Protein-protein interaction stabilizers

Abstract

Described herein, inter alia, are stabilizers of protein-protein interactions and methods of using the same.

Description

PATENT Attorney Docket No.: 048536-778001WO PROTEIN-PROTEIN INTERACTION STABILIZERS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 611,511 filed December 18, 2023, which is incorporated herein by reference in its entirety and for all purposes. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (048536- 778001WO_Sequence_Listing_ST26.xml; Size: 66,676 bytes; and Date of Creation: December 9, 2024) are hereby incorporated by reference in their entirety. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0003] This invention was made with government support under grant no. R01 GM147696, awarded by The National Institutes of Health. The government has certain rights in the invention. BACKGROUND

[0004] The stabilization of protein-protein interactions (PPIs) has emerged as a promising strategy in chemical biology and drug discovery. For hub proteins, such as 14-3-3, that interact with hundreds of other proteins, the identification of suitable starting points for stabilizing specific interactions can be challenging. Disclosed herein, inter alia, are solutions to these and other problems in the art. BRIEF SUMMARY

[0005] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula:

[0006] L3is:

[0007] The symbol n is an integer from 0 to 4.

[0008] Ring A is aryl, heteroaryl, or spirocyclic cycloalkyl.

[0009] L1is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR10-, -C(O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10A-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, 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.

[0010] L2is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20A-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, 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.

[0011] R1is hydrogen, halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, −NR1CNR1AR1B, −ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -C(NR1C)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or E.

[0012] E is an electrophilic moiety.

[0013] R2is independently oxo, halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, −NR2CNR2AR2B, −ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -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 R2substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0014] The symbol z2 is an integer from 0 to 5.

[0015] R3is independently oxo, halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3, -OCHX32, -CN, -SOn3R3D, -SOv3NR3AR3B, −NR3CNR3AR3B, −ONR3AR3B, -NR3CC(O)NR3AR3B, -N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -OC(O)R3C, -OC(O)OR3C, -C(O)NR3AR3B, -OC(O)NR3AR3B, -OR3D, -SR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -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.

[0016] The symbol z3 is an integer from 0 to 13.

[0017] R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4, R10, R10A, R20, and R20Aare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, 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; R1Aand R1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2Aand R2Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0018] Each X1, X2, and X3is independently –F, -Cl, -Br, or –I. The symbols n1, n2, and n3 are independently an integer from 0 to 4. The symbols m1, m2, m3, v1, v2, and v3 are independently 1 or 2.

[0019] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0020] In an aspect is provided a method of treating a cancer in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0021] In an aspect is provided a method of treating a developmental disorder in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0022] In an aspect is provided a method of increasing the amount of a 14-3-3 protein– CRAF protein complex in a subject, the method including administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof.

[0023] In an aspect is provided a method of increasing the amount of a 14-3-3 protein–RAF protein complex in a subject, the method including administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof.

[0024] In an aspect is provided a method of increasing the amount of a 14-3-3 protein– mutant CRAF protein complex in a subject, the method including administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] FIGS. 1A-1F. FIG. 1A: RAS-RAF-MEK-ERK pathway. FIG. 1B: Inhibiting and activating sites on A-, B- and C-RAF. Sequences for phosphorylation sites. FIG. 1C: Proposed mechanism for monomer to dimer transition for C-RAF, based on B-RAF cryo EMstructures. FIG. 1D: Crystal structure of cotylenin-A bound to the inhibiting 14-3-3ζ / C- RAF259 complex (PDB 4IHL). FIG. 1E: Top: Crystal structure of 1074202 / 14-3-3σ / ERα (PDB 8AWG), bottom crystal structure of fragment TC521 / 14-3-3σ / p65 (PDB 6YOW). FIG. 1F: Fragment merging and general scaffold for 14-3-3σ / C-RAF259 stabilizers.

[0026] FIGS. 2A-2J. Connecting the two fragments (modification I) and further aryl ring modifications (II). FIG. 2A: MS bar graphs at 1 μM compound, 100 nM 14-3-3σ (10:1 ratio). C-RAF259 data are shown in grey, apo data (in the absence of peptide) are shown in black. For each compound, time course experiments were performed with measurements at 1 h, 8 h, 16 h and 24 h. FIG. 2B: Bar graphs of FA compound titration pEC50 values after overnight incubation. C-RAF259 data are shown in grey. FIG. 2C: Crystal structure of 14-3-3σ, C- RAF259 (right stick structure in enlarged view), and 12 (left stick structure in enlarged view). FIG. 2D: Interactions of 12 at the 14-3-3 σ / C-RAF259 interface. FIG. 2E: Movement of helix 9 of 14-3-3 σ comparing the binary (dark grey) with ternary (light grey) 14-3-3 σ / C- RAF / (12) structures. FIG. 2F: Crystal structure of 14-3-3σ, C-RAF259 (bottom stick structure), and 21 (top stick structure). FIG. 2G: Overlay of analogs 12 (bottom stick structure) and 21 (top stick structure). FIG. 2H: Interactions of 23 (dark grey stick structure on the left) at the 14-3-3σ / C-RAF interface are shown in black dashes and water molecules as dots. FIG. 2I: Left: crystal structures of 12 / 22 / 23 with 14-3-3σ and C-RAF259 (overlay). Middle: detailed interactions of 23 / 14-3-3σ / C-RAF25910-mer (left) and 12-mer (right). Interacting water molecules are shown as spheres. Right: overlay of the structures. FIG. 2J: Left: Binary complex of 14-3-3σ with C-RAF pS25912-mer peptide. Right: ternary complex of 23 / 14-3-3σ / C-RAF pS25912-mer peptide. Movement of helix 9 is indicated by a gray arrow.

[0027] FIGS. 3A-3E. Poly-substitutions on the aryl ring and aliphatic analogs. FIG. 3A: MS bar graphs at 1 μM compound, 100 nM 14-3-3σ (10:1 ratio). C-RAF259 data are shown in grey, apo data (in the absence of peptide) are shown in black. For each compound, time course experiments were performed with measurements at 1 h, 8 h, 16 h, and 24 h. FIG. 3B: Bar graphs of FA compound titration pEC50 values after overnight incubation. C-RAF259 data are shown in grey. Interactions of analog 29 (FIG. 3C) and analog 37 (FIG. 3D) at the 14-3-3σ (grey) / C-RAF259 (right stick structure) interface. FIG. 3E: Structural overlay of analogs 22, 29, 32, and 37.

[0028] FIGS. 4A-4E. Piperidine replacements (III). FIG. 4A: MS bar graphs at 1 μM compound, 100 nM 14-3-3σ (10:1 ratio). C-RAF259 data are shown in grey, apo data (in the absence of peptide) are shown in black. For each compound, time course experiments were performed with measurements at 1 h, 8 h, 16 h, and 24 h. FIG. 4B: Bar graphs of FA compound titration pEC50 values after overnight incubation. C-RAF259 data are shown in grey. FIG. 4C: Interactions of 70 (left stick structures) at the 14-3-3 (grey) / C-RAF259 (right stick structures) interface. FIG. 4D: Hydrogen bond network between 14-3-3 residues (white), C-RAF259 (left stick structures), and 70, mediated by water. FIG. 4E: Structural overlay of analogs 37 and 70.

[0029] FIGS. 5A-5G. Combinations of spirocycles and optimized aryl ring variations (modification V). FIG. 5A: MS bar graphs at 1 μM compound, 100 nM 14-3-3σ (10:1 ratio). C-RAF259 data are shown in grey, apo data (in the absence of peptide) are shown in black. For each compound, time course experiments were performed with measurements at 1 h, 8 h, 16 h, and 24 h. FIG. 5B: Bar graphs of FA compound titration pEC50values after overnight incubation. C-RAF259 data are shown in grey. Interactions of 78 (FIG. 5C) and 86 (FIG. 5D) at the 14-3-3σ (grey) / C-RAF259 (right stick structure) interface. Structural overlays of analogs 70 and 83 (FIG. 5E), and 78 and 86 (FIG. 5F). FIG. 5G: Crystal structure of 78 (sticks) with 14-3-3σ / C-RAF25912-mer (left) and overlay of the two ternary complexes (right).

[0030] FIGS. 6A-6C. FIG. 6A: Chemical structures of compounds tested in biochemical assays for all inhibiting RAF sites. FIG. 6B: MS bar graphs at 1 μM compound, 100 nM 14- 3-3σ (10:1 ratio), C-RAF259 data (top left), A-RAF214 (middle left), B-RAF365 (bottom left). For each compound apo bar graphs are shown in black. Time course experiments were performed with measurements at 1 h, 8 h, 16 h, and 24 h. FIG. 6C: Fold-stabilization observed in FA protein titrations after overnight incubation in the presence of 100 μΜ compound, 10 nM C-RAF259 (top right), A-RAF214 (middle right), B-RAF365 (bottom right). Data are shown in Tables 5A and 5B for the MS and Table 6 for the FA.

[0031] FIGS. 7A-7G. Evaluation of MGs in cell assays. FIG. 7A: 14-3-3σ / C-RAF NanoBRET schematic (left) and dose-response curves in HEK293T cells. FIG. 7B: Co-IP Western blots and quantification. FIG. 7C: Protection of phosphorylation of the C-RAF pS259 site in HEK293T cells. FIG. 7D: 14-3-3σ / A-RAF NanoBRET dose-responses. FIG. 7E: 14-3-3σ / B-RAF NanoBRET dose-responses. FIG. 7F: N-RAS / C-RAF NanoBRET,100% was considered the DMSO mBU and 0% the mBU value of NRAS / C-RAF R89L, which does not bind to C-RAF. FIG. 7G: C-RAF / C-RAF NanoBRET dose-response curves.

[0032] FIGS. 8A-8D. Comparison of 14-3-3 / full length client structure with 14-3- 3 / phosphopeptides. FIG. 8A: Cryo-EM structure of 14-3-3ζ (dark grey cartoon) bound to full-length B-RAF (middle grey cartoon) and MEK (top dark grey cartoon), PDB 6NYB. FIG. 8B: Close-up view of B-RAF365 inhibiting site (left monomer, sticks) and B-RAF729 activating site (right monomer, sticks) bound to 14-3-3ζ (dark grey cartoon), PDB 6NYB. FIG. 8C: Left monomer: 14-3-3 ζ (grey cartoon) bound to C-RAF259 phosphopeptide (sticks), PDB 4IHL. Right monomer: 14-3-3σ (grey cartoon) bound to C-RAF621 phosphopeptide (sticks), PDB 4IEA. FIG. 8D: Overview of assays. Mass spectrometry time- course experiments were performed at 1 h, 8 h, 16 h, and 24 h in the presence of C-RAF259 phosphopeptide. Bar graphs were used to represent % bound at 1 μΜ compound concentration (10:1 [protein]:[compound] ratio). Fluorescence anisotropy compound titrations were perfumed in the presence of FAM-labeled C-RAF259 phosphopeptide. EC50values were calculated from the overnight measurement. pEC50 bar graphs represent the positive log EC50 value.

[0033] FIG. 9. MS dose-response curves (apo) for compounds discussed in FIGS. 2A-2H.

[0034] FIG. 10. MS dose-response curves (C-RAF259) for compounds discussed in FIGS. 2A-2H.

[0035] FIG. 11. FA dose-response curves with C-RAF259 for compounds discussed in FIGS. 2A-2H.

[0036] FIG. 12. FA protein titrations at 100 μΜ compound with 10 nM of C-RAF259. Measured KD values are indicated in the legend.

[0037] FIG. 13. MS dose-response curves (apo) for compounds discussed in FIGS. 3A-3E.

[0038] FIG. 14. MS dose-response curves (C-RAF259) for compounds discussed in FIGS. 3A-3E.

[0039] FIG. 15. FA dose-response curves with C-RAF259 for compounds discussed in FIGS. 3A-3E.

[0040] FIG. 16. MS dose-response curves (apo) for compounds discussed in FIGS. 4A-4E.

[0041] FIG. 17. MS dose-response curves (C-RAF259) for compounds discussed in FIGS. 4A-4E.

[0042] FIG. 18. FA dose-response curves with C-RAF259 for compounds discussed in FIGS. 4A-4E.

[0043] FIG. 19. FA protein titrations at 100 μΜ compound with 10 nM of C-RAF259. Measured KD values are indicated in the legend.

[0044] FIG. 20. MS dose-response curves (Apo, C-RAF259) and FA dose-response curves with C-RAF259 for compounds with halogenated warheads.

[0045] FIG. 21. MS dose-response curves (Apo, C-RAF259) and FA dose-response curves with C-RAF259 for compounds discussed in FIGS. 5A-5G.

[0046] FIG. 22. MS dose-response curves (A-RAF214) for compounds discussed in FIGS. 5A-5G.

[0047] FIG. 23. MS dose-response curves (B-RAF365) for compounds discussed in FIGS. 5A-5G.

[0048] FIG. 24. FA protein titrations at 100 μΜ compound with 10 nM of A-RAF214. Measured KD values are indicated in the legend.

[0049] FIG. 25. FA protein titrations at 100 μΜ compound with 10 nM of B-RAF365. Measured KDvalues are indicated in the legend.

[0050] FIG. 26. FA protein titrations at 100 μΜ compound with 10 nM of A-RAF582.

[0051] FIG. 27. FA protein titrations at 100 μΜ compound with 10 nM of B-RAF729.

[0052] FIG. 28. FA protein titrations at 100 μΜ compound with 10 nM of C-RAF621.

[0053] FIGS. 29A-29C. Biochemical data of CRAFWTstabilizers restoring binding affinity in Noonan syndrome mutants. FA protein titrations at 100 μΜ compound (analogs 22 and 23) and 10 nM C-RAFWTor C-RAF mutants (CRAFR256S, CRAFS257L, CRAFP261A, CRAFV263A).

[0054] FIGS. 30A-30B. Biochemical data of CRAFWTstabilizers restoring binding affinity in Noonan syndrome mutants. FA protein titrations at 100 μΜ compound (analogs 22, 23, 78, 83) and 10 nM C-RAF mutants (CRAFR256S, CRAFP261A, CRAFS257L, CRAFV263A).

[0055] FIGS. 31A-31B. Biochemical data of CRAFWTstabilizers restoring binding affinity in Noonan syndrome mutants. FA protein titrations at 100 μΜ compound (analogs 29, 32, 37, 70, 79, 86) and 10 nM C-RAF mutants (CRAFR256S, CRAFP261A, CRAFS257L, CRAFV263A).

[0056] FIG. 32. Cell data for compound 22 enhancing phosphorylation of CRAFWTand Noonan syndrome mutants (CRAFS259A, CRAFR256S, CRAFS257L, CRAFP261A, CRAFV263A). Quantification as normalized intensity and % increase of phosphorylation (bar graphs and table).

[0057] FIG. 33. Cell data for compound 79 enhancing phosphorylation of CRAFWTand Noonan syndrome mutants (CRAFS259A, CRAFR256S, CRAFS257L, CRAFP261A, CRAFV263A). Quantification as normalized intensity and % increase of phosphorylation (bar graphs and table).

[0058] FIGS. 34A-34B. Crystallography with RAF isoforms and FA selectivity panel. FIG. 34A: Crystal structures of 23 (top) and 78 (bottom) with 14-3-3σ / C-RAF-259 (left), 14- 3-3σ / A-RAF214 (middle) and 14-3-3σ / B-RAF365 (right) 12-mer peptides. Interacting water molecules are shown as spheres. FIG. 34B: FA selectivity panel for 23 with 14-3-3σ and 80 client peptides. Compound 23 was tested at 10.5 μΜ (EC90). Four client hits were identified: SOS1, TAZ, KC1A and TSC2.

[0059] FIG. 35. Densities and crystal structures with 14-3-3σ / A-RAF pS21412-mer peptide. Top right: binary complex. Middle and bottom: ternary complexes of 22, 23, 78, and 86 with A-RAF pS21412-mer peptide and 14-3-3σ. Close-up views on interacting amino acids. Interacting water molecules are shown as spheres. 2Fo-Fc electron density maps (mesh) were contoured at 1σ.

[0060] FIG. 36. Densities and crystal structures with 14-3-3σ / B-RAF pS36512-mer peptide. Top right: binary complex. Middle and bottom: ternary complexes of 22, 23, 78, and 86 with B-RAF pS36512-mer peptide and 14-3-3σ. Close-up views on interacting amino acids. Interacting water molecules are shown as spheres. 2Fo-Fc electron density maps (mesh) were contoured at 1σ.

[0061] FIG. 37. Overlays of ternary complexes for 23 and 78 with A-RAF pS214, B-RAF pS365 and C-RAF pS259. Close-up views on peptide conformations.

[0062] FIGS. 38A-38D. FIG. 38A: FA selectivity panel for 22 with 14-3-3σ and 80 client peptides. Compound 22 was tested at 10.5 μΜ (EC90). Six client hits were identified: SOS1,TAZ, ARGH2, H31, KC1A, and TSC2. FIG. 38B: Phospho-sites and sequences around the phopsho-site for client peptides that emerged as hits. FIG. 38C: FA compound dose-response follow-up for the four common clients. FIG. 38D: FA protein titrations follow-up. EC50 values, appKds and fold-stabilization are shown in Table 8 and Table 9.

[0063] FIGS. 39A-39B. FIG. 39A: 14-3-3σ / C-RAF NanoBRET dose-response data in HEK293T cells. FIG. 39B: 14-3-3 C38N / C-RAF NanoBRET dose-response data in HEK293T cells.

[0064] FIGS. 40A-40B. FIG. 40A: Co-IP for 22, comparing endogenous and transfected C-RAF. FIG. 40B: Protection of phosphorylation of C-RAF pS259 site in MIA PaCa-2 cells.

[0065] FIGS. 41A-41B. FIG. 41A: 14-3-3σ / A-RAF NanoBRET dose-response data in HEK293T cells. FIG. 41B: 14-3-3σ / B-RAF NanoBRET dose-response data in HEK293T cells.

[0066] FIG. 42. Protection of phosphorylation of A-RAF pS214 site in HEK293T cells. The assay was performed with the pS259 C-RAF antibody.

[0067] FIG. 43. MS dose-response curves (B-RAF36515-mer peptide).

[0068] FIG. 44. FA protein titrations (B-RAF36515-mer peptide).

[0069] FIG. 45. MS dose-response curves (C-RAF25915-mer peptide).

[0070] FIG. 46. FA protein titrations (C-RAF25915-mer peptide). DETAILED DESCRIPTION I. Definitions

[0071] 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.

[0072] 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., -CH2O- is equivalent to -OCH2-.

[0073] 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 combinationthereof, 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). In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. 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 alkenyl includes one or more double bonds. An alkynyl includes one or more triple bonds.

[0074] 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, -CH2CH2CH2CH2-. 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. The term “alkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne. In embodiments, the alkylene is fully saturated. In embodiments, the alkylene is monounsaturated. In embodiments, the alkylene is polyunsaturated. An alkenylene includes one or more double bonds. An alkynylene includes one or more triple bonds.

[0075] 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, and 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., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group isattached 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, -S-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(CH3)-CH3, -O-CH3, -O-CH2-CH3, 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). The term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and / or one or more triple bonds in additional to the one or more double bonds. The term “heteroalkynyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and / or one or more double bonds in additional to the one or more triple bonds. In embodiments, the heteroalkyl is fully saturated. In embodiments, the heteroalkyl is monounsaturated. In embodiments, the heteroalkyl is polyunsaturated.

[0076] 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, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. 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 -SO2R'. 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 notredundant 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. The term “heteroalkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene. The term “heteroalkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyne. In embodiments, the heteroalkylene is fully saturated. In embodiments, the heteroalkylene is monounsaturated. In embodiments, the heteroalkylene is polyunsaturated. A heteroalkenylene includes one or more double bonds. A heteroalkynylene includes one or more triple bonds.

[0077] 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. In embodiments, the cycloalkyl is fully saturated. In embodiments, the cycloalkyl is monounsaturated. In embodiments, the cycloalkyl is polyunsaturated. In embodiments, the heterocycloalkyl is fully saturated. In embodiments, the heterocycloalkyl is monounsaturated. In embodiments, the heterocycloalkyl is polyunsaturated.

[0078] In embodiments, the term “cycloalkyl” means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system. In embodiments, monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In embodiments, cycloalkyl groups are fully saturated. A bicyclic or multicyclic cycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkyl ring and wherein the multiple rings are attachedto the parent molecular moiety through any carbon atom contained within a cycloalkyl ring of the multiple rings.

[0079] In embodiments, a cycloalkyl is a cycloalkenyl. The term “cycloalkenyl” is used in accordance with its plain ordinary meaning. In embodiments, a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system. A bicyclic or multicyclic cycloalkenyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkenyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkenyl ring of the multiple rings.

[0080] In embodiments, the term “heterocycloalkyl” means a monocyclic, bicyclic, or a multicyclic heterocycloalkyl ring system. In embodiments, heterocycloalkyl groups are fully saturated. A bicyclic or multicyclic heterocycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a heterocycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heterocycloalkyl ring of the multiple rings.

[0081] 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.

[0082] 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.

[0083] 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 and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within an aryl ring of the multiple rings. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein thenitrogen 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 and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heteroaromatic ring of the multiple rings). 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.

[0084] 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 orheterocycloalkyl 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.

[0085] The symbol “ ” denotes the point of attachment of a chemical moiety to theremainder of a molecule or chemical formula.

[0086] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.

[0087] 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:.

[0088] 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, -N3, -CF3, -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.

[0089] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0090] 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', -NRC(NR'R''R''')=NR'''', -NRC(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -NR'SO2R'', -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., -CF3and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0091] 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)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -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 unsubstitutedheteroaryl. 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.

[0092] 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.

[0093] 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-formingsubstituents 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.

[0094] 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)2NR'-, 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)2NR'-. 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.

[0095] As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si). In embodiments, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0096] A “substituent group,” as used herein, means a group selected from the following moieties: (A) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, 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 4membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, 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-C10aryl, C10aryl, 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 (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6-C10aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (i) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8alkyl, C1-C6alkyl, 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-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), 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- C10aryl, C10aryl, 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 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6-C10aryl, C10aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (a) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4alkyl), 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-C6cycloalkyl), 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 (b) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6- C10aryl, C10aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, 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-C10aryl, C10aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0097] 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 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-C10aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0098] 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-C8alkyl, 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- C7cycloalkyl, 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 phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 6 membered heteroaryl.

[0099] 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 groupsare 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.

[0100] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20alkyl, 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-C20alkylene, 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 C3-C8cycloalkylene, 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 C6-C10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

[0101] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8alkyl, 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 C6-C10aryl, 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-C8alkylene, 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 C6-C10 arylene, and / or each substituted or unsubstituted heteroarylene is asubstituted 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.

[0102] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and / or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is substituted (e.g., is a 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, respectively).

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] In a recited claim or chemical formula description herein, each R substituent or L linker that is described as being “substituted” without reference as to the identity of any chemical moiety that composes the “substituted” group (also referred to herein as an “opensubstitution” on an R substituent or L linker or an “openly substituted” R substituent or L linker), the recited R substituent or L linker may, in embodiments, be substituted with one or more first substituent groups as defined below.

[0108] The first substituent group is denoted with a corresponding first decimal point numbering system such that, for example, R1may be substituted with one or more first substituent groups denoted by R1.1, R2may be substituted with one or more first substituent groups denoted by R2.1, R3may be substituted with one or more first substituent groups denoted by R3.1, R4may be substituted with one or more first substituent groups denoted by R4.1, R5may be substituted with one or more first substituent groups denoted by R5.1, and the like up to or exceeding an R100that may be substituted with one or more first substituent groups denoted by R100.1. As a further example, R1Amay be substituted with one or more first substituent groups denoted by R1A.1, R2Amay be substituted with one or more first substituent groups denoted by R2A.1, R3Amay be substituted with one or more first substituent groups denoted by R3A.1, R4Amay be substituted with one or more first substituent groups denoted by R4A.1, R5Amay be substituted with one or more first substituent groups denoted by R5A.1and the like up to or exceeding an R100Amay be substituted with one or more first substituent groups denoted by R100A.1. As a further example, L1may be substituted with one or more first substituent groups denoted by RL1.1, L2may be substituted with one or more first substituent groups denoted by RL2.1, L3may be substituted with one or more first substituent groups denoted by RL3.1, L4may be substituted with one or more first substituent groups denoted by RL4.1, L5may be substituted with one or more first substituent groups denoted by RL5.1and the like up to or exceeding an L100which may be substituted with one or more first substituent groups denoted by RL100.1. Thus, each numbered R group or L group (alternatively referred to herein as RWWor LWWwherein “WW” represents the stated superscript number of the subject R group or L group) described herein may be substituted with one or more first substituent groups referred to herein generally as RWW.1or RLWW.1, respectively. In turn, each first substituent group (e.g., R1.1, R2.1, R3.1, R4.1, R5.1… R100.1; R1A.1, R2A.1, R3A.1, R4A.1, R5A.1… R100A.1; RL1.1, RL2.1, RL3.1, RL4.1, RL5.1… RL100.1) may be further substituted with one or more second substituent groups (e.g., R1.2, R2.2, R3.2, R4.2, R5.2… R100.2; R1A.2, R2A.2, R3A.2, R4A.2, R5A.2… R100A.2; RL1.2, RL2.2, RL3.2, RL4.2, RL5.2… RL100.2, respectively). Thus, each first substituent group, which may alternatively be represented herein as RWW.1as described above, may be further substituted with one or more second substituent groups, which may alternatively be represented herein as RWW.2.

[0109] Finally, each second substituent group (e.g., R1.2, R2.2, R3.2, R4.2, R5.2… R100.2; R1A.2, R2A.2, R3A.2, R4A.2, R5A.2… R100A.2; RL1.2, RL2.2, RL3.2, RL4.2, RL5.2… RL100.2) may be further substituted with one or more third substituent groups (e.g., R1.3, R2.3, R3.3, R4.3, R5.3… R100.3; R1A.3, R2A.3, R3A.3, R4A.3, R5A.3… R100A.3; RL1.3, RL2.3, RL3.3, RL4.3, RL5.3… RL100.3; respectively). Thus, each second substituent group, which may alternatively be represented herein as RWW.2as described above, may be further substituted with one or more third substituent groups, which may alternatively be represented herein as RWW.3. Each of the first substituent groups may be optionally different. Each of the second substituent groups may be optionally different. Each of the third substituent groups may be optionally different.

[0110] Thus, as used herein, RWWrepresents a substituent recited in a claim or chemical formula description herein which is openly substituted. “WW” represents the stated superscript number of the subject R group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). Likewise, LWWis a linker recited in a claim or chemical formula description herein which is openly substituted. Again, “WW” represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). As stated above, in embodiments, each RWWmay be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RWW.1; each first substituent group, RWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RWW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RWW.3. Similarly, each LWWlinker may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RLWW.1; each first substituent group, RLWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RLWW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RLWW.3. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. For example, if RWWis phenyl, the said phenyl group is optionally substituted by one or more RWW.1groups as defined herein below, e.g., when RWW.1is RWW.2-substituted or unsubstituted alkyl, examples of groups so formed include but are not limited to itself optionally substituted by 1 or more RWW.2, which RWW.2is optionally substituted by one or more RWW.3. By way of example when the RWWgroup is phenyl substituted by RWW.1, which is methyl, the methyl group may be further substituted to form groups including but not limited to:.

[0111] RWW.1is independently oxo, halogen, -CXWW.13, -CHXWW.12, -CH2XWW.1, -OCXWW.13, -OCH2XWW.1, -OCHXWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW.2-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RWW.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), RWW.2-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.2-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), RWW.2-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.2-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, RWW.1is independently oxo, halogen, -CXWW.13, -CHXWW.12, -CH2XWW.1, -OCXWW.13, -OCH2XWW.1, -OCHXWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, 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). XWW.1is independently –F, -Cl, -Br, or –I.

[0112] RWW.2is independently oxo, halogen, -CXWW.23, -CHXWW.22, -CH2XWW.2, -OCXWW.23, -OCH2XWW.2, -OCHXWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW.3-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RWW.3-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), RWW.3-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.3-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), RWW.3-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.3-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, RWW.2is independently oxo, halogen, -CXWW.23, -CHXWW.22, -CH2XWW.2, -OCXWW.23, -OCH2XWW.2, -OCHXWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, 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). XWW.2is independently –F, -Cl, -Br, or –I.

[0113] RWW.3is independently oxo, halogen, -CXWW.33, -CHXWW.32, -CH2XWW.3, -OCXWW.33, -OCH2XWW.3, -OCHXWW.32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, 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). XWW.3is independently –F, -Cl, -Br, or –I.

[0114] Where two different RWWsubstituents are joined together to form an openly substituted ring (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl), in embodiments the openly substituted ring may be independently substituted with one or more first substituent groups, referred to herein as RWW.1; each first substituent group, RWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RWW.2; and each second substituent group,unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RWW.3; and each third substituent group, RWW.3, is unsubstituted. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. In the context of two different RWWsubstituents joined together to form an openly substituted ring, the “WW” symbol in the RWW.1, RWW.2and RWW.3refers to the designated number of one of the two different RWWsubstituents. For example, in embodiments where R100Aand R100Bare optionally joined together to form an openly substituted ring, RWW.1is R100A.1, RWW.2is R100A.2, and RWW.3is R100A.3. Alternatively, in embodiments where R100Aand R100Bare optionally joined together to form an openly substituted ring, RWW.1is R100B.1, RWW.2is R100B.2, and RWW.3is R100B.3. RWW.1, RWW.2and RWW.3in this paragraph are as defined in the preceding paragraphs.

[0115] RLWW.1is independently oxo, halogen, -CXLWW.13, -CHXLWW.12, -CH2XLWW.1, -OCXLWW.13, -OCH2XLWW.1, -OCHXLWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RLWW.2-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RLWW.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), RLWW.2-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.2-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), RLWW.2-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RLWW.2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). In embodiments, RLWW.1is independently oxo, halogen, -CXLWW.13, -CHXLWW.12, -CH2XLWW.1, -OCXLWW.13, -OCH2XLWW.1, -OCHXLWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, 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). XLWW.1is independently –F, -Cl, -Br, or –I.

[0116] RLWW.2is independently oxo, halogen, -CXLWW.23, -CHXLWW.22, -CH2XLWW.2, -OCXLWW.23, -OCH2XLWW.2, -OCHXLWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RLWW.3-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RLWW.3-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), RWW.3-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.3-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), RLWW.3-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RLWW.3-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, RLWW.2is independently oxo, halogen, -CXLWW.23, -CHXLWW.22, -CH2XLWW.2, -OCXLWW.23, -OCH2XLWW.2, -OCHXLWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, 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). XLWW.2is independently –F, -Cl, -Br, or –I.

[0117] RLWW.3is independently oxo, halogen, -CXLWW.33, -CHXLWW.32, -CH2XLWW.3, -OCXLWW.33, -OCH2XLWW.3, -OCHXLWW.32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, 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). XLWW.3is independently –F, -Cl, -Br, or –I.

[0118] In the event that any R group recited in a claim or chemical formula description set forth herein (RWWsubstituent) is not specifically defined in this disclosure, then that R group (RWWgroup) is hereby defined as independently oxo, halogen, -CXWW3, -CHXWW2, -CH2XWW, -OCXWW3, -OCH2XWW, -OCHXWW2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW.1-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RWW.1-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), RWW.1-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.1-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), RWW.1-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.1-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWWis independently –F, -Cl, -Br, or –I. Again, “WW” represents the stated superscript number of the subject R group (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). RWW.1, RWW.2, and RWW.3are as defined above.

[0119] In the event that any L linker group recited in a claim or chemical formula description set forth herein (i.e., an LWWsubstituent) is not explicitly defined, then that L group (LWWgroup) is herein defined as independently a bond, –O-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, –NHC(NH)NH-, -C(O)O-, -OC(O)-, -S-, -SO2-, -SO2NH-, RLWW.1- substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RLWW.1-substitutedor 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), RLWW.1-substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.1-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), RLWW.1-substituted or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or RLWW.1- substituted or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Again, “WW” represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). RLWW.1, as well as RLWW.2and RLWW.3are as defined above.

[0120] Certain compounds of the present disclosure 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 disclosure. The compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and / or isolate. The present disclosure 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.

[0121] 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.

[0122] 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.

[0123] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.

[0124] 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 disclosure.

[0125] 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 by13C- or14C-enriched carbon are within the scope of this disclosure.

[0126] The compounds of the present disclosure 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 (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0127] 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.

[0128] As used herein, the terms “bioconjugate” and “bioconjugate linker” refer to the resulting association between atoms or molecules of bioconjugate reactive groups or bioconjugate reactive moieties. The association can be direct or indirect. For example, a conjugate between a first bioconjugate reactive group (e.g., –NH2, –COOH, –N- hydroxysuccinimide, or –maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate) provided herein can be direct, e.g., by covalent bond or linker (e.g., a first linker of second linker), or indirect, e.g., by non-covalent bond (e.g., electrostatic interactions (e.g., ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups)including, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, for example, March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198, American Chemical Society, Washington, D.C., 1982. In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., –N- hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., –sulfo–N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine).

[0129] Useful bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example: (a) carboxyl groups and various derivatives thereof including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters; (b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.; (c) haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom; (d) dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido or maleimide groups; (e) aldehyde or ketone groups such that subsequent derivatization is possible via formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition; (f) sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides; (g) thiol groups, which can be converted todisulfides, reacted with acyl halides, or bonded to metals such as gold, or react with maleimides; (h) amine or sulfhydryl groups (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized; (i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc.; (j) epoxides, which can react with, for example, amines and hydroxyl compounds; (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis; (l) metal silicon oxide bonding; (m) metal bonding to reactive phosphorus groups (e.g., phosphines) to form, for example, phosphate diester bonds; (n) azides coupled to alkynes using copper catalyzed cycloaddition click chemistry; and (o) biotin conjugate can react with avidin or streptavidin to form an avidin- biotin complex or streptavidin-biotin complex.

[0130] The bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein. Alternatively, a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group. In embodiments, the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group.

[0131] “Analog,” “analogue,” or “derivative” 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.

[0132] 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 C1-C20 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.

[0133] 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 substitutedwith 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 R13substituents are present, each R13substituent may be distinguished as R13.A, R13.B, R13.C, R13.D, etc., wherein each of R13.A, R13.B, R13.C, R13.D, etc. is defined within the scope of the definition of R13and optionally differently. Where an R moiety, group, or substituent as disclosed herein is attached through the representation of a single bond and the R moiety, group, or substituent is oxo, a person having ordinary skill in the art will immediately recognize that the oxo is attached through a double bond in accordance with the normal rules of chemical valency.

[0134] Descriptions of compounds of the present disclosure 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.

[0135] 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 disclosure 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 disclosure 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 disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0136] Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure 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.

[0137] 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.

[0138] In addition to salt forms, the present disclosure 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 disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.

[0139] Certain compounds of the present disclosure 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 disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0140] 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.

[0141] “Co-administer” 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 co-administered to the patient. Co-administration 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).

[0142] 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.

[0143] The terms “treating” or “treatment” refers to any indicia of success in the treatment 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 ofdegeneration 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, 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 not prophylactic treatment.

[0144] An “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 signaling pathway, 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” when referred to in this context. 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. An “activity increasing amount,” as used herein, refers to an amount of agonist required to increase the activity of an enzyme relative to the absence of the agonist. A “function increasing amount,” as used herein, refers to the amount of agonist required to increase the function of an enzyme or protein relative to the absence of the agonist. 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 ofPharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0145] “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 (e.g., signaling pathway) of a protein in the absence of a compound as described herein (including embodiments, examples, figures, or Tables).

[0146] “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 which can be produced in the reaction mixture.

[0147] 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 cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In some embodiments contacting includes allowing a compound described herein to interact with a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) that is involved in a signaling pathway.

[0148] As defined herein, the term “activation,” “activate,” “activating” and the like in reference to a protein refers to conversion of a protein into a biologically active derivative from an initial inactive or deactivated state. The terms reference activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease.

[0149] The terms “agonist,” “activator,” “upregulator,” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. The agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist.

[0150] As defined herein, the term “inhibition,” “inhibit,” “inhibiting” and the like in reference to a cellular component-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the cellular component (e.g., decreasing the signaling pathway stimulated by a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)), relative to the activity or function of the cellular component in the absence of the inhibitor. In embodiments inhibition means negatively affecting (e.g., decreasing) the concentration or levels of the cellular component relative to the concentration or level of the cellular component in the absence of the inhibitor. In some embodiments, inhibition refers to reduction of a disease or symptoms of disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway (e.g., reduction of a pathway involving the cellular component). Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating the signaling pathway or enzymatic activity or the amount of a cellular component.

[0151] The terms “inhibitor,” “repressor,” “antagonist,” or “downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein. The antagonist can decrease expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist.

[0152] 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 (e.g., a target may be a cellular component (e.g., protein, ion, lipid, virus, lipiddroplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) relative to the absence of the composition.

[0153] 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.).

[0154] 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.

[0155] “Patient”, “patient in need thereof”, “subject”, 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 embodiments, a patient is human. In embodiments, a patient in need thereof is human. In embodiments, a subject is human. In embodiments, a subject in need thereof is human.

[0156] “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. In some embodiments, the disease is a disease related to (e.g., caused by) a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In embodiments, the disease is a cancer (e.g., biliary tract cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, ganglia cancer, leukemia, lymphoma, liver cancer, lung cancer, pancreatic cancer, prostate cancer, skin cancer, soft tissue cancer, stomach cancer, testicular cancer, thyroid cancer, glioma, or melanoma). In embodiments, the disease is a developmental disorder (e.g., Noonan syndrome).

[0157] As used herein, the term "cancer" refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinomas and sarcomas. 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 and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus medulloblastoma, colorectal cancer, or 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, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, 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.

[0158] 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.

[0159] As used herein, the term “lymphoma” refers to a group of cancers affecting hematopoietic and lymphoid tissues. It begins in lymphocytes, the blood cells that are found primarily in lymph nodes, spleen, thymus, and bone marrow. Two main types of lymphoma are non-Hodgkin lymphoma and Hodgkin’s disease. Hodgkin’s disease represents approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed- Sternberg malignant B lymphocytes. Non-Hodgkin’s lymphomas (NHL) can be classified based on the rate at which cancer grows and the type of cells involved. There are aggressive (high grade) and indolent (low grade) types of NHL. Based on the type of cells involved, there are B-cell and T-cell NHLs. Exemplary B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt’s lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T- cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.

[0160] 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.

[0161] 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.

[0162] 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, preinvasivecarcinoma, 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.

[0163] As used herein, the terms "metastasis," "metastatic," and "metastatic cancer" can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part. “Metastatic cancer” is also called “Stage IV cancer.” Cancer occurs at an originating site, e.g., breast, which site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or originating site acquire the ability to penetrate and infiltrate surrounding normal tissue in the local area and / or the ability to penetrate the walls of the lymphatic system or vascular system circulating through the system to other sites and tissues in the body. A second clinically detectable tumor formed from cancer cells of a primary tumor is referred to as a metastatic or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor at the site of the breast consists of abnormal lung cells and not abnormal breast cells. The secondary tumor in the breast is referred to a metastatic lung cancer. Thus, the phrase metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors. The phrases non- metastatic cancer or subjects with cancer that is not metastatic refers to diseases in which subjects have a primary tumor but not one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject with or with a history of a primary lung tumor and with one or more secondary tumors at a second location or multiple locations, e.g., in the breast.

[0164] The terms “cutaneous metastasis” or “skin metastasis” refer to secondary malignant cell growths in the skin, wherein the malignant cells originate from a primary cancer site (e.g., breast). In cutaneous metastasis, cancerous cells from a primary cancer site may migrate to the skin where they divide and cause lesions. Cutaneous metastasis may result from the migration of cancer cells from breast cancer tumors to the skin.

[0165] The term “visceral metastasis” refer to secondary malignant cell growths in the interal organs (e.g., heart, lungs, liver, pancreas, intestines) or body cavities (e.g., pleura, peritoneum), wherein the malignant cells originate from a primary cancer site (e.g., head and neck, liver, breast). In visceral metastasis, cancerous cells from a primary cancer site may migrate to the internal organs where they divide and cause lesions. Visceral metastasis may result from the migration of cancer cells from liver cancer tumors or head and neck tumors to internal organs.

[0166] As used herein, the term “K-Ras-associated cancer” refers to any cancer caused by aberrant activity or signaling of K-Ras or mutant K-Ras. In embodiments, the K-Ras- associated cancer is biliary tract cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, ganglia cancer, leukemia, lymphoma, liver cancer, lung cancer, pancreatic cancer, prostate cancer, skin cancer, soft tissue cancer, stomach cancer, testicular cancer, or thyroid cancer. .

[0167] The term “developmental disorder” refers to a disorder characterized by one or more impairments in physical, learning, language, or behavior areas. Exemplary developmental disorders include, but are not limited to, anxiety, attention- deficit / hyperactivity disorder, autism spectrum disorders, cerebral palsy, conduct disorder, depression, developmental disabilities, getal alcohol spectrum disorders, fragile X syndrome, hearing loss, hemophilia, intellectual disability, jaundice and kernicterus, language disorders, learning disorders, muscular dystrophy, oppositional defiant disorder, obsessive-compulsive disorder, post-traumatic stress disorder, sickle cell disease, spina bifida, Tourette syndrome, and vision loss. In embodiments, the developmental disorder is a RASopathy.

[0168] As used herein, the term “RASopathy” refers to a disease caused by germline mutations of genes encoding components of the RAS / MAPK signaling pathway. In embodiments, the RASopathy is a mosaic RASopathy. In embodiments, the RASopathy is a germline RASopathy. In embodiments, the RASopathy is a developmental syndrome. In embodiments, the RASopathy is Noonan syndrome. In embodiments, the RASopathy is epidermal nevus. In embodiments, the RASopathy is Schimmelpenning syndrome. In embodiments, the RASopathy is sebaceous nevus. In embodiments, the RASopathy is talipes equinovarus (e.g., congenital talipes equinovarus). In embodiments, the RASopathy is PIK3CA-related overgrowth syndrome (PROS). In embodiments, the RASopathy is PTEN- Hamartoma of the soft tissue (PHOST). In embodiments, the RASopathy is fibroadiposeovergrowth, hemihyperplasia-multiple lipomatosis, congenital lipomatous overgrowth, vascular malformations, epidermal nevus, spinal and skeletal syndrome, macrodactyly syndrome, megalocephaly syndrome, or congenital diffuse infiltrative lipomatosis. In embodiments, the RASopathy is Klippel-Trenaunay syndrome (KTS), venous malformation, or lymphatic malformation. In embodiments, the RASopathy is capillary malformation-AV malformation syndrome. In embodiments, the RASopathy is autoimmune lymphoproliferative syndrome. In embodiments, the RASopathy is cardiofaciocutaneous syndrome. In embodiments, the RASopathy is hereditary gingival fibromatosis type 1. In embodiments, the RASopathy is neurofibromatosis type 1. In embodiments, the RASopathy is Costello syndrome. In embodiments, the RASopathy is Legius syndrome.

[0169] As used herein, the term “wild-type CRAF-associated cancer” refers to a cancer caused by aberrant activity or signaling of wild-type CRAF. In embodiments, the wild-type CRAF-associated cancer is biliary tract cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, ganglia cancer, leukemia, lymphoma, liver cancer, lung cancer, pancreatic cancer, prostate cancer, skin cancer, soft tissue cancer, stomach cancer, testicular cancer, or thyroid cancer.

[0170] As used herein, the term “pan-RAF-associated cancer” refers to a cancer caused by aberrant activity or signaling of ARAF, BRAF, and / or CRAF. In embodiments, the pan- RAF-associated cancer is glioma or melanoma.

[0171] The term “drug” is used in accordance with its common meaning and refers to a substance which has a physiological effect (e.g., beneficial effect, is useful for treating a subject) when introduced into or to a subject (e.g., in or on the body of a subject or patient). A drug moiety is a radical of a drug.

[0172] A “detectable agent,” “detectable compound,” “detectable label,” or “detectable moiety” is a substance (e.g., element), molecule, or composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means. For example, detectable agents include18F,32P,33P,45Ti,47Sc,52Fe,59Fe,62Cu,64Cu,67Cu,67Ga,68Ga,77As,86Y,90Y,89Sr,89Zr,94Tc,94Tc,99mTc,99Mo,105Pd,223Ra,225Ac, Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu,32P, fluorophore (e.g., fluorescent dyes), modified oligonucleotides (e.g.,moieties described in PCT / US2015 / 022063, which is incorporated herein by reference), electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide ("SPIO") nanoparticles, SPIO nanoparticle aggregates, monochrystalline iron oxide nanoparticles, monochrystalline iron oxide, nanoparticle contrast agents, liposomes or other delivery vehicles containing Gadolinium chelate ("Gd-chelate") molecules, Gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium- 82), fluorodeoxyglucose (e.g., fluorine-18 labeled), any gamma ray emitting radionuclides, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g., including microbubble shells including albumin, galactose, lipid, and / or polymers; microbubble gas core including air, heavy gas(es), perfluorcarbon, nitrogen, octafluoropropane, perflexane lipid microsphere, perflutren, etc.), iodinated contrast agents (e.g., iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate, metrizoate, ioxaglate), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide.

[0173] Radioactive substances (e.g., radioisotopes) that may be used as imaging and / or labeling agents in accordance with the embodiments of the disclosure include, but are not limited to,18F,32P,33P,45Ti,47Sc,52Fe,59Fe,62Cu,64Cu,67Cu,67Ga,68Ga,77As,86Y,90Y,89Sr,199Au,211At,211Pb,212Bi,212Pb,213Bi,223Ra, and225Ac. Paramagnetic ions that may be used as additional imaging agents in accordance with the embodiments of the disclosure include, but are not limited to, ions of transition and lanthanide metals (e.g., metals having atomic numbers of 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu.

[0174] “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 ofpharmaceutically 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.

[0175] 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.

[0176] As used herein, the term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about includes the specified value.

[0177] As used herein, the term “administering” is used in accordance with its plain and ordinary meaning and includes 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). 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. By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after theadministration of one or more additional therapies. The compounds of the invention can be administered alone or can be co-administered to the patient. Co-administration 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 by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0178] The compounds described herein can be used in combination with one another, with other active agents known to be useful in treating a disease associated with cells expressing a disease associated cellular component, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.

[0179] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co- administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and / or adjunctive agents may be linked or conjugated to one another.

[0180] In therapeutic use for the treatment of a disease, compound utilized in the pharmaceutical compositions of the present invention may be administered at the initial dosage of about 0.001 mg / kg to about 1000 mg / kg daily. A daily dose range of about 0.01 mg / kg to about 500 mg / kg, or about 0.1 mg / kg to about 200 mg / kg, or about 1 mg / kg to about 100 mg / kg, or about 10 mg / kg to about 50 mg / kg, can be used. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound or drug being employed. For example, dosages can be empirically determined considering the type and stage of disease (e.g., cancer) diagnosed in a particular patient. The dose administered to a patient, in the context of the present invention, should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration of a compound in a particular patient.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. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

[0181] 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, disease associated with a cellular component) 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 in part) the substance or substance activity or function or the disease or a symptom of the disease may be treated by modulating (e.g., inhibiting or activating) the substance (e.g., cellular component). 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.

[0182] The term “aberrant” as used herein refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity 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.

[0183] The term “electrophilic” as used herein refers to a chemical group that is capable of accepting electron density. An “electrophilic substituent,” “electrophilic chemical moiety,” or “electrophilic moiety” refers to an electron-poor chemical group, substituent, or moiety (monovalent chemical group), which may react with an electron-donating group, such as a nucleophile, by accepting an electron pair or electron density to form a bond.

[0184] “Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density.

[0185] The term “isolated,” when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined usinganalytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.

[0186] The term “amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ- carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an α carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms “non-naturally occurring amino acid” and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.

[0187] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0188] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may in embodiments 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 polymers.

[0189] An amino acid or nucleotide base “position” is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end). Due to deletions, insertions, truncations, fusions, and the like that must be taken into account when determining an optimal alignment, in general the amino acid residue number in a test sequence determined by simply countingfrom the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence. For example, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence.

[0190] The terms “numbered with reference to” or “corresponding to,” when used in the context of the numbering of a given amino acid or polynucleotide sequence, refers to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence.

[0191] An amino acid residue in a protein “corresponds” to a given residue when it occupies the same essential structural position within the protein as the given residue. For example, a selected residue in a selected protein corresponds to C38 of human 14-3-3σ protein when the selected residue occupies the same essential spatial or other structural relationship as C38 of human 14-3-3σ protein. In some embodiments, where a selected protein is aligned for maximum homology with the human 14-3-3σ protein, the position in the aligned selected protein aligning with C38 is said to correspond to C38. Instead of a primary sequence alignment, a three dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with the human 14-3-3σ protein and the overall structures compared. In this case, an amino acid that occupies the same essential position as C38 in the structural model is said to correspond to the C38 residue.

[0192] The term “protein complex” is used in accordance with its plain ordinary meaning and refers to a protein which is associated with an additional substance (e.g., another protein, protein subunit, or a compound). Protein complexes typically have defined quaternary structure. The association between the protein and the additional substance may be a covalent bond. In embodiments, the association between the protein and the additional substance (e.g., compound) is via non-covalent interactions. In embodiments, a protein complex refers to a group of two or more polypeptide chains. Proteins in a protein complexare linked by non-covalent protein–protein interactions. A non-limiting example of a protein complex is the proteasome.

[0193] The term “protein aggregate” is used in accordance with its plain ordinary meaning and refers to an aberrant collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are often associated with diseases (e.g., amyloidosis). In embodiments, when a protein misfolds as a result of a change in the amino acid sequence or a change in the native environment which disrupts normal non-covalent interactions, and the misfolded protein is not corrected or degraded, the unfolded / misfolded protein may aggregate. There are three main types of protein aggregates that may form: amorphous aggregates, oligomers, and amyloid fibrils. In embodiments, protein aggregates are termed aggresomes.

[0194] The term “client protein” as used herein refers to a protein that is capable of binding to another protein (e.g., a 14-3-3 protein). In embodiments, the client protein interaction with the other protein is stabilized with chemical compound as set forth herein.

[0195] The term “14-3-3 protein” as used herein refers to a protein (or portion thereof) that is a member of the 14-3-3 protein family, including, but not limited to, the various human isoforms (β, γ, ε, ζ, η, τ / θ and σ). When specified, the term can refer to a specific isoform or group of isoforms. In embodiments, the term refers to the σ isoform. In embodiments, the 14-3-3 proteins influence the function of bound phosphoserine and / or threonine phosphorylated proteins via a variety of mechanisms including sequestering them from cellular targets, controlling their enzymatic activity, relocating them or acting as adaptor molecules in mediating the association of two distinct client proteins. Thus, in embodiments, 14-3-3 proteins regulate pathways involved in growth factor signaling and cell cycle progression. The 14-3-3 protein may interact with more than 300 different partners (client proteins), including Raf kinases, heat shock proteins, oncogenes, and tumor suppressors. 14- 3-3 proteins are central regulators in many biological processes and pathologies. In embodiments, 14-3-3 binding antagonizes multiple transcription factors that act as oncogenic drivers. In embodiments, 14-3-3 protein binds to a RAF (e.g., ARAF, BRAF, CRAF, or mutant CRAF) protein, and reduces the transcriptional activity of the RAF (e.g., ARAF, BRAF, CRAF, or mutant CRAF) protein. A “14-3-3 protein–RAF (e.g., ARAF, BRAF, CRAF, or mutant CRAF) protein complex” is the complex formed when the 14-3-3 protein binds to a RAF (e.g., ARAF, BRAF, CRAF, or mutant CRAF) protein. In embodiments, the 14-3-3 protein is bound noncovalently to a RAF (e.g., ARAF, BRAF, CRAF, or mutantCRAF) protein. In embodiments, the 14-3-3 protein is 14-3-3σ (14-3-3sigma) (e.g., Entrez 2810, UniProt P31947, RefSeq NP_006133). In embodiments, the 14-3-3 protein is 14-3-3β (14-3-3beta) (e.g., Entrez 7529, UniProt P31946, Q4VY19, RefSeq NP_003395). In embodiments, the 14-3-3 protein is 14-3-3ε (14-3-3epsilon) (e.g., Entrez 7531, UniProt P62258, RefSeq NP_006752). In embodiments, the 14-3-3 protein is 14-3-3η (14-3-3eta) (e.g., Entrez 7533, UniProt Q04917, RefSeq NP_003396). In embodiments, the 14-3-3 protein is 14-3-3γ (14-3-3gamma) (e.g., Entrez 7532, UniProt P61981, RefSeq NP_36611). In embodiments, the 14-3-3 protein is 14-3-3τ (14-3-3tau) (e.g., Entrez 10971, UniProt P27348, RefSeq NP_006817). In embodiments, the 14-3-3 protein is 14-3-3ζ (14-3-3zeta) (e.g., Entrez 7534, UniProt P63104, RefSeq NP_003397).

[0196] In embodiments, the 14-3-3 protein is phosphorylated. In embodiments, the 14-3-3 client is a phosphoserine protein. In embodiments, the 14-3-3 client is a phosphothreonine protein. In embodiments, the 14-3-3 client is a phosphorylated peptide (a phosphopeptide) derived from the 14-3-3 client protein. In embodiments, the 14-3-3 client is a phosphorylated peptide (phosphopeptide) representing the 14-3-3 protein binding motif of the client protein.

[0197] The term “RAF proto-oncogene serine / threonine-protein kinase” or “C-RAF” or “CRAF” refers to a protein (including homologs, isoforms, and functional fragments thereof) that is part of the ERK1 / 2 pathway. The term includes any recombinant or naturally- occurring form of C-RAF variants thereof that maintain C-RAF activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype C- RAF). In embodiments, C-RAF is encoded by the RAF1 gene. In embodiments, C-RAF has the amino acid sequence set forth in or corresponding to Entrez 5894, UniProt P04049, RefSeq (protein) NP_002871.1, RefSeq (protein) NP_001341618, RefSeq (protein) NP_001341619, RefSeq (protein) NP_001341620, RefSeq (protein) NP_001341621, RefSeq (protein) NP_001341622, RefSeq (protein) NP_001341623, or RefSeq (protein) NP_001341624. In embodiments, C-RAF has the following amino acid sequence: MEHIQGAWKTISNGFGFKDAVFDGSSCISPTIVQQFGYQRRASDDGKLTDPSKTSNTI RVFLPNKQRTVVNVRNGMSLHDCLMKALKVRGLQPECCAVFRLLHEHKGKKARLD WNTDAASLIGEELQVDFLDHVPLTTHNFARKTFLKLAFCDICQKFLLNGFRCQTCGY KFHEHCSTKVPTMCVDWSNIRQLLLFPNSTIGDSGVPALPSLTMRRMRESVSRMPVS SQHRYSTPHAFTFNTSSPSSEGSLSQRQRSTSTPNVHMVSTTLPVDSRMIEDAIRSHSE SASPSALSSSPNNLSPTGWSQPKTPVPAQRERAPVSGTQEKNKIRPRGQRDSSYYWEIEASEVMLSTRIGSGSFGTVYKGKWHGDVAVKILKVVDPTPEQFQAFRNEVAVLRKT RHVNILLFMGYMTKDNLAIVTQWCEGSSLYKHLHVQETKFQMFQLIDIARQTAQGM DYLHAKNIIHRDMKSNNIFLHEGLTVKIGDFGLATVKSRWSGSQQVEQPTGSVLWM APEVIRMQDNNPFSFQSDVYSYGIVLYELMTGELPYSHINNRDQIIFMVGRGYASPDL SKLYKNCPKAMKRLVADCVKKVKEERPLFPQILSSIELLQHSLPKINRSASEPSLHRA AHTEDINACTLTTSPRLPVF (SEQ ID NO: 1).

[0198] The term “mutant CRAF” as used herein refers to a CRAF protein with an amino acid mutation relative to SEQ ID NO: 1. For example, CRAF(S259A) corresponds to a protein of SEQ ID NO: 1, wherein the serine at position 259 is replaced with alanine.

[0199] The term “serine / threonine-protein kinase A-Raf” or “A-RAF” or “ARAF” refers to a protein (including homologs, isoforms, and functional fragments thereof) that is part of the MAPK signalling pathway. The term includes any recombinant or naturally-occurring form of A-RAF variants thereof that maintain A-RAF activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype A-RAF). In embodiments, A-RAF is encoded by the ARAF gene. In embodiments, A-RAF has the amino acid sequence set forth in or corresponding to Entrez 369, UniProt P10398, UniProt Q96115, RefSeq (protein) NP_001243125.1, RefSeq (protein) NP_001243126.1, or RefSeq (protein) NP_001645.1.

[0200] The term “proto-oncogene B-Raf”, “serine / threonine-protein kinase B-Raf” or “B- RAF” or “BRAF” refers to a protein (including homologs, isoforms, and functional fragments thereof) that is part of the MAPK signalling pathway. The term includes any recombinant or naturally-occurring form of B-RAF variants thereof that maintain B-RAF activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype B-RAF). In embodiments, B-RAF is encoded by the BRAF gene. In embodiments, B-RAF has the amino acid sequence set forth in or corresponding to Entrez 673, UniProt P15056, RefSeq (protein) NP_004324.2, RefSeq (protein) NP_001341538, RefSeq (protein) NP_001361173, RefSeq (protein) NP_001361187, RefSeq (protein) NP_001365396, RefSeq (protein) NP_001365397, RefSeq (protein) NP_001365398, RefSeq (protein) NP_001365399, RefSeq (protein) NP_001365400, RefSeq (protein) NP_001365401, RefSeq (protein) NP_001365402, RefSeq (protein) NP_001365403, or RefSeq (protein) NP_001365404.

[0201] In embodiments, “selective” or “selectivity” or the like in reference to a compound or agent refers to the compound’s or agent’s ability to cause an increase or decrease in activity of a particular molecular target (e.g., protein, enzyme, etc.) preferentially over one or more different molecular targets (e.g., a compound having selectivity toward C-RAF would preferentially inhibit C-RAF over other RAF proteins). In embodiments, a “C-RAF-selective compound” refers to a compound (e.g., compounds described herein) having selectivity towards C-RAF. In embodiments, the compound (e.g., compound described herein) is about 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, or about 100-fold more selective for C- RAF over one or more of the A-RAF or B-RAF proteins. In embodiments, the compound (e.g., compound described herein) is at least 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50- fold, or at least 100-fold more selective for C-RAF over one or more of the A-RAF or B-RAF proteins. II. Compounds

[0202] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula:

[0204] The symbol n is an integer from 0 to 4.

[0205] Ring A is aryl (e.g., C6-C10 or phenyl), heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), or spirocyclic cycloalkyl (e.g., C5-C11, C5-C10, C5-C8, or C5- C7).

[0206] L1is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR10-, -C(O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10A-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), 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., C3-C8, C3-C6, C4-C6, or C5-C6), 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).

[0207] L2is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20A-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), 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., C3-C8, C3-C6, C4-C6, or C5-C6), 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-C10or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0208] R1is hydrogen, halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, −NR1CNR1AR1B, −ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, 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., 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-C10or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), or E.

[0209] E is an electrophilic moiety.

[0210] R2is independently oxo, halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, −NR2CNR2AR2B, −ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, 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., 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); two R2substituents may optionally be joined to form a 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-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0211] The symbol z2 is an integer from 0 to 5.

[0212] R3is independently oxo, halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3, -OCHX32, -CN, -SOn3R3D, -SOv3NR3AR3B, −NR3CNR3AR3B, −ONR3AR3B, -NR3CC(O)NR3AR3B, -N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -OC(O)R3C, -OC(O)OR3C, -C(O)NR3AR3B, -OC(O)NR3AR3B, -OR3D, -SR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, 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., 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), orsubstituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0213] The symbol z3 is an integer from 0 to 13.

[0214] R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4, R10, R10A, R20, and R20Aare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, 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., 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); R1Aand R1Bsubstituents bonded to the same nitrogen atom 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) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R2Aand R2Bsubstituents bonded to the same nitrogen atom 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) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R3Aand R3Bsubstituents bonded to the same nitrogen atom 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) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0215] Each X1, X2, and X3is independently –F, -Cl, -Br, or –I.

[0216] The symbols n1, n2, and n3 are independently an integer from 0 to 4.

[0217] The symbols m1, m2, m3, v1, v2, and v3 are independently 1 or 2.

[0218] In embodiments, Ring A is phenyl, 5 to 6 membered heteroaryl, or spirocyclic C5- C11cycloalkyl. In embodiments, Ring A is phenyl, pyridyl, or spirocyclic C5-C10cycloalkyl.In embodiments, Ring A is phenyl. In embodiments, Ring A is pyridyl. In embodiments, Ring A is spirocyclic C5-C10 cycloalkyl..

[0221] In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4.

[0222] In embodiments, a substituted L1(e.g., 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 L1is 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, when L1is substituted, it is substituted with at least one substituent group. In embodiments, when L1is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L1is substituted, it is substituted with at least one lower substituent group.

[0223] In embodiments, L1is a bond. In embodiments, L1is -C(O)-. In embodiments, L1is -C(O)O-. In embodiments, L1is -OC(O)-. In embodiments, L1is -O-. In embodiments, L1is -S-. In embodiments, L1is -NR10-. In embodiments, L1is -NH-. In embodiments, L1is -C(O)NR10-. In embodiments, L1is -C(O)NH-. In embodiments, L1is -NR10C(O)-. Inembodiments, L1is -NHC(O)-. In embodiments, L1is -NR10C(O)O-. In embodiments, L1is -NHC(O)O-. In embodiments, L1is -OC(O)NR10-. In embodiments, L1is -OC(O)NH-. In embodiments, L1is -NR10C(O)NR10A-. In embodiments, L1is -NHC(O)NH-. In embodiments, L1is -S(O)2-. In embodiments, L1is -NR10S(O)2-. In embodiments, L1is -NHS(O)2-. In embodiments, L1is -S(O)2NR10-. In embodiments, L1is -S(O)2NH-. In embodiments, L1is unsubstituted C1-C4 alkylene. In embodiments, L1is unsubstituted methylene. In embodiments, L1is unsubstituted ethylene. In embodiments, L1is unsubstituted propylene. In embodiments, L1is unsubstituted n-propylene. In embodiments, L1is unsubstituted isopropylene. In embodiments, L1is unsubstituted butylene. In embodiments, L1is unsubstituted n-butylene. In embodiments, L1is unsubstituted isobutylene. In embodiments, L1is unsubstituted tert-butylene. In embodiments, L1is substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L1is oxo- substituted 2 to 6 membered heteroalkylene. In embodiments, L1is unsubstituted 2 to 6 membered heteroalkylene.

[0224] In embodiments, a substituted R10(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R10is 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, when R10is substituted, it is substituted with at least one substituent group. In embodiments, when R10is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R10is substituted, it is substituted with at least one lower substituent group.

[0225] In embodiments, R10is hydrogen. In embodiments, R10is unsubstituted C1-C4 alkyl. In embodiments, R10is unsubstituted methyl. In embodiments, R10is unsubstituted ethyl. In embodiments, R10is unsubstituted propyl. In embodiments, R10is unsubstituted n- propyl. In embodiments, R10is unsubstituted isopropyl. In embodiments, R10is unsubstituted butyl. In embodiments, R10is unsubstituted n-butyl. In embodiments, R10is unsubstituted isobutyl. In embodiments, R10is unsubstituted tert-butyl.

[0226] In embodiments, a substituted R10A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substitutedheteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R10Ais 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, when R10Ais substituted, it is substituted with at least one substituent group. In embodiments, when R10Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R10Ais substituted, it is substituted with at least one lower substituent group.

[0227] In embodiments, R10Ais hydrogen. In embodiments, R10Ais unsubstituted C1-C4 alkyl. In embodiments, R10Ais unsubstituted methyl. In embodiments, R10Ais unsubstituted ethyl. In embodiments, R10Ais unsubstituted propyl. In embodiments, R10Ais unsubstituted n-propyl. In embodiments, R10Ais unsubstituted isopropyl. In embodiments, R10Ais unsubstituted butyl. In embodiments, R10Ais unsubstituted n-butyl. In embodiments, R10Ais unsubstituted isobutyl. In embodiments, R10Ais unsubstituted tert-butyl.

[0228] In embodiments, a substituted L2(e.g., 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 L2is 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, when L2is substituted, it is substituted with at least one substituent group. In embodiments, when L2is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L2is substituted, it is substituted with at least one lower substituent group.

[0229] In embodiments, L2is a bond. In embodiments, L2is -C(O)-. In embodiments, L2is -C(O)O-. In embodiments, L2is -OC(O)-. In embodiments, L2is -O-. In embodiments, L2is -S-. In embodiments, L2is –NR20-. In embodiments, L2is -NH-. In embodiments, L2is -C(O)NR20-. In embodiments, L2is -C(O)NH-. In embodiments, L2is –NR20C(O)-. In embodiments, L2is -NHC(O)-. In embodiments, L2is –NR20C(O)O-. In embodiments, L2is -NHC(O)O-. In embodiments, L2is -OC(O)NR20-. In embodiments, L2is -OC(O)NH-. In embodiments, L2is –NR20C(O)NR20A-. In embodiments, L2is -NHC(O)NH-. Inembodiments, L2is -S(O)2-. In embodiments, L2is –NR20S(O)2-. In embodiments, L2is -NHS(O)2-. In embodiments, L2is -S(O)2NR20-. In embodiments, L2is -S(O)2NH-. In embodiments, L2is unsubstituted C1-C4 alkylene. In embodiments, L2is unsubstituted methylene. In embodiments, L2is unsubstituted ethylene. In embodiments, L2is unsubstituted propylene. In embodiments, L2is unsubstituted n-propylene. In embodiments, L2is unsubstituted isopropylene. In embodiments, L2is unsubstituted butylene. In embodiments, L2is unsubstituted n-butylene. In embodiments, L2is unsubstituted isobutylene. In embodiments, L2is unsubstituted tert-butylene. In embodiments, L2is substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L2is oxo- substituted 2 to 6 membered heteroalkylene. In embodiments, L2is unsubstituted 2 to 6 membered heteroalkylene.

[0230] In embodiments, L2is a bond or unsubstituted C1-C6 alkylene. In embodiments, L2is a bond, unsubstituted methylene, unsubstituted ethylene, or unsubstituted propylene.

[0231] In embodiments, a substituted R20(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R20is 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, when R20is substituted, it is substituted with at least one substituent group. In embodiments, when R20is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R20is substituted, it is substituted with at least one lower substituent group.

[0232] In embodiments, R20is hydrogen. In embodiments, R20is unsubstituted C1-C4alkyl. In embodiments, R20is unsubstituted methyl. In embodiments, R20is unsubstituted ethyl. In embodiments, R20is unsubstituted propyl. In embodiments, R20is unsubstituted n- propyl. In embodiments, R20is unsubstituted isopropyl. In embodiments, R20is unsubstituted butyl. In embodiments, R20is unsubstituted n-butyl. In embodiments, R20is unsubstituted isobutyl. In embodiments, R20is unsubstituted tert-butyl.

[0233] In embodiments, a substituted R20A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, orlower substituent group; wherein if the substituted R20Ais 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, when R20Ais substituted, it is substituted with at least one substituent group. In embodiments, when R20Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R20Ais substituted, it is substituted with at least one lower substituent group.

[0234] In embodiments, R20Ais hydrogen. In embodiments, R20Ais unsubstituted C1-C4alkyl. In embodiments, R20Ais unsubstituted methyl. In embodiments, R20Ais unsubstituted ethyl. In embodiments, R20Ais unsubstituted propyl. In embodiments, R20Ais unsubstituted n-propyl. In embodiments, R20Ais unsubstituted isopropyl. In embodiments, R20Ais unsubstituted butyl. In embodiments, R20Ais unsubstituted n-butyl. In embodiments, R20Ais unsubstituted isobutyl. In embodiments, R20Ais unsubstituted tert-butyl.

[0235] In embodiments, -L1-L2- is a bond. In embodiments, -L1-L2- is –NH-. In embodiments, -L1-L2- is. In embodiments, -L1-L2- is.

[0236] In embodiments,. embodiments,. In embodiments,. embodiments,.embodiments,. embodiments,.

[0237] In embodiments,. embodiments, –L1-L2-L3- isembodiments,. embodiments, –L1-L2-L3- isembodiments,. , . embodiments,. embodiments, –L1-L2-L3- is. , . embodiments,

[0238] In embodiments, a substituted R1(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1is 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, when R1is substituted, it is substituted with at least one substituent group. In embodiments, when R1is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1is substituted, it is substituted with at least one lower substituent group.

[0239] In embodiments, a substituted R1A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1Ais 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, when R1Ais substituted, it is substituted with at least one substituent group. In embodiments, when R1Ais substituted, it issubstituted with at least one size-limited substituent group. In embodiments, when R1Ais substituted, it is substituted with at least one lower substituent group.

[0240] In embodiments, a substituted R1B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1Bis 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, when R1Bis substituted, it is substituted with at least one substituent group. In embodiments, when R1Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1Bis substituted, it is substituted with at least one lower substituent group.

[0241] In embodiments, a substituted ring formed when R1Aand R1Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R1Aand R1Bsubstituents bonded to the same nitrogen atom are joined 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, when the substituted ring formed when R1Aand R1Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R1Aand R1Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R1Aand R1Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0242] In embodiments, a substituted R1C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1Cis 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 lowersubstituent group may optionally be different. In embodiments, when R1Cis substituted, it is substituted with at least one substituent group. In embodiments, when R1Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1Cis substituted, it is substituted with at least one lower substituent group.

[0243] In embodiments, a substituted R1D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1Dis 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, when R1Dis substituted, it is substituted with at least one substituent group. In embodiments, when R1Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1Dis substituted, it is substituted with at least one lower substituent group.

[0244] In embodiments, R1Ais hydrogen. In embodiments, R1Ais unsubstituted C1-C4 alkyl. In embodiments, R1Ais unsubstituted methyl. In embodiments, R1Ais unsubstituted ethyl. In embodiments, R1Ais unsubstituted propyl. In embodiments, R1Ais unsubstituted n- propyl. In embodiments, R1Ais unsubstituted isopropyl. In embodiments, R1Ais unsubstituted butyl. In embodiments, R1Ais unsubstituted n-butyl. In embodiments, R1Ais unsubstituted isobutyl. In embodiments, R1Ais unsubstituted tert-butyl.

[0245] In embodiments, R1Bis hydrogen. In embodiments, R1Bis unsubstituted C1-C4alkyl. In embodiments, R1Bis unsubstituted methyl. In embodiments, R1Bis unsubstituted ethyl. In embodiments, R1Bis unsubstituted propyl. In embodiments, R1Bis unsubstituted n- propyl. In embodiments, R1Bis unsubstituted isopropyl. In embodiments, R1Bis unsubstituted butyl. In embodiments, R1Bis unsubstituted n-butyl. In embodiments, R1Bis unsubstituted isobutyl. In embodiments, R1Bis unsubstituted tert-butyl.

[0246] In embodiments, R1Cis hydrogen. In embodiments, R1Cis unsubstituted C1-C4alkyl. In embodiments, R1Cis unsubstituted methyl. In embodiments, R1Cis unsubstituted ethyl. In embodiments, R1Cis unsubstituted propyl. In embodiments, R1Cis unsubstituted n- propyl. In embodiments, R1Cis unsubstituted isopropyl. In embodiments, R1Cis unsubstituted butyl. In embodiments, R1Cis unsubstituted n-butyl. In embodiments, R1Cis unsubstituted isobutyl. In embodiments, R1Cis unsubstituted tert-butyl.

[0247] In embodiments, R1Dis hydrogen. In embodiments, R1Dis unsubstituted C1-C4alkyl. In embodiments, R1Dis unsubstituted methyl. In embodiments, R1Dis unsubstituted ethyl. In embodiments, R1Dis unsubstituted propyl. In embodiments, R1Dis unsubstituted n- propyl. In embodiments, R1Dis unsubstituted isopropyl. In embodiments, R1Dis unsubstituted butyl. In embodiments, R1Dis unsubstituted n-butyl. In embodiments, R1Dis unsubstituted isobutyl. In embodiments, R1Dis unsubstituted tert-butyl.

[0248] In embodiments, R1is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -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.

[0249] In embodiments, R1is hydrogen. In embodiments, R1is halogen. In embodiments, R1is –F. In embodiments, R1is –Cl. In embodiments, R1is –Br. In embodiments, R1is –I. In embodiments, R1is -CCl3. In embodiments, R1is -CBr3. In embodiments, R1is -CF3. In embodiments, R1is -CI3. In embodiments, R1is -CH2Cl. In embodiments, R1is -CH2Br. In embodiments, R1is -CH2F. In embodiments, R1is -CH2I. In embodiments, R1is -CHCl2. In embodiments, R1is -CHBr2. In embodiments, R1is -CHF2. In embodiments, R1is -CHI2. In embodiments, R1is –CN. In embodiments, R1is –OH. In embodiments, R1is -NH2. In embodiments, R1is –COOH. In embodiments, R1is -C(NR1C)NR1AR1B. In embodiments, R1is -C(NH)NH2. In embodiments, R1is -C(NH)NHOH. In embodiments, R1is -C(O)NR1AR1B. In embodiments, R1is -CONH2. In embodiments, R1is -NO2. In embodiments, R1is –SH. In embodiments, R1is -SO3H. In embodiments, R1is -OSO3H. In embodiments, R1is -SO2NH2. In embodiments, R1is −NHNH2. In embodiments, R1is −ONH2. In embodiments, R1is −NHC(O)NH2. In embodiments, R1is -NHSO2H. In embodiments, R1is -NHC(O)H. In embodiments, R1is -NHC(O)OH. In embodiments, R1is –NHOH. In embodiments, R1is -OCCl3. In embodiments, R1is -OCBr3. In embodiments, R1is -OCF3. In embodiments, R1is -OCI3. In embodiments, R1is -OCH2Cl. In embodiments, R1is -OCH2Br. In embodiments, R1is -OCH2F. In embodiments, R1is -OCH2I. In embodiments, R1is -OCHCl2. In embodiments, R1is -OCHBr2. Inembodiments, R1is -OCHF2. In embodiments, R1is -OCHI2. In embodiments, R1is -SF5. In embodiments, R1is -N3. In embodiments, R1is unsubstituted C1-C4 alkyl. In embodiments, R1is unsubstituted methyl. In embodiments, R1is unsubstituted ethyl. In embodiments, R1is unsubstituted propyl. In embodiments, R1is unsubstituted n-propyl. In embodiments, R1is unsubstituted isopropyl. In embodiments, R1is unsubstituted butyl. In embodiments, R1is unsubstituted n-butyl. In embodiments, R1is unsubstituted isobutyl. In embodiments, R1is unsubstituted tert-butyl. In embodiments, R1is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R1is unsubstituted methoxy. In embodiments, R1is unsubstituted ethoxy. In embodiments, R1is unsubstituted propoxy. In embodiments, R1is unsubstituted n-propoxy. In embodiments, R1is unsubstituted isopropoxy. In embodiments, R1is unsubstituted butoxy.

[0250] In embodiments, R1is substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R1is. In embodiments, R1is. n em o men s, s . In embodiments, R1is -SH. In embodiments, R1is –(CH2)n1A-SH, wherein n is an integer from 0 to 10. In embodiments, n1A is 0. In embodiments, n1A is 1. In embodiments, n1A is 2. In embodiments, n1A is 3. In embodiments, n1A is 4. In embodiments, n1A is 5. In embodiments, n1A is 6. In embodiments, n1A is 7. In embodiments, n1A is 8. In embodiments, n1A is 9. In embodiments, n1A is 10.

[0251] In embodiments, R1is E. In embodiments, E is

[0252] R11, R12, R13, and R14are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2,−NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, 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., 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-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0253] X11, X12, and X13are independently –F, -Cl, -Br, or –I.

[0254] In embodiments,. embodiments,. embodiments,. embodiments,. embodiments, E is. In embodiments,. embodiments, E is. , .

[0255] In embodiments,,. , . embodiments,.

[0256] In embodiments, a substituted R11(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, orlower substituent group; wherein if the substituted R11is 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, when R11is substituted, it is substituted with at least one substituent group. In embodiments, when R11is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R11is substituted, it is substituted with at least one lower substituent group.

[0257] In embodiments, R11is hydrogen. In embodiments, R11is unsubstituted C1-C4alkyl. In embodiments, R11is unsubstituted methyl. In embodiments, R11is unsubstituted ethyl. In embodiments, R11is unsubstituted propyl. In embodiments, R11is unsubstituted n- propyl. In embodiments, R11is unsubstituted isopropyl. In embodiments, R11is unsubstituted butyl. In embodiments, R11is unsubstituted n-butyl. In embodiments, R11is unsubstituted isobutyl. In embodiments, R11is unsubstituted tert-butyl.

[0258] In embodiments, a substituted R12(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R12is 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, when R12is substituted, it is substituted with at least one substituent group. In embodiments, when R12is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R12is substituted, it is substituted with at least one lower substituent group.

[0259] In embodiments, R12is hydrogen. In embodiments, R12is unsubstituted C1-C4alkyl. In embodiments, R12is unsubstituted methyl. In embodiments, R12is unsubstituted ethyl. In embodiments, R12is unsubstituted propyl. In embodiments, R12is unsubstituted n- propyl. In embodiments, R12is unsubstituted isopropyl. In embodiments, R12is unsubstituted butyl. In embodiments, R12is unsubstituted n-butyl. In embodiments, R12is unsubstituted isobutyl. In embodiments, R12is unsubstituted tert-butyl.

[0260] In embodiments, a substituted R13(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, orlower substituent group; wherein if the substituted R13is 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, when R13is substituted, it is substituted with at least one substituent group. In embodiments, when R13is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R13is substituted, it is substituted with at least one lower substituent group.

[0261] In embodiments, R13is hydrogen. In embodiments, R13is unsubstituted C1-C4alkyl. In embodiments, R13is unsubstituted methyl. In embodiments, R13is unsubstituted ethyl. In embodiments, R13is unsubstituted propyl. In embodiments, R13is unsubstituted n- propyl. In embodiments, R13is unsubstituted isopropyl. In embodiments, R13is unsubstituted butyl. In embodiments, R13is unsubstituted n-butyl. In embodiments, R13is unsubstituted isobutyl. In embodiments, R13is unsubstituted tert-butyl.

[0262] In embodiments, a substituted R14(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R14is 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, when R14is substituted, it is substituted with at least one substituent group. In embodiments, when R14is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R14is substituted, it is substituted with at least one lower substituent group.

[0263] In embodiments, R14is hydrogen. In embodiments, R14is unsubstituted C1-C4alkyl. In embodiments, R14is unsubstituted methyl. In embodiments, R14is unsubstituted ethyl. In embodiments, R14is unsubstituted propyl. In embodiments, R14is unsubstituted n- propyl. In embodiments, R14is unsubstituted isopropyl. In embodiments, R14is unsubstituted butyl. In embodiments, R14is unsubstituted n-butyl. In embodiments, R14is unsubstituted isobutyl. In embodiments, R14is unsubstituted tert-butyl.

[0264] In embodiments, R11, R12, R13, and R14are hydrogen.

[0265] In embodiments, a substituted R2(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R2is 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, when R2is substituted, it is substituted with at least one substituent group. In embodiments, when R2is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2is substituted, it is substituted with at least one lower substituent group.

[0266] In embodiments, a substituted ring formed when two R2substituents are joined (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when two R2substituents are joined 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, when the substituted ring formed when two R2substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R2substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R2substituents are joined is substituted, it is substituted with at least one lower substituent group.

[0267] In embodiments, a substituted R2A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R2Ais 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, when R2Ais substituted, it is substituted with at least one substituent group. In embodiments, when R2Ais substituted, it issubstituted with at least one size-limited substituent group. In embodiments, when R2Ais substituted, it is substituted with at least one lower substituent group.

[0268] In embodiments, a substituted R2B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R2Bis 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, when R2Bis substituted, it is substituted with at least one substituent group. In embodiments, when R2Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2Bis substituted, it is substituted with at least one lower substituent group.

[0269] In embodiments, a substituted ring formed when R2Aand R2Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R2Aand R2Bsubstituents bonded to the same nitrogen atom are joined 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, when the substituted ring formed when R2Aand R2Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R2Aand R2Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R2Aand R2Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0270] In embodiments, a substituted R2C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R2Cis 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 lowersubstituent group may optionally be different. In embodiments, when R2Cis substituted, it is substituted with at least one substituent group. In embodiments, when R2Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2Cis substituted, it is substituted with at least one lower substituent group.

[0271] In embodiments, a substituted R2D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R2Dis 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, when R2Dis substituted, it is substituted with at least one substituent group. In embodiments, when R2Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2Dis substituted, it is substituted with at least one lower substituent group.

[0272] In embodiments, R2Ais independently hydrogen. In embodiments, R2Ais independently unsubstituted C1-C4 alkyl. In embodiments, R2Ais independently unsubstituted methyl. In embodiments, R2Ais independently unsubstituted ethyl. In embodiments, R2Ais independently unsubstituted propyl. In embodiments, R2Ais independently unsubstituted n-propyl. In embodiments, R2Ais independently unsubstituted isopropyl. In embodiments, R2Ais independently unsubstituted butyl. In embodiments, R2Ais independently unsubstituted n-butyl. In embodiments, R2Ais independently unsubstituted isobutyl. In embodiments, R2Ais independently unsubstituted tert-butyl.

[0273] In embodiments, R2Bis independently hydrogen. In embodiments, R2Bis independently unsubstituted C1-C4alkyl. In embodiments, R2Bis independently unsubstituted methyl. In embodiments, R2Bis independently unsubstituted ethyl. In embodiments, R2Bis independently unsubstituted propyl. In embodiments, R2Bis independently unsubstituted n-propyl. In embodiments, R2Bis independently unsubstituted isopropyl. In embodiments, R2Bis independently unsubstituted butyl. In embodiments, R2Bis independently unsubstituted n-butyl. In embodiments, R2Bis independently unsubstituted isobutyl. In embodiments, R2Bis independently unsubstituted tert-butyl.

[0274] In embodiments, R2Cis independently hydrogen. In embodiments, R2Cis independently unsubstituted C1-C4 alkyl. In embodiments, R2Cis independentlyunsubstituted methyl. In embodiments, R2Cis independently unsubstituted ethyl. In embodiments, R2Cis independently unsubstituted propyl. In embodiments, R2Cis independently unsubstituted n-propyl. In embodiments, R2Cis independently unsubstituted isopropyl. In embodiments, R2Cis independently unsubstituted butyl. In embodiments, R2Cis independently unsubstituted n-butyl. In embodiments, R2Cis independently unsubstituted isobutyl. In embodiments, R2Cis independently unsubstituted tert-butyl.

[0275] In embodiments, R2Dis independently hydrogen. In embodiments, R2Dis independently unsubstituted C1-C4alkyl. In embodiments, R2Dis independently unsubstituted methyl. In embodiments, R2Dis independently unsubstituted ethyl. In embodiments, R2Dis independently unsubstituted propyl. In embodiments, R2Dis independently unsubstituted n-propyl. In embodiments, R2Dis independently unsubstituted isopropyl. In embodiments, R2Dis independently unsubstituted butyl. In embodiments, R2Dis independently unsubstituted n-butyl. In embodiments, R2Dis independently unsubstituted isobutyl. In embodiments, R2Dis independently unsubstituted tert-butyl.

[0276] R2is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, −NR2CNR2AR2B, −ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, 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., 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); two R2substituents may optionally be joined to form a 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-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0277] In embodiments, R2is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -C(O)H, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, 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.

[0278] In embodiments, R2is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -C(O)H, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, 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.

[0279] In embodiments, R2is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -C(O)H, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted C1-C4alkyl, or substituted or unsubstituted 2 to 4 membered heteroalkyl.

[0280] In embodiments, R2is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -C(O)H, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 4 membered heteroalkyl.

[0281] In embodiments, R2is independently oxo. In embodiments, R2is independently halogen. In embodiments, R2is independently –F. In embodiments, R2is independently –Cl. In embodiments, R2is independently –Br. In embodiments, R2is independently –I. Inembodiments, R2is independently -CCl3. In embodiments, R2is independently -CBr3. In embodiments, R2is independently -CF3. In embodiments, R2is independently -CI3. In embodiments, R2is independently -CH2Cl. In embodiments, R2is independently -CH2Br. In embodiments, R2is independently -CH2F. In embodiments, R2is independently -CH2I. In embodiments, R2is independently -CHCl2. In embodiments, R2is independently -CHBr2. In embodiments, R2is independently -CHF2. In embodiments, R2is independently -CHI2. In embodiments, R2is independently –CN. In embodiments, R2is independently –OH. In embodiments, R2is independently -NH2. In embodiments, R2is independently -C(O)R2C, wherein R2Cis as described herein, including in embodiments. In embodiments, R2is independently -C(O)H. In embodiments, R2is independently -C(O)OR2C, wherein R2Cis as described herein, including in embodiments. In embodiments, R2is independently –COOH. In embodiments, R2is independently -C(O)CH3. In embodiments, R2is independently -CONH2. In embodiments, R2is independently -NO2. In embodiments, R2is independently –SH. In embodiments, R2is independently -SO3H. In embodiments, R2is independently -OSO3H. In embodiments, R2is independently -SO2NH2. In embodiments, R2is independently −NHNH2. In embodiments, R2is independently −ONH2. In embodiments, R2is independently −NHC(O)NH2. In embodiments, R2is independently -NHSO2H. In embodiments, R2is independently -NHC(O)H. In embodiments, R2is independently -NHC(O)OH. In embodiments, R2is independently –NHOH. In embodiments, R2is independently -OCCl3. In embodiments, R2is independently -OCBr3. In embodiments, R2is independently -OCF3. In embodiments, R2is independently -OCI3. In embodiments, R2is independently -OCH2Cl. In embodiments, R2is independently -OCH2Br. In embodiments, R2is independently -OCH2F. In embodiments, R2is independently -OCH2I. In embodiments, R2is independently -OCHCl2. In embodiments, R2is independently -OCHBr2. In embodiments, R2is independently -OCHF2. In embodiments, R2is independently -OCHI2. In embodiments, R2is independently -SF5. In embodiments, R2is independently -N3. In embodiments, R2is independently unsubstituted C1-C4 alkyl. In embodiments, R2is independently unsubstituted methyl. In embodiments, R2is independently unsubstituted ethyl. In embodiments, R2is independently unsubstituted propyl. In embodiments, R2is independently unsubstituted n-propyl. In embodiments, R2is independently unsubstituted isopropyl. In embodiments, R2is independently unsubstituted butyl. In embodiments, R2is independently unsubstituted n-butyl. In embodiments, R2is independently unsubstituted isobutyl. In embodiments, R2is independently unsubstitutedtert-butyl. In embodiments, R2is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R2is independently unsubstituted methoxy. In embodiments, R2is independently unsubstituted ethoxy. In embodiments, R2is independently unsubstituted propoxy. In embodiments, R2is independently unsubstituted n-propoxy. In embodiments, R2is independently unsubstituted isopropoxy. In embodiments, R2is independently unsubstituted butoxy.

[0282] In embodiments, R2is independently halogen, -CF3, -OCF3, -CN, -C(O)H, unsubstituted C1-C4alkyl, or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R2is independently –F, -Cl, -Br, -I, -CF3, -OCF3, -CN, -C(O)H, unsubstituted methyl, or unsubstituted methoxy.

[0283] 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. In embodiments, z2 is 5.

[0284] In embodiments, a substituted R3(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R3is 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, when R3is substituted, it is substituted with at least one substituent group. In embodiments, when R3is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3is substituted, it is substituted with at least one lower substituent group.

[0285] In embodiments, a substituted R3A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R3Ais 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, when R3Ais substituted, it is substituted with at least one substituent group. In embodiments, when R3Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3Ais substituted, it is substituted with at least one lower substituent group.

[0286] In embodiments, a substituted R3B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R3Bis 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, when R3Bis substituted, it is substituted with at least one substituent group. In embodiments, when R3Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3Bis substituted, it is substituted with at least one lower substituent group.

[0287] In embodiments, a substituted ring formed when R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined 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, when the substituted ring formed when R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0288] In embodiments, a substituted R3C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R3Cis 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, when R3Cis substituted, it is substituted with at least one substituent group. In embodiments, when R3Cis substituted, it issubstituted with at least one size-limited substituent group. In embodiments, when R3Cis substituted, it is substituted with at least one lower substituent group.

[0289] In embodiments, a substituted R3D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R3Dis 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, when R3Dis substituted, it is substituted with at least one substituent group. In embodiments, when R3Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3Dis substituted, it is substituted with at least one lower substituent group.

[0290] In embodiments, R3Ais independently hydrogen. In embodiments, R3Ais independently unsubstituted C1-C4alkyl. In embodiments, R3Ais independently unsubstituted methyl. In embodiments, R3Ais independently unsubstituted ethyl. In embodiments, R3Ais independently unsubstituted propyl. In embodiments, R3Ais independently unsubstituted n-propyl. In embodiments, R3Ais independently unsubstituted isopropyl. In embodiments, R3Ais independently unsubstituted butyl. In embodiments, R3Ais independently unsubstituted n-butyl. In embodiments, R3Ais independently unsubstituted isobutyl. In embodiments, R3Ais independently unsubstituted tert-butyl.

[0291] In embodiments, R3Bis independently hydrogen. In embodiments, R3Bis independently unsubstituted C1-C4 alkyl. In embodiments, R3Bis independently unsubstituted methyl. In embodiments, R3Bis independently unsubstituted ethyl. In embodiments, R3Bis independently unsubstituted propyl. In embodiments, R3Bis independently unsubstituted n-propyl. In embodiments, R3Bis independently unsubstituted isopropyl. In embodiments, R3Bis independently unsubstituted butyl. In embodiments, R3Bis independently unsubstituted n-butyl. In embodiments, R3Bis independently unsubstituted isobutyl. In embodiments, R3Bis independently unsubstituted tert-butyl.

[0292] In embodiments, R3Cis independently hydrogen. In embodiments, R3Cis independently unsubstituted C1-C4alkyl. In embodiments, R3Cis independently unsubstituted methyl. In embodiments, R3Cis independently unsubstituted ethyl. In embodiments, R3Cis independently unsubstituted propyl. In embodiments, R3Cisindependently unsubstituted n-propyl. In embodiments, R3Cis independently unsubstituted isopropyl. In embodiments, R3Cis independently unsubstituted butyl. In embodiments, R3Cis independently unsubstituted n-butyl. In embodiments, R3Cis independently unsubstituted isobutyl. In embodiments, R3Cis independently unsubstituted tert-butyl.

[0293] In embodiments, R3Dis independently hydrogen. In embodiments, R3Dis independently unsubstituted C1-C4 alkyl. In embodiments, R3Dis independently unsubstituted methyl. In embodiments, R3Dis independently unsubstituted ethyl. In embodiments, R3Dis independently unsubstituted propyl. In embodiments, R3Dis independently unsubstituted n-propyl. In embodiments, R3Dis independently unsubstituted isopropyl. In embodiments, R3Dis independently unsubstituted butyl. In embodiments, R3Dis independently unsubstituted n-butyl. In embodiments, R3Dis independently unsubstituted isobutyl. In embodiments, R3Dis independently unsubstituted tert-butyl.

[0294] R3is independently halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3, -OCHX32, -CN, -SOn3R3D, -SOv3NR3AR3B, −NR3CNR3AR3B, −ONR3AR3B, -NR3CC(O)NR3AR3B, -N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -OC(O)R3C, -OC(O)OR3C, -C(O)NR3AR3B, -OC(O)NR3AR3B, -OR3D, -SR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, 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., 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-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0295] In embodiments, R3is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -C(O)H, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, 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.

[0296] In embodiments, R3is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -C(O)H, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, 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.

[0297] In embodiments, R3is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.

[0298] In embodiments, R3is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.

[0299] In embodiments, R3is independently oxo. In embodiments, R3is independently halogen. In embodiments, R3is independently –F. In embodiments, R3is independently –Cl. In embodiments, R3is independently –Br. In embodiments, R3is independently –I. In embodiments, R3is independently -CCl3. In embodiments, R3is independently -CBr3. In embodiments, R3is independently -CF3. In embodiments, R3is independently -CI3. In embodiments, R3is independently -CH2Cl. In embodiments, R3is independently -CH2Br. In embodiments, R3is independently -CH2F. In embodiments, R3is independently -CH2I. In embodiments, R3is independently -CHCl2. In embodiments, R3is independently -CHBr2. In embodiments, R3is independently -CHF2. In embodiments, R3is independently -CHI2. In embodiments, R3is independently –CN. In embodiments, R3is independently –OH. In embodiments, R3is independently -NH2. In embodiments, R3is independently –COOH. In embodiments, R3is independently -CONH2. In embodiments, R3is independently -NO2. Inembodiments, R3is independently –SH. In embodiments, R3is independently -SO3H. In embodiments, R3is independently -OSO3H. In embodiments, R3is independently -SO2NH2. In embodiments, R3is independently −NHNH2. In embodiments, R3is independently −ONH2. In embodiments, R3is independently −NHC(O)NH2. In embodiments, R3is independently -NHSO2H. In embodiments, R3is independently -NHC(O)H. In embodiments, R3is independently -NHC(O)OH. In embodiments, R3is independently –NHOH. In embodiments, R3is independently -OCCl3. In embodiments, R3is independently -OCBr3. In embodiments, R3is independently -OCF3. In embodiments, R3is independently -OCI3. In embodiments, R3is independently -OCH2Cl. In embodiments, R3is independently -OCH2Br. In embodiments, R3is independently -OCH2F. In embodiments, R3is independently -OCH2I. In embodiments, R3is independently -OCHCl2. In embodiments, R3is independently -OCHBr2. In embodiments, R3is independently -OCHF2. In embodiments, R3is independently -OCHI2. In embodiments, R3is independently -SF5. In embodiments, R3is independently -N3. In embodiments, R3is independently unsubstituted C1-C4 alkyl. In embodiments, R3is independently unsubstituted methyl. In embodiments, R3is independently unsubstituted ethyl. In embodiments, R3is independently unsubstituted propyl. In embodiments, R3is independently unsubstituted n-propyl. In embodiments, R3is independently unsubstituted isopropyl. In embodiments, R3is independently unsubstituted butyl. In embodiments, R3is independently unsubstituted n-butyl. In embodiments, R3is independently unsubstituted isobutyl. In embodiments, R3is independently unsubstituted tert-butyl. In embodiments, R3is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R3is independently unsubstituted methoxy. In embodiments, R3is independently unsubstituted ethoxy. In embodiments, R3is independently unsubstituted propoxy. In embodiments, R3is independently unsubstituted n-propoxy. In embodiments, R3is independently unsubstituted isopropoxy. In embodiments, R3is independently unsubstituted butoxy.

[0300] In embodiments, R3is independently halogen or unsubstituted C1-C4alkyl. In embodiments, R3is independently –F or unsubstituted methyl.

[0301] In embodiments, z3 is 0. In embodiments, z3 is 1. In embodiments, z3 is 2. In embodiments, z3 is 3. In embodiments, z3 is 4. In embodiments, z3 is 5. In embodiments, z3 is 6. In embodiments, z3 is 7. In embodiments, z3 is 8. In embodiments, z3 is 9. Inembodiments, z3 is 10. In embodiments, z3 is 11. In embodiments, z3 is 12. In embodiments, z3 is 13.

[0302] In embodiments, a substituted R4(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4is 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, when R4is substituted, it is substituted with at least one substituent group. In embodiments, when R4is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4is substituted, it is substituted with at least one lower substituent group.

[0303] In embodiments, R4is hydrogen. In embodiments, R4is unsubstituted C1-C4 alkyl. In embodiments, R4is unsubstituted methyl. In embodiments, R4is unsubstituted ethyl. In embodiments, R4is unsubstituted propyl. In embodiments, R4is unsubstituted n-propyl. In embodiments, R4is unsubstituted isopropyl. In embodiments, R4is unsubstituted butyl. In embodiments, R4is unsubstituted n-butyl. In embodiments, R4is unsubstituted isobutyl. In embodiments, R4is unsubstituted tert-butyl.

[0304] In embodiments, when R1is substituted, R1is substituted with one or more first substituent groups denoted by R1.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.1substituent group is substituted, the R1.1substituent group is substituted with one or more second substituent groups denoted by R1.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.2substituent group is substituted, the R1.2substituent group is substituted with one or more third substituent groups denoted by R1.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1, R1.1, R1.2, and R1.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R1, R1.1, R1.2, and R1.3, respectively.

[0305] In embodiments, when R1Ais substituted, R1Ais substituted with one or more first substituent groups denoted by R1A.1as explained in the definitions section above in thedescription of “first substituent group(s)”. In embodiments, when an R1A.1substituent group is substituted, the R1A.1substituent group is substituted with one or more second substituent groups denoted by R1A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A.2substituent group is substituted, the R1A.2substituent group is substituted with one or more third substituent groups denoted by R1A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1A, R1A.1, R1A.2, and R1A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R1A, R1A.1, R1A.2, and R1A.3, respectively.

[0306] In embodiments, when R1Bis substituted, R1Bis substituted with one or more first substituent groups denoted by R1B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.1substituent group is substituted, the R1B.1substituent group is substituted with one or more second substituent groups denoted by R1B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.2substituent group is substituted, the R1B.2substituent group is substituted with one or more third substituent groups denoted by R1B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1B, R1B.1, R1B.2, and R1B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R1B, R1B.1, R1B.2, and R1B.3, respectively.

[0307] In embodiments, when R1Aand R1Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R1A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A.1substituent group is substituted, the R1A.1substituent group is substituted with one or more second substituent groups denoted by R1A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A.2substituent group is substituted, the R1A.2substituent group is substituted with one or more third substituent groups denoted by R1A.3as explained in the definitions section above in the description of “first substituent group(s)”. Inthe above embodiments, R1A.1, R1A.2, and R1A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R1A.1, R1A.2, and R1A.3, respectively.

[0308] In embodiments, when R1Aand R1Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R1B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.1substituent group is substituted, the R1B.1substituent group is substituted with one or more second substituent groups denoted by R1B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.2substituent group is substituted, the R1B.2substituent group is substituted with one or more third substituent groups denoted by R1B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1B.1, R1B.2, and R1B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R1B.1, R1B.2, and R1B.3, respectively.

[0309] In embodiments, when R1Cis substituted, R1Cis substituted with one or more first substituent groups denoted by R1C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1C.1substituent group is substituted, the R1C.1substituent group is substituted with one or more second substituent groups denoted by R1C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1C.2substituent group is substituted, the R1C.2substituent group is substituted with one or more third substituent groups denoted by R1C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1C, R1C.1, R1C.2, and R1C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R1C, R1C.1, R1C.2, and R1C.3, respectively.

[0310] In embodiments, when R1Dis substituted, R1Dis substituted with one or more first substituent groups denoted by R1D.1as explained in the definitions section above in thedescription of “first substituent group(s)”. In embodiments, when an R1D.1substituent group is substituted, the R1D.1substituent group is substituted with one or more second substituent groups denoted by R1D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1D.2substituent group is substituted, the R1D.2substituent group is substituted with one or more third substituent groups denoted by R1D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1D, R1D.1, R1D.2, and R1D.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R1D, R1D.1, R1D.2, and R1D.3, respectively.

[0311] In embodiments, when R2is substituted, R2is substituted with one or more first substituent groups denoted by R2.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.1substituent group is substituted, the R2.1substituent group is substituted with one or more second substituent groups denoted by R2.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.2substituent group is substituted, the R2.2substituent group is substituted with one or more third substituent groups denoted by R2.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2, R2.1, R2.2, and R2.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2, R2.1, R2.2, and R2.3, respectively.

[0312] In embodiments, when two R2substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R2.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.1substituent group is substituted, the R2.1substituent group is substituted with one or more second substituent groups denoted by R2.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.2substituent group is substituted, the R2.2substituent group is substituted with one or more third substituent groups denoted by R2.3as explained in the definitions section above in the description of “first substituent group(s)”. In the aboveembodiments, R2, R2.1, R2.2, and R2.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2, R2.1, R2.2, and R2.3, respectively.

[0313] In embodiments, when R2Ais substituted, R2Ais substituted with one or more first substituent groups denoted by R2A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2A.1substituent group is substituted, the R2A.1substituent group is substituted with one or more second substituent groups denoted by R2A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2A.2substituent group is substituted, the R2A.2substituent group is substituted with one or more third substituent groups denoted by R2A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2A, R2A.1, R2A.2, and R2A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2A, R2A.1, R2A.2, and R2A.3, respectively.

[0314] In embodiments, when R2Bis substituted, R2Bis substituted with one or more first substituent groups denoted by R2B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.1substituent group is substituted, the R2B.1substituent group is substituted with one or more second substituent groups denoted by R2B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.2substituent group is substituted, the R2B.2substituent group is substituted with one or more third substituent groups denoted by R2B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2B, R2B.1, R2B.2, and R2B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2B, R2B.1, R2B.2, and R2B.3, respectively.

[0315] In embodiments, when R2Aand R2Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R2A.1as explained in the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R2A.1substituent group is substituted, the R2A.1substituent group is substituted with one or more second substituent groups denoted by R2A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2A.2substituent group is substituted, the R2A.2substituent group is substituted with one or more third substituent groups denoted by R2A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2A.1, R2A.2, and R2A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R2A.1, R2A.2, and R2A.3, respectively.

[0316] In embodiments, when R2Aand R2Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R2B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.1substituent group is substituted, the R2B.1substituent group is substituted with one or more second substituent groups denoted by R2B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.2substituent group is substituted, the R2B.2substituent group is substituted with one or more third substituent groups denoted by R2B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2B.1, R2B.2, and R2B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R2B.1, R2B.2, and R2B.3, respectively.

[0317] In embodiments, when R2Cis substituted, R2Cis substituted with one or more first substituent groups denoted by R2C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2C.1substituent group is substituted, the R2C.1substituent group is substituted with one or more second substituent groups denoted by R2C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2C.2substituent group is substituted, the R2C.2substituent group is substituted with one or more third substituent groups denoted by R2C.3as explained in the definitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R2C, R2C.1, R2C.2, and R2C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2C, R2C.1, R2C.2, and R2C.3, respectively.

[0318] In embodiments, when R2Dis substituted, R2Dis substituted with one or more first substituent groups denoted by R2D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2D.1substituent group is substituted, the R2D.1substituent group is substituted with one or more second substituent groups denoted by R2D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2D.2substituent group is substituted, the R2D.2substituent group is substituted with one or more third substituent groups denoted by R2D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2D, R2D.1, R2D.2, and R2D.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2D, R2D.1, R2D.2, and R2D.3, respectively.

[0319] In embodiments, when R3is substituted, R3is substituted with one or more first substituent groups denoted by R3.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.1substituent group is substituted, the R3.1substituent group is substituted with one or more second substituent groups denoted by R3.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.2substituent group is substituted, the R3.2substituent group is substituted with one or more third substituent groups denoted by R3.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3, R3.1, R3.2, and R3.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3, R3.1, R3.2, and R3.3, respectively.

[0320] In embodiments, when R3is substituted, R3is substituted with one or more first substituent groups denoted by R3.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.1substituent group is substituted, the R3.1substituent group is substituted with one or more second substituentgroups denoted by R3.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.2substituent group is substituted, the R3.2substituent group is substituted with one or more third substituent groups denoted by R3.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3, R3.1, R3.2, and R3.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3, R3.1, R3.2, and R3.3, respectively.

[0321] In embodiments, when R3Ais substituted, R3Ais substituted with one or more first substituent groups denoted by R3A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3A.1substituent group is substituted, the R3A.1substituent group is substituted with one or more second substituent groups denoted by R3A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3A.2substituent group is substituted, the R3A.2substituent group is substituted with one or more third substituent groups denoted by R3A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3A, R3A.1, R3A.2, and R3A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3A, R3A.1, R3A.2, and R3A.3, respectively.

[0322] In embodiments, when R3Bis substituted, R3Bis substituted with one or more first substituent groups denoted by R3B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3B.1substituent group is substituted, the R3B.1substituent group is substituted with one or more second substituent groups denoted by R3B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3B.2substituent group is substituted, the R3B.2substituent group is substituted with one or more third substituent groups denoted by R3B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3B, R3B.1, R3B.2, and R3B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3B, R3B.1, R3B.2, and R3B.3, respectively.

[0323] In embodiments, when R3Aand R3Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R3A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3A.1substituent group is substituted, the R3A.1substituent group is substituted with one or more second substituent groups denoted by R3A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3A.2substituent group is substituted, the R3A.2substituent group is substituted with one or more third substituent groups denoted by R3A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3A.1, R3A.2, and R3A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R3A.1, R3A.2, and R3A.3, respectively.

[0324] In embodiments, when R3Aand R3Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R3B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3B.1substituent group is substituted, the R3B.1substituent group is substituted with one or more second substituent groups denoted by R3B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3B.2substituent group is substituted, the R3B.2substituent group is substituted with one or more third substituent groups denoted by R3B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3B.1, R3B.2, and R3B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R3B.1, R3B.2, and R3B.3, respectively.

[0325] In embodiments, when R3Cis substituted, R3Cis substituted with one or more first substituent groups denoted by R3C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3C.1substituent group is substituted, the R3C.1substituent group is substituted with one or more second substituentgroups denoted by R3C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3C.2substituent group is substituted, the R3C.2substituent group is substituted with one or more third substituent groups denoted by R3C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3C, R3C.1, R3C.2, and R3C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3C, R3C.1, R3C.2, and R3C.3, respectively.

[0326] In embodiments, when R3Dis substituted, R3Dis substituted with one or more first substituent groups denoted by R3D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3D.1substituent group is substituted, the R3D.1substituent group is substituted with one or more second substituent groups denoted by R3D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3D.2substituent group is substituted, the R3D.2substituent group is substituted with one or more third substituent groups denoted by R3D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3D, R3D.1, R3D.2, and R3D.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3D, R3D.1, R3D.2, and R3D.3, respectively.

[0327] In embodiments, when R4is substituted, R4is substituted with one or more first substituent groups denoted by R4.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.1substituent group is substituted, the R4.1substituent group is substituted with one or more second substituent groups denoted by R4.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.2substituent group is substituted, the R4.2substituent group is substituted with one or more third substituent groups denoted by R4.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4, R4.1, R4.2, and R4.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4, R4.1, R4.2, and R4.3, respectively.

[0328] In embodiments, when R10is substituted, R10is substituted with one or more first substituent groups denoted by R10.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10.1substituent group is substituted, the R10.1substituent group is substituted with one or more second substituent groups denoted by R10.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10.2substituent group is substituted, the R10.2substituent group is substituted with one or more third substituent groups denoted by R10.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10, R10.1, R10.2, and R10.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R10, R10.1, R10.2, and R10.3, respectively.

[0329] In embodiments, when R10Ais substituted, R10Ais substituted with one or more first substituent groups denoted by R10A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10A.1substituent group is substituted, the R10A.1substituent group is substituted with one or more second substituent groups denoted by R10A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10A.2substituent group is substituted, the R10A.2substituent group is substituted with one or more third substituent groups denoted by R10A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10A, R10A.1, R10A.2, and R10A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R10A, R10A.1, R10A.2, and R10A.3, respectively.

[0330] In embodiments, when R11is substituted, R11is substituted with one or more first substituent groups denoted by R11.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R11.1substituent group is substituted, the R11.1substituent group is substituted with one or more second substituent groups denoted by R11.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R11.2substituent group is substituted, the R11.2substituent group is substituted with one or more third substituent groups denoted by R11.3as explained in the definitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R11, R11.1, R11.2, and R11.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R11, R11.1, R11.2, and R11.3, respectively.

[0331] In embodiments, when R12is substituted, R12is substituted with one or more first substituent groups denoted by R12.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R12.1substituent group is substituted, the R12.1substituent group is substituted with one or more second substituent groups denoted by R12.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R12.2substituent group is substituted, the R12.2substituent group is substituted with one or more third substituent groups denoted by R12.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R12, R12.1, R12.2, and R12.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R12, R12.1, R12.2, and R12.3, respectively.

[0332] In embodiments, when R13is substituted, R13is substituted with one or more first substituent groups denoted by R13.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R13.1substituent group is substituted, the R13.1substituent group is substituted with one or more second substituent groups denoted by R13.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R13.2substituent group is substituted, the R13.2substituent group is substituted with one or more third substituent groups denoted by R13.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R13, R13.1, R13.2, and R13.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R13, R13.1, R13.2, and R13.3, respectively.

[0333] In embodiments, when R14is substituted, R14is substituted with one or more first substituent groups denoted by R14.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R14.1substituent group is substituted, the R14.1substituent group is substituted with one or more second substituentgroups denoted by R14.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R14.2substituent group is substituted, the R14.2substituent group is substituted with one or more third substituent groups denoted by R14.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R14, R14.1, R14.2, and R14.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R14, R14.1, R14.2, and R14.3, respectively.

[0334] In embodiments, when R20is substituted, R20is substituted with one or more first substituent groups denoted by R20.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20.1substituent group is substituted, the R20.1substituent group is substituted with one or more second substituent groups denoted by R20.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20.2substituent group is substituted, the R20.2substituent group is substituted with one or more third substituent groups denoted by R20.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R20, R20.1, R20.2, and R20.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R20, R20.1, R20.2, and R20.3, respectively.

[0335] In embodiments, when R20Ais substituted, R20Ais substituted with one or more first substituent groups denoted by R20A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20A.1substituent group is substituted, the R20A.1substituent group is substituted with one or more second substituent groups denoted by R20A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20A.2substituent group is substituted, the R20A.2substituent group is substituted with one or more third substituent groups denoted by R20A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R20A, R20A.1, R20A.2, and R20A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R20A, R20A.1, R20A.2, and R20A.3, respectively.

[0336] In embodiments, when L1is substituted, L1is substituted with one or more first substituent groups denoted by RL1.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL1.1substituent group is substituted, the RL1.1substituent group is substituted with one or more second substituent groups denoted by RL1.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL1.2substituent group is substituted, the RL1.2substituent group is substituted with one or more third substituent groups denoted by RL1.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L1, RL1.1, RL1.2, and RL1.3have values corresponding to the values of LWW, RLWW.1, RLWW.2, and RLWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein LWW, RLWW.1, RLWW.2, and RLWW.3are L1, RL1.1, RL1.2, and RL1.3, respectively.

[0337] In embodiments, when L2is substituted, L2is substituted with one or more first substituent groups denoted by RL2.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL2.1substituent group is substituted, the RL2.1substituent group is substituted with one or more second substituent groups denoted by RL2.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL2.2substituent group is substituted, the RL2.2substituent group is substituted with one or more third substituent groups denoted by RL2.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L2, RL2.1, RL2.2, and RL2.3have values corresponding to the values of LWW, RLWW.1, RLWW.2, and RLWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein LWW, RLWW.1, RLWW.2, and RLWW.3are L2, RL2.1, RL2.2, and RL2.3, respectively.

[0338] In embodiments, the compound has the formula: In embodiments, the compound has the formula:. In embodiments, the compound has the formula: O Cl N H N F S OO. In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula: .formula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:. In embodiments, the compound has theformula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:. In embodiments, the compound has theformula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:. embodiments, the compound has the formula:. In embodiments, the compound has theformula:. In embodiments, the compound has the formula:. In embodiments, the compound has the. , formula:. In embodiments, the compound has the formula:. In embodiments, the compound has the.. , p ula:O Cl N Cl F N SF OO. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula: In embodiments, the compound has the formula:. In embodiments, the compound has the formula:.

[0339] In embodiments, the compound is useful as a comparator compound. In embodiments, the comparator compound can be used to assess the activity of a test compound as set forth in an assay described herein (e.g., in the examples section, figures, or tables).

[0340] In embodiments, the compound is a compound as described herein, including in embodiments. In embodiments the compound is a compound described herein (e.g., in the examples section, figures, tables, or claims). III. Pharmaceutical compositions

[0341] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0342] In embodiments, the pharmaceutical composition includes an effective amount of the compound. In embodiments, the pharmaceutical composition includes a therapeutically effective amount of the compound.

[0343] In embodiments, the compound is a compound of formula (I), including all embodiments thereof. IV. Methods of use

[0344] In an aspect is provided a method of treating a cancer in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0345] In embodiments, the compound is a compound of formula (I), including all embodiments thereof.

[0346] In embodiments, the cancer is a wild-type CRAF-associated cancer. In embodiments, the cancer (e.g., wild-type CRAF-associated cancer) is biliary tract cancer. In embodiments, the cancer (e.g., wild-type CRAF-associated cancer) is bladder cancer. In embodiments, the cancer (e.g., wild-type CRAF-associated cancer) is breast cancer. In embodiments, the cancer (e.g., wild-type CRAF-associated cancer) is cervical cancer. In embodiments, the cancer (e.g., wild-type CRAF-associated cancer) is colon cancer. In embodiments, the cancer (e.g., wild-type CRAF-associated cancer) is ganglia cancer. In embodiments, the cancer (e.g., wild-type CRAF-associated cancer) is leukemia. In embodiments, the cancer is lymphoma. In embodiments, the cancer (e.g., wild-type CRAF- associated cancer) is liver cancer. In embodiments, the cancer (e.g., wild-type CRAF- associated cancer) is lung cancer. In embodiments, the cancer (e.g., wild-type CRAF- associated cancer) is pancreatic cancer. In embodiments, the cancer (e.g., wild-type CRAF- associated cancer) is prostate cancer. In embodiments, the cancer (e.g., wild-type CRAF- associated cancer) is skin cancer. In embodiments, the cancer (e.g., wild-type CRAF- associated cancer) is soft tissue cancer. In embodiments, the cancer (e.g., wild-type CRAF- associated cancer) is stomach cancer. In embodiments, the cancer (e.g., wild-type CRAF- associated cancer) is testicular cancer. In embodiments, the cancer (e.g., wild-type CRAF- associated cancer) is thyroid cancer. In embodiments, the cancer (e.g., wild-type CRAF- associated cancer) is a K-Ras-associated cancer.

[0347] In embodiments, wherein the cancer is a wild-type CRAF-associated cancer, L3is:

[0348] In embodiments, wherein the cancer is a wild-type CRAF-associated cancer, the compound has the formula:

[0349] In embodiments, the cancer is a pan-RAF-associated cancer. In embodiments, the cancer (e.g., pan-RAF-associated cancer) is glioma. In embodiments, the cancer (e.g., pan- RAF-associated cancer) is pediatric glioma. In embodiments, the cancer (e.g., pan-RAF- associated cancer) is melanoma.

[0350] In embodiments, wherein the cancer is a pan-RAF-associated cancer, L3is:

[0351] In embodiments, wherein the cancer is a pan-RAF-associated cancer, the compound has the formula:.

[0352] In an aspect is provided a method of treating a developmental disorder in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0353] In embodiments, the compound is a compound of formula (I), including all embodiments thereof.

[0354] In embodiments, the developmental disorder is Noonan syndrome.

[0355] In embodiments for treating the developmental disorder, the compound has the formula:,

[0356] In an aspect is provided a method of increasing the amount of a 14-3-3 protein– CRAF protein complex in a subject, the method including administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the 14-3-3 protein–CRAF protein complex includes a 14-3-3 protein bound noncovalently to a CRAF protein. In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased relative to the absence of the compound.

[0357] In an aspect is provided a method of increasing the amount of a 14-3-3 protein– CRAF protein complex in a cell, the method including contacting the cell with a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the 14-3-3 protein–CRAF protein complex includes a 14-3-3 protein bound noncovalently to a CRAF protein. In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased relative to the absence of the compound.

[0358] In embodiments, L3is:

[0359] In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by about 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by about 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by about 2-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by about 5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by about 10-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by about 25-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by about 50-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by about 100-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by about 250-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by about 500-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein– CRAF protein complex is increased by about 1000-fold relative to a control (e.g., absence of the compound).

[0360] In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by at least 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-,60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by at least 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by at least 2-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by at least 5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by at least 10-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by at least 25-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by at least 50-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by at least 100-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by at least 250-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by at least 500-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–CRAF protein complex is increased by at least 1000-fold relative to a control (e.g., absence of the compound).

[0361] In an aspect is provided a method of increasing the amount of a 14-3-3 protein–RAF protein complex in a subject, the method including administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the 14-3-3 protein–RAF protein complex includes a 14-3-3 protein bound noncovalently to a RAF protein. In embodiments, the amount of the 14-3-3 protein–RAF protein complex is increased relative to the absence of the compound.

[0362] In an aspect is provided a method of increasing the amount of a 14-3-3 protein–RAF protein complex in a cell, the method including contacting the cell with a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the 14-3-3 protein–CRAF protein complex includes a 14-3-3 protein bound noncovalently to a RAF protein. In embodiments, the amount of the 14-3-3 protein–RAF protein complex is increased relative to the absence of the compound.

[0363] In embodiments, the 14-3-3 protein–RAF protein complex is a 14-3-3 protein– ARAF protein complex, a 14-3-3 protein–BRAF protein complex, or a 14-3-3 protein–CRAF protein complex. In embodiments, the 14-3-3 protein–RAF protein complex is a 14-3-3 protein–ARAF protein complex. In embodiments, the 14-3-3 protein–RAF protein complex is a 14-3-3 protein–BRAF protein complex. In embodiments, the 14-3-3 protein–RAF protein complex is a 14-3-3 protein–CRAF protein complex.

[0364] In embodiments, L3is:

[0365] In embodiments, the amount of the 14-3-3 protein–RAF protein complex (e.g., 14- 3-3 protein–ARAF protein complex, 14-3-3 protein–BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by about 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–RAF protein complex (e.g., 14-3-3 protein–ARAF protein complex, 14-3-3 protein–BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by about 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–RAF protein complex (e.g., 14-3-3 protein–ARAF protein complex, 14-3-3 protein–BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by about 2-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–RAF protein complex (e.g., 14-3-3 protein–ARAF protein complex, 14-3-3 protein– BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by about 5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–RAF protein complex (e.g., 14-3-3 protein–ARAF protein complex, 14-3- 3 protein–BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by about 10-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–RAF protein complex (e.g., 14-3-3 protein– ARAF protein complex, 14-3-3 protein–BRAF protein complex, and / or 14-3-3 protein– CRAF protein complex) is increased by about 25-fold relative to a control (e.g., absence ofthe compound). In embodiments, the amount of the 14-3-3 protein–RAF protein complex (e.g., 14-3-3 protein–ARAF protein complex, 14-3-3 protein–BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by about 50-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–RAF protein complex (e.g., 14-3-3 protein–ARAF protein complex, 14-3-3 protein–BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by about 100-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14- 3-3 protein–RAF protein complex (e.g., 14-3-3 protein–ARAF protein complex, 14-3-3 protein–BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by about 250-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–RAF protein complex (e.g., 14-3-3 protein–ARAF protein complex, 14-3-3 protein–BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by about 500-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–RAF protein complex (e.g., 14-3-3 protein–ARAF protein complex, 14-3-3 protein–BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by about 1000-fold relative to a control (e.g., absence of the compound).

[0366] In embodiments, the amount of the 14-3-3 protein–RAF protein complex (e.g., 14- 3-3 protein–ARAF protein complex, 14-3-3 protein–BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by at least 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–RAF protein complex (e.g., 14-3-3 protein–ARAF protein complex, 14-3-3 protein–BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by at least 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–RAF protein complex (e.g., 14-3-3 protein–ARAF protein complex, 14-3-3 protein–BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by at least 2-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14- 3-3 protein–RAF protein complex (e.g., 14-3-3 protein–ARAF protein complex, 14-3-3 protein–BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by at least 5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–RAF protein complex (e.g., 14-3-3 protein–ARAF proteincomplex, 14-3-3 protein–BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by at least 10-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–RAF protein complex (e.g., 14-3-3 protein–ARAF protein complex, 14-3-3 protein–BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by at least 25-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–RAF protein complex (e.g., 14-3-3 protein–ARAF protein complex, 14-3-3 protein–BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by at least 50-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14- 3-3 protein–RAF protein complex (e.g., 14-3-3 protein–ARAF protein complex, 14-3-3 protein–BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by at least 100-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–RAF protein complex (e.g., 14-3-3 protein–ARAF protein complex, 14-3-3 protein–BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by at least 250-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–RAF protein complex (e.g., 14-3-3 protein–ARAF protein complex, 14-3-3 protein–BRAF protein complex, and / or 14-3- 3 protein–CRAF protein complex) is increased by at least 500-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–RAF protein complex (e.g., 14-3-3 protein–ARAF protein complex, 14-3-3 protein–BRAF protein complex, and / or 14-3-3 protein–CRAF protein complex) is increased by at least 1000-fold relative to a control (e.g., absence of the compound).

[0367] In an aspect is provided a method of increasing the amount of a 14-3-3 protein– mutant CRAF protein complex in a subject, the method including administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the 14-3-3 protein–mutant CRAF protein complex includes a 14-3-3 protein bound noncovalently to a mutant CRAF protein. In embodiments, the amount of the 14-3-3 protein– mutant CRAF protein complex is increased relative to the absence of the compound.

[0368] In an aspect is provided a method of increasing the amount of a 14-3-3 protein– mutant CRAF protein complex in a cell, the method including contacting the cell with a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the 14-3-3 protein–mutant CRAF protein complex includes a 14-3-3 protein boundnoncovalently to a CRAF protein. In embodiments, the amount of the 14-3-3 protein–mutant CRAF protein complex is increased relative to the absence of the compound.

[0369] In embodiments, the 14-3-3 protein–mutant CRAF protein complex is a 14-3-3 protein–CRAF(S259A) protein complex, a 14-3-3 protein–CRAF(R256S) protein complex, a 14-3-3 protein–CRAF(S257L) protein complex, a 14-3-3 protein–CRAF(P261A) protein complex, or a 14-3-3 protein–CRAF(V263A) protein complex. In embodiments, the 14-3-3 protein–mutant CRAF protein complex is a 14-3-3 protein–CRAF(S259A) protein complex. In embodiments, the 14-3-3 protein–mutant CRAF protein complex is a 14-3-3 protein– CRAF(R256S) protein complex. In embodiments, the 14-3-3 protein–mutant CRAF protein complex is a 14-3-3 protein–CRAF(S257L) protein complex. In embodiments, the 14-3-3 protein–mutant CRAF protein complex is a 14-3-3 protein–CRAF(P261A) protein complex. In embodiments, the 14-3-3 protein–mutant CRAF protein complex is a 14-3-3 protein– CRAF(V263A) protein complex.

[0370] In embodiments, the amount of the 14-3-3 protein–mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) protein complex, 14-3-3 protein–CRAF(R256S) protein complex, 14-3-3 protein–CRAF(S257L) protein complex, 14-3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein–CRAF(V263A) protein complex) is increased by about 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14- 3-3 protein–mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) protein complex, 14-3-3 protein–CRAF(R256S) protein complex, 14-3-3 protein–CRAF(S257L) protein complex, 14-3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein– CRAF(V263A) protein complex) is increased by about 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) protein complex, 14-3-3 protein– CRAF(R256S) protein complex, 14-3-3 protein–CRAF(S257L) protein complex, 14-3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein–CRAF(V263A) protein complex) is increased by about 2-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) protein complex, 14-3-3 protein–CRAF(R256S) protein complex, 14- 3-3 protein–CRAF(S257L) protein complex, 14-3-3 protein–CRAF(P261A) protein complex,or 14-3-3 protein–CRAF(V263A) protein complex) is increased by about 5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein– mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) protein complex, 14-3-3 protein–CRAF(R256S) protein complex, 14-3-3 protein–CRAF(S257L) protein complex, 14- 3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein–CRAF(V263A) protein complex) is increased by about 10-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–mutant CRAF protein complex (e.g., 14-3- 3 protein–CRAF(S259A) protein complex, 14-3-3 protein–CRAF(R256S) protein complex, 14-3-3 protein–CRAF(S257L) protein complex, 14-3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein–CRAF(V263A) protein complex) is increased by about 25-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14- 3-3 protein–mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) protein complex, 14-3-3 protein–CRAF(R256S) protein complex, 14-3-3 protein–CRAF(S257L) protein complex, 14-3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein– CRAF(V263A) protein complex) is increased by about 50-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) protein complex, 14-3-3 protein– CRAF(R256S) protein complex, 14-3-3 protein–CRAF(S257L) protein complex, 14-3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein–CRAF(V263A) protein complex) is increased by about 100-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) protein complex, 14-3-3 protein–CRAF(R256S) protein complex, 14- 3-3 protein–CRAF(S257L) protein complex, 14-3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein–CRAF(V263A) protein complex) is increased by about 250-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) protein complex, 14-3-3 protein–CRAF(R256S) protein complex, 14-3-3 protein–CRAF(S257L) protein complex, 14-3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein–CRAF(V263A) protein complex) is increased by about 500-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) protein complex, 14-3-3 protein– CRAF(R256S) protein complex, 14-3-3 protein–CRAF(S257L) protein complex, 14-3-3protein–CRAF(P261A) protein complex, or 14-3-3 protein–CRAF(V263A) protein complex) is increased by about 1000-fold relative to a control (e.g., absence of the compound).

[0371] In embodiments, the amount of the 14-3-3 protein–mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) protein complex, 14-3-3 protein–CRAF(R256S) protein complex, 14-3-3 protein–CRAF(S257L) protein complex, 14-3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein–CRAF(V263A) protein complex) is increased by at least 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14- 3-3 protein–mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) protein complex, 14-3-3 protein–CRAF(R256S) protein complex, 14-3-3 protein–CRAF(S257L) protein complex, 14-3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein– CRAF(V263A) protein complex) is increased by at least 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) protein complex, 14-3-3 protein– CRAF(R256S) protein complex, 14-3-3 protein–CRAF(S257L) protein complex, 14-3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein–CRAF(V263A) protein complex) is increased by at least 2-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) protein complex, 14-3-3 protein–CRAF(R256S) protein complex, 14- 3-3 protein–CRAF(S257L) protein complex, 14-3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein–CRAF(V263A) protein complex) is increased by at least 5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein– mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) protein complex, 14-3-3 protein–CRAF(R256S) protein complex, 14-3-3 protein–CRAF(S257L) protein complex, 14- 3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein–CRAF(V263A) protein complex) is increased by at least 10-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–mutant CRAF protein complex (e.g., 14-3- 3 protein–CRAF(S259A) protein complex, 14-3-3 protein–CRAF(R256S) protein complex, 14-3-3 protein–CRAF(S257L) protein complex, 14-3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein–CRAF(V263A) protein complex) is increased by at least 25-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14- 3-3 protein–mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) proteincomplex, 14-3-3 protein–CRAF(R256S) protein complex, 14-3-3 protein–CRAF(S257L) protein complex, 14-3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein– CRAF(V263A) protein complex) is increased by at least 50-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) protein complex, 14-3-3 protein– CRAF(R256S) protein complex, 14-3-3 protein–CRAF(S257L) protein complex, 14-3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein–CRAF(V263A) protein complex) is increased by at least 100-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) protein complex, 14-3-3 protein–CRAF(R256S) protein complex, 14- 3-3 protein–CRAF(S257L) protein complex, 14-3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein–CRAF(V263A) protein complex) is increased by at least 250-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) protein complex, 14-3-3 protein–CRAF(R256S) protein complex, 14-3-3 protein–CRAF(S257L) protein complex, 14-3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein–CRAF(V263A) protein complex) is increased by at least 500-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the 14-3-3 protein–mutant CRAF protein complex (e.g., 14-3-3 protein–CRAF(S259A) protein complex, 14-3-3 protein– CRAF(R256S) protein complex, 14-3-3 protein–CRAF(S257L) protein complex, 14-3-3 protein–CRAF(P261A) protein complex, or 14-3-3 protein–CRAF(V263A) protein complex) is increased by at least 1000-fold relative to a control (e.g., absence of the compound).

[0372] In an aspect is provided a method of forming a 14-3-3 protein–RAF (e.g., ARAF, BRAF, CRAF, or mutant CRAF) protein–compound complex, the method including combining a 14-3-3 protein, a RAF (e.g., ARAF, BRAF, CRAF, or mutant CRAF) protein, and a compound described herein, or a pharmaceutically acceptable salt thereof, in a reaction vessel, cell, or organism, thereby forming the 14-3-3 protein–RAF (e.g., ARAF, BRAF, CRAF, or mutant CRAF) protein–compound complex bound together noncovalently.

[0373] In an aspect is provided a method of stabilizing a 14-3-3 protein–RAF (e.g., ARAF, BRAF, CRAF, or mutant CRAF) protein complex, the method including contacting the 14-3- 3 protein–RAF (e.g., ARAF, BRAF, CRAF, or mutant CRAF) protein complex with a compound described herein, or a pharmaceutically acceptable salt thereof.

[0374] In embodiments, the stabilizing occurs in a cell. In embodiments, the stabilizing occurs in an organism. In embodiments, the stabilizing occurs in a cell in an organism.

[0375] In embodiments, R1(i.e., R1of formula (I) and embodiments thereof) is capable of forming a covalent bond with Cys38 of a 14-3-3 protein, and the sulfonyl moiety (i.e., the sulfonyl moiety attached to L3in formula (I) and embodiments thereof) is capable of forming non-covalent interactions with the 14-3-3 protein and a client protein (e.g., C-RAF protein). In embodiments, R1is capable of forming a covalent bond with Cys38 of a 14-3-3 protein, the sulfonyl moiety is capable of forming non-covalent interactions with the 14-3-3 protein and a client protein (e.g., C-RAF protein), and R2(i.e., R2of formula (I) and embodiments thereof) is capable of forming non-covalent interactions with the 14-3-3 protein and a client protein (e.g., C-RAF protein). In embodiments, R1is capable of forming a covalent bond with Cys38 of the 14-3-3 protein. In embodiments, R1is capable of forming a non-covalent interaction with R41 of the 14-3-3 protein. In embodiments, the sulfonyl moiety is capable of forming non-covalent interactions with K122 of the 14-3-3 protein and T260 of the C-RAF protein. In embodiments, R2is capable of forming non-covalent interactions with D215, L218, and I219 of the 14-3-3 protein and V263 of the C-RAF protein. In embodiments, L3(i.e., L3of formula (I) and embodiments thereof) is capable of forming non-covalent interactions with N42 of the 14-3-3 protein. In embodiments, the 14-3-3 protein–RAF (e.g., ARAF, BRAF, CRAF, or mutant CRAF) protein–compound complex includes one or more water molecules. V. Embodiments

[0376] Embodiment P1. A compound, or a pharmaceutically acceptable salt thereof, having the formula:wherein L3is:n is an integer from 0 to 4; Ring A is aryl, heteroaryl, or spirocyclic cycloalkyl; L1is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR10-, -C(O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10A-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, 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; L2is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20A-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, 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; R1is hydrogen, halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, −NR1CNR1AR1B, −ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -C(NR1C)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or E; E is an electrophilic moiety; R2is independently oxo, halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, −NR2CNR2AR2B, −ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -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 R2substituents 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 5; R3is independently oxo, halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3, -OCHX32, -CN, -SOn3R3D, -SOv3NR3AR3B, −NR3CNR3AR3B, −ONR3AR3B, -NR3CC(O)NR3AR3B, -N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -OC(O)R3C, -OC(O)OR3C, -C(O)NR3AR3B, -OC(O)NR3AR3B, -OR3D, -SR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -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; z3 is an integer from 0 to 13; R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4, R10, R10A, R20, and R20Aare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, 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; R1Aand R1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2Aand R2Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1, X2, and X3is independently –F, -Cl, -Br, or –I; n1, n2, and n3 are independently an integer from 0 to 4; and m1, m2, m3, v1, v2, and v3 are independently 1 or 2.

[0377] Embodiment P2. The compound of embodiment P1, wherein Ring A is phenyl, pyridyl, or spirocyclic C5-C10 cycloalkyl.

[0378] Embodiment P3. The compound of embodiment P1, wherein

[0379] Embodiment P4. The compound of one of embodiments P1 to P3, wherein R2is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -C(O)H, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted C1-C4alkyl, or substituted or unsubstituted 2 to 4 membered heteroalkyl.

[0380] Embodiment P5. The compound of one of embodiments P1 to P3, wherein R2is independently halogen, -CF3, -OCF3, -CN, -C(O)H, unsubstituted C1-C4alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

[0381] Embodiment P6. The compound of one of embodiments P1 to P3, wherein R2is independently –F, -Cl, -Br, -I, -CF3, -OCF3, -CN, -C(O)H, unsubstituted methyl, or unsubstituted methoxy.

[0382] Embodiment P7. The compound of one of embodiments P1 to P6, wherein z2 is 1, 2, or 3.

[0383] Embodiment P8. The compound of one of embodiments P1 to P3, wherein z2 is 0.

[0385] Embodiment P10. The compound of one of embodiments P1 to P9, wherein n is 0 or 1.

[0386] Embodiment P11. The compound of one of embodiments P1 to P10, wherein L1is a bond or –NR10-.

[0387] Embodiment P12. The compound of one of embodiments P1 to P10, wherein L1is a bond or –NH-.

[0388] Embodiment P13. The compound of one of embodiments P1 to P12, wherein L2is a bond or unsubstituted C1-C6 alkylene.

[0389] Embodiment P14. The compound of one of embodiments P1 to P12, wherein L2is a bond, unsubstituted methylene, unsubstituted ethylene, or unsubstituted propylene.

[0390] Embodiment P15. The compound of one of embodiments P1 to P10, wherein –L1-L2- is a bond,

[0391] Embodiment P16. The compound of one of embodiments P1 to P15, wherein R3is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.

[0392] Embodiment P17. The compound of one of embodiments P1 to P15, wherein R3is independently halogen or unsubstituted C1-C4alkyl.

[0393] Embodiment P18. The compound of one of embodiments P1 to P15, wherein R3is independently –F or unsubstituted methyl.

[0394] Embodiment P19. The compound of one of embodiments P1 to P18, wherein z3 is 1 or 2.

[0395] Embodiment P20. The compound of one of embodiments P1 to P14, wherein z3 is 0.

[0396] Embodiment P21. The compound of one of embodiments P1 to P10, wherein,

[0397] Embodiment P22. The compound of one of embodiments P1 to P21, wherein R1is E.

[0398] Embodiment P23. The compound of embodiment P22, wherein E isR11, R12, R13, and R14are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -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; and X11, X12, and X13are independently –F, -Cl, -Br, or –I.

[0399] Embodiment P24. The compound of embodiment P23, wherein R11, R12, R13, and R14are hydrogen.

[0400] Embodiment P25. The compound of embodiment P23, wherein R13is –F.

[0401] Embodiment P26. The compound of embodiment P23, wherein X11, X12, and X13are independently hydrogen or –Cl.

[0402] Embodiment P27. The compound of one of embodiments P1 to P21, wherein R1is

[0403] Embodiment P28. The compound of embodiment P1, having the formula:

[0404] Embodiment P29. A pharmaceutical composition comprising the compound of one of embodiments P1 to P28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0405] Embodiment P30. A method of treating a cancer in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of the compound of one of embodiments P1 to P28, or a pharmaceutically acceptable salt thereof.

[0406] Embodiment P31. The method of embodiment P30, wherein the cancer is biliary tract cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, ganglia cancer, leukemia, lymphoma, liver cancer, lung cancer, pancreatic cancer, prostate cancer, skin cancer, soft tissue cancer, stomach cancer, testicular cancer, or thyroid cancer.

[0407] Embodiment P32. The method of embodiment P30, wherein the cancer is a K- Ras-associated cancer.

[0408] Embodiment P33. The method of embodiment P31 or P32, wherein L3is: ,

[0409] Embodiment P34. The method of embodiment P31 or P32, wherein the compound has the formula:

[0410] Embodiment P35. The method of embodiment P30, wherein the cancer is glioma or melanoma.

[0411] Embodiment P36. The method of embodiment P30, wherein the glioma is pediatric glioma.

[0412] Embodiment P37. The method of embodiment P35 or P36, wherein L3is:

[0413] Embodiment P38. The method of embodiment P35 or P36, wherein the compound has the formula:.

[0414] Embodiment P39. A method of treating a developmental disorder in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of the compound of one of embodiments P1 to P28, or a pharmaceutically acceptable salt thereof.

[0415] Embodiment P40. The method of embodiment P39, wherein the developmental disorder is Noonan syndrome.

[0416] Embodiment P41. The method of embodiment P39 or P40, wherein the compound has the formula:

[0417] Embodiment P42. A method of increasing t...

Claims

WHAT IS CLAIMED IS:

1. A compound, or a pharmaceutically acceptable salt thereof, having the formula:n is an integer from 0 to 4; Ring A is aryl, heteroaryl, or spirocyclic cycloalkyl; L1is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR10-, -C(O)NR10-, -NR10C(O)-, -NR10C(O)O-, -OC(O)NR10-, -NR10C(O)NR10A-, -S(O)2-, -NR10S(O)2-, -S(O)2NR10-, 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; L2is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR20-, -C(O)NR20-, -NR20C(O)-, -NR20C(O)O-, -OC(O)NR20-, -NR20C(O)NR20A-, -S(O)2-, -NR20S(O)2-, -S(O)2NR20-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R1is hydrogen, halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, −NR1CNR1AR1B, −ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -C(NR1C)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or E; E is an electrophilic moiety; R2is independently oxo, halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, −NR2CNR2AR2B, −ONR2AR2B, -NR2CC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -OC(O)R2C, -OC(O)OR2C, -C(O)NR2AR2B, -OC(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -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 R2substituents 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 5; R3is independently oxo, halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3, -OCHX32, -CN, -SOn3R3D, -SOv3NR3AR3B, −NR3CNR3AR3B, −ONR3AR3B, -NR3CC(O)NR3AR3B, -N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -OC(O)R3C, -OC(O)OR3C, -C(O)NR3AR3B, -OC(O)NR3AR3B, -OR3D, -SR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -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; z3 is an integer from 0 to 13; R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4, R10, R10A, R20, and R20Aare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3,-OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, 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; R1Aand R1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2Aand R2Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1, X2, and X3is independently –F, -Cl, -Br, or –I; n1, n2, and n3 are independently an integer from 0 to 4; and m1, m2, m3, v1, v2, and v3 are independently 1 or 2.

2. The compound of claim 1, wherein Ring A is phenyl, pyridyl, or spirocyclic C5-C10 cycloalkyl..

4. The compound of claim 1, wherein R2is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -C(O)H, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 4 membered heteroalkyl.

5. The compound of claim 1, wherein R2is independently halogen, -CF3, -OCF3, -CN, -C(O)H, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

6. The compound of claim 1, wherein R2is independently –F, -Cl, -Br, -I, -CF3, -OCF3, -CN, -C(O)H, unsubstituted methyl, or unsubstituted methoxy.

7. The compound of claim 1, wherein z2 is 1, 2, or 3.

8. The compound of claim 1, wherein z2 is 0..

10. The compound of claim 1, wherein n is 0 or 1.

11. The compound of claim 1, wherein L1is a bond or –NR10-.

12. The compound of claim 1, wherein L1is a bond or –NH-.

13. The compound of claim 1, wherein L2is a bond or unsubstituted C1-C6alkylene.

14. The compound of claim 1, wherein L2is a bond, unsubstituted methylene, unsubstituted ethylene, or unsubstituted propylene.

15. The compound of claim 1, wherein –L1-L2- is a bond, –NH-,16. The compound of claim 1, wherein R3is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted C1-C4alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.

17. The compound of claim 1, wherein R3is independently halogen or unsubstituted C1-C4alkyl.

18. The compound of claim 1, wherein R3is independently –F or unsubstituted methyl.

19. The compound of claim 1, wherein z3 is 1 or 2.

20. The compound of claim 1, wherein z3 is 0.

21. The compound of claim 1, wherein –L1-L2-L3- is:

22. The compound of claim 1, wherein R1is E.

23. The compound of claim 22, wherein E is ,R11, R12, R13, and R14are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl,-OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -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; and X11, X12, and X13are independently –F, -Cl, -Br, or –I.

24. The compound of claim 23, wherein R11, R12, R13, and R14are hydrogen.

25. The compound of claim 23, wherein R13is –F.

26. The compound of claim 23, wherein X11, X12, and X13are independently hydrogen or –Cl.

27. The compound of claim 1, wherein R1is28. The compound of claim 1, having the formula:

29. A pharmaceutical composition comprising the compound of one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

30. A method of treating a cancer in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of the compound of one of claims 1 to 28, or a pharmaceutically acceptable salt thereof.

31. The method of claim 30, wherein the cancer is biliary tract cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, ganglia cancer, leukemia, lymphoma, liver cancer, lung cancer, pancreatic cancer, prostate cancer, skin cancer, soft tissue cancer, stomach cancer, testicular cancer, or thyroid cancer.

32. The method of claim 30, wherein the cancer is a K-Ras-associated cancer.

33. The method of claim 31, wherein L3is:

34. The method of claim 31, wherein the compound has the formula:

35. The method of claim 30, wherein the cancer is glioma or melanoma.

36. The method of claim 30, wherein the glioma is pediatric glioma.

37. The method of claim 35, wherein L3is:

38. The method of claim 35, wherein the compound has the formula:

39. A method of treating a developmental disorder in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of the compound of one of claims 1 to 28, or a pharmaceutically acceptable salt thereof.

40. The method of claim 39, wherein the developmental disorder is Noonan syndrome.

41. The method of claim 39, wherein the compound has the formula:, ,.

42. A method of increasing the amount of a 14-3-3 protein–CRAF protein complex in a subject, the method including administering to the subject the compound of one of claims 1 to 28, or a pharmaceutically acceptable salt thereof.

43. The method of claim 42, wherein L3is:

44. A method of increasing the amount of a 14-3-3 protein–RAF protein complex in a subject, the method including administering the compound of one of claims 1 to 28, or a pharmaceutically acceptable salt thereof.

45. The method of claim 44, wherein the 14-3-3 protein–RAF protein complex is a 14-3-3 protein–ARAF protein complex, a 14-3-3 protein–BRAF protein complex, or a 14-3-3 protein–CRAF protein complex.

46. The method of claim 44, wherein L3is:

47. A method of increasing the amount of a 14-3-3 protein–mutant CRAF protein complex in a subject, the method including administering the compound of one of claims 1 to 28, or a pharmaceutically acceptable salt thereof.

48. The method of claim 47, wherein the 14-3-3 protein–mutant CRAF protein complex is a 14-3-3 protein–CRAF(S259A) protein complex, a 14-3-3 protein– CRAF(R256S) protein complex, a 14-3-3 protein–CRAF(S257L) protein complex, a 14-3-3 protein–CRAF(P261A) protein complex, or a 14-3-3 protein–CRAF(V263A) protein complex.

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