17B , -OR ^17D , -NR ^17A SO2R ^17D , -NR ^17A C(O)R ^17C , -NR ^17A C(O)OR ^17C , -NR ^17A OR ^17C , -OCX ¹⁷ 3,

-OCHX ¹⁷ ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ¹⁸ is independently hydrogen, -CX ¹⁸ ₃ , -CHX ¹⁸ ₂ , - CH2X ¹⁸ , -C(O)R ^18C , -C(O)OR ^18C , -C(O)NR ^18A R ^18B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ^15A , R ^15B , R ^15C , R ^15D , R ^16A , R ^16B , R ^16C , R ^16D , R ^17A , R ^17B , R ^17C , R ^17D , R ^18A , R ^18B , R ^18C , R ^18D , are independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^15A and R ^15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^16A and R ^16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^17A and R ^17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^18A and R ^18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X ¹⁵ , X ¹⁶ , X ¹⁷ and X ¹⁸ is independently–F, -Cl, -Br, or–I; n15, n16, n17, v15, v16, and v17, are independently an integer from 0 to 4; and m15, m16, and m17 are independently and integer from 1 to 2.

[0575] Embodiment 50. The compound of embodiment 49, wherein R ¹⁵ , R ¹⁶ , R ¹⁷ , and R ¹⁸ are hydrogen. [0576] Embodiment 51. The compound of one of embodiments 49 to 50, wherein E is: . [0577] Embodiment 52. The compound of embodiment 27, having the formula: . [0578] Embodiment 53. A pharmaceutical composition comprising a Reticulon 4 inhibitor and a pharmaceutically acceptable excipient. [0579] Embodiment 54. The pharmaceutical comp i i n f m im n h r in the

Reticulon 4 inhibitor is the compound has the formula: (I), wherein,

R ¹ is independently halogen, -CX ¹ ₃ , -CHX ¹ ₂ , -CH ₂ X ¹ , -OCX ¹ ₃ , - OCH ₂ X ¹ , -OCHX ¹ ₂ , -CN, -SO _n1 R ^1D , -SO _v1 NR ^1A R ^1B , -NHC(O)NR ^1A R ^1B , -N(O) _m1 , -NR ^1A R ^1B , -C( O)R ^1C , -C(O)-OR ^1C , -C(O)NR ^1A R ^1B , -OR ^1D , -NR ^1A SO2R ^1D , -NR ^1A C(O)R ^1C , -NR ^1A C(O)OR ^1C , -N R ^1A OR ^1C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or

unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z1 is an integer from 0 to 5;

R ² is independently halogen, -CX ² ₃ , -CHX ² ₂ , -CH ₂ X ² , -OCX ² ₃ , - OCH ₂ X ² , -OCHX ² ₂ , -CN, -SO _n2 R ^2D , -SO _v2 NR ^2A R ^2B , -NHC(O)NR ^2A R ^2B , -N(O) _m2 , -NR ^2A R ^2B , -C( O)R ^2C , -C(O)-OR ^2C , -C(O)NR ^2A R ^2B , -OR ^2D , -NR ^2A SO2R ^2D , -NR ^2A C(O)R ^2C , -NR ^2A C(O)OR ^2C , -N R ^2A OR ^2C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or

unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z2 is an integer from 0 to 4;

L ¹ is a

bond, -S(O)2-, -NR ⁴ -, -O-, -S-, -C(O)-, -C(O)NR ⁴ -, -NR ⁴ C(O)-, -NR ⁴ C(O)NH-, -NHC(O)NR ⁴ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted

heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁴ is hydrogen, -CX ⁴ ₃ , -CHX ⁴ ₂ , -CH ₂ X ⁴ , -OCX ⁴ ₃ , - OCH ₂ X ⁴ , -OCHX ⁴ ₂ , -CN, -C(O)R ^4A , -C(O)-OR ^4A , -C(O)NR ^4A R ^4B , -OR ^4A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

L ² is a

bond, -S(O)2-, -NR ⁵ -, -O-, -S-, -C(O)-, -C(O)NR ⁵ -, -NR ⁵ C(O)-, -NR ⁵ C(O)NH-, -NHC(O)NR ⁵ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted

heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁵ is hydrogen, -CX ⁵ ₃ , -CHX ⁵ ₂ , -CH ₂ X ⁵ , -OCX ⁵ ₃ , - OCH2X ⁵ , -OCHX ⁵ 2, -CN, -C(O)R ^5A , -C(O)-OR ^5A , -C(O)NR ^5A R ^5B , -OR ^5A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

E is an electrophilic moiety;

Each R ^1A , R ^1B , R ^1C , R ^1D , R ^2A , R ^2B , R ^2C , R ^2D , R ^4A , R ^4B , R ^5A , and R ^5B is independently hydrogen, -CX ₃ , -CN, -COOH, -CONH ₂ , -CHX ₂ , -CH ₂ X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^2A and R ^2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^4A and R ^4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^5A and R ^5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X ¹ , X ² , X ⁴ , and X ⁵ is independently–F, -Cl, -Br, or–I;

n1, n2, n4, and n5 are independently an integer from 0 to 4; and

m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2.

[0580] Embodiment 55. A method of inhibiting reticulon 4 protein activity, said method comprising contacting a reticulon 4 protein with an effective amount of a Reticulon 4 inhibitor, wherein said Reticulon 4 inhibitor contacts one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. [0581] Embodiment 56. The method of embodiment 55, wherein the Reticulon 4 inhibitor is an antisense nucleic acid, antibody, or a compound. [0582] Embodiment 57. The method of embodiment 55 or 56, wherein said Reticulon 4

inhibitor is a compound having the formula:

wherein,

R ¹ is independently halogen, -CX ¹ ₃ , -CHX ¹ ₂ , -CH ₂ X ¹ , -OCX ¹ ₃ , - OCH2X ¹ , -OCHX ¹ 2, -CN, -SOn1R ^1D , -SOv1NR ^1A R ^1B , -NHC(O)NR ^1A R ^1B , -N(O)m1, -NR ^1A R ^1B , -C( O)R ^1C , -C(O)-OR ^1C , -C(O)NR ^1A R ^1B , -OR ^1D , -NR ^1A SO2R ^1D , -NR ^1A C(O)R ^1C , -NR ^1A C(O)OR ^1C , -N R ^1A OR ^1C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or

unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z1 is an integer from 0 to 5;

R ² is independently halogen, -CX ² ₃ , -CHX ² ₂ , -CH ₂ X ² , -OCX ² ₃ , - OCH2X ² , -OCHX ² 2, -CN, -SOn2R ^2D , -SOv2NR ^2A R ^2B , -NHC(O)NR ^2A R ^2B , -N(O)m2, -NR ^2A R ^2B , -C( O)R ^2C , -C(O)-OR ^2C , -C(O)NR ^2A R ^2B , -OR ^2D , -NR ^2A SO ₂ R ^2D , -NR ^2A C(O)R ^2C , -NR ^2A C(O)OR ^2C , -N R ^2A OR ^2C , -N ₃ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or

unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z2 is an integer from 0 to 4;

L ¹ is a

bond, -S(O)2-, -NR ⁴ -, -O-, -S-, -C(O)-, -C(O)NR ⁴ -, -NR ⁴ C(O)-, -NR ⁴ C(O)NH-, -NHC(O)NR ⁴ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁴ is hydrogen, -CX ⁴ 3, -CHX ⁴ 2, -CH2X ⁴ , -OCX ⁴ 3, - OCH2X ⁴ , -OCHX ⁴ 2, -CN, -C(O)R ^4A , -C(O)-OR ^4A , -C(O)NR ^4A R ^4B , -OR ^4A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

L ² is a

bond, -S(O) ₂ -, -NR ⁵ -, -O-, -S-, -C(O)-, -C(O)NR ⁵ -, -NR ⁵ C(O)-, -NR ⁵ C(O)NH-, -NHC(O)NR ⁵ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted

heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁵ is hydrogen, -CX ⁵ 3, -CHX ⁵ 2, -CH2X ⁵ , -OCX ⁵ 3, - OCH ₂ X ⁵ , -OCHX ⁵ ₂ , -CN, -C(O)R ^5A , -C(O)-OR ^5A , -C(O)NR ^5A R ^5B , -OR ^5A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

E is an electrophilic moiety;

Each R ^1A , R ^1B , R ^1C , R ^1D , R ^2A , R ^2B , R ^2C , R ^2D , R ^4A , R ^4B , R ^5A , and R ^5B is independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^2A and R ^2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^4A and R ^4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^5A and R ^5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X ¹ , X ² , X ⁴ , and X ⁵ is independently–F, -Cl, -Br, or–I; n1, n2, n4, and n5 are independently an integer from 0 to 4; and

m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2.

[0583] Embodiment 58. The method of embodiment 57, wherein the compound is covalently bonded to the amino acid corresponding to C1101 of SEQ ID NO:331. [0584] Embodiment 59. A reticulon 4 protein covalently bonded to a compound having the formula:

wherein,

R ¹ is independently halogen, -CX ¹ 3, -CHX ¹ 2, -CH2X ¹ , -OCX ¹ 3, - OCH2X ¹ , -OCHX ¹ 2, -CN, -SOn1R ^1D , -SOv1NR ^1A R ^1B , -NHC(O)NR ^1A R ^1B , -N(O)m1, -NR ^1A R ^1B , -C( O)R ^1C , -C(O)-OR ^1C , -C(O)NR ^1A R ^1B , -OR ^1D , -NR ^1A SO ₂ R ^1D , -NR ^1A C(O)R ^1C , -NR ^1A C(O)OR ^1C , -N R ^1A OR ^1C , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or

unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z1 is an integer from 0 to 5;

R ² is independently halogen, -CX ² 3, -CHX ² 2, -CH2X ² , -OCX ² 3, - OCH2X ² , -OCHX ² 2, -CN, -SOn2R ^2D , -SOv2NR ^2A R ^2B , -NHC(O)NR ^2A R ^2B , -N(O)m2, -NR ^2A R ^2B , -C( O)R ^2C , -C(O)-OR ^2C , -C(O)NR ^2A R ^2B , -OR ^2D , -NR ^2A SO ₂ R ^2D , -NR ^2A C(O)R ^2C , -NR ^2A C(O)OR ^2C , -N R ^2A OR ^2C , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or

unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z2 is an integer from 0 to 4;

L ¹ is a

bond, -S(O)2-, -NR ⁴ -, -O-, -S-, -C(O)-, -C(O)NR ⁴ -, -NR ⁴ C(O)-, -NR ⁴ C(O)NH-, -NHC(O)NR ⁴ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁴ is hydrogen, -CX ⁴ 3, -CHX ⁴ 2, -CH2X ⁴ , -OCX ⁴ 3, - OCH2X ⁴ , -OCHX ⁴ 2, -CN, -C(O)R ^4A , -C(O)-OR ^4A , -C(O)NR ^4A R ^4B , -OR ^4A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

L ² is a

bond, -S(O) ₂ -, -NR ⁵ -, -O-, -S-, -C(O)-, -C(O)NR ⁵ -, -NR ⁵ C(O)-, -NR ⁵ C(O)NH-, -NHC(O)NR ⁵ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted

heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁵ is hydrogen, -CX ⁵ 3, -CHX ⁵ 2, -CH2X ⁵ , -OCX ⁵ 3, - OCH ₂ X ⁵ , -OCHX ⁵ ₂ , -CN, -C(O)R ^5A , -C(O)-OR ^5A , -C(O)NR ^5A R ^5B , -OR ^5A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

E is an electrophilic moiety;

Each R ^1A , R ^1B , R ^1C , R ^1D , R ^2A , R ^2B , R ^2C , R ^2D , R ^4A , R ^4B , R ^5A , and R ^5B is independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^2A and R ^2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^4A and R ^4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^5A and R ^5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X ¹ , X ² , X ⁴ , and X ⁵ is independently–F, -Cl, -Br, or–I; n1, n2, n4, and n5 are independently an integer from 0 to 4; and

m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2; wherein the reticulon 4 protein is covalently bonded to said compound through said reacted electrophilic moiety.

[0585] Embodiment 60. The Reticulon 4 protein of embodiment 59, wherein the compound is bonded to a cysteine residue of the protein. [0586] Embodiment 61. The reticulon 4 protein of one of embodiments 59 to 60, wherein the compound is covalently bonded to an amino acid corresponding to C1101 of SEQ ID

NO:331. [0587] Embodiment 62. A compound having the formula:

wherein,

R ¹ is independently halogen, -CX ¹ 3, -CHX ¹ 2, -CH2X ¹ , -OCX ¹ 3, - OCH ₂ X ¹ , -OCHX ¹ ₂ , -CN, -SO _n1 R ^1D , -SO _v1 NR ^1A R ^1B , -NHC(O)NR ^1A R ^1B , -N(O) _m1 , -NR ^1A R ^1B , -C( O)R ^1C , -C(O)-OR ^1C , -C(O)NR ^1A R ^1B , -OR ^1D , -NR ^1A SO2R ^1D , -NR ^1A C(O)R ^1C , -NR ^1A C(O)OR ^1C , -N R ^1A OR ^1C , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R ¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or

unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z1 is an integer from 0 to 5;

R ² is independently halogen, -CX ² 3, -CHX ² 2, -CH2X ² , -OCX ² 3, - OCH ₂ X ² , -OCHX ² ₂ , -CN, -SO _n2 R ^2D , -SO _v2 NR ^2A R ^2B , -NHC(O)NR ^2A R ^2B , -N(O) _m2 , -NR ^2A R ^2B , -C( O)R ^2C , -C(O)-OR ^2C , -C(O)NR ^2A R ^2B , -OR ^2D , -NR ^2A SO2R ^2D , -NR ^2A C(O)R ^2C , -NR ^2A C(O)OR ^2C , -N R ^2A OR ^2C , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R ² substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z2 is an integer from 0 to 4;

L ¹ is a

bond, -S(O)2-, -NR ⁴ -, -O-, -S-, -C(O)-, -C(O)NR ⁴ -, -NR ⁴ C(O)-, -NR ⁴ C(O)NH-, -NHC(O)NR ⁴ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted

heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁴ is hydrogen, -CX ⁴ ₃ , -CHX ⁴ ₂ , -CH ₂ X ⁴ , -OCX ⁴ ₃ , - OCH2X ⁴ , -OCHX ⁴ 2, -CN, -C(O)R ^4A , -C(O)-OR ^4A , -C(O)NR ^4A R ^4B , -OR ^4A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

L ² is a

bond, -S(O) ₂ -, -NR ⁵ -, -O-, -S-, -C(O)-, -C(O)NR ⁵ -, -NR ⁵ C(O)-, -NR ⁵ C(O)NH-, -NHC(O)NR ⁵ -, - C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted

heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R ⁵ is hydrogen, -CX ⁵ 3, -CHX ⁵ 2, -CH2X ⁵ , -OCX ⁵ 3, - OCH2X ⁵ , -OCHX ⁵ 2, -CN, -C(O)R ^5A , -C(O)-OR ^5A , -C(O)NR ^5A R ^5B , -OR ^5A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

E is an electrophilic moiety;

Each R ^1A , R ^1B , R ^1C , R ^1D , R ^2A , R ^2B , R ^2C , R ^2D , R ^4A , R ^4B , R ^5A , and R ^5B is independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^1A and R ^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^2A and R ^2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^4A and R ^4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^5A and R ^5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X ¹ , X ² , X ⁴ , and X ⁵ is independently–F, -Cl, -Br, or–I; n1, n2, n4, and n5 are independently an integer from 0 to 4; and m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2.

[0588] Embodiment 63. The compound of embodiment 62, wherein the compound has the

[0589] Embodiment 64. The compound of embodiment 1, wherein the compound has the

[0590] Embodiment 65. The compound of embodiment 1, wherein the compound has the

formula: (II). [0591] Embodiment 66. The compound of embodiment 1, wherein the compound has the

[0592] Embodiment 67. The compound of one of embodiments 62 to 66, wherein R ¹ is independently halogen, -CX ¹ 3, -CHX ¹ 2, -CH2X ¹ , -OCX ¹ 3, - OCH ₂ X ¹ , -OCHX ¹ ₂ , -CN, -SR ^1D , -NR ^1A R ^1B , -C(O)R ^1C , -C(O)OR ^1C , -C(O)NR ^1A R ^1B , -OR ^1D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0593] Embodiment 68. The compound of one of embodiments 62 to 66, wherein R ¹ is independently halogen, -CX ¹ 3, -CHX ¹ 2, -CH2X ¹ , -OCX ¹ 3, - OCH2X ¹ , -OCHX ¹ 2, -CN, -SH, -NH2, -C(O)OH, -C(O)NH2, -OH, substituted or unsubstituted C1-C8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl. [0594] Embodiment 69. The compound of one of embodiments 62 to 66, wherein R ¹ is independently halogen, -CX ¹ ₃ , -CHX ¹ ₂ , -CH ₂ X ¹ , -OCX ¹ ₃ , - OCH2X ¹ , -OCHX ¹ 2, -CN, -SH, -NH2, -C(O)OH, -C(O)NH2, -OH, substituted or unsubstituted C1-C8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. [0595] Embodiment 70. The compound of one of embodiments 62 to 66, wherein R ¹ is independently–Cl. [0596] Embodiment 71. The compound of embodiment 62, wherein two adjacent R ¹ substituents are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0597] Embodiment 72. The compound of embodiment 62, wherein two adjacent R ¹ substituents are joined to form an unsubstituted cycloalkyl. [0598] Embodiment 73. The compound of embodiment 62, wherein two adjacent R ¹ substituents are joined to form an unsubstituted C3-C6 cycloalkyl. [0599] Embodiment 74. The compound of one of embodiments 62 to 73, wherein L ¹ is a bond, substituted or unsubstituted C ₁ -C ₈ alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene. [0600] Embodiment 75. The compound of one of embodiments 62 to 73, wherein L ¹ is a bond. [0601] Embodiment 76. The compound of one of embodiments 62 to 75, wherein L ² is– NR ⁵ - or substituted or unsubstituted heterocycloalkylene comprising a ring nitrogen bonded directly to E. [0602] Embodiment 77. The compound of one of embodiments 62 to 75, wherein L ² is– NR ⁵ -. [0603] Embodiment 78. The compound of embodiment 77, wherein R ⁵ is hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. [0604] Embodiment 79. The compound of embodiment 77, wherein R ⁵ is hydrogen or unsubstituted C ₁ -C ₃ alkyl. [0605] Embodiment 80. The compound of embodiment 77, wherein R ⁵ is hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted hexyl, or unsubstituted benzyl. [0606] Embodiment 81. The compound of embodiment 77, wherein R ⁵ is hydrogen. [0607] Embodiment 82. The compound of one of embodiments 62 to 81, wherein E is a covalent cysteine modifier moiety. [0608] Embodiment 83. The compound of one of embodiments 62 to 81, wherein E is:

R ¹⁵ is independently hydrogen, halogen, CX ¹⁵ 3, -CHX ¹⁵ 2, - CH ₂ X ¹⁵ , -CN, -SO _n15 R ^15D , -SO _v15 NR ^15A R ^15B ,−NHNR ^15A R ^15B ,−ONR ^15A R ^15B ,

−NHC=(O)NHNR ^15A R ^15B ,

−NHC(O)NR ^15A R ^15B , -N(O) _m15 , -NR ^15A R ^15B , -C(O)R ^15C , -C(O)-OR ^15C , -C(O)NR ^15A R ^15B , -OR ^15D , -NR ^15A SO ₂ R ^15D , -NR ^15A C(O)R ^15C , -NR ^15A C(O)OR ^15C , -NR ^15A OR ^15C , -OCX ¹⁵ ₃ , -OCHX ¹⁵ ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ¹⁶ is independently hydrogen, halogen, CX ¹⁶ ₃ , -CHX ¹⁶ ₂ , - CH2X ¹⁶ , -CN, -SOn16R ^16D , -SOv16NR ^16A R ^16B ,−NHNR ^16A R ^16B ,−ONR ^16A R ^16B ,

−NHC=(O)NHNR ^16A R ^16B ,

−NHC(O)NR ^16A R ^16B , -N(O) _m16 , -NR ^16A R ^16B , -C(O)R ^16C , -C(O)-OR ^16C , -C(O)NR ^16A R ^16B , -OR ^16D , -NR ^16A SO ₂ R ^16D , -NR ^16A C(O)R ^16C , -NR ^16A C(O)OR ^16C , -NR ^16A OR ^16C , -OCX ¹⁶ ₃ , -OCHX ¹⁶ ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ¹⁷ is independently hydrogen, halogen, CX ¹⁷ 3, -CHX ¹⁷ 2, - CH2X ¹⁷ , -CN, -SOn17R ^17D , -SOv17NR ^17A R ^17B ,−NHNR ^17A R ^17B ,−ONR ^17A R ^17B ,

−NHC=(O)NHNR ^17A R ^17B ,

−NHC(O)NR ^17A R ^17B , -N(O)m17, -NR ^17A R ^17B , -C(O)R ^17C , -C(O)-OR ^17C , -C(O)NR ^17A R ^17B , -OR ^17D , -NR ^17A SO2R ^17D , -NR ^17A C(O)R ^17C , -NR ^17A C(O)OR ^17C , -NR ^17A OR ^17C , -OCX ¹⁷ 3,

-OCHX ¹⁷ 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ¹⁸ is independently hydrogen, -CX ¹⁸ 3, -CHX ¹⁸ 2, - CH ₂ X ¹⁸ , -C(O)R ^18C , -C(O)OR ^18C , -C(O)NR ^18A R ^18B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ^15A , R ^15B , R ^15C , R ^15D , R ^16A , R ^16B , R ^16C , R ^16D , R ^17A , R ^17B , R ^17C , R ^17D , R ^18A , R ^18B , R ^18C , R ^18D , are independently hydrogen, -CX ₃ , -CN, -COOH, -CONH ₂ , -CHX ₂ , -CH ₂ X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^15A and R ^15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^16A and R ^16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^17A and R ^17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R ^18A and R ^18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X ¹⁵ , X ¹⁶ , X ¹⁷ and X ¹⁸ is independently–F, -Cl, -Br, or–I; n15, n16, n17, v15, v16, and v17, are independently an integer from 0 to 4; and m15, m16, and m17 are independently and integer from 1 to 2.

[0609] Embodiment 84. The compound of embodiment 83, wherein R ¹⁵ , R ¹⁶ , R ¹⁷ , and R ¹⁸ are hydrogen. [0610] Embodiment 85. The compound of one of embodiments 82 to 83, wherein E is: . [0611] Embodiment 86. The compound of embodiment 62, having the formula: . IX. Examples

I. Chemoproteomics-Enabled Covalent Ligand Screen Reveals a Cysteine Hotspot in Reticulon 4 that Impairs ER Morphology and Cancer

Pathogenicity

[0612] Chemical genetics has arisen as a powerful approach for identifying novel anti-cancer agents. However, a major bottleneck in chemical genetics is identifying the targets of leads that arise from screens. Here, we generated and screened a library of cysteine-reactive fragment- based covalent ligands for agents that impair colorectal cancer pathogenicity and coupled the discovery of lead compounds with target identification using isotopic tandem orthogonal proteolysis-enabled activity-based protein profiling (isoTOP-ABPP) platforms. Through this coupled approach, we discovered a cysteine-reactive acrylamide DKM 3-30 that impaired colorectal cancer cell pathogenicity through targeting C1101 on reticulon 4 (RTN4). This protein has been established as a critical mediator of endoplasmic reticulum tubular network formation. We show here that covalent modification of C1101 on RTN4 by DKM 3-30 or genetic knockdown of RTN4 impairs endoplasmic reticulum and nuclear envelope morphology and colorectal cancer pathogenicity. RTN4 is a novel colorectal cancer therapeutic target and we detemined a unique druggable hotspot within RTN4 that can be targeted by covalent ligands to impair colorectal cancer pathogenicity. Our results underscore the utility of coupling the screening of fragment-based covalent ligands with isoTOP-ABPP platforms for mining the proteome for novel druggable nodes that can be targeted for cancer therapy. [0613] Traditional strategies for cancer target discovery oftentimes involve searching for proteins or genes that may be dysregulated or mutated in tumors, which may miss promising therapeutic targets that may not necessarily be changing in expression or activity. Screening chemical libraries for anti-cancer small-molecules using chemical genetics strategies have arisen as a powerful complementary approach to traditional target discovery approaches for mining druggable nodes that can be pharmacologically interrogated in cancer ^3,4 . However, a major challenge with chemical genetics is identifying the targets of leads that arise from screens.

Oftentimes, lead compounds must be derivatized to either bear bioorthogonal and/or

photoaffinity handles or conjugated to beads to facilitate chemoproteomic target identification ⁴ . However, these approaches oftentimes require additional synthetic efforts to make analogs of the lead molecule and alter the structure of the molecule, which hinder or may prevent target identification. [0614] Here, we have generated a library of 75 cysteine-reactive fragment-based covalent ligands and coupled the screening of this library with an isotopic tandem orthogonal proteolysis- enabled activity-based protein profiling (isoTOP-ABPP) platform to rapidly couple the identification of covalent ligands that impair colorectal cancer pathogenicity with the

identification of its direct targets and druggable hotspots within these targets (FIG.1A). IsoTOP- ABPP uses reactivity-based chemical probes to map proteome-wide reactive, functional, and ligandable hotspots. When used in a competitive manner, covalent small-molecules can be competed against the binding of their corresponding reactivity-based probes to rapidly identify the targets of these molecules ^5–7 . In this case, upon identifying a cysteine-reactive lead fragment, lead molecules can be competed against a broad cysteine-reactive probe to subsequently identify its targets and the specific sites of labeling. [0615] There are several advantages to this overall approach. First, our library already introduces specific covalent interactions through the incorporation of cysteine-reactive acrylamide and chloroacetamide warheads, thus avoiding the necessity for introducing photoaffinity handles for target identification. Recent studies have shown that the reactivity of these scaffolds can be tempered and made to confer substantial selectivity through appending small-molecular weight fragments ⁶ . Also, because these compounds are small molecular weight fragment-based covalent ligands, they can sample more macromolecular protein space and enable interrogation of more druggable nodes, a notion explored by many pharmaceutical companies with fragment-based ligand discovery ⁸ . Second, the advantage of this approach is that the lead molecule itself can be directly competed against reactivity-based probes for target identification without the need for additional derivatization or synthetic efforts. [0616] We screened our cysteine-reactive ligand library of acrylamides and chloroacetamides to identify compounds that impair colorectal cancer cell survival and proliferation in the highly metastatic and tumorigenic SW620 colorectal cancer cells (FIG.1B, Table 1). We identified a lead acrylamide DKM 3-30 as a hit from this screen which significantly impaired both serum- free cell survival and proliferation in SW620 colorectal cancer cells (FIG.1C, 1D). We next wanted to determine whether DKM 3-30 impaired tumor growth in vivo in immune-deficient mice without causing overt toxicity. We initiated daily intraperitoneal treatments with this compound ten days after subcutaneous injection of SW620 cells and establishment of tumors. Strikingly, we observed initial regression and a sustained impairment in tumor growth from daily treatment of DKM 3-30, without any changes in body weight or any signs of overt toxicity (FIG. 1E, FIG.5). Taken together, our data suggested that DKM 3-30 significantly impaired SW620 colorectal cancer pathogenicity both in culture and in vivo. [0617] Table 1. Covalent ligand screening data. SW620 cells were treated with either DMSO or cysteine-reactive fragment (50 µM) for 48 h after which serum-free cell survival or proliferation were assessed by Hoescht staining. Shown are average and sem values from n=3/group.

[0618] We next performed isoTOP-ABPP studies to identify the direct targets of these lead compounds. We competed either vehicle or DKM 3-30 against labeling of SW620 proteomes with a broad cysteine-reactive probe, iodoacetamide-alkyne (IAyne), followed by appending probe-labeled proteins with a biotin-azide tag bearing a TEV protease recognition site and an isotopically light (for vehicle-treated) or heavy (for fragment-treated) tags via copper catalyzed azide-alkyne cycloaddition (CuAAC) ^6,9 . We then combined control and treated proteomes in a 1:1 ratio, enriched probe-labeled proteins with avidin, and digested proteomes with trypsin. Avidin-enriched probe-modified tryptic peptides were released by TEV protease digestion for subsequent quantitative proteomic analysis. Through these studies, we identified the top hit for DKM 3-30 as C1101 in reticulon 4 (RTN4, Uniprot ID Q9NQC3-1) with a light to heavy ratio of 3.0 (FIG.2A; Table 2). We further validated this hit by competing DKM 3-30 against IAyne labeling of pure human RTN4 protein using gel-based ABPP methods (FIG.2A). [0619] Table 2. IsoTOP-ABPP analyses of DKM 3-5 and DKM 3-30 in SW620 cells. SW620 cell proteomes were pre-treated with DMSO or DKM 3-5 (50 µM) or DKM 3-30 (50 µM) for 30 min at 37ºC prior to labeling of proteomes with IAyne (100 µM) for 1h at room temperature. Proteomes were then subjected to copper-catalyzed azide-alkyne cycloaddition with a biotin- azide tag bearing an isotopically light (for DMSO-treated) versus heavy (for ligand-treated) valine and a TEV protease recognition site. Proteomes were then mixed in a 1:1 ratio and probe- modified peptides were enriched and released by TEV protease for subsequent quantitative proteomic analysis. The data was filtered for only those probe-modified peptides that were identified in at least 2 out of 3 runs. Ratios for the same redundant probe-modified peptides and peptides across runs were averaged. Top hits of covalent ligands were confirmed to have more than one light to heavy ratio greater than 2. Shown below are the final consolidated and averaged light to heavy ratios for those peptides only observed in at least 2 out of 3 biological replicates for isoTOP-ABPP studies with DKM 3-5 and DKM 3-30, respectively.

[0620] To determine the relevance of RTN4 in colorectal cancer, we performed isoTOP-ABPP analysis to quantitatively map proteome-wide reactivity of cysteines in pooled primary human colorectal tumors through comparative ratiometric analysis of IAyne labeling at 100 (heavy) versus 10 µM (light) concentrations. Previous studies by Weerapana et al. have shown that hyper-reactive cysteines, which show saturated IAyne labeling at lower concentrations and thus exhibit a lower (<3) heavy to light ratio, are highly enriched in functional cysteines, compared to those sites that are not hyper-reactive that show heavy to light ratios of ~10 ¹⁰ . We identify RTN4 labeling of C1101 in primary human colorectal tumors. RTN4 C1101 shows a ratio of 6.2 indicating that this cysteine is not hyper-reactive (FIG.2B). Our data thus show that RTN4 is present and that C1101 within RTN4 is accessible in primary human colorectal tumors. [0621] We further confirm the relevance of RTN4 in colorectal cancer by showing that transient or stable knockdown of RTN4 by RNA interference phenocopies the impaired survival, proliferation, and anti-tumorigenic effects observed with DKM 3-30 in SW620 colorectal cancer cells (FIGS.2C-2D). To further confirm that the cell viability impairments conferred by DKM 3- 30 are due to RTN4, we tested the effect of this compound in mouse embryonic fibroblasts (MEF) with or without the expression of human RTN4. Mouse Rtn4 possesses a serine instead of cysteine at the analogous site to human RTN4(C1101). We show that DKM 3-30 does not show viability impairments in GFP-expressing MEF cells but induces apoptosis in MEF cells expressing human RTN4-GFP (FIG.12). [0622] RTN4 is known to be a critical mediator of endoplasmic reticulum (ER) tubule formation ^11–13 . Interestingly, Voeltz et al. found that tubular ER network formation in a reconstituted in vitro system was disrupted by thiol modifying agents and discovered that xenopus RTN4 was responsible for this action ¹⁵ . Intriguingly, one of these cysteines, C952 of xenopus RTN4 ¹² , corresponds to C1101 of human RTN4 identified in our study (FIG.6). C1101 is present in all human RTN4 isoforms, but is absent in other reticulon family members (RTN1- 3) (FIG.7). This cysteine is positioned within a cytosolically exposed linker between two tandem hydrophobic regions (FIG.3A), which allow RTN4 to adopt a characteristic wedge- shaped hairpin conformation required for generating highly curved membranes and tubular ER structures ¹³ . A solution NMR structure of a mouse RTN4 fragment revealed that this linker region forms a compact helical bundle with a portion associated with the membrane ¹⁴ and a threaded homology model of the human RTN4 linker region indicates that C1101 is present in a cytosolically accessible helix (FIG.3A). [0623] We postulated that covalent modification of RTN4(C1101) by DKM 3-30 would impact the formation of ER tubular networks in cells. We attempted to analyze the effects of DKM 3-30 in SW620 colorectal cancer cells, and while the images suggest alterations in the ER morphology (FIG.8), the reticular nature of the ER was difficult to visualize in this cell type. Therefore, we utilized U2OS osteosarcoma cells, which are a well-established cell line for the analysis of ER morphology. As expected, control U2OS cells expressing the ER marker GFP- Sec61β displayed a highly reticular ER with clearly visible tubular ER in the cell periphery (FIG. 3B). Treatment of U2OS cells with DKM 3-30 for 8 hr and 16 hr resulted in a striking loss of nearly all peripheral ER tubules and an increase in ER that exhibited sheet-like morphology (FIG.3B). To more precisely define the temporal dynamics of DKM 3-30 on ER structure, we performed time-lapse imaging of GFP-Sec61β expressing cells (FIG.3C). In contrast to vehicle- treated control cells (FIG.3C), treatment with DKM 3-30 resulted in the loss of peripheral ER tubules and the accumulation of sheet-like ER structures (FIG.3D). The alterations in the ER morphology were evident as early as 0.5-1 hr and the ER architecture became progressively more distorted, with some cells exhibiting extremely aberrant, circular ER structures (FIG.9A- 9B). Consistent with the importance of RTN4 in ER structure, siRNA-mediated depletion of RTN4 resulted in the appearance of similarly altered ER morphologies (FIGS.3E,F). Together, these results suggest that DKM 3-30 acutely impairs RTN4 function in ER tubules formation or maintenance. [0624] Cell division requires elaborate rearrangements in the ER and the nuclear envelope to ensure correct inheritance of DNA and segregation of DNA within a single nucleus ¹⁵ . During prophase the nuclear envelope retracts into the ER and then reforms during telophase. The reticulon family of proteins, and the transition between ER tubules and sheets, have been implicated in nuclear envelope assembly and disassembly during mitosis ^16–18 . Time-lapse imaging of mitotic cells revealed that control cells divided rapidly (~50-60 min) (FIG.4A). In contrast, DKM 3-30-treated cells exhibited prolonged mitosis (~3-4 hr) (FIG.4B), possibly reflecting complications in the division process. Indeed, following mitosis, DKM 3-30-treated cells contained aberrant nuclei that were bisected by GFP-Sec61β positive structures (FIG.4B). Distortions in the nuclear envelope were also frequently observed during interphase in DKM 3- 30-treated cells, including multi-lobed, cloverleaf-like nuclear envelope morphologies that often preceded cell death (FIG.4C). Thus, disrupting RTN4-mediated ER remodeling may impair colorectal cancer pathogenicity by altering ER homeostasis and nuclear envelope assembly and disassembly during mitosis. [0625] We also synthesized analogs of DKM 3-30 and showed that YP 1-46 demonstrated less displacement of IAyne labelling of RTN4, whereas AMR 1-125 exhibited ~7-fold improved potency compared to DKM 3-30. We further showed that AMR 1-125, but not YP 1-46, impaired cell survival in U2OS and SW620 cells and ER morphology in U2OS cells (FIGS. 11A-11C). [0626] In summary, we identify RTN4 as a novel colorectal cancer therapeutic target, and reveal a unique druggable hotspot within this classically undruggable protein, which can be targeted by cysteine-reactive ligands such as DKM 3-30 to impair ER and nuclear envelope morphology and colorectal cancer pathogenicity. We also show that DKM 3-30 impairs osteosarcoma cell survival as well, suggesting that RTN4 may have broader impacts upon other types of cancers. We recognize that DKM 3-30 may have additional off-targets that may contribute its anti-cancer activity, but nonetheless show compelling evidence that DKM 3-30 and its analogs phenocopy what is observed with RTN4 knockdown and that DKM 3-30 confers sensitivity in MEF cells only when expressing human RTN4. DKM 3-30 and AMR 1-125 may serve as initial starting points for subsequent medicinal chemistry to develop a more potent and selective RTN4 inhibitors for cancer therapy. Overall, we highlight the utility of coupling the screening of covalent ligand libraries with isoTOP-ABPP for mining the proteome for novel druggable nodes that can be targeted for cancer therapy. [0627] Methods. [0628] Materials. IAyne was obtained from CHESS Gmbh. Heavy and light TEV-biotin tags were synthesized per previously described methods ^5,21 . [0629] Synthesis of Cysteine Fragment Library. The synthesis of the cysteine-reactive ligand library is described below. All compounds in the library were confirmed to be >95 % pure. [0630] Cell Culture. SW620 cells were purchased from ATCC. SW620 cells were grown in L- 15 media with 10% fetal bovine serum (FBS) in ambient CO ₂ . U2OS cells were grown in DMEM media supplemented with 10% FBS at 37 ^o C with 5% CO2. [0631] Survival and Proliferation Assays. Cells were plated the evening before the experiment, and allowed to adhere overnight. For serum-free cell survival assays, cells were plated in media not containing FBS. For cell proliferation assays, cells were plated in regular media. For the chemical genetics screen, cells were treated with either DMSO or the cysteine-reactive fragment for 48 h and cell viability was assessed by Hoescht stain using our previously described methods ²² . [0632] Tumor Xenograft Growth Studies. C.B17 SCID male mice (6-8 weeks old) were injected subcutaneously into the flank with 2,000,000 cells in serum-free media. For

pharmacological treatments, mice were exposed by intraperitoneal (ip) injection with either vehicle (18:1:1 PBS/ethanol/PEG40) or 50 mg/kg DKM 3-30 once per day starting ten days after the initiation of the xenograft experiment and until the completion of the study. Tumors were measured every 7 days by caliper measurements. Animal experiments were conducted in accordance with the guidelines of the Institutional Animal Care and Use Committee of the University of California, Berkeley. [0633] IsoTOP-ABPP Analysis. IsoTOP-ABPP analyses were performed as previously described ^5–7 . For competitive IsoTOP-ABPP, SW620 cell lysates were pre-incubated with DMSO vehicle or DKM 3-30 (50 µM) for 30 min at 37ºC in phosphate-buffered saline (PBS), and then labeled with IAyne (100 µM) for 1 h at room temperature. They were subsequently treated with isotopically light (control) or heavy (treated) TEV-biotin (100 µM) and CuAAC was performed as previously described ^5,6 . For analysis of cysteine reactivity in primary colorectal tumor tissue, tumors were pooled and incubated with either 100 µM IAyne and isotopically heavy TEV-biotin or 10 µM IAyne and isotopically light TEV-biotin followed by CuAAC. Proteins were precipitated over one hour and pelleted by centrifugation at 6500 x g. Proteins were washed 3 times with cold methanol then denatured and resolubilized by heating in 1.2% SDS/PBS to 85º C for 5 min. Insoluble components were precipitated by centrifugation at 6500 x g and soluble proteome was diluted in 5 ml PBS, for a final concentration of 0.2% SDS. Labeled proteins were bound to avidin-agarose beads (170 µL resuspended beads/sample, Thermo Pierce) while rotating overnight at 4ºC. Bead-linked proteins were enriched by washing three times each in PBS and water, then resuspended in 6 M urea/PBS (Sigma-Aldrich) and reduced in dithiothreitol (1 mM, Sigma-Aldrich), alkylated with iodoacetamide (18 mM, Sigma-Aldrich), then washed and resuspended in 2 M urea/PBS with 1 mM calcium chloride and trypsinized overnight with 0.5 µg/µl sequencing grade trypsin (Promega). Tryptic peptides were discarded and beads were washed three times each in PBS and water, then washed with one wash of TEV buffer containing 1 µM DTT. TEV-biotin tag was digested overnight in TEV buffer containing 1 µM DTT and 5 µL Ac-TEV protease at 29ºC. Peptides were diluted in water and acidified with final concentration of 5% formic acid (1.2 M, Spectrum). [0634] Peptides from all proteomic experiments were pressure-loaded onto a 250 mm inner diameter fused silica capillary tubing packed with 4 cm of Aqua C18 reverse-phase resin (Phenomenex # 04A-4299) which was previously equilibrated on an Agilent 600 series HPLC using gradient from 100% buffer A to 100% buffer B over 10 min, followed by a 5 min wash with 100% buffer B and a 5 min wash with 100% buffer A. The samples were then attached using a MicroTee PEEK 360 µm fitting (Thermo Fisher Scientific #p-888) to a 13 cm laser pulled column packed with 10 cm Aqua C18 reverse-phase resin and 3 cm of strong-cation exchange resin for isoTOP-ABPP studies. Samples were analyzed using an Q Exactive Plus mass spectrometer (Thermo Fisher Scientific) using a 5-step Multidimensional Protein

Identification Technology (MudPIT) program, using 0 %, 25 %, 50 %, 80 %, and 100 % salt bumps of 500 mM aqeous ammonium acetate and using a gradient of 5-55 % buffer B in buffer A (buffer A: 95:5 water:acetonitrile, 0.1 % formic acid; buffer B 80:20 acetonitrile:water, 0.1 % formic acid). Data was collected in data-dependent acquisition mode with dynamic exclusion enabled (60 s). One full MS (MS1) scan (400-1800 m/z) was followed by 15 MS2 scans (ITMS) of the nth most abundant ions. Heated capillary temperature was set to 200º C and the nanospray voltage was set to 2.75 kV. [0635] Data were extracted in the form of MS1 and MS2 files using Raw Extractor 1.9.9.2 (Scripps Research Institute) and searched against the Uniprot mouse database using ProLuCID search methodology in IP2 v.3 (Integrated Proteomics Applications, Inc) ²³ . Cysteine residues were searched with a static modification for carboxyaminomethylation (+57.02146) and up to two differential modifications for methionine oxidation and either the light or heavy TEV tags (+464.28596 or +470.29977, respectively). Peptides were required to have at least one tryptic end and to contain the TEV modification. ProLUCID data was filtered through DTASelect to achieve a peptide false-positive rate below 1%. [0636] Gel-Based ABPP. Gel-based ABPP methods were performed as previously described ²⁴ . Recombinant RTN4 (0.06 µg) protein (RTN4-Fisher Scientific) were pre-treated with DMSO or DKM 3-30, respectively, for 1 h at 37ºC in an incubation volume of 50 µL PBS, and were subsequently treated with IAyne (10 µM final concentration) for 30 min at 37ºC. CuAAC was performed to append rhodamine-azide onto IAyne probe-labeled proteins. The samples were separated by SDS/PAGE and scanned using a ChemiDoc MP (Bio-Rad Laboratories, Inc).

Inhibition of target labeling was assessed by densitometry using ImageStudio Light software. [0637] RTN4 Knockdown. Targets were knocked down transiently with siRNA or stably with shRNA as previously described ^22,25 . For siRNA studies, SW620 cells (200,000 cells/well) were seeded overnight after which siControl (non-targeting siRNA) or siRTN4 oligonucleotides (5 pooled siRNAs targeting each target purchased from Dharmacon) were transfected into cells using Dharmafect 1. Cells were harvested after 48 h for qPCR and for seeding for cell viability assays. [0638] For shRNA studies, shControl (targeting GFP) or shRTN4 constructs (purchased from Sigma) were transfected into HEK293T cells alongside lentiviral vectors using FuGENE.

Lentivirus was collected from filtered cultured medium 48 h post-transfection and used to infect the target cancer cell line with Polybrene (0.01 mg/ml) Target cells were selected over 3 days with 1 mg/ml puromycin. The short hairpin sequences for the generation of RTN4 knockdown lines were:

CCGGGCAGTGTTGATGTGGGTATTTCTCGAGAAATACCCACATCAACACTGCTTTTT TG (SEQ ID NO:328) and

CCGGGCTATATCTGAGGAGTTGGTTCTCGAGAACCAACTCCTCAGATATAGCTTTTT TG (SEQ ID NO:329). The control shRNA was targeted against GFP with the target sequence GCAAGCTGACCCTGAAGTTCAT (SEQ ID NO:330). Knockdown was confirmed by qPCR. [0639] qPCR. qPCR was performed using the manufacturer’s protocol for Fisher Maxima SYBR Green with 10 mM primer concentrations or for Bio-Rad SsoAdvanced Universal Probes Supermix. Primer sequences for Fisher Maxima SYBR Green were derived from Harvard Primer Bank. Primer sequences for Bio-Rad SsoAdvanced Universal Probes Supermix were designed with Primer 3 Plus. [0640] Fluorescence microscopy. SW620 and U2OS cells were transiently transfected with a plasmid encoding GFP-tagged Sec61β using fuGENE6 (Roche) according to the manufacturer’s instructions. Transfected cells plated on poly-L-lysine treated coverslips were treated, washed in PBS, and fixed by incubation in 4% paraformaldehyde in PBS for 10 min. Fixed cells were washed extensively in PBS and nuclei stained by addition of 4',6-diamidino-2-phenylindole (DAPI) (Thermo Fisher Scientific) for 10 min. Coverslips were mounted using Fluoromount-G (SouthernBiotech) and visualized using a DeltaVision Elite microscope outfitted with a 60x oil immersion objective. Acquired stacks of images of fixed cells were deconvolved and analyzed using SoftWoRx and ImageJ. For time-lapse imaging of live cells, transfected cells were plated on poly-L-lysine treated glass-bottom 4-well imaging chambers (Lab-Tek II; Thermo Fisher Scientific). Imaging was performed using a DeltaVision Elite microscope encased in a chamber that was maintained at 37°C and was continuously perfused with humidified 5% CO2. Acquired images were analyzed using SoftWoRx and ImageJ. [0641] Homology modeling and multiple sequence alignments. The threaded homology model of the human Rtn4 (amino acids 1054-1120 of Rtn4a) on the NMR solution structure of the corresponding region of mouse Rtn4 (PDB 2KO2) was generated using Protein

Homology/analogY Recognition Engine V 2.0 (Phyre2). Figures were made using PyMOL. Multiple sequence alignments were generated using Clustal Omega and figures were made using BoxShade. [0642] Primary Human Colorectal Tumors. Eligible patients completed written consent for our tissue banking protocol that is approved by the University of Alabama at Birmingham Institutional Review Board. During the colorectal tumor resection, a 1 cm ³ portion of the tumor was dissected free of the fresh resection specimen, divided into 4-5 aliquots, placed into 1.5 mL cryovials, flash frozen, and stored at -80°C. Adjacent non-tumor bearing colorectal tissue was also collected and banked in a similar manner. [0643] General synthetic methods [0644] Chemicals and reagents were purchased from major commercial suppliers and used without further purification. Reactions were performed under a nitrogen atmosphere unless otherwise noted. Silica gel flash column chromatography was performed using EMD or Sigma Aldrich silica gel 60 (230-400 mesh). Proton and carbon nuclear magnetic resonance ( ¹ H NMR and ¹³ C NMR) data was acquired on a Bruker AVB 400, AVQ 400, or AV 600 spectrometer at the University of California, Berkeley. High resolution mass spectrum were obtained from the QB3 mass spectrometry facility at the University of California, Berkeley using positive or negative electrospray ionization (+ESI or -ESI). Yields are reported as a single run. [0645] General Procedure A. The amine (1 eq.) was dissolved in DCM (5 mL/mmol) and cooled to 0 ^o C. To the solution was added acryloyl chloride (1.2 eq.) followed by triethylamine (1.2 eq.). The solution was warmed to room temperature and stirred overnight. The solution was then washed with brine and the crude product was purified by silica gel chromatography (and recrystallization if necessary) to afford the corresponding acrylamide. [0646] General Procedure B. The amine (1 eq.) was dissolved in DCM (5 mL/mmol) and cooled to 0 ^o C. To the solution was added chloroacetyl chloride (1.2 eq.) followed by

triethylamine (1.2 eq.). The solution was warmed to room temperature and stirred overnight. The solution was then washed with brine and the crude product was purified by silica gel

chromatography (and recrystallization if necessary) to afford the corresponding chloroacetamide.

[0647] N-(4-benzoylphenyl)acrylamide (DKM 2-117). Following General Procedure A starting from 4-aminobenzophenone (587 mg, 3.0 mmol), product was obtained after silica gel chromatography (10% to 30% ethyl acetate in hexanes) in 37% yield as a yellow solid (275 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 8.77 (s, 1H), 7.80-7.73 (m, 6H), 7.57 (tt, J = 1.5, 7.4 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 6.46 (dd, J = 1.616.9 Hz, 1H), 6.37 (dd, J = 9.9, 16.9 Hz, 1H), 5.75 (dd, J = 1.6, 9.9 Hz, 1H). ¹³ C NMR (100MHz, CDCl3): δ 196.3, 164.4, 142.3, 137.8, 133.0, 132.5, 131.7, 131.0, 130.0, 128.8, 128.4, 119.3. HRMS (+ESI): Calculated: 252.1019 (C ₁₆ H ₁₄ NO ₂ ). Observed: 252.1014.

[0648] N-([1,1'-biphenyl]-4-ylmethyl)acrylamide (DKM 2-37). Following General Procedure A starting from 4-phenylbenzylamine (552 mg, 3.0 mmol), product was obtained after silica gel chromatography (0% to 80% ethyl acetate in hexanes) in 10% yield as an off-white solid (73 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 7.58-7.55 (m, 4H), 7.44 (t, J = 7.5 Hz, 2H), 7.38-7.33 (m, 3H), 6.35 (dd, J = 1.3, 17.0 Hz, 1H), 6.13 (dd, J = 10.3, 17.0 Hz, 1H), 6.01 (s, 1H), 5.68 (dd, J = 1.3, 10.3 Hz, 1H), 4.56 (d, J = 5.8 Hz, 2H). ¹³ C NMR (100MHz, CDCl3): δ 165.5, 140.77, 140.73, 137.2, 130.7, 128.9, 128.5, 127.6, 127.5, 127.2, 127.1, 43.5. HRMS (+ESI): Calculated: 238.1226 (C ₁₆ H ₁₆ NO). Observed: 238.1224.

[0649] 2-Chloro-N-(4-phenylbutan-2-yl)acetamide (DKM 2-76). Following General

Procedure B starting from 1-methyl-3-phenylpropylamine (614 mg, 4.1 mmol) product was obtained after silica gel chromatography (0% to 30% ethyl acetate in hexanes) in 81% yield as a white solid (662 mg). ¹ H NMR (400MHz, CDCl3): δ 7.34-7.31 (m, 2H), 7.24-7.21 (m, 3H), 6.55 (d, J = 7.4 Hz, 1H), 4.15-4.07 (m, 1H), 4.04 (s, 2H), 2.70 (t, J = 8.2 Hz, 2H), 1.89-1.83 (m, 2H), 1.26 (d, J = 6.4 Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 165.1, 141.3, 128.4, 128.2, 125.9, 45.7, 42.7, 381, 32.3, 20.7. HRMS (+ESI): Calculated: 226.0993 (C12H17ClNO). Observed: 226.0992.

[0650] 2-chloro-N-(4-fluorobenzyl)acetamide (DKM 2-80). Following General Procedure B starting from 4-fluorobenzylamine (369 mg, 2.9 mmol) product was obtained after silica gel chromatography (0% to 30% ethyl acetate in hexanes) in 77% yield as a white solid (452 mg). ¹ H NMR (400MHz, CDCl3): δ 7.28-7.24 (m, 2H), 7.05-7.01 (m, 2H), 6.97 (s, 1H), 4.45 (d, J = 5.6 Hz, 2H), 4.09 (s, 2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 166.1, 163.6, 161.2, 133.20, 133.17, 129.64, 129.56, 115.9, 115.7, 43.2, 42.7. HRMS (-ESI): Calculated: 200.0284 (C9H8NOClF). Observed: 200.0284.

[0651] N-(benzo[d][1,3]dioxol-5-yl)acrylamide (DKM 2-86). Following General Procedure A starting from 3,4-(methylenedioxy)aniline (486 mg, 2.9 mmol), product was obtained after silica gel chromatography (0% to 30% ethyl acetate in hexanes) in 68% yield as a white solid (438 mg). ¹ H NMR (400MHz, (CD3)2SO): δ 10.05 (s, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.02 (dd, J = 2.0, 8.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.38 (dd, J = 10.1, 17.0 Hz, 1H), 6.22 (dd, J = 2.1, 17.0 Hz, 1H), 5.99 (s, 2H), 5.72 (dd, J = 2.1, 10.1 Hz, 1H). ¹³ C NMR (100MHz, (CD3)2SO): δ 162.8, 147.0, 143.1, 133.4, 131.8, 126.5, 112.1, 108.1, 101.4, 101.0. HRMS (+ESI): Calculated:

192.0655 (C ₁₀ H ₁₀ NO ₃ ). Observed: 192.0651.

[0652] 2-chloro-N-(2,3-dihydro-1H-inden-4-yl)acetamide (DKM 2-91). Following General Procedure B starting from 4-aminoindan (372 mg, 2.8 mmol) product was obtained after silica gel chromatography (0% to 40% ethyl acetate in hexanes) in 49% yield as an off-white solid (289 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 8.19 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 4.16 (s, 2H), 2.94 (t, J = 7.6 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H), 2.10 (quint, J = 7.5 Hz, 2H). ¹³ C NMR (100MHz, CDCl3): δ 163.8, 145.5, 134.5, 132.8, 127.3, 121.6, 118.5, 43.1, 33.2, 29.8, 24.8. HRMS (+ESI): Calculated: 210.0680 (C ₁₁ H ₁₃ ClNO).

Observed: 210.0680.

[0653] 2-Chloro-N-(2-chlorobenzyl)acetamide (DKM 2-94). Following General Procedure B starting from 2-chlorobenzylamine (432 mg, 3.1 mmol) product was obtained after silica gel chromatography (0% to 30% ethyl acetate in hexanes) in 67% yield as a white solid (443 mg). ¹ H NMR (400MHz, CDCl3): δ 7.36-7.18 (m, 5H), 4.51 (d, J = 6.4 Hz, 2H), 4.01 (s, 2H). ¹³ C NMR (100MHz, CDCl3): δ 166.1, 134.7, 133.5129.8, 129.5, 129.1, 127.1, 42.5, 41.6. HRMS (- ESI): Calculated: 215.9988 (C9H8NOCl2). Observed: 215.9988.

[0654] N-(4'-cyano-[1,1'-biphenyl]-4-yl)acrylamide (DKM 2-98). Following General

Procedure A starting from 4-(4-aminophenyl)benzonitrile (387 mg, 2.0 mmol), product was obtained after silica gel chromatography (1% to 2% ethyl methanol in DCM) in 70% yield as a yellow solid (348 mg). ¹ H NMR (600MHz, (D ₃ C) ₂ CO): 9.52 (s, 1H), 7.90-7.89 (m, 2H), 7.87- 7.86 (m, 2H), 7.84-.7.82 (m, 2H), 7.73-7.71 (m, 2H), 6.49 (dd, J = 10.0, 16.9 Hz, 1H), 6.39 (dd, J = 2.0, 16.9 Hz, 1H), 5.76 (dd, J = 2.0, 10.0 Hz, 1H). ¹³ C NMR (150MHz, (D3C)2CO): δ 164.3, 145.7, 140.9, 134.8, 133.6, 132.7, 128.5, 128.2, 127.6, 120.8, 119.5, 111.3. HRMS (-ESI):

Calculated: 247.0877 (C ₁₆ H ₁₁ N ₂ O). Observed: 247.0875.

[0655] N-(4-(methylthio)phenyl)acrylamide (DKM 3-10). Following General Procedure A starting from 4-(methylthio)aniline (405 mg, 2.9 mmol), product was obtained after silica gel chromatography (10% to 40% ethyl acetate in hexanes) in 64% yield as a clear oil (362 mg). ¹ H NMR (400MHz, MeOD): δ 7.59-7.56 (m, 2H), 7.26-7.22 (m, 2H), 6.42 (dd, J = 9.6, 17.0 Hz, 1H), 6.34 (dd, J = 2.3, 17.0 Hz, 1H), 5.75 (dd, J = 2.3, 9.6 Hz, 1H), 2.45 (s, 3H). ¹³ C NMR (100MHz, MeOD): δ 166.0, 137.2, 135.4, 132.4, 128.6, 127.7, 121.9, 16.4. HRMS (+ESI): Calculated: 194.0634 (C10H12NOS). Observed: 194.0631.

[0656] N-(4'-ethyl-[1,1'-biphenyl]-4-yl)acrylamide (DKM 3-16). Following General

Procedure A starting from 4-amino-4-ethylbiphenyl (386 mg, 2.0 mmol), product was obtained after silica gel chromatography (10% to 70% ethyl acetate in hexanes) in 65% yield as a white solid (164 mg). ¹ H NMR (400MHz, (CD3)2CO): δ 7.82 (d, J = 8.2 Hz, 2H), 7.62-7.59 (m, 2H), 7.58-7.54 (m, 2H), 7.29 (d, J = 8.2 Hz, 2H), 6.47 (dd, J = 9.9, 16.9 Hz, 1H), 6.36 (dd, J = 2.2, 16.9 Hz, 1H), 5.72 (dd, J = 2.2, 9.9 Hz, 1H), 2.67 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H). ¹³ C NMR (100MHz, (CD3)2CO): δ 164.1, 144.0, 139.5, 13.9, 137.1, 132.9, 129.3, 127.9, 127.4, 127.2, 120.7, 29.2, 16.2. HRMS (+ESI): Calculated: 252.1383 (C ₁₇ H ₁₈ NO). Observed:

252.1379.

[0657] N,N-diphenylacrylamide (DKM 3-70). A solution of diphenylamine (347 mg, 2.1 mmol) in DCM (10 mL) was cooled to 0 ^o C. To the solution was added acryloyl chloride (222 mg, 2.5 mmol) followed by triethylamine (279 mg, 2.8 mmol). The solution was allowed to warm to room temperature and stirred overnight. The solution was washed with brine and citric acid and the crude product was purified via silica gel chromatography (20% to 60% ethyl acetate in hexanes) to afford the product in 24% yield as a dark yellow oil (112 mg). ¹ H NMR

(400MHz, CDCl3): δ 7.43-7.28 (m, 10H), 6.52 (dd, J = 2.0, 16.8 Hz, 1H), 6.25 (dd, J = 10.2, 16.8 Hz, 1H), 5.67 (dd, J = 1.8, 10.2 Hz, 1H). ¹³ C NMR (100MHz, CDCl3): δ 165.8, 142.6, 129.7, 129.3, 128.5, 127.0. HRMS (+ESI): Calculated: 246.0889 (C ₁₅ H ₁₃ NONa). Observed: 246.0887.

[0658] 2-Chloro-N-(4-phenoxyphenyl)acetamide (TRH 1-23). Following General Procedure B starting from 4-phenoxyaniline (370 mg, 2.0 mmol) product was obtained after silica gel chromatography (10% to 30% ethyl acetate in hexanes) in 46% yield as a white solid (315 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 8.42 (s, 1H), 7.52-7.48 (m, 2H), 7.35-7.31 (m, 2H), 7.10 (t, J = 7.3 Hz, 1H), 7.01-6.98 (m, 4H), 4.17 (s, 2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 164.2, 157.2, 154.4, 132.1, 129.8, 123.4, 122.2, 119.4, 118.7, 42.9. HRMS (-ESI): Calculated: 260.0484 (C ₁₄ H ₁₁ NO ₂ Cl). Observed: 260.0482.

[0659] N-(4-(trifluoromethyl)phenyl)acrylamide (TRH 1-50). Following General Procedure A starting from 4-(trifluoromethyl)aniline (328 mg, 2.0 mmol), product was obtained after silica gel chromatography (10% to 30% ethyl acetate in hexanes) in 55% yield as a white solid (239 mg). ¹ H NMR (400MHz, MeOD): δ 7.78 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H), 6.44-6.32 (m, 2H), 5.75 (dd, J = 8.4, 2.8 Hz, 1H). ¹³ C NMR (100MHz, MeOD): δ 166.3, 143.3, 132.1, 128.6, 127.04, 127.00, 126.97, 126.93, 126.6, 124.3, 120.9. HRMS (-ESI): Calculated: 214.0485 (C10H7NOF3). Observed: 214.0484.

[0660] 2-Chloro-N-(2-methylbenzyl)acetamide (TRH 1-55). Following General Procedure B starting from 2-methylbenzylamine (239 mg, 2.0 mmol) product was obtained after silica gel chromatography (30% ethyl acetate in hexanes) and recrystallization from 5% ethyl acetate in hexanes in 64% yield as a white solid (191 mg). ¹ H NMR (400 MHz, CDCl3): δ 7.25-7.19 (m, 4H), 6.85 (s, 1H), 4.46 (d, J = 5.6 Hz, 2H), 4.04 (s, 2H), 2.33 (s, 3H). ¹³ C NMR (100 MHz, CDCl3): δ 165.8, 136.4, 135.0, 130.6, 128.4, 128.0, 126.3, 42.6, 42.0, 19.0. HRMS (-ESI): Calculated: 196.0535 (C10H11NOCl). Observed: 196.0534.

[0661] N-benzylacrylamide (DKM 2-31). Following General Procedure A starting from benzylamine (334 mg, 3.1 mmol), product was obtained after silica gel chromatography (0% to 50% ethyl acetate in hexanes) in 75% yield as a white solid (376 mg). ¹ H NMR (400MHz, CDCl3): δ 7.28-7.18 (m, 6H), 6.19-6.16 (m, 2H), 5.53 (dd, J = 4.6, 7.3 Hz, 1H), 4.36 (d, J = 5.9 Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 165.8, 138.1, 130.8, 128.6, 127.7, 127.3, 126.5, 43.5. HRMS (+ESI): Calculated: 162.0913 (C ₁₀ H ₁₂ NO). Observed: 162.0912. [0662] N-(4-phenylbutan-2-yl)acrylamide (DKM 2-32). Following General Procedure A starting from 1-methyl-3-phenylpropylamine (606 mg, 4.0 mmol), product was obtained after silica gel chromatography (0% to 50% ethyl acetate in hexanes) in 89% yield as a clear oil (735 mg). ¹ H NMR (400MHz, CDCl3): δ 7.32-7.29 (m, 2H), 7.23-7.20 (m, 3H), 6.84 (d, J = 8.4 Hz, 1H), 6.36-6.24 (m, 2H), 5.64 (dd, J = 2.8, 9.2 Hz, 1H), 4.21-4.14 (m, 1H), 2.70 (t, J = 7.8 Hz, 2H), 1.93-1.77 (m, 2H), 1.24 (d, J = 6.4 Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 165.1, 141.7, 131.3, 128.3, 128.2, 125.80, 125.77, 45.1, 38.4, 32.5, 20.8. HRMS (+ESI): Calculated: 204.1383 (C13H18NO). Observed: 204.1380. [0663] N-(4-methoxybenzyl)acrylamide (DKM 2-33). Following General Procedure A starting from 4-methoxybenzylamine (424 mg, 3.1 mmol), product was obtained after silica gel chromatography (0% to 50% ethyl acetate in hexanes) in 60% yield as a clear oil (343 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 7.14 (d, J = 8.8 Hz, 2H), 6.85 (s, 1H), 6.79 (d, J = 8.4 Hz, 2H), 6.24- 6.14 (m, 2H), 5.56 (dd, J = 2.0, 9.6 Hz, 1H), 4.33 (d, J = 5.6 Hz, 2H), 3.73 (s, 3H). ¹³ C NMR (100MHz, CDCl3): δ 165.6, 158.9, 130.9, 130.3, 129.1, 126.4, 113.9, 55.2, 42.9. HRMS (+ESI): Calculated: 192.1019 (C ₁₁ H ₁₄ NO ₂ ). Observed:192.1017.

[0664] N-(4-fluorobenzyl)acrylamide (DKM 2-34). Following General Procedure A starting from 4-fluorobenzylamine (368 mg, 2.9 mmol), product was obtained after silica gel

chromatography (0% to 60% ethyl acetate in hexanes) in 52% yield as an off-white solid (276 mg). ¹ H NMR (400MHz, CDCl3): δ 7.24-7.19 (m, 2H), 6.97 (t, J = 8.5 Hz, 2H), 6.42 (s, 1H), 6.27 (d, J = 17.0 Hz, 1H), 6.12 (dd, J = 17.0, 10.2 Hz, 1H), 5.63 (d, J = 10.2 Hz, 1H), 4.42 (d, J = 5.8 Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 165.7, 163.5, 134.0, 130.6, 129.6, 129.5, 127.0, 115.7, 115.5, 43.0. HRMS (+ESI): Calculated: 180.0819 (C10H11NOF). Observed: 180.0818.

[0665] Ethyl 4-acryloylpiperazine-1-carboxylate (DKM 2-39). Following General Procedure A starting from ethyl 1-piperazinecarboxylate (477 mg, 3.0 mmol), product was obtained after silica gel chromatography (0% to 70% ethyl acetate in hexanes) in 58% yield as a yellow oil (372 mg). ¹ H NMR (400MHz, CDCl3): δ 6.46 (dd, J = 10.5, 16.8 Hz, 1H), 6.18 (dd, J = 1.9, 16.8 Hz), 5.60 (dd, J = 1.9, 10.5 Hz), 4.03 (q, J = 7.1 Hz, 2H), 3.54 (s, 2H), 3.44 (s, 2H), 3.39- 3.36 (m, 4H), 1.15 (t, J = 7.1 Hz, 3H). ¹³ C NMR (100MHz, CDCl3): δ 165.3, 155.1, 128.2, 127.1, 61.5, 45.4, 43.6, 43.3, 41.5, 14.5. HRMS (+ESI): Calculated: 213.1234 (C10H17N2O3). Observed: 213.1232.

[0666] N-(2,5-difluorophenyl)acrylamide (DKM 2-40). Following General Procedure A starting from 2,5-difluoroaniline (369 mg, 2.9 mmol), product was obtained after silica gel chromatography (0% to 15% ethyl acetate in hexanes) in 27% yield as a white solid (141 mg). ¹ H NMR (400MHz, (CD3)2CO): δ 9.26 (s, 1H), 8.29-8.24 (m, 1H), 7.24-7.18 (m, 1H), 6.90-6.84 (m, 1H), 6.67 (dd, J = 10.2, 16.9 Hz, 1H), 6.41 (dd, J = 1.9, 16.9 Hz, 1H), 5.79 (dd, J = 1.9, 10.2 Hz, 1H). ¹³ C NMR (100MHz, (CD ₃ ) ₂ CO): δ 164.6, 160.4, 151.0, 148.7, 132.0, 128.9, 128.8, 128.5, 116.7, 116.6, 116.5, 116.4, 111.1, 111.0, 110.8, 110.7, 110.0, 109.7. HRMS (+ESI):

Calculated: 184.0568 (C9H8 F2NO). Observed: 184.0567.

[0667] N-phenethylacrylamide (DKM 2-42). Following General Procedure A starting from phenylethylamine (367 mg, 3.0 mmol), product was obtained after silica gel chromatography (0% to 50% ethyl acetate in hexanes) in 85% yield as a yellow oil (450 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 7.30-7.18 (m, 5H), 6.63 (s, 1H), 6.25 (dd, J = 1.8, 17.0 Hz, 1H), 6.13 (dd, J = 10.0, 17.0 Hz 1H), 5.59 (dd, J = 1.6, 10.0 Hz, 1H), 3.56 (q, J = 6.8 Hz, 2H), 2.85 (t, J = 7.3 Hz, 2H). ¹³ C NMR (100MHz, CDCl3): δ 165.8, 138.8, 131.0, 128.7, 128.6, 126.4, 126.1, 40.8, 35.6.

HRMS (+ESI): Calculated: 176.1070 (C11H14NO). Observed: 176.1068.

[0668] N-(4-bromobenzyl)acrylamide (DKM 2-43). Following General Procedure A starting from 4-bromobenzylamine (535 mg, 2.9 mmol), product was obtained after silica gel

chromatography (0% to 50% ethyl acetate in hexanes) in 59% yield as a white solid (407 mg). ¹ H NMR (400MHz, CDCl3): δ 7.37 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 7.00 (s, 1H), 6.24-6.10 (m, 2H), 5.59 (dd, J = 2.0, 9.7 Hz, 1H), 4.32 (d, J = 6.0 Hz , 2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 165.9, 137.2, 131.7, 130.6, 129.4, 126.9, 121.2, 42.8. HRMS (+ESI): Calculated: 240.0019 (C ₁₀ H ₁₁ BrNO). Observed: 240.0016.

[0669] N-(3,5-dimethylbenzyl)acrylamide (DKM 2-47). Following General Procedure A starting from 3,5-dimethylbenzylamine (257 mg, 1.9 mmol), product was obtained after silica gel chromatography (0% to 40% ethyl acetate in hexanes) in 77% yield as a white solid (276 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 6.89-6.87 (m, 4H), 6.26 (dd, J = 2.1, 17.0 Hz, 1H), 6.18 (dd, J = 9.7, 17.0 Hz, 1H) 5.59 (dd, J = 2.1, 9.7 Hz, 1H), 4.35 (d, J = 6.0 Hz, 2H), 2.28 (s, 6H). ¹³ C NMR (100MHz, CDCl3): δ 165.6, 138.1, 138.0, 130.9, 129.0, 126.3, 125.6, 43.4, 12.2. HRMS (+ESI): Calculated: 190.1226 (C12H16NO). Observed: 190.1225.

[0670] 1-(pyrrolidin-1-yl)prop-2-en-1-one (DKM 2-48). Following General Procedure A starting from pyrrolidine (223 mg, 3.1 mmol), product was obtained after silica gel

chromatography (0% to 80% ethyl acetate in hexanes) in 38% yield as a pale yellow oil (148 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 6.40 (dd, J = 10.0, 16.8 Hz, 1H), 6.29 (dd, J = 2.4, 16.8 Hz, 1H), 5.60 (dd, J = 2.4, 10.0 Hz, 1H), 3.48 (t, J = 6.8 Hz, 4H), 1.91 (quint, J = 6.7 Hz, 2H), 1.82 (quint, J = 6.7 Hz, 2H). ¹³ C NMR (100MHz, CDCl3): δ 164.4, 128.8, 127.2, 46.6, 45.9, 26.1, 24.3. HRMS (+ESI): Calculated: 126.0913 (C ₇ H ₁₂ NO). Observed: 126.0912.

[0671] 1-morpholinoprop-2-en-1-one (DKM 2-49). Following General Procedure A starting from morpholine (273 mg, 3.1 mmol), product was obtained after silica gel chromatography (0% to 80% ethyl acetate in hexanes) in 46% yield as a yellow oil (205 mg). ¹ H NMR (400MHz, CDCl3): δ 6.45 (dd, J = 10.5, 16.8 Hz, 1H), 6.20 (dd, J = 1.9, 16.8 Hz, 1H), 5.61 (dd, J = 1.9, 10.5 Hz, 1H), 5.38 (s, 6H), 3.46 (s, 2H). ¹³ C NMR (100MHz, CDCl3): δ 165.3, 128.1, 126.9, 66.6, 46.0, 42.1. HRMS (+ESI): Calculated: 142.0863 (C ₇ H ₁₂ NO ₂ ). Observed: 142.0861.

[0672] N-(3-phenylpropyl)acrylamide (DKM 2-50). Following General Procedure A starting from 3-phenyl-1-propylamine (275 mg, 2.0 mmol), product was obtained after silica gel chromatography (0% to 60% ethyl acetate in hexanes) in 58% yield as a yellow oil (223 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 7.29-7.25 (m, 2H), 7.20-7.16 (m, 3H), 6.99 (s, 1H), 6.29-6.17 (m, 2H), 5.59 (dd, J = 2.6, 9.0 Hz, 1H), 3.34 (q, J = 6.7 Hz, 2H), 2.65 (t, J = 7.6 Hz, 2H), 1.87 (quint, J = 7.4 Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 166.0, 141.4, 131.1, 128.33, 128.26, 125.9, 39.2, 33.2, 31.0. HRMS (+ESI): Calculated: 190.1226 (C ₁₂ H ₁₆ NO). Observed: 190.1225.

[0673] N-(2-(2-methoxyphenoxy)ethyl)acrylamide (DKM 2-58). Following General

Procedure A starting from 2-(2-methoxyphenoxy)ethanamine (509 mg, 3.0 mmol), product was obtained after silica gel chromatography (0% to 30% ethyl acetate in hexanes) in 70% yield as a yellow oil (470 mg). ¹ H NMR (400MHz, CDCl3): δ 6.95-6.84 (m, 4H), 6.77 (s, 1H), 6.26 (d, J = 17.1 Hz, 1H), 6.11 (dd, J = 10.2, 17.1 Hz, 1H), 5.59 (d, J = 10.2 Hz, 1H), 4.07 (t, J = 5.2 Hz, 2H), 3.79 (s, 3H), 3.69 (q, J = 5.4 Hz, 2H). ¹³ C NMR (100MHz, CDCl3): δ 165.7, 149.6, 147.7, 130.8, 126.4, 122.1, 121.0, 114.8, 111.8, 68.5, 55.7, 38.9. HRMS (+ESI): Calculated: 244.0944 (C12H15NO3Na). Observed: 244.0940.

[0674] N-([1,1'-biphenyl]-2-ylmethyl)acrylamide (DKM 2-59). Following General Procedure A starting from 2-phenylbenzylamine (202 mg, 1.1 mmol), product was obtained after silica gel chromatography (0% to 40% ethyl acetate in hexanes) in 70% yield as a yellow oil (184 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 7.41-7.22 (m, 9H), 6.16 (dd, J = 1.2, 17.2 Hz, 1H), 6.03-5.97 (m, 2H), 5.55 (dd, J = 1.2, 10.0 Hz, 1H), 4.44 (d, J = 5.6 Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 165.3, 141.6, 140.6, 135.2, 1306, 130.2, 129.0, 128.7, 128.4,127.8, 127.4, 127.3, 126.4, 41.4. HRMS (+ESI): Calculated: 238.1226 (C16H16NO). Observed: 238.1223.

[0675] N-(2-chlorobenzyl)acrylamide (DKM 2-60). Following General Procedure A starting from 2-chlorobenzylamine (406 mg, 2.9 mmol), product was obtained after silica gel chromatography (0% to 30% ethyl acetate in hexanes) in 34% yield as a white solid (162 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 7.34-30 (m, 2H), 7.20-7.16 (m, 2H), 6.84 (s, 1H), 6.25 (dd, J = 2.0, 17.0 Hz, 1H), 6.16 (dd, J = 9.7, 17.0 Hz, 2H), 5.60 (dd, J = 2.0, 9.7 Hz, 1H), 4.52 (d, J = 6.1 Hz, 2H). ¹³ C NMR (100MHz, CDCl3): δ 165.9, 135.5, 133.5, 130.6, 129.8, 129.5, 128.8, 127.1, 126.8, 41.4. HRMS (+ESI): Calculated: 196.0524 (C ₁₀ H ₁₁ ClNO). Observed: 196.0521

[0676] N-(2-nitrobenzyl)acrylamide (DKM 2-62). Following General Procedure A starting from 2-nitrobenzylamine hydrochloride (406 mg, 2.9 mmol) with an extra equivalent of triethylamine, product was obtained after silica gel chromatography (50% ethyl acetate in hexanes) in 42% yield as a yellow solid (255 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 7.98 (dd, J = 1.1, 8.2 Hz, 1H), 7.58-7.52 (m, 2H), 7.41-7.37 (m, 1H), 7.03 (s, 1H), 6.22 (dd, J = 2.0, 17.0 Hz, 1H), 6.14 (dd, J = 9.7, 17.0 Hz, 1H), 5.59 (dd, J = 2.0, 9.7 Hz, 1H), 4.68 (d, J = 6.4 Hz, 2H). ¹³ C NMR (100MHz, CDCl3): δ 165.8, 148.2, 134.1, 133.6, 131.9, 130.4, 128.7, 127.1, 125.1, 41.2. HRMS (+ESI): Calculated: 207.0764 (C ₁₀ H ₁₁ N ₂ O ₃ ). Observed: 207.0760.

[0677] N-(2,3-dihydro-1H-inden-4-yl)acrylamide (DKM 2-84). Following General Procedure A starting from 4-aminoindan (402 mg, 3.0 mmol), product was obtained after silica gel chromatography (30% ethyl acetate in hexanes) in 59% yield as a white solid (332 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 7.72 (d, J = 7.5 Hz, 1H), 7.54 (s, 1H), 7.10 (t, J = 7.7 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 6.40-6.26 (m, 2H), 5.69 (dd, J = 1.9, 9.7 Hz, 1H), 2.91 (t, J = 7.4 Hz, 2H), 2.78 (t, J = 7.4 Hz, 2H), 2.05 (quint, J = 7.4 Hz, 2H). ¹³ C NMR (100MHz, CDCl3): 163.5, 145.3, 134.4, 133.6, 131.2, 127.5, 127.2, 12.0, 19.2, 33.2, 30.1, 24.8. HRMS (+ESI): Calculated:

188.1070 (C ₁₂ H ₁₄ NO). Observed:188.1069.

[0678] Ethyl 4-acrylamidobenzoate (DKM 2-85). Following General Procedure A starting from benzocaine (486 mg, 2.9 mmol), product was obtained after silica gel chromatography (0% to 30% ethyl acetate in hexanes) in 68% yield as a white solid (438 mg). ¹ H NMR (400MHz, CDCl3): δ 9.39 (s, 1H), 7.95 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 6.43-6.41 (m, 2H), 5.71 (dd, J = 4.7, 6.9 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 1.33 (s, J = 7.1 Hz, 3H). ¹³ C NMR (100MHz, CDCl3): δ 166.5, 164.6, 142.5, 131.0, 130.6, 128.4, 125.7, 119.4, 61.0, 14.2. HRMS (-ESI): Calculated: 218.0823 (C ₁₂ H ₁₂ NO ₃ ). Observed: 218.0822.

[0679] N-benzyl-N-methylacrylamide (DKM 2-95). Following General Procedure A starting from N-methylbenzylamine (350 mg, 2.9 mmol), product was obtained after silica gel chromatography (20% ethyl acetate in hexanes) in 60% yield as a clear oil (304 mg). ¹ H NMR (~48:52 rotamer ratio, asterisks denote minor peaks, 400MHz, CDCl3): δ 7.34-7.23 (m, 4H), 7.16 (s, 1H), 7.14 ^* (s, 1H), 6.61 (dd, J = 10.4, 16.8 Hz, 1H), 6.57 ^* (dd, J = 10.4, 16.8 Hz, 1H), 6.38 (dd, J = 1.9, 16.8 Hz, 1H), 6.36 ^* (dd, J = 1.9, 16.8 Hz, 1H), 5.71 (dd, J = 1.9, 10.4 Hz, 1H), 5.64 ^* (dd, J = 1.9, 10.4 Hz), 4.63 (s, 2H), 4.56 ^* (s, 2H), 2.98 ^* (s, 3H), 2.96 (s, 3H). ¹³ C NMR

(100MHz, CDCl3): δ 167.0, 166.4, 137.1, 136.5, 128.8, 128.5, 128.2, 128.0, 17.62, 127.59, 127.3, 126.3, 53.3, 51.0, 34.8, 34.0. HRMS (+ESI): Calculated: 176.1070 (C ₁₁ H ₁₄ NO).

Observed:176.1070.

[0680] 1-(4-phenylpiperidin-1-yl)prop-2-en-1-one (DKM 2-97). Following General Procedure A starting from 4-phenylpiperidine (331 mg, 2.1 mmol), product was obtained after silica gel chromatography (0% to 50% ethyl acetate in hexanes) in 86% yield as a yellow oil (379 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 7.32-7.28 (m, 2H), 7.22-7.17 (m, 3H), 6.62 (dd, J = 10.6, 16.8 Hz, 1H), 6.30 (dd, J = 1.9, 16.8 Hz, 1H), 5.68 (dd, J = 1.9, 10.6, Hz, 1H), 4.82 (d, J = 12.9 Hz, 1H), 4.11 (d, J = 13.2 Hz, 1H), 3.15 (t, J = 8.5 Hz, 1H), 2.78-2.67 (m, 2H), 1.90 (d, J = 12.9 Hz, 2H), 1.64 (quint, J = 12.3 Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ ): 165.3, 145.0, 128.5, 127.8, 127.4, 126.6, 126.4, 46.4, 42.7, 33.9, 32.7. HRMS (+ESI): Calculated: 216.1383 (C14H18NO).

Observed: 216.1383.

[0681] N-(2-morpholinoethyl)acrylamide (DKM 2-100). Following General Procedure A starting from 2-morpholinoethylamine (580 mg, 3.0 mmol), product was obtained after silica gel chromatography (2% to 6% methanol in dichloromethane) in 33% yield as a white solid (184 mg). ¹ H NMR (400MHz, CDCl3): δ 6.39 (s, 1H), 6.21 (dd, J = 1.7, 17.0 Hz, 1H), 6.08 (dd, J = 10.1, 17.0 Hz, 1H), 5.56 (dd, J = 1.7, 10.1 Hz, 1H), 3.63 (t, J = 4.6 Hz, 4H), 3.36 (q, J = 6.2 Hz, 2H), 2.45 (t, J = 6.2 Hz, 2H), 2.40-2.38 (m, 4H). ¹³ C NMR (100MHz, CDCl3): δ 165.5, 130.9, 126.2, 66.9, 57.0, 53.3, 35.7. HRMS (+ESI): Calculated: 185.1285 (C9H17N2O2). Observed: 185.1280.

[0682] 1-(indolin-1-yl)prop-2-en-1-one (DKM 2-101). Following General Procedure A starting from indoline (580 mg, 3.0 mmol), product was obtained after silica gel chromatography (0% to 20% ethyl acetate in hexanes) in 56% yield as a green solid (285 mg). ¹ H NMR

(400MHz, CDCl ₃ ): δ 8.30 (d, J = 7.7 Hz, 1H), 7.22-7.17 (m, 2H), 7.03 (t, J = 7.9 Hz, 1H), 6.60- 6.48 (m, 2H), 5.79 (dd, J = 2.6, 9.5 Hz, 1H), 4.15 (t, J = 8.5 Hz, 2H), 3.20 (t, J = 8.1, 2H). ¹³ C NMR (100MHz, CDCl3): δ 163.6, 142.6, 131.5, 129.0, 128.6, 127.2, 124.4, 123.8, 117.2, 47.8, 27.7. HRMS (+ESI): Calculated: 174.0913 (C ₁₁ H ₁₂ NO). Observed: 174.0911.

[0683] N-butylacrylamide (DKM 2-102). Following General Procedure A starting from butylamine (223 mg, 3.0 mmol), product was obtained after silica gel chromatography (20% ethyl acetate in hexanes) in 61% yield as a clear oil (237 mg). ¹ H NMR (400MHz, (CDCl3): δ 6.81 (s, 1H), 6.21-6.10 (m, 2H), 5.52 (dd, J = 3.6, 8.3 Hz, 1H), 3.26-3.21 (m, 2H), 1.48-1.41 (m, 2H), 1.33-1.23 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 166.0, 131.2, 125.6, 39.3, 31.5, 20.1, 13.7. HRMS (+ESI): Calculated: 128.1070 (C7H14NO). Observed: 128.1068.

[0684] N-(3-methoxypropyl)acrylamide (DKM 2-103). Following General Procedure A starting from 3-methoxypropylamine (274 mg, 3.1 mmol), product was obtained after silica gel chromatography (35% to 60% ethyl acetate in hexanes) in 54% yield as a clear oil (236 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 6.84 (s, 1H), 6.15 (dd, J = 2.0, 17.0 Hz.1H), 6.07 (dd, J = 9.8, 17.0 Hz, 1H), 5.51 (dd, J = 2.0, 9.8 Hz, 1H), 3.39 (t, J = 5.9 Hz, 2H), 3.33 (q, J = 6.3 Hz, 2H), 3.25 (s, 3H), 1.72 (quint, J = 6.3 Hz, 2H). ¹³ C NMR (100MHz, CDCl3): δ 165.8, 131.2, 125.7, 71.3, 58.7, 37.7, 29.0. HRMS (+ESI): Calculated: 144.1019 (C ₇ H ₁₄ NO ₂ ). Observed: 144.1017.

[0685] N-cyclohexylacrylamide (DKM 2-106). Following General Procedure A starting from cyclohexylamine (292 mg, 2.9 mmol), product was obtained after silica gel chromatography (20% to 30% ethyl acetate in hexanes) in 86% yield as a white solid (313 mg). ¹ H NMR

(400MHz, (CDCl ₃ ): δ 6.55 (d, J = 6.7 Hz, 1H), 6.21-6.09 (m, 2H), 5.51 (dd, J = 2.5, 9.1 Hz, 1H), 3.79-3.70 (m, 1H), 1.86-1.82 (m, 2H), 1.67-1.63 (m, 2H), 1.56-1.52 (m, 1H), 1.28-1.21 (m, 2H), 1.16-1.05 (m, 3H). ¹³ C NMR (100MHz, CDCl3): δ 164.8, 131.5, 125.7, 48.3, 32.9, 25.5, 24.9. HRMS (+ESI): Calculated: 154.1226 (C ₉ H ₁₆ NO). Observed: 154.1224.

[0686] N-(4-chlorophenyl)acrylamide (DKM 2-107). Following General Procedure A starting from 4-chloroaniline (386 mg, 3.0 mmol), product was obtained after silica gel chromatography (0% to 40% ethyl acetate in hexanes) followed by recrystallization from toluene in 31% yield as a white solid (168 mg). ¹ H NMR (400MHz, (CD3)2CO): δ 9.47 (s, 1H), 7.77-7.74 (m, 2H), 7.35- 7.31 (m, 2H), 6.43 (dd, J = 9.6, 16.9 Hz, 1H), 6.35 (dd, J = 2.5, 16.9 Hz, 1H), 5.73 (dd, J = 2.5, 9.6 Hz, 1H). ¹³ C NMR (100MHz, (CD ₃ ) ₂ CO): δ 164.1, 139.0, 132.5, 129.5, 128., 127.5, 121.7. HRMS (-ESI): Calculated: 180.0222 (C9H7NOCl). Observed: 180.0221.

[0687] N-cyclopentylacrylamide (DKM 2-108). Following General Procedure A starting from cyclopentylamine (257 mg, 3.0 mmol), product was obtained after silica gel chromatography (20% to 30% ethyl acetate in hexanes) in 55% yield as a colorless oil (229 mg). ¹ H NMR (400MHz, (CDCl ₃ ): δ 6.70 (s, 1H), 6.21-6.10 (m, 2H), 5.51 (dd, J = 3.5, 8.5 Hz, 1H), 5.53-5.50 (sex, J = 7.1 Hz, 1H), 1.94-1.86 (m, 2H), 1.65-1.46 (m, 4H), 1.41-1.32 (m, 2H). ¹³ C NMR (100MHz, CDCl3): δ 165.4, 131.3, 125.7, 51.1, 32.9, 23.8. HRMS (+ESI): Calculated: 140.1070 (C ₈ H ₁₄ NO). Observed: 140.1067.

[0688] 1-(4-methoxypiperidin-1-yl)prop-2-en-1-one (DKM 2-109). Following General Procedure A starting from 4-methoxypiperidine (461 mg, 3.0 mmol), product was obtained after silica gel chromatography (40% to 60% ethyl acetate in hexanes) in 75% yield as a pale yellow oil (386 mg). ¹ H NMR (400MHz, (CDCl3): δ 6.45 (dd, J = 10.6, 16.8 Hz, 1H), 6.09 (dd, J = 2.0, 16.8 Hz, 1H), 5.51 (dd, J = 2.0, 10.6 Hz, 1H), 3.80-3.74 (m, 1H), 3.65-3.58 (m, 1H), 3.33-3.17 (m, 6H), 1.74-1.67 (m, 2H), 1.47-1.39 (m, 2H). ¹³ C NMR (100MHz, CDCl3): δ 165.1, 127.6, 127.2, 75.0, 55.5, 42.7, 38.9, 31.1, 29.9. HRMS (+ESI): Calculated: 170.1176 (C9H16NO2). Observed: 170.1176.

[0689] N-(3,4-dimethoxybenzyl)acrylamide (DKM 2-110). Following General Procedure A starting from 3,4-dimethoxybenzylamine (497 mg, 3.0 mmol), product was obtained after silica gel chromatography (30% to 40% ethyl acetate in hexanes) in 65% yield as a white solid (425 mg). ¹ H NMR (400MHz, CDCl3): δ 7.07 (s, 1H), 6.70-6.64 (m, 3H), 6.18-6.08 (m, 2H), 5.50 (dd, J = 3.1, 8.8 Hz, 1H), 4.26 (d, J = 5.8 Hz, 2H), 3.70 (d, J = 7.8 Hz, 6H). ¹³ C NMR (400MHz, CDCl ₃ ): δ 165.5, 148.7, 148.0, 130.73, 130.67, 126.2, 119.9, 110.98, 110.96, 55.64, 55.55, 43.12. HRMS (+ESI): Calculated: 222.1125 (C12H16NO3). Observed: 222.1121.

[0690] tert-butyl 4-acryloylpiperazine-1-carboxylate (DKM 2-111). Following General Procedure A starting from 1-boc-piperazine (552 mg, 3.0 mmol), product was obtained after silica gel chromatography (50% to 70% ethyl acetate in hexanes) in 75% yield as a pale yellow oil (534 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 6.48 (dd, J = 10.5, 16.8 Hz, 1H), 6.20 (dd, J = 1.8, 16.8 Hz, 1H), 5.60 (dd, J = 1.8, 10.5 Hz, 1H), 3.55 (s, 2H), 3.44 (s, 2H), 3.36-3.34 (m, 4H), 1.37 (s, 9H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 165.4, 154.4, 128.2, 127.2, 80.2, 45.5, 41.7, 28.3.

HRMS (+ESI): Calculated: 241.1547 (C ₁₂ H ₂₁ N ₂ O ₃ ). Observed: 241.1543.

[0691] N-(2-phenoxyethyl)acrylamide (DKM 2-113). Following General Procedure A starting from 2-phenoxyethylamine (279 mg, 2.0 mmol), product was obtained after silica gel chromatography (30% to 70% ethyl acetate in hexanes) in 61% yield as a white solid (239 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 7.31-7.25 (m, 2H), 6.98-6.94 (m, 1H), 6.90-6.87 (m, 2H), 6.58 (s, 1H), 6.31 (dd, J = 1.6, 17.0 Hz, 1H), 6.17 (dd, J = 10.2, 17.0 Hz, 1H), 5.64 (dd, J = 1.6, 10.2 Hz, 1H), 4.05 (t, J = 5.2 Hz, 2H), 3.73 (q, J = 5.4 Hz, 2H). ¹³ C NMR (100MHz, CDCl3): δ 165.9, 158.4, 130.7, 129.6, 126.7, 121.2, 114.4, 66.5, 39.1. HRMS (+ESI): Calculated: 192.1019 (C11H14NO2). Observed: 192.1016.

[0692] N,N-dicyclohexylacrylamide (DKM 2-114). Following General Procedure A starting from dicyclohexylamine (537 mg, 3.0 mmol), product was obtained after silica gel

chromatography (20% to 40% ethyl acetate in hexanes) in 55% yield as a white solid (382 mg). ¹ H NMR (400MHz, CDCl3): δ 6.49 (dd, J = 10.6, 16.8 Hz, 1H), 6.11 (dd, J = 1.9, 16.8 Hz, 1H), 5.49 (dd, J = 2.0, 10.6 Hz, 1H), 3.45 (s, 1H), 3.22 (s, 1H), 2.22 (s, 2H), 1.74-1.49 (m, 12H), 1.22- 1.07 (m, 6H). ¹³ C NMR (100MHz, CDCl3): δ 166.2, 130.9, 125.5, 57.5, 55.6, 31.6, 30.1, 26.4, 26.0, 25.3. HRMS (+ESI): Calculated: 236.2009 (C ₁₅ H ₂₆ NO). Observed: 236.2004.

[0693] N-(4-(trifluoromethyl)benzyl)acrylamide (DKM 2-116). Following General Procedure A starting from 4-(trifluoromethyl)benzylamine (516 mg, 2.9 mmol), product was obtained after silica gel chromatography (20% to 30% ethyl acetate in hexanes) in 24% yield as a white solid (165 mg). ¹ H NMR (600MHz, CDCl ₃ ): δ 7.53 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 6.58 (s, 1H), 6.28 (dd, J = 1.5, 17.0 Hz, 1H), 6.14 (dd, J = 10.1, 17.0 Hz, 1H), 5.64 (dd, J = 1.5, 10.1 Hz, 1H), 4.50 (d, J = 6.0 Hz, 2H). ¹³ C NMR (150MHz, CDCl3): δ 165.9, 142.3, 130.5, 130.0, 129.7, 128.0, 127.3, 125.73, 125.69, 12566, 125.62, 43.1. HRMS (-ESI): Calculated: 228.0642 (C11H9NOF3). Observed: 228.0641.

[0694] Ethyl 1-acryloylpiperidine-4-carboxylate (DKM 2-120). Following General Procedure A starting from ethyl isonipecotate (459 mg, 2.9 mmol), product was obtained after silica gel chromatography (20% to 45% ethyl acetate in hexanes) in 71% yield as a pale yellow liquid (440 mg). ¹ H NMR (400MHz, CDCl3): δ 6.40 (dd, J = 10.6, 16.8 Hz, 1H), 6.04 (dd, J = 2.0, 16.8 Hz, 1H), 5.47 (dd, J = 2.0, 10.6 Hz, 1H), 4.23 (d, J = 13.21H), 3.93 (q, J = 7.1 Hz, 2H), 3.76 (d, J = 14.0 Hz, 1H), 2.99 (t, J = 11.8 Hz, 1H), 2.70 (t, J = 11.5 Hz, 1H), 2.37 (tt, J = 4.1, 10.7 Hz, 1H), 1.77-1.73 (m, 2H), 1.51-1.42 (m, 2H), 1.05 (t, J = 7.1 Hz, 3H). ¹³ C NMR (100MHz, CDCl3): δ 173.7, 165.0, 127.5, 127.2, 60., 44.7, 41.0, 40.5, 28.2, 27.4, 13.8. HRMS (+ESI): Calculated: 212.1281 (C ₁₁ H ₁₈ NO ₃ ). Observed: 212.1276.

[0695] N-benzhydrylacrylamide (DKM 3-4). Following General Procedure A starting from benzhydrylamine (459 mg, 3.0 mmol), product was obtained after silica gel chromatography (0% to 20% ethyl acetate in hexanes) and recrystallization from toluene in 15% yield as a white solid (110 mg). ¹ H NMR (400MHz, (CD3)2CO): δ 7.35-7.23 (m, 10H), 6.45 (dd, J = 10.2, 17.0 Hz, 1H), 6.36-6.34 (m, 1H), 6.25 (dd, J = 2.2, 17.0 Hz, 1H), 5.61 (dd, J = 2.2, 10.2 Hz, 1H). ¹³ C NMR (100MHz, (CD3)2CO): δ 164.84, 164.76, 143.51, 143.48, 132.51, 132.47, 129.4, 128.5, 1280, 126.3, 57.5, 57.4. HRMS (+ESI): Calculated: 238.1226 (C16H16NO). Observed: 238.1222.

[0696] 1-(4-phenylpiperazin-1-yl)prop-2-en-1-one (DKM 3-5). Following General Procedure A starting from 1-phenylpiperazine (479 mg, 3.0 mmol), product was obtained after silica gel chromatography (30% to 70% ethyl acetate in hexanes) in 87% yield as a yellow oil (555 mg). ¹ H NMR (400MHz, CDCl ₃ ): 7.30-7.25 (m, 2H), 6.92-6.87 (m, 3H), 6.60 (dd, J = 10.5, 16.8 Hz 1H), 6.33 (dd, J = 2.0, 16.8 Hz, 1H), 5.72 (dd, J = 2.0, 10.5 Hz, 1H), 3.81 (s, 2H), 3.66 (s, 2H), 3.14 (t, J = 5.2 Hz, 4H). ¹³ C NMR (100MHz, CDCl3): δ 165.0, 150.6, 18.9, 127.8, 127.1, 120.2, 116.3, 49.4, 48.9, 45.3, 41.5. HRMS (+ESI): Calculated: 217.1335 (C13H17N2O). Observed: 217.1332.

[0697] N-(4-acetylphenyl)acrylamide (DKM 3-7). Following General Procedure A starting from 4-aminoacetophenone (398 mg, 2.9 mmol), product was obtained after silica gel chromatography (20% to 50% ethyl acetate in hexanes) in 45% yield as a white solid (253 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 8.40 (s, 1H), 7.92 (d, J = 8.7 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 6.46 (dd, J = 1.3, 16.9 Hz, 1H), 6.34 (dd, J = 10.1, 16.9 Hz, 1H), 5.79 (dd, J = 1.3, 10.1 Hz, 1H), 2.57 (s, 3H). ¹³ C NMR (100MHz, CDCl3): δ 197.5, 164.1, 142.5, 133.0, 130.9, 129.9, 128.9, 119.4, 26.6. HRMS (+ESI): Calculated: 190.0863 (C ₁₁ H ₁₂ NO ₂ ). Observed: 190.0858.

[0698] 1-(4-methylpiperidin-1-yl)prop-2-en-1-one (DKM 3-8). Following General Procedure A starting from 4-methylpiperidine (295 mg, 3.0 mmol), product was obtained after silica gel chromatography (10% to 30% ethyl acetate in hexanes) in 84% yield as a yellow oil (385 mg). ¹ H NMR (400MHz, CDCl3): δ 6.51 (dd, J = 10.6, 16.5 Hz, 1H), 6.16 (dd, J = 2.0, 16.5 Hz, 1H), 5.57 (dd, J = 2.0, 10.6 Hz, 1H), 4.53 (d, J = 13.1 Hz, 1H), 3.88 (d, J = 13.3 Hz, 1H), 2.99-2.92 (m, 1H), 2.55 (td, J = 2.1, 12.8 Hz, 1H), 1.62 (d, J = 13.1 Hz, 2H), 1.57-1.49 (m, 1H), 1.10-0.98 (m, 2H), 0.87 (d, J = 6.5 Hz, 3H). ¹³ C NMR (100MHz, CDCl3): δ 165.2, 128.0, 127.0, 46.2, 42.4, 34.7, 33.7, 31.1, 21.7. HRMS (+ESI): Calculated: 154.1226 (C9H16NO). Observed:

154.1224.

[0699] N-(2,2-diethoxyethyl)acrylamide (DKM 3-9). Following General Procedure A starting from aminoacetaldehyde diethyl acetal (402 mg, 3.0 mmol), product was obtained after silica gel chromatography (10% to 40% ethyl acetate in hexanes) in 75% yield as a clear oil (313 mg). ¹ H NMR (400MHz, CDCl ₃ ): 6.25-6.19 (m, 2H), 6.09 (dd, J = 10.1, 17.0 Hz, 1H), 5.56 (dd, J = 1.7, 10.1 Hz, 1H), 4.48 (t, J = 5.3 Hz, 1H), 3.64 (dq, J = 7.1, 9.4 Hz, 2H), 3.47 (dq, J = 7.1, 9.4 Hz, 2H), 3.38 (t, J = 5.6 Hz, 2H), 1.13 (t, J = 7.1 Hz, 6H). ¹³ C NMR (100MHz, CDCl3): δ 165.7, 130.6, 126.4, 100.6, 62.8, 42.0, 15.2. HRMS (+ESI): Calculated: 188.1281 (C ₉ H ₁₈ NO ₃ ).

Observed: 188.1278.

[0700] 1-acryloylpiperidine-4-carbonitrile (DKM 3-11). Following General Procedure A starting from piperidine-4-carbonitrile (329 mg, 3.0 mmol), product was obtained after silica gel chromatography (30% to 70% ethyl acetate in hexanes) in 48% yield as a colorless oil (234 mg). ¹ H NMR (400MHz, CDCl3): 6.49 (dd, J = 10.6, 16.8 Hz, 1H), 6.19 (d, J = 1.9, 16.8 Hz, 1H), 5.64 (dd, J = 1.9, 10.6 Hz, 1H), 3.77-3.46 (m, 4H), 2.88-2.82 (sept, J = 3.9 Hz, 1H), 1.90-1.73 (m, 4H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 165.4, 128.3, 127.3,120.8, 43.8, 39.9, 29.1, 28.1, 26.3. HRMS (+ESI): Calculated: 165.1022 (C9H13N2O). Observed:165.1020.

[0701] N-(3-(methylthio)propyl)acrylamide (DKM 3-12). Following General Procedure A starting from 3-(methylthio)propylamine (313 mg, 3.0 mmol), product was obtained after silica gel chromatography (20% to 60% ethyl acetate in hexanes) in 69% yield as a colorless oil (328 mg). ¹ H NMR (400MHz, CDCl3): δ 6.79 (s, 1H), 6.19 (dd, J = 2.2, 17.0 Hz, 1H), 6.11 (dd, J = 9.6, 17.0 Hz, 1H), 5.55 (dd, J = 2.2, 9.6 Hz, 1H), 3.35 (q, J = 6.5 Hz, 2H), 2.47 (t, J = 7.2 Hz, 2H), 2.02 (s, 3H), 1.78 (quint, J = 7.0 Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 165.9, 131.0, 126.1, 38.6, 31.6, 28.6, 15.4. HRMS (+ESI): Calculated: 160.0791 (C7H14NOS). Observed: 160.0788.

[0702] N-(cyclohexylmethyl)acrylamide (DKM 3-13). Following General Procedure A starting from cyclohexanemethylamine (331 mg, 2.9 mmol), product was obtained after silica gel chromatography (10% to 50% ethyl acetate in hexanes) in 67% yield as a pale yellow solid (330 mg). ¹ H NMR (400MHz, CDCl3): 6.51 (s, 1H), 6.22 (dd, J = 2.5, 17.0 Hz, 1H) 6.15 (dd, J = 9.3, 17.0 Hz, 1H), 5.55 (dd, J = 2.5, 9.3 Hz, 1H), 3.11 (t, J = 6.5 Hz, 2H), 1.70-1.58 (m, 5H), 1.51- 1.40 (m, 1H), 1.22-1.04 (m, 3H), 0.93-0.83 (m, 2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 165.9, 131.2, 125.9, 45.9, 38.0, 30.9, 26.4, 25.8. HRMS (+ESI): Calculated: 168.1383 (C10H18NO). Observed: 168.1380.

[0703] 1-(4-(4-acetylphenyl)piperazin-1-yl)prop-2-en-1-one (DKM 3-29). Following General Procedure A starting from 4’-piperazinoacetophenone (607 mg, 3.0 mmol), product was obtained after silica gel chromatography (50% to 85% ethyl acetate in hexanes) in 65% yield as a yellow solid (496 mg). ¹ H NMR (400MHz, CDCl3): δ 7.79 (d, J = 9.0 Hz, 2H), 6.78 (d, J = 9.0 Hz, 2H), 6.54 (dd, J = 10.5, 16.8 Hz, 1H), 6.25 (dd, J = 1.9, 16.8 Hz, 1H), 5.66 (dd, J = 1.9, 10.5 Hz, 1H), 3.75 (s, 2H), 3.66 (s, 2H), 3.31-3.29 (m, 4H), 2.42 (s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 196.3, 165.2, 153.4, 130.2, 128.3, 127.9, 127.0, 113.5, 47.3, 47.0, 45.0, 41.2, 26.0. HRMS (+ESI): Calculated: 259.1441(C15H19N2O2). Observed: 259.1436.

[0704] N-(4-(4-chlorophenoxy)phenyl)acrylamide (DKM 3-30). Following General Procedure A starting from 4-(4-chlorophenoxy)aniline (440 mg, 2.0 mmol), product was obtained after silica gel chromatography (10% to 30% ethyl acetate in hexanes) in 33% yield as a white solid (180 mg). ¹ H NMR (400MHz, CDCl3): δ 8.00 (s, 1H), 7.56 (d, J = 8.9 Hz, 2H), 7.29-7.25 (m, 2H), 6.96-6.88 (m, 4H), 6.43 (dd, J = 1.4, 16.9 Hz, 1H), 6.30 (dd, J = 10.1, 16.9 Hz, 1H), 5.75 (dd, J = 1.4, 10.1 Hz, 1H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 163.9, 156.2, 153.4, 133.7, 131.2, 129.8, 128.2, 128.0, 122.1, 119.8, 119.7. HRMS (+ESI): Calculated: 272.0484 (C15H11NO2Cl). Observed:272.0479.

[0705] N-(4-fluorophenyl)acrylamide (DKM 3-31). Following General Procedure A starting from 4-fluoroaniline (239 mg, 2.2 mmol), product was obtained after silica gel chromatography (20% to 30% ethyl acetate in hexanes) in 16% yield as a white solid (56 mg). ¹ H NMR

(600MHz, MeOD): δ 7.64-7.60 (m, 2H), 7.07-7.03 (m, 2H), 6.41 (dd, J = 9.8, 17.0 Hz, 1H), 6.35 (dd, J = 2.1, 17.0 Hz, 1H), 5.76 (dd, J = 2.1, 9.8 Hz, 1H). ¹³ C NMR (150MHz, MeOD): δ 166.0, 161.56, 160.0, 135.93, 135.91, 132.3, 127.8, 123.2, 123.1, 116.4, 116.2. HRMS (-ESI):

Calculated: 164.0517 (C9H7NOC). Observed: 164.0517.

[0706] N-(sec-butyl)acrylamide (DKM 3-32). Following General Procedure A starting from sec-butylamine (222 mg, 3.0 mmol), product was obtained after silica gel chromatography (10% to 40% ethyl acetate in hexanes) in 74% yield as a yellow oil (287 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 6.56 (d, J = 5.6 Hz, 1H), 6.17 (s, 1H), 6.16 (d, J = 3.5 Hz, 1H), 5.51 (dd, J = 4.3, 7.6 Hz, 1H), 3.93-3.83 (m, 1H), 1.47-1.36 (m, 2H), 1.06 (d, J = 6.6 Hz, 3H), 0.82 (t, J = 7.5 Hz, 3H). ¹³ C NMR (100MHz, CDCl3): δ 165.2, 131.4, 125.6, 46.6, 29.5, 20.2, 10.4. HRMS (+ESI):

Calculated: 128.1070 (C ₇ H ₁₄ NO). Observed: 128.1069.

[0707] 1-(4-(4-methoxyphenyl)piperazin-1-yl)prop-2-en-1-one (DKM 3-36). Following General Procedure A starting from 1-(4-methoxyphenyl)piperazine (388 mg, 2.0 mmol), product was obtained after silica gel chromatography (20% to 80% ethyl acetate in hexanes) in 29% yield as a white solid (143 mg). ¹ H NMR (400MHz, CDCl3): δ 6.87-6.79 (m, 4H), 6.57 (dd, J = 10.5, 16.8 Hz, 1H), 6.28 (dd, J = 1.9, 16.8 Hz, 1H), 5.68 (dd, J = 1.9, 10.5 Hz, 1H), 3.79 (s, 2H), 3.72 (s, 3H), 3.66 (s, 2H), 3.01 (t, J = 5.1 Hz, 4H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 165.2, 154.3, 145.1, 128.0, 127.3, 118.8, 114.4, 55.4, 51.3, 50.7, 45.8, 41.9. HRMS (+ESI): Calculated:

247.1441 (C14H19N2O2). Observed: 247.1443.

[0708] N-tritylacrylamide (DKM 3-41). Following General Procedure A starting from triphenylmethylamine (386 mg, 1.5 mmol), product was obtained after silica gel chromatography (5% to 30% ethyl acetate in hexanes) in 74% yield as a white solid (346 mg). ¹ H NMR

(400MHz, CDCl3): δ 7.38-7.27 (m, 15H), 6.83 (s, 1H), 6.28-6.26 (m, 2H), 5.66 (dd, J = 3.9, 7.2 Hz, 1H). ¹³ C NMR (100MHz, CDCl3): δ 164.6, 144.6, 131.5, 128.8, 128.1, 127.2, 127.1, 70.7. HRMS (+ESI): Calculated: 314.1539 (C ₂₂ H ₂₀ NO). Observed: 314.1542.

[0709] (E)-N-(3,7-dimethylocta-2,6-dien-1-yl)acrylamide (DKM 3-42). Following General Procedure A starting from geranylamine (462 mg, 3.0 mmol), product was obtained after silica gel chromatography (10% to 40% ethyl acetate in hexanes) in 23% yield as a colorless oil (141 mg). ¹ H NMR (400MHz, CDCl3): δ 6.25 (dd, J = 1.5, 17.0 Hz, 1H), 6.09 (dd, J = 10.2, 17.0 Hz, 1H), 5.83 (s, 1H), 5.59 (dd, J = 1.5, 10.2 Hz), 5.22-5.18 (m, 1H), 5.07-5.03 (m, 1H), 3.90 (t, J = 6.2 Hz, 2H), 2.09-2.03 (m, 2H), 2.00-1.97 (m, 2H), 1.65 (s, 6H), 1.57 (s, 3H). ¹³ C NMR

(100MHz, CDCl3): δ 165.5, 140.2, 131.8, 131.0, 126.2, 123.9, 119.7, 39.6, 37.6, 265, 25.8, 17.8, 16.4. HRMS (+ESI): Calculated: 208.1696 (C13H22NO). Observed: 208.1697.

[0710] N-(benzo[d][1,3]dioxol-5-ylmethyl)acrylamide (DKM 3-43). Following General Procedure A starting from piperonylamine (312 mg, 2.1 mmol), product was obtained after silica gel chromatography (20% to 50% ethyl acetate in hexanes) in 74% yield as a white solid (315 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 6.78 (s, 1H), 6.71 (s, 1H), 6.68 (s, 2H), 6.22 (dd, J = 1.9, 17.0 Hz, 1H), 6.13 (dd, J = 9.9, 17.0 Hz, 1H), 5.87 (s, 2H), 5.58 (dd, J = 1.9, 9.9 Hz, 1H), 4.30 (d, J = 5.8 Hz, 2H). ¹³ C NMR (100MHz, CDCl3): δ 165.7, 147.8, 146.9, 132.0, 130.8, 126.6, 121.1, 108.4, 108.2, 101.0, 43.4. HRMS (+ESI): Calculated: 206.0812 (C11H12NO3). Observed: 206.0808.

[0711] N-decylacrylamide (TRH 1-12). Following General Procedure A starting from decylamine (479 mg, 3.0 mmol), product was obtained after silica gel chromatography (20% to 40% ethyl acetate in hexanes) in 26% yield as a white solid (163 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 6.54 (s, 1H), 6.21 (dd, J = 2.0, 16.9 Hz, 1H) 6.13 (dd, J = 9.7, 16.9 Hz, 1H), 5.55 (dd, J = 2.0, 9.7 Hz, 1H), 3.25 (q, J = 6.7 Hz, 2H), 1.50-1.45 (m, 2H), 1.29-1.20 (m, 14H), 0.83 (t, J = 6.7 Hz, 3H). ¹³ C NMR (100MHz, CDCl3): δ 165.8, 131.2, 125.9, 71.9, 39.7, 31.9, 29.6, 29.6, 29.38, 29.35, 27.0, 22.7, 14.1. HRMS (+ESI): Calculated: 212.2009 (C ₁₃ H ₂₆ NO). Observed: 212.2009.

[0712] N-(2,4-dimethoxybenzyl)acrylamide (TRH 1-13). Following General Procedure A starting from 2,4-dimethoxybenzylamine (514 mg, 3.0 mmol), product was obtained after silica gel chromatography (20% to 60% ethyl acetate in hexanes) in 11% yield as a white solid (73 mg). ¹ H NMR (400MHz, CDCl3): δ 7.17 (d, J = 8.1 Hz, 1H), 6.43-6.39 (m, 2H), 6.26-6.22 (m, 2H), 6.07 (dd, J = 10.7, 17.0 Hz, 1H), 5.57 (dd, J = 1.4, 10.7 Hz, 1H), 4.41 (d, J = 5.8 Hz, 2H), 3.79 (s, 3H), 3.77 (s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 165.2, 160.6, 158.6, 131.1, 130.7, 126.2, 118.7, 104.0, 98.6, 55.5, 55.4, 39.0. HRMS (+ESI): Calculated: 222.1125 (C12H16NO3). Observed: 222.1124.

[0713] N-Phenylacrylamide (TRH 1-19). Following General Procedure A starting from aniline (277 mg, 3.0 mmol), product was obtained after recrystallization from a 1:20 ethyl acetate:hexanes mixture in 46% yield as a white solid (200 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 8.59 (s, 1H), 7.63 (d, J = 7.9 Hz, 2H), 7.30 (t, J = 7.9 Hz, 2H), 7.11 (t, J = 7.4 Hz, 1H), 6.44-6.33 (m, 2H), 5.70 (dd, J = 2.8, 8.9 Hz, 1H). ¹³ C NMR (100MHz, CDCl3): δ 164.3, 138.0, 131.4, 129.0, 127.7, 124.6, 120.5. HRMS (+ESI): Calculated: 148.0757 (C9H10NO). Observed:

148.0754.

[0714] N-(1-phenylethyl)acrylamide (TRH 1-20). Following General Procedure A starting from 1-phenylethan-1-amine (387 mg, 3.0 mmol), product was obtained after silica gel chromatography (5% to 20% ethyl acetate in hexanes) in 46% yield as a white solid (315 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 7.61 (d, J = 7.8 Hz, 1H) 7.37-7.24 (m, 5H), 6.33-6.24 (m, 2H), 5.57 (dd, J = 4.8, 7.9 Hz, 1H), 5.20 (quint, J = 7.2 Hz, 1H), 1.49 (d, J = 7.0 Hz, 3H). ¹³ C NMR (100MHz, CDCl3): δ 165.0, 143.4, 131.1, 128.4, 126.9, 126.0, 126.0, 48.7, 21.8. HRMS (+ESI): Calculated: 176.1070 (C11H14NO). Observed: 176.1067.

[0715] 1-(2-ethylpiperidin-1-yl)prop-2-en-1-one (TRH 1-27). Following General Procedure A starting from 2-ethylpiperidine (238 mg, 2.0 mmol), product was obtained after silica gel chromatography (5% to 30% ethyl acetate in hexanes) in 72% yield as a white solid (253 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 6.41 (dd, J = 10.6, 16.7 Hz, 1H), 6.03 (d, J = 16.4 Hz, 1H), 5.43 (dd, J = 2.0, 10.6 Hz, 1H), 4.54-4.34 (m, 1H), 3.77-3.58 (m, 1H), 2.93-2.42 (m, 1H), 1.61-1.06 (m, 8H), 0.66 (t, J = 7.5 Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 165.9, 130.0, 129.1 ,128.4, 126.6, 54.4, 49.6, 41.1, 36.5, 28.8, 27.5, 26.2, 25.2, 23.0, 22.1, 18.8, 10.4. HRMS (+ESI):

Calculated: 168.1383 (C10H18NO). Observed: 168.1380.

[0716] N-(4-methoxyphenyl)acrylamide (TRH 1-32). Following General Procedure A starting from p-anisidine (258 mg, 2.0 mmol), product was obtained after silica gel chromatography (10% to 50% ethyl acetate in hexanes) in 58% yield as a white solid (216 mg). ¹ H NMR

(400MHz, CDCl ₃ ): δ 8.94 (s, 1H), 7.48 (d, J = 9.1 Hz, 2H), 6.78 (d, J = 9.1 Hz, 2H), 6.34 (d, J = 5.6 Hz, 2H), 5.61 (t, J = 5.9 Hz, 1H), 3.73 (s, 3H). ¹³ C NMR (100MHz, CDCl3): δ 164.3, 156.4, 131.4, 131.1, 127., 122.3, 114.0, 55.4. HRMS (+ESI): Calculated: 178.0863 (C10H12O2N). Observed: 178.0859.

[0717] N-(2-methylbenzyl)acrylamide (TRH 1-54). Following General Procedure A starting from 2-methylbenzylamine (240 mg, 2.0 mmol), product was obtained after silica gel chromatography (30% to 40% ethyl acetate in hexanes) in 73% yield as a white solid (257 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 7.26-7.12 (m, 4H), 6.66 (s, 1H), 6.24-6.12 (m, 2H), 5.57 (dd, J = 9.5, 2.2 Hz, 1H), 4.39 (d, J = 5.4 Hz, 2H), 2.27 (s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 165.6, 136.3, 135.7, 130.7, 130.4, 128.4, 127.6, 126.4, 126.1, 41.6, 19.0. HRMS (+ESI): Calculated: 176.1070 (C11H14NO). Observed: 176.1067.

[0718] Ethyl 4-(2-chloroacetyl)piperazine-1-carboxylate (DKM 2-52). Following General Procedure B starting from ethyl 1-piperazinecarboxylate (477 mg, 3.0 mmol) product was obtained after silica gel chromatography (0% to 80% ethyl acetate in hexanes) in 80% yield as a pale yellow oil (569 mg). ¹ H NMR (400MHz, CDCl3): δ 4.04-3.99 (m, 4H), 3.48-3.34 (m, 8H), 1.14 (t, J = 7.1 Hz, 3H). ¹³ C NMR (100MHz, CDCl3): δ 165.1, 155.0, 61.5, 45.8, 43.3, 43.0, 41.7, 40.7, 14.4. HRMS (+SI): Calculated: 235.0844 (C ₉ H ₁₆ ClN ₂ O ₃ ). Observed: 235.0842.

[0719] N-benzyl-2-chloroacetamide (DKM 2-67). Following General Procedure B starting from benzylamine (430 mg, 3.1 mmol) product was obtained after silica gel chromatography (0% to 30% ethyl acetate in hexanes) in 70% yield as a white solid (416 mg). ¹ H NMR

(400MHz, CDCl ₃ ): δ 7.40-7.31 (m, 5H), 7.08 (s, 1s), 4.50 (d, J = 5.8 Hz, 2H), 4.09 (s, 2H). ¹³ C NMR (100MHz, CDCl3): δ 166.0, 137.4, 128.8, 127.8, 43.8, 42.6. HRMS (-ESI): Calculated: 182.0378 (C9H9NOCl). Observed:182.0378.

[0720] 2-Chloro-1-(pyrrolidin-1-yl)ethan-1-one (DKM 2-71). Following General Procedure B starting from pyrrolidine (511 mg, 3.0 mmol) product was obtained after silica gel

chromatography (0% to 30% ethyl acetate in hexanes) in 83% yield as a clear oil (368 mg). ¹ H NMR (400MHz, CDCl3): δ 3.94 (s, 2H), 3.41 (quint, J = 7.2 Hz, 4H), 1.91 (quint, J = 6.3 Hz, 2H), 1.80 (quint, J = 6.6 Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 164.7, 46.5, 46.3, 42.1, 26.1, 24.1. HRMS (+ESI): Calculated: 170.0343 (C6H10ClNNaO). Observed: 170.0343.

[0721] 2-Chloro-N-decylacetamide (DKM 2-72). Following General Procedure B starting from decylamine (472 mg, 3.0 mmol) product was obtained after silica gel chromatography (0% to 40% ethyl acetate in hexanes) in 81% yield as a white solid (555 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 6.71 (s, 1H), 3.97 (s, 2H), 3.22 (q, J = 6.8 Hz, 2H), 1.51-1.44 (m, 2H), 1.24-1.19 (m, 14 H), 0.81 (t, J = 6.8 Hz, 3H). ¹³ C NMR (100MHz, CDCl3): δ 165.8, 42.7, 39.9, 31.9, 29.5, 29.29, 29.27, 29.22, 26.8, 22.6, 14.1. HRMS (+ESI): Calculated: 234.1619 (C12H25ClNO). Observed:234.1618.

[0722] 2-chloro-N-(4-methoxybenzyl)acetamide (DKM 2-83). Following General Procedure B starting from 4-methoxybenzylamine (430 mg, 3.1 mmol) product was obtained after silica gel chromatography (0% to 40% ethyl acetate in hexanes) in 55% yield as an off-white solid (369 mg). ¹ H NMR (400MHz, CDCl ₃ ): δ 7.20 (d, J = 8.6 Hz, 2H), 6.91 (s, 1H), 6.86 (d, J = 8.6 Hz, 2H), 4.40 (d, J = 5.7 Hz, 2H), 4.05 (s, 2H), 3.78 (s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 165.9, 159.2, 129.4, 129.2, 114.2, 55.3, 43.4, 42.7. HRMS (+ESI): Calculated: 214.0629

(C ₁₀ H ₁₃ ClNO ₂ ). Observed: 214.0627.

[0723] 2-chloro-N-(3,4-dimethoxybenzyl)acetamide (DKM 2-93). Following General Procedure B starting from 3,4-dimethoxybenzylamine (517 mg, 3.1 mmol) product was obtained after silica gel chromatography (0% to 50% ethyl acetate in hexanes) in 55% yield as an off- white solid (416 mg). ¹ H NMR (400MHz, CDCl3): δ 6.97 (s, 1H), 6.77 (m, 3H), 4.35 (d, J = 5.8 Hz, 2H), 4.01 (s, 2H), 3.81 (s, 3H), 3.80 (s, 3H). ¹³ C NMR (100MHz, CDCl3): δ 165.8, 149.0, 148.5, 129.8, 120.1, 111.13, 111.07, 55.83, 55.79, 43.6, 42.5. HRMS (+ESI): Calculated:

266.0554 (C11H14NO3ClNa). Observed: 266.0553.

[0724] 2-Chloro-N-methyl-N-propylacetamide (TRH 1-53). Following General Procedure B starting from N-methylpropylamine (147 mg, 2.0 mmol) product was obtained after silica gel chromatography (30% to 40% ethyl acetate in hexanes) in 64% yield as a white solid (191 mg). ¹ H NMR (~46:54 rotamer ratio, asterisks denote minor peaks, 400 MHz, CDCl ₃ ): δ 4.03 ^* (s, 2H), 4.02 (s, 2H), 3.28 ^* (t, J = 7.4 Hz, 2H), 3.23 (t, J = 7.5 Hz, 2H), 3.00 (s, 3H), 2.88 ^* (s, 3H), 1.64- 1.56 ^* (m, 2H), 1.53-1.46 (m, 2H), 0.87 ^* (t, J = 7.5 Hz, 3H), 0.83 (t, J = 7.5 Hz, 3H). ¹³ C NMR (asterisks denote minor rotamer peaks, 100 MHz, CDCl ₃ ): δ 166.4, 166.3 ^* , 51.9 ^* , 49.8, 41.5, 40.9 ^* , 35.6, 33.6 ^* , 21.6 ^* , 20.1, 11.1, 11.0 ^* . HRMS (+ESI): Calculated: 150.0680 (C6H13NOCl). Observed: 150.0678. [0725] Synthesis and Characterization of YP 1-46

[0726] N-(4-(4-methoxyphenoxy)phenyl)acrylamide (YP-1-46). To a solution of 4- methoxyphenol (622 mg, 5 mmol) in DMF (2 mL) was added potassium carbonate (1.38 g, 10 mmol). After 10 minutes of stirring, 1-fluoro-4-nitrobenzene (0.43 mL, 4 mmol) was added and the reaction was stirred overnight. As the reaction was not complete by TLC after 21 hours, the reaction was heated to 90 degrees for 1 hour at which point the reaction was found to be complete. The reaction was then diluted with water and extracted three times with ethyl acetate. The combined organics were dried with magnesium sulfate and concentrated to give 1.07 g of crude 1-methox-4-(nitrophenoxy)benzene as a yellow solid that was used without further purification. [0727] To a stirring solution of the resulting crude (490 mg, ~2 mmol) and 10% palladium on activated charcoal (49 mg) in methanol (4 mL) was added triethylsilane (2.33 g, 20 mmol) dropwise through an addition funnel under a nitrogen-filled balloon. After 30 min, the mixture was filtered through celite and the solvent was removed in vacuo. Without further purification, the obtained crude product was dissolved in DCM (10 mL) and the resultant solution was cooled to 0 ^o C. To the solution was added acryloyl chloride (217 mg, 2.4 mmol) followed by triethylamine (243 mg, 2.4 mmol). The solution was allowed to warm to room temperature after 20 min and stirred overnight. The solution was washed two times with brine and the crude product was purified via silica gel chromatography (30% to 70% ethyl acetate in hexanes) to afford 161 mg of the product as a white solid (33% yield over 3 steps). ¹ H NMR (400MHz, CDCl3): δ 7.94 (s, 1H), 7.50-7.48 (m, 2H), 6.96-6.92 (m, 2H), 6.90-6.84 (m, 4H), 6.40 (dd, J = 1.6, 16.8 Hz, 1H), 6.27 (dd, J = 10.1, 16.8 Hz, 1H), (dd, J = 1.6, 10.1 Hz, 1H), 3.79 (s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 163.8, 155.8, 155.1, 150.4, 132.6, 131.1, 127.6, 121.9, 120.5, 118.2, 114.9, 55.7. HRMS (+ESI): Calculated: 270.1125 (C ₁₆ H ₁₆ NO ₃ ). Observed: 270.1125. [0728] Synthesis and Characterization of AMR 1-125

[0729] N-(4-(4-(tert-butyl)phenoxy)phenyl)acrylamide (AMR 1-125)

[0730] An oven dried round bottom flask was charged with a magnetic stir bar, copper (I) iodide (38mg, 0.2 mmol), N-Boc-4-hydroxyaniline (502mg, 2.4 mmol), potassium carbonate (552.8mg, 2 mmol), and crushed 4 angstrom sieves (~200mg). The flask was evacuated and filled with nitrogen twice. Under nitrogen, 1-Bromo-4-tert-butylbenzene (346uL, 2 mmol) and N,N′-Dimethyl-1,2-cyclohexanediamine (62uL, 0.2 mmol) were added along with 2mL of butyronitrile. The flask was allowed to react at 70C for 24 hours. At the end of the reaction, the mixture was diluted with CH2Cl2 and rinsed through Celite to remove inorganic salts and other solids. The crude reaction mixture was purified using column chromatograph (10% ethyl acetate in hexanes). The product was a yellow oil (yield 31%).

[0731] An oven dried round bottom flask was charged with the amine starting material (154.2mg, 0.6mmol) along with dry CH ₂ Cl ₂ and allowed to cool to 0C. Acryloyl chloride (69.4mg, 0.8mmol) was then added to the flask, followed by triethylamine (196uL, 1.4mmol), and the reaction was allowed to come to room temperature overnight. At the end of the reaction, the mixture was washed with brine and then purified using column chromatography (10% ethyl acetate in hexanes). The product was a waxy, white solid (yield <10%). ¹ H NMR (900MHz, CDCl3): δ 7.51 (d, 2H, J=8.5Hz), δ 7.31 (d, 2H, J=8.5Hz), δ 6.97 (m, 2H, ), δ 6.90 (m, 2H, ), δ 6.42 (d, 1H, J=16.8Hz), δ 6.22 (dd,1H, J=16.8, 10.3 Hz), δ 5.75 (m, 1H, ), δ 1.3 (s, 9H). ¹³ C NMR (900MHz, CDCl ₃ ): δ 163.4, 155.1, 154.2, 146.3, 133.0, 131.2, 127.9, 126.7, 121.7, 119.5, 118.3, 34.5, 31.7, 29.9. HRMS (+ESI): Calculated: 296.1645 (C19H21NO2) Observed: 296.1643. [0732] General Procedure Synthetic Scheme for derivatives

[0733] Derivatives being synthesized

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