Fluorescent probes and uses thereof

Abstract

Described herein, inter alia, are fluorescent probes and uses thereof.

Description

PATENT Attorney Docket No.: 052103-530001WO FLUORESCENT PROBES AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 645,002 filed May 9, 2024, which is incorporated herein by reference in its entirety and for all 5 purposes. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] This invention was made with government support under Grant Number GM148221 awarded by the National Institutes of Health and under Grant Number DE-SC0023184 10 awarded by the US Department of Energy. The government has certain rights in the invention. BACKGROUND

[0003] Near-infrared (NIR) fluorophores are foundational for fluorescence imaging in multicellular organisms. However, their fluorescence brightness, defined as molar extinction 15 coefficient (ε) multiplied by fluorescence quantum yield (ΦF), often pales when compared to that of visible dyes. Although strategies exist to effectively enhance the brightness of visible dyes, these approaches lead to marginal improvements in NIR dyes. Disclosed herein, inter alia, are solutions to these and other problems in the art. BRIEF SUMMARY 20

[0004] In an aspect is provided a compound, or a salt thereof, having the formula:

[0005] D1and D2are independently an electron donating moiety. A1and A2are independently an electron accepting moiety. The symbols n1 and n2 are independently 0 or 1. 25

[0006] W1is N or C(R11). 1

[0007] R11is hydrogen, deuterium, 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 -L1-R20. 5

[0008] L1is a bond or a divalent linker.

[0009] R20is a substituted or unsubstituted aryl, a monovalent form of a biomolecule, or a monovalent form of a drug.

[0010] R1and R6are independently hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, 10 substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0011] R2, R3, R4, and R5are independently hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or 15 substituted or unsubstituted heteroaryl.

[0012] R7, R8, R9, and R10are independently hydrogen, deuterium, or halogen.

[0013] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 20

[0014] In an aspect is provided a method of detecting a target substance, the method including contacting a sample with a compound described herein, or a salt thereof; and detecting an emission light from the compound, the emission light indicating the presence of the target substance.

[0015] In an aspect is provided a method of imaging a cell, the method including: (i) 25 contacting the cell with a compound described herein, or a salt thereof, including in embodiments; (ii) illuminating the cell with a first wavelength of light; and (iii) imaging the cell by detecting a second wavelength of light; wherein the first wavelength of light and the second wavelength of light are different.

[0016] In an aspect is provided a method of measuring changes in membrane potential in 30 an excitable cell, the method including: (i) contacting the excitable cell with a compound 2described herein, or a salt thereof; (ii) stimulating the excitable cell to evoke action potentials; and (iii) measuring action potential firing by optical or electrical sampling. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIGS.1A-1D. Approaches to improve the fluorescence brightness of small 5 molecule dyes. FIG.1A: Traditional methods that improve fluorescent brightness of UV / Vis dyes typically work less effectively on NIR dyes. FIG.1B: Potential energy surfaces illustrating vibronic coupling between S0and S1for UV / Vis and NIR dyes. FIG.1C: Multiple resonance effect (MRE) and the first MRE-based structural design that improved color purity of OLED devices. FIG.1D: Our MRE-inspired design of brighter, 10 biocompatible NIR dyes.

[0018] FIGS.2A-2H. Design, synthesis and photophysical property evaluations of MRE- inspired NIR fluorophores. FIG.2A: Structures and synthetic scheme of TMRs and oO6Rs bearing different functional groups at 10’- position. Absorption and emission spectra (FIG. 2B), and fluorescent lifetimes (FIG.2C) of a representative KeTMR / KeoO6R pair in 15 dichloromethane at room temperature. Energy gap law evaluation of TMRs (FIG.2D) and oO6Rs (FIG.2E). TMR scaffold exhibited a much higher linearity (r2=0.987) of Lnknragainst Eg than oO6R scaffold (r2=0.533). Linear correlations of brightness booster factor (BBF) (FIG.2F), φFbooster factor (QYBF) (FIG.2G) and emission maximum difference (ΔEmmax = Emmax,TMR – Emmax,oO6R) (FIG.2H) against the Emmax of TMRs. The shades 20 below the linear fits represent the prediction interval with 95% confidence.

[0019] FIGS.3A-3L. FIG.3A: Structures of ortho- and para-substituted oxygen containing 6-membered rhodamimnes. FIGS.3B-3D: Normalized plot of absorbance or fluorescence intensity vs. wavelength for NR700 (FIG.3B), NR702 (FIG.3C), and NR778 (FIG.3D). FIG.3E: Structures of OTMR and STMR and the corresponding oO6R dyes (OoO6R and 25 SoO6R). FIG.3F: Synthesis of Oo6R, STMR, and SoO6R. FIGS.3G-3H: Normalized plot of absorbance or fluorescence intensity vs. wavelength for OTMR and OoO6R (FIG.3G) and STMR and SoO6R (FIG.3H). FIG.3I: Synthesis of SOoO6R and SO2oO6R. FIG.3J: Synthesis of SOTMR. FIG.3K: Normalized plot of absorbance or fluorescence intensity vs. wavelength for SoO6R, SOoO6R, and SO2oO6R. FIG.3L: Photophysical properties of 30 SoO6R.

[0020] FIGS.4A-4F. Application of MRE concept to a different oxazine fluorophore scaffold. Structures (FIG.4A) and photophysical property summary (FIG.4B) of reported 3NR751, NR751-Az and MRE-guided NR746. FIG.4C: Image of NR751-Az (left) and NR746 (right) taken using the Lago in vivo imaging system. FIG.4D: Locations of dye (NR751-Az and NR746, 50 uM, 100 µL) injection into a living mice. FIG.4E: Images of mice showing fluorescence of their left and right hindlimb. FIG.4F: Data analysis of FIG. 5 4E, showing the fluorescence of right hindlimb (NR746 injected area) are 3.4-fold higher than the left hindlimb (NR751-Az) injected area. DETAILED DESCRIPTION I. Definitions

[0021] The abbreviations used herein have their conventional meaning within the chemical 10 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.

[0022] 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 15 -OCH2-.

[0023] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di-, and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C1-C1020 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 25 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 30 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. 4

[0024] 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 5 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 10 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.

[0025] 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 15 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 is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples 20 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-OCH3and -CH2-O-Si(CH3)3. A heteroalkyl moiety may include one 25 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 30 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 5more 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 5 saturated. In embodiments, the heteroalkyl is monounsaturated. In embodiments, the heteroalkyl is polyunsaturated.

[0026] 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 10 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, 15 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 not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add 20 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 25 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.

[0027] The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” 30 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, 6cyclopropyl, 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, 5 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 10 embodiments, the heterocycloalkyl is monounsaturated. In embodiments, the heterocycloalkyl is polyunsaturated.

[0028] 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 15 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 attached to the parent molecular moiety through any carbon atom contained within a cycloalkyl ring of the multiple rings. 20

[0029] 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 25 through any carbon atom contained within a cycloalkenyl ring of the multiple rings.

[0030] 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 30 the multiple rings are attached to the parent molecular moiety through any atom contained within a heterocycloalkyl ring of the multiple rings. 7

[0031] 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, 5 difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0032] 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 10 substituted or unsubstituted heteroaryl.

[0033] 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 15 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 the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple 20 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 25 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. 30 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 8benzimidazolyl, 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- 5 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,” 10 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.

[0034] 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. 15 Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, 20 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, 25 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.

[0035] The symbol “ ” denotes the point of attachment of a chemical moiety to the30 remainder of a molecule or chemical formula.

[0036] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom. 9

[0037] 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:. 5

[0038] 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 10 embodiments, the alkylarylene is unsubstituted.

[0039] 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. 15

[0040] 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', 20 -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, 25 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 30 when more than one of these groups is present. When R' and R'' are attached to the same 10nitrogen 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 5 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).

[0041] 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', 10 -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 15 independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' 20 groups when more than one of these groups is present.

[0042] 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 25 (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 30 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 11is 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 5 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 10 floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.

[0043] 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 15 embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring- forming substituents attached to a single member of a cyclic base structure create a 20 spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0044] 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. 25 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 30 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 12preferably 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. 5

[0045] In embodiments, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0046] 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, 10 -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, -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 15 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-C10aryl, C10aryl, or phenyl), or 20 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-C8cycloalkyl, C3-C6cycloalkyl, or C5-C625 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: 30 (i) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, 13-OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4alkyl), 5 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-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or 10 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-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 15 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, 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: 20 (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, -NHSO2H, -NHC(O)H, 25 -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-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered 30 heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10aryl, C10aryl, or phenyl), or 14unsubstituted 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 5 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, 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 10 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, -NHSO2H,15 -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, 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-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered 20 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).

[0047] A “size-limited substituent” or “ size-limited substituent group,” as used herein, 25 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-C8cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a 30 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. 15

[0048] 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 5 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 phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 6 membered heteroaryl. 10

[0049] 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 15 arylene, and / or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.

[0050] In other embodiments of the compounds herein, each substituted or unsubstituted 20 alkyl may be 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- 25 C10aryl, 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 30 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-C10arylene, and / or each substituted 16or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

[0051] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8alkyl, each substituted or unsubstituted heteroalkyl is a substituted or 5 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 C6-C10aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered 10 heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 15 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.

[0052] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or 20 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 25 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., 30 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 17alkylene, 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 5 aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene, respectively).

[0053] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted 10 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, 15 each substituent group is different.

[0054] 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 20 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. 25

[0055] 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 30 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. 18

[0056] 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 5 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 10 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.

[0057] 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 15 chemical moiety that composes the “substituted” group (also referred to herein as an “open substitution” 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.

[0058] The first substituent group is denoted with a corresponding first decimal point 20 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 25 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 30 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 19or 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 5 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, 10 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 15 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.

[0059] 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; 20 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 25 optionally different. Each of the third substituent groups may be optionally different.

[0060] 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 30 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 20to 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 5 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 10 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 15 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:

[0061] RWW.1is independently oxo, halogen, -CXWW.13, -CHXWW.12, -CH2XWW.1, 20 -OCXWW.13, -OCH2XWW.1, -OCHXWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW.2-substituted or unsubstituted alkyl (e.g., C1-C8, 21C1-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 5 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, 10 -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NHNH2, ^NHC(O)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 15 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.

[0062] RWW.2is independently oxo, halogen, -CXWW.23, -CHXWW.22, -CH2XWW.2, 20 -OCXWW.23, -OCH2XWW.2, -OCHXWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)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),25 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-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, 30 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, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1- 22C2), 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 5 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.

[0063] 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, -NHSO2H,10 -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 15 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.

[0064] 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 20 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, RWW.2, may bunsubstituted 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. 25 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 30 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 23R100B.2, and RWW.3is R100B.3. RWW.1, RWW.2and RWW.3in this paragraph are as defined in the preceding paragraphs.

[0065] RLWW.1is independently oxo, halogen, -CXLWW.13, -CHXLWW.12, -CH2XLWW.1, -OCXLWW.13, -OCH2XLWW.1, -OCHXLWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, 5 -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)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- 10 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 6 membered). In embodiments, RLWW.1is independently oxo, halogen, -CXLWW.13, -CHXLWW.12, -CH2XLWW.1, -OCXLWW.13, 15 -OCH2XLWW.1, -OCHXLWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)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 20 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.

[0066] RLWW.2is independently oxo, halogen, -CXLWW.23, -CHXLWW.22, -CH2XLWW.2, 25 -OCXLWW.23, -OCH2XLWW.2, -OCHXLWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)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),30 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 24(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, 5 -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)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 10 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.

[0067] RLWW.3is independently oxo, halogen, -CXLWW.33, -CHXLWW.32, -CH2XLWW.3, -OCXLWW.33, -OCH2XLWW.3, -OCHXLWW.32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, 15 -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)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 20 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.

[0068] 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 25 (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, -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 30 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 25membered, 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 5the subject R group (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). RWW.1, RWW.2, and RWW.3 areas defined above.

[0069] 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-, 10 -NHC(O)-, -NHC(O)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-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), 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., 15 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 20 RLWW.3are as defined above.

[0070] 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 25 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 30 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. 26

[0071] 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.

[0072] It will be apparent to one skilled in the art that certain compounds of this disclosure 5 may exist in isomeric forms, all such isomeric forms of the compounds being within the scope of the disclosure.

[0073] 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. 10

[0074] 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.

[0075] 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 15 center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0076] 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 20 by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0077] 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 25 (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.

[0078] 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 30 amino acid. It is specifically contemplated that each member of the Markush group should be 27considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.

[0079] As used herein, the terms “bioconjugate” and “bioconjugate linker” refer to the resulting association between atoms or molecules of bioconjugate reactive groups or 5 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 10 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) 15 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 20 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 25 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 30 (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). 28

[0080] 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) 5 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 10 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 to 15 disulfides, 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 20 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. 25

[0081] 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 30 sulfhydryl group.

[0082] “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 29similar 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 5 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.

[0083] 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 10 alkyl or heteroaryl group, is “substituted with an unsubstituted C1-C20alkyl, 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.

[0084] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted 15 with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple 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 20 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. 25

[0085] 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 30 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 30molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

[0086] 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 5 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 10 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, 15 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 20 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. 25

[0087] 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, 30 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. 31

[0088] 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. 5

[0089] 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 10 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.

[0090] 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 15 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.

[0091] 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 20 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 notassociated 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 25 polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is recombinant.

[0092] “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 30 patient. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the 32preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).

[0093] 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 5 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 10 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.

[0094] 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 15 subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, 20 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.

[0095] An “effective amount” is an amount sufficient for a compound to accomplish a 25 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 30 “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 33“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. 5 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 10 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 15 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 of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, 20 Williams & Wilkins).

[0096] “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 25 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).

[0097] “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 30 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 34from 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.

[0098] 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 5 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, 10 virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) that is involved in a signaling pathway.

[0099] 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 15 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.

[0100] 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 20 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.

[0101] As defined herein, the term “inhibition,” “inhibit,” “inhibiting” and the like in 25 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 30 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 35cellular 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 5 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.

[0102] The terms “inhibitor,” “repressor,” “antagonist,” or “downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or 10 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. 15

[0103] 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, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or 20 macromolecule)) relative to the absence of the composition.

[0104] 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, 25 immunofluorescence, immunohistochemistry, etc.).

[0105] 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 30 property or function of the target molecule or the amount of the target molecule. 36

[0106] “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, 5 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.

[0107] “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 10 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).

[0108] As used herein, the term “cancer” refers to all types of cancer, neoplasm or 15 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. 20 Additional examples include, Hodgkin’s Disease, Non-Hodgkin’s Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, esophageal 25 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.

[0109] The term “leukemia” refers broadly to progressive, malignant diseases of the blood- 30 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 37chronic; (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, 5 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, 10 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, 15 plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling’s leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0110] 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 20 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 25 (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, 30 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 38are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.

[0111] 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 5 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, 10 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 15 sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0112] 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, 20 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.

[0113] 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 25 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 30 carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, 39carcinoma 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 5 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, 10 lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive 15 carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma 20 telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

[0114] 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 25 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 30 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 40lung 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 5 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.

[0115] The terms “cutaneous metastasis” and “skin metastasis” refer to secondary 10 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.

[0116] The term “visceral metastasis” refers to secondary malignant cell growths in the 15 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 20 internal organs.

[0117] 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. 25

[0118] 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, 30105Rh,111Ag,111In,123I,124I,125I,131I,142Pr,143Pr,149Pm,153Sm,154-158Gd,161Tb,166Dy,166Ho, 169Er,175Lu,177Lu,186Re,188Re,189Re,194Ir,198Au,199Au,211At,211Pb,212Bi,212Pb,213Bi, 223Ra,225Ac, Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, 41Tm, 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 5 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- 10 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.), 15 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. 20

[0119] 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, 89Zr,94Tc,94Tc,99mTc,99Mo,105Pd,105Rh,111Ag,111In,123I,124I,125I,131I,142Pr,143Pr,149Pm, 153Sm,154-158Gd,161Tb,166Dy,166Ho,169Er,175Lu,177Lu,186Re,188Re,189Re,194Ir,198Au, 25199Au,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. 30

[0120] “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 42significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, 5 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. 10 One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0121] 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 15 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.

[0122] 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 20 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.

[0123] 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 25 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- 30 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 43composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies, for example cancer therapies such as chemotherapy, hormonal therapy, radiotherapy, or immunotherapy. The compounds of the invention can be administered alone or can be co-administered to the patient. Co- 5 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, 10 emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0124] 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. 15

[0125] 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 20 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.

[0126] 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 25 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 30 empirically determined considering the type and stage of disease 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 44dose 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 5 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.

[0127] 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, 10 disease associated with a cellular component) means that the disease 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 15 target for treatment of the disease.

[0128] 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 20 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.

[0129] “Biological sample” or “sample” refer to materials obtained from or derived from a subject or patient. A biological sample includes sections of tissues such as biopsy. Such 25 samples include bodily fluids such as blood and blood fractions or products (e.g., serum, plasma, platelets, red blood cells, and the like), sputum, tissue, cultured cells (e.g., primary cultures, explants, and transformed cells), stool, urine, and the like. In embodiments, a biological sample is blood. In embodiments, a biological sample is a tumor cell. In embodiments, a biological sample is a tumor. 30

[0130] 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 45(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.

[0131] “Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density. 5

[0132] As used herein, “biomolecule” is used in its customary sense and refers to a molecule found in nature or derivatives thereof, including macromolecules such as proteins, carbohydrates, lipids, and nucleic acids, as well as small molecules such as primary metabolites, secondary metabolites, and natural products. A biomolecule may be present as a moiety attached to the remainder of a compound. A biomolecule includes but is not limited 10 to nucleic acids (e.g., DNA and RNA), peptide nucleic acids, sugars, peptides, proteins, antibodies, aptamers, lipids, small molecule affinity ligands (e.g., inhibitors, biotin, and haptens).

[0133] 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 15 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 using analytical 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. 20

[0134] 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 25 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 30 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 46terms “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.

[0135] 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 5 Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0136] 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 10 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.

[0137] 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 15 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 counting from 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 20 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 25 to any amino acid in the corresponding sequence.

[0138] 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. An amino acid residue in a 30 protein “corresponds” to a given residue when it occupies the same essential structural position within the protein as the given residue. 47

[0139] 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 5 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 complex are linked by non-covalent protein–protein interactions. A non-limiting example of a protein complex is the proteasome. 10

[0140] 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). Typically, 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 15 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. II. Compounds

[0141] In an aspect is provided a compound, or a salt thereof, having the formula: 20

[0142] D1and D2are independently an electron donating moiety.

[0143] A1and A2are independently an electron accepting moiety.

[0144] The symbols n1 and n2 are independently 0 or 1.

[0145] W1is N or C(R11). 25

[0146] R11is hydrogen, deuterium, 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 4membered, 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), 5 substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), or -L1-R20.

[0147] L1is a bond or a divalent linker.

[0148] R20is a substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), a monovalent form of a biomolecule, or a monovalent form of a drug. 10

[0149] R1and R6are independently hydrogen, deuterium, 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 15 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).

[0150] R2, R3, R4, and R5are independently hydrogen, deuterium, halogen, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted 20 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 25 membered, or 5 to 6 membered).

[0151] R7, R8, R9, and R10are independently hydrogen, deuterium, or halogen.

[0152] In embodiments, the compound has the formula: 491, n2, W1, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10are as described herein, including in embodiments.

[0153] In embodiments, the compound has the formula:1, n2, W1, R1, R2, R3, R4, R5, R6, R7, R8, 5 R9, and R10are as described herein, including in embodiments.

[0154] In embodiments, the compound has the formula:re as described herein, including in embodiments.

[0155] I10 wherein R12and R13are as described herein, including in embodiments. In embodiments, D1In embodiments, D1isembodiments, D1isIn embodiments, D1is

[0156] R12and R13are independently hydrogen, deuterium, halogen, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted aryl 50(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).

[0157] In embodiments, Dwherein R12and R13are as described herein, including in embodiments. In embodiments, D25, In embodiments, D2isembodiments, D2is. In embodiments, D2is.

[0158] In embodiments, a substituted R12(e.g., substituted alkyl, 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 10 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, 15 when R12is substituted, it is substituted with at least one lower substituent group.

[0159] In embodiments, R12is independently hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R12is independently hydrogen, deuterium, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted phenyl, or substituted or 20 unsubstituted 5 to 6 membered heteroaryl.

[0160] In embodiments, R12is independently hydrogen. In embodiments, R12is independently deuterium. In embodiments, R12is independently halogen. In embodiments, R12is independently –F. In embodiments, R12is independently –Cl. In embodiments, R12is independently –Br. In embodiments, R12is independently –I. In embodiments, R12is 25 independently unsubstituted C1-C4alkyl. In embodiments, R12is independently unsubstituted methyl. In embodiments, R12is independently unsubstituted ethyl. In embodiments, R12is independently unsubstituted propyl. In embodiments, R12is independently unsubstituted n- propyl. In embodiments, R12is independently unsubstituted isopropyl. In embodiments, R1251is independently unsubstituted butyl. In embodiments, R12is independently unsubstituted n- butyl. In embodiments, R12is independently unsubstituted isobutyl. In embodiments, R12is independently unsubstituted tert-butyl. In embodiments, R12is independently unsubstituted phenyl. 5

[0161] In embodiments, a substituted R13(e.g., substituted alkyl, 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 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 10 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.

[0162] In embodiments, R13is independently hydrogen, deuterium, halogen, substituted or 15 unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R13is independently hydrogen, deuterium, halogen, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0163] In embodiments, R13is independently hydrogen. In embodiments, R13is 20 independently deuterium. In embodiments, R13is independently halogen. In embodiments, R13is independently –F. In embodiments, R13is independently –Cl. In embodiments, R13is independently –Br. In embodiments, R13is independently –I. In embodiments, R13is independently unsubstituted C1-C4 alkyl. In embodiments, R13is independently unsubstituted methyl. In embodiments, R13is independently unsubstituted ethyl. In embodiments, R13is25 independently unsubstituted propyl. In embodiments, R13is independently unsubstituted n- propyl. In embodiments, R13is independently unsubstituted isopropyl. In embodiments, R13is independently unsubstituted butyl. In embodiments, R13is independently unsubstituted n- butyl. In embodiments, R13is independently unsubstituted isobutyl. In embodiments, R13is independently unsubstituted tert-butyl. In embodiments, R13is independently unsubstituted 30 phenyl. 52[ , 5 10R16, and R17are as described herein, including in embodiments. In embodiments, A1is 5 ,wherein R14, R15, R16, and R17are as described herein, including in embodiments. In embodiments, A1isIn embodiments, A1is 10, In embodiments, A1isembodiments, A1isIn embodiments, A1isn embodiments, A1is. In embodiments, An embodiments, A1is 54. In embodiments, A1is. In embodiments, A1is. n embodiments, A1is. In embodiments, A1is. In embodiments, A1is . In embodiments, As . In embodiments, A1is . In embodiments, A1is 5eembodiments, A1is. , . In embodiments, A1is. n embodiments, A1isbodiments, A1isn 10 embodiments, AIn embodiments, A1isIn embodiments, A1isembodiments, A1is. In embodiments, AIn embodiments, A1is. , . , . In embodiments, A1is. In embodiments, A1is. In embodiments, A1is. , . In embodiments, A15 embodiments, A1is. In embodiments, AIn embodiments, A1is. , . In embodiments, A1isembodiments, Ambodiments, A1is. In embodiments, A1is, In embodiments, A1embodiments, A1isIn embodiments, A1isIn embodiments, A1is 10, In embodiments, A1isn embodiments, A1isIn embodiments, A1isIn embodiments, A1is 56. , . In embodiments, A1isembodiments, A1is. In embodiments, A1is. In embodiments, A1is. , . In embodiments, A1isembodiments, A1is. In embodiments, A1is. In embodiments, A1is 5. , . In embodiments, A1isembodiments, A1is. In embodiments, A1is. In embodiments, A1is. , . In embodiments, A1isembodiments, A

[0165] R14, R15, R16, and R17are independently hydrogen, -ORA, substituted or 10 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 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).

[0166] RAis independently hydrogen or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or 15 C1-C2). 57[embodiments, A1is. In embodiments, A1is . In embodiments, A1is 5 e [ , 105R16, and R17are as described herein, including in embodiments. In embodiments, A2is 10,wherein R14, R15, R16, and R17are as described herein, including in embodiments. In embodiments, A2is. In embodiments, A2is 5. , . In embodiments, A2isembodiments, A2is. In embodiments, A2is. In embodiments, A2ismbodiments, A2is, In embodiments, A2isembodiments, A2isIn embodiments, A2isIn embodiments, A2is 10, In embodiments, A2isn embodiments, A2isIn embodiments, A2isIn embodiments, A2is 60, mbodiments, A2isembodiments, Abodiments, A2is. , . In embodiments, A2isembodiments, A2is. In embodiments, Abodiments, A2is 5mbodiments, A2is . In embodiments, A2is . In embodiments, Ambodiments, A2is. In embodiments, A2is. , . In embodiments, A2embodiments, A2isIn embodiments, Abodiments, A2isn 10 embodiments, A2is. In embodiments, A is . In embodiments, A2is 61n embodiments, A2is. In embodiments, Ambodiments, A2is. , . In embodiments, A2isembodiments, Ambodiments, A2is. In embodiments, A2is 5. , . In embodiments, A2n embodiments, A2is. In embodiments, A2is. In embodiments, A2is. , . In embodiments, A2isembodiments, A2is. In embodiments, A2is. In embodiments, A2is 14, In embodiments, A2isn 10 embodiments, A2isIn embodiments, A2isIn embodiments, A2is 14, In embodiments, A2is . In embodiments, A2isIn embodiments, A2isIn embodiments, A2is 62. , . In embodiments, A2isembodiments, A2is. In embodiments, A2is. In embodiments, A2is. , . In embodiments, A2is. In e 5 [embodiments, A2isn embodiments, A2ise 10

[0170] In embodiments, a substituted R14(e.g., substituted alkyl, substituted heteroalkyl, 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 63substituent 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 5 substituent group. In embodiments, when R14is substituted, it is substituted with at least one lower substituent group.

[0171] In embodiments, R14is independently hydrogen, -ORA, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R14is independently hydrogen, -ORA, 10 substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0172] In embodiments, R14is independently hydrogen. In embodiments, R14is independently -ORA, wherein RAis as described herein, including in embodiments. n 15 embodiments, R14is independently -OH. In embodiments, R14is independently unsubstituted C1-C4 alkyl. In embodiments, R14is independently unsubstituted methyl. In embodiments, R14is independently unsubstituted ethyl. In embodiments, R14is independently unsubstituted propyl. In embodiments, R14is independently unsubstituted n-propyl. In embodiments, R14is independently unsubstituted isopropyl. In embodiments, R14is independently 20 unsubstituted butyl. In embodiments, R14is independently unsubstituted n-butyl. In embodiments, R14is independently unsubstituted isobutyl. In embodiments, R14is independently unsubstituted tert-butyl. In embodiments, R14is independently unsubstituted phenyl.

[0173] In embodiments, a substituted R15(e.g., substituted alkyl, substituted heteroalkyl, 25 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 R15is 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 30 embodiments, when R15is substituted, it is substituted with at least one substituent group. In embodiments, when R15is substituted, it is substituted with at least one size-limited 64substituent group. In embodiments, when R15is substituted, it is substituted with at least one lower substituent group.

[0174] In embodiments, R15is independently hydrogen, -ORA, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted 5 or unsubstituted heteroaryl. In embodiments, R15is independently hydrogen, -ORA, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0175] In embodiments, R15is independently hydrogen. In embodiments, R15is 10 independently -ORA, wherein RAis as described herein, including in embodiments. n embodiments, R15is independently -OH. In embodiments, R15is independently unsubstituted C1-C4 alkyl. In embodiments, R15is independently unsubstituted methyl. In embodiments, R15is independently unsubstituted ethyl. In embodiments, R15is independently unsubstituted propyl. In embodiments, R15is independently unsubstituted n-propyl. In embodiments, R1515 is independently unsubstituted isopropyl. In embodiments, R15is independently unsubstituted butyl. In embodiments, R15is independently unsubstituted n-butyl. In embodiments, R15is independently unsubstituted isobutyl. In embodiments, R15is independently unsubstituted tert-butyl. In embodiments, R15is independently unsubstituted phenyl. 20

[0176] In embodiments, a substituted R16(e.g., substituted alkyl, substituted heteroalkyl, 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 R16is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited 25 substituent group, and / or lower substituent group may optionally be different. In embodiments, when R16is substituted, it is substituted with at least one substituent group. In embodiments, when R16is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R16is substituted, it is substituted with at least one lower substituent group. 30

[0177] In embodiments, R16is independently hydrogen, -ORA, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R16is independently hydrogen, -ORA, 65substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0178] In embodiments, R16is independently hydrogen. In embodiments, R16is 5 independently -ORA, wherein RAis as described herein, including in embodiments. n embodiments, R16is independently -OH. In embodiments, R16is independently unsubstituted C1-C4 alkyl. In embodiments, R16is independently unsubstituted methyl. In embodiments, R16is independently unsubstituted ethyl. In embodiments, R16is independently unsubstituted propyl. In embodiments, R16is independently unsubstituted n-propyl. In embodiments, R1610 is independently unsubstituted isopropyl. In embodiments, R16is independently unsubstituted butyl. In embodiments, R16is independently unsubstituted n-butyl. In embodiments, R16is independently unsubstituted isobutyl. In embodiments, R16is independently unsubstituted tert-butyl. In embodiments, R16is independently unsubstituted phenyl. 15

[0179] In embodiments, a substituted R17(e.g., substituted alkyl, substituted heteroalkyl, 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 R17is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited 20 substituent group, and / or lower substituent group may optionally be different. In embodiments, when R17is substituted, it is substituted with at least one substituent group. In embodiments, when R17is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R17is substituted, it is substituted with at least one lower substituent group. 25

[0180] In embodiments, R17is independently hydrogen, -ORA, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R17is independently hydrogen, -ORA, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 30 membered heteroaryl.

[0181] In embodiments, R17is independently hydrogen. In embodiments, R17is independently -ORA, wherein RAis as described herein, including in embodiments. n 66embodiments, R17is independently -OH. In embodiments, R17is independently unsubstituted C1-C4 alkyl. In embodiments, R17is independently unsubstituted methyl. In embodiments, R17is independently unsubstituted ethyl. In embodiments, R17is independently unsubstituted propyl. In embodiments, R17is independently unsubstituted n-propyl. In embodiments, R175 is independently unsubstituted isopropyl. In embodiments, R17is independently unsubstituted butyl. In embodiments, R17is independently unsubstituted n-butyl. In embodiments, R17is independently unsubstituted isobutyl. In embodiments, R17is independently unsubstituted tert-butyl. In embodiments, R17is independently unsubstituted phenyl. 10

[0182] In embodiments, RAis independently hydrogen. In embodiments, RAis independently unsubstituted C1-C4 alkyl. In embodiments, RAis independently unsubstituted methyl. In embodiments, RAis independently unsubstituted ethyl. In embodiments, RAis independently unsubstituted propyl. In embodiments, RAis independently unsubstituted n- propyl. In embodiments, RAis independently unsubstituted isopropyl. In embodiments, RA15 is independently unsubstituted butyl. In embodiments, RAis independently unsubstituted n- butyl. In embodiments, RAis independently unsubstituted isobutyl. In embodiments, RAis independently unsubstituted tert-butyl. In embodiments, RAis independently unsubstituted phenyl. In embodiments, each RAis different.

[0183] In embodiments, n1 is 0. In embodiments, n1 is 1. 20

[0184] In embodiments, n2 is 0. In embodiments, n2 is 1.

[0185] In embodiments, L1is a bond. In embodiments, L1is a divalent linker.

[0186] In embodiments, L1is -L101-L102-L103-L104-L105-.

[0187] L101is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR101, -C(O)NR101-, -NR101C(O)-, -NR101C(O)O-, -OC(O)NR101-, -NR101C(O)NR101A-, -S(O)2-, -NR101S(O)2-, 25 -S(O)2NR101-, 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), 30 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). 67

[0188] L102is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR102, -C(O)NR102-, -NR102C(O)-, -NR102C(O)O-, -OC(O)NR102-, -NR102C(O)NR102A-, -S(O)2-, -NR102S(O)2-, -S(O)2NR102-, 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 5 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). 10

[0189] L103is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR103, -C(O)NR103-, -NR103C(O)-, -NR103C(O)O-, -OC(O)NR103-, -NR103C(O)NR103A-, -S(O)2-, -NR103S(O)2-, -S(O)2NR103-, 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 15 (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).

[0190] L104is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR104, -C(O)NR104-, 20 -NR104C(O)-, -NR104C(O)O-, -OC(O)NR104-, -NR104C(O)NR104A-, -S(O)2-, -NR104S(O)2-, -S(O)2NR104-, 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 25 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).

[0191] L105is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR105, -C(O)NR105-, -NR105C(O)-, -NR105C(O)O-, -OC(O)NR105-, -NR105C(O)NR105A-, -S(O)2-, -NR105S(O)2-, 30 -S(O)2NR105-, 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 68(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). 5

[0192] R101, R101A, R102, R102A, R103, R103A, R104, R104A, R105, and R105Aare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH 2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 10 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, 15 or 5 to 6 membered).

[0193] In embodiments, a substituted L101(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 L101is 20 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 L101is substituted, it is substituted with at least one substituent group. In embodiments, when L101is substituted, it is substituted with at least one size-limited 25 substituent group. In embodiments, when L101is substituted, it is substituted with at least one lower substituent group.

[0194] In embodiments, L101is a bond. In embodiments, L101is -C(O)-. In embodiments, L101is -C(O)O-. In embodiments, L101is -OC(O)-. In embodiments, L101is -O-. In embodiments, L101is -S-. In embodiments, L101is -NR101-. In embodiments, L101is -NH-. 30 In embodiments, L101is -C(O)NR101-. In embodiments, L101is -C(O)NH-. In embodiments, L101is -NR101C(O)-. In embodiments, L101is -NHC(O)-. In embodiments, L101is -NR101C(O)O-. In embodiments, L101is -NHC(O)O-. In embodiments, L10169is -OC(O)NR101-. In embodiments, L101is -OC(O)NH-. In embodiments, L101is -NR101C(O)NR101A-. In embodiments, L101is -NHC(O)NH-. In embodiments, L101is -S(O)2-. In embodiments, L101is -NR101S(O)2-. In embodiments, L101is -NHS(O)2-. In embodiments, L101is -S(O)2NR101-. In embodiments, L101is -S(O)2NH-. In embodiments, 5 L101is unsubstituted C1-C4alkylene. In embodiments, L101is unsubstituted methylene. In embodiments, L101is unsubstituted ethylene. In embodiments, L101is unsubstituted propylene. In embodiments, L101is unsubstituted n-propylene. In embodiments, L101is unsubstituted isopropylene. In embodiments, L101is unsubstituted butylene. In embodiments, L101is unsubstituted n-butylene. In embodiments, L101is unsubstituted 10 isobutylene. In embodiments, L101is unsubstituted tert-butylene. In embodiments, L101is substituted or unsubstituted phenylene.

[0195] In embodiments, a substituted R101(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 15 lower substituent group; wherein if the substituted R101is 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 R101is substituted, it is substituted with at least one substituent group. In embodiments, when R101is substituted, it is 20 substituted with at least one size-limited substituent group. In embodiments, when R101is substituted, it is substituted with at least one lower substituent group.

[0196] In embodiments, R101is hydrogen. In embodiments, R101is unsubstituted C1-C4 alkyl. In embodiments, R101is unsubstituted methyl. In embodiments, R101is unsubstituted ethyl. In embodiments, R101is unsubstituted propyl. In embodiments, R101is unsubstituted 25 n-propyl. In embodiments, R101is unsubstituted isopropyl. In embodiments, R101is unsubstituted butyl. In embodiments, R101is unsubstituted n-butyl. In embodiments, R101is unsubstituted isobutyl. In embodiments, R101is unsubstituted tert-butyl.

[0197] In embodiments, a substituted R101A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted 30 heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R101Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower 70substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R101Ais substituted, it is substituted with at least one substituent group. In embodiments, when R101Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R101A5 is substituted, it is substituted with at least one lower substituent group.

[0198] In embodiments, R101Ais hydrogen. In embodiments, R101Ais unsubstituted C1-C4alkyl. In embodiments, R101Ais unsubstituted methyl. In embodiments, R101Ais unsubstituted ethyl. In embodiments, R101Ais unsubstituted propyl. In embodiments, R101Ais unsubstituted n-propyl. In embodiments, R101Ais unsubstituted isopropyl. In embodiments, 10 R101Ais unsubstituted butyl. In embodiments, R101Ais unsubstituted n-butyl. In embodiments, R101Ais unsubstituted isobutyl. In embodiments, R101Ais unsubstituted tert- butyl.

[0199] In embodiments, a substituted L102(e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted 15 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 L102is 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 20 embodiments, when L102is substituted, it is substituted with at least one substituent group. In embodiments, when L102is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L102is substituted, it is substituted with at least one lower substituent group.

[0200] In embodiments, L102is a bond. In embodiments, L102is -C(O)-. In embodiments, 25 L102is -C(O)O-. In embodiments, L102is -OC(O)-. In embodiments, L102is -O-. In embodiments, L102is -S-. In embodiments, L102is -NR102-. In embodiments, L102is -NH-. In embodiments, L102is -C(O)NR102-. In embodiments, L102is -C(O)NH-. In embodiments, L102is -NR102C(O)-. In embodiments, L102is -NHC(O)-. In embodiments, L102is -NR102C(O)O-. In embodiments, L102is -NHC(O)O-. In embodiments, L10230 is -OC(O)NR102-. In embodiments, L102is -OC(O)NH-. In embodiments, L102is -NR102C(O)NR102A-. In embodiments, L102is -NHC(O)NH-. In embodiments, L102is -S(O)2-. In embodiments, L102is -NR102S(O)2-. In embodiments, L102is -NHS(O)2-. In 71embodiments, L102is -S(O)2NR102-. In embodiments, L102is -S(O)2NH-. In embodiments, L102is unsubstituted C1-C4 alkylene. In embodiments, L102is unsubstituted methylene. In embodiments, L102is unsubstituted ethylene. In embodiments, L102is unsubstituted propylene. In embodiments, L102is unsubstituted n-propylene. In embodiments, L102is 5 unsubstituted isopropylene. In embodiments, L102is unsubstituted butylene. In embodiments, L102is unsubstituted n-butylene. In embodiments, L102is unsubstituted isobutylene. In embodiments, L102is unsubstituted tert-butylene. In embodiments, L102is substituted or unsubstituted phenylene.

[0201] In embodiments, a substituted R102(e.g., substituted alkyl, substituted heteroalkyl, 10 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 R102is 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 15 substituent group may optionally be different. In embodiments, when R102is substituted, it is substituted with at least one substituent group. In embodiments, when R102is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R102is substituted, it is substituted with at least one lower substituent group.

[0202] In embodiments, R102is hydrogen. In embodiments, R102is unsubstituted C1-C420 alkyl. In embodiments, R102is unsubstituted methyl. In embodiments, R102is unsubstituted ethyl. In embodiments, R102is unsubstituted propyl. In embodiments, R102is unsubstituted n-propyl. In embodiments, R102is unsubstituted isopropyl. In embodiments, R102is unsubstituted butyl. In embodiments, R102is unsubstituted n-butyl. In embodiments, R102is unsubstituted isobutyl. In embodiments, R102is unsubstituted tert-butyl. 25

[0203] In embodiments, a substituted R102A(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 R102Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower 30 substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R102Ais substituted, it is substituted with at least one substituent group. In embodiments, when R102Ais substituted, 72it is substituted with at least one size-limited substituent group. In embodiments, when R102Ais substituted, it is substituted with at least one lower substituent group.

[0204] In embodiments, R102Ais hydrogen. In embodiments, R102Ais unsubstituted C1-C4 alkyl. In embodiments, R102Ais unsubstituted methyl. In embodiments, R102Ais 5 unsubstituted ethyl. In embodiments, R102Ais unsubstituted propyl. In embodiments, R102Ais unsubstituted n-propyl. In embodiments, R102Ais unsubstituted isopropyl. In embodiments, R102Ais unsubstituted butyl. In embodiments, R102Ais unsubstituted n-butyl. In embodiments, R102Ais unsubstituted isobutyl. In embodiments, R102Ais unsubstituted tert- butyl. 10

[0205] In embodiments, a substituted L103(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 L103is substituted with a plurality of groups selected from substituent groups, size-limited 15 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 L103is substituted, it is substituted with at least one substituent group. In embodiments, when L103is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L103is substituted, it is substituted with at least one 20 lower substituent group.

[0206] In embodiments, L103is a bond. In embodiments, L103is -C(O)-. In embodiments, L103is -C(O)O-. In embodiments, L103is -OC(O)-. In embodiments, L103is -O-. In embodiments, L103is -S-. In embodiments, L103is -NR103-. In embodiments, L103is -NH-. In embodiments, L103is -C(O)NR103-. In embodiments, L103is -C(O)NH-. In embodiments,25 L103is -NR103C(O)-. In embodiments, L103is -NHC(O)-. In embodiments, L103is -NR103C(O)O-. In embodiments, L103is -NHC(O)O-. In embodiments, L103is -OC(O)NR103-. In embodiments, L103is -OC(O)NH-. In embodiments, L103is -NR103C(O)NR103A-. In embodiments, L103is -NHC(O)NH-. In embodiments, L103is -S(O)2-. In embodiments, L103is -NR103S(O)2-. In embodiments, L103is -NHS(O)2-. In 30 embodiments, L103is -S(O)2NR103-. In embodiments, L103is -S(O)2NH-. In embodiments, L103is unsubstituted C1-C4 alkylene. In embodiments, L103is unsubstituted methylene. In embodiments, L103is unsubstituted ethylene. In embodiments, L103is unsubstituted 73propylene. In embodiments, L103is unsubstituted n-propylene. In embodiments, L103is unsubstituted isopropylene. In embodiments, L103is unsubstituted butylene. In embodiments, L103is unsubstituted n-butylene. In embodiments, L103is unsubstituted isobutylene. In embodiments, L103is unsubstituted tert-butylene. In embodiments, L103is 5 substituted or unsubstituted phenylene.

[0207] In embodiments, a substituted R103(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 R103is substituted with a plurality of 10 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 R103is substituted, it is substituted with at least one substituent group. In embodiments, when R103is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R103is 15 substituted, it is substituted with at least one lower substituent group.

[0208] In embodiments, R103is hydrogen. In embodiments, R103is unsubstituted C1-C4 alkyl. In embodiments, R103is unsubstituted methyl. In embodiments, R103is unsubstituted ethyl. In embodiments, R103is unsubstituted propyl. In embodiments, R103is unsubstituted n-propyl. In embodiments, R103is unsubstituted isopropyl. In embodiments, R103is 20 unsubstituted butyl. In embodiments, R103is unsubstituted n-butyl. In embodiments, R103is unsubstituted isobutyl. In embodiments, R103is unsubstituted tert-butyl.

[0209] In embodiments, a substituted R103A(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 25 lower substituent group; wherein if the substituted R103Ais 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 R103Ais substituted, it is substituted with at least one substituent group. In embodiments, when R103Ais substituted,30 it is substituted with at least one size-limited substituent group. In embodiments, when R103Ais substituted, it is substituted with at least one lower substituent group. 74

[0210] In embodiments, R103Ais hydrogen. In embodiments, R103Ais unsubstituted C1-C4alkyl. In embodiments, R103Ais unsubstituted methyl. In embodiments, R103Ais unsubstituted ethyl. In embodiments, R103Ais unsubstituted propyl. In embodiments, R103Ais unsubstituted n-propyl. In embodiments, R103Ais unsubstituted isopropyl. In embodiments, 5 R103Ais unsubstituted butyl. In embodiments, R103Ais unsubstituted n-butyl. In embodiments, R103Ais unsubstituted isobutyl. In embodiments, R103Ais unsubstituted tert- butyl.

[0211] In embodiments, a substituted L104(e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted 10 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 L104is 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 15 embodiments, when L104is substituted, it is substituted with at least one substituent group. In embodiments, when L104is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L104is substituted, it is substituted with at least one lower substituent group.

[0212] In embodiments, L104is a bond. In embodiments, L104is -C(O)-. In embodiments, 20 L104is -C(O)O-. In embodiments, L104is -OC(O)-. In embodiments, L104is -O-. In embodiments, L104is -S-. In embodiments, L104is -NR104-. In embodiments, L104is -NH-. In embodiments, L104is -C(O)NR104-. In embodiments, L104is -C(O)NH-. In embodiments, L104is -NR104C(O)-. In embodiments, L104is -NHC(O)-. In embodiments, L104is -NR104C(O)O-. In embodiments, L104is -NHC(O)O-. In embodiments, L10425 is -OC(O)NR104-. In embodiments, L104is -OC(O)NH-. In embodiments, L104is -NR104C(O)NR104A-. In embodiments, L104is -NHC(O)NH-. In embodiments, L104is -S(O)2-. In embodiments, L104is -NR104S(O)2-. In embodiments, L104is -NHS(O)2-. In embodiments, L104is -S(O)2NR104-. In embodiments, L104is -S(O)2NH-. In embodiments, L104is unsubstituted C1-C4alkylene. In embodiments, L104is unsubstituted methylene. In 30 embodiments, L104is unsubstituted ethylene. In embodiments, L104is unsubstituted propylene. In embodiments, L104is unsubstituted n-propylene. In embodiments, L104is unsubstituted isopropylene. In embodiments, L104is unsubstituted butylene. In 75embodiments, L104is unsubstituted n-butylene. In embodiments, L104is unsubstituted isobutylene. In embodiments, L104is unsubstituted tert-butylene. In embodiments, L104is substituted or unsubstituted phenylene.

[0213] In embodiments, a substituted R104(e.g., substituted alkyl, substituted heteroalkyl, 5 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 R104is 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 10 substituent group may optionally be different. In embodiments, when R104is substituted, it is substituted with at least one substituent group. In embodiments, when R104is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R104is substituted, it is substituted with at least one lower substituent group.

[0214] In embodiments, R104is hydrogen. In embodiments, R104is unsubstituted C1-C4 15 alkyl. In embodiments, R104is unsubstituted methyl. In embodiments, R104is unsubstituted ethyl. In embodiments, R104is unsubstituted propyl. In embodiments, R104is unsubstituted n-propyl. In embodiments, R104is unsubstituted isopropyl. In embodiments, R104is unsubstituted butyl. In embodiments, R104is unsubstituted n-butyl. In embodiments, R104is unsubstituted isobutyl. In embodiments, R104is unsubstituted tert-butyl. 20

[0215] In embodiments, a substituted R104A(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 R104Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower 25 substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R104Ais substituted, it is substituted with at least one substituent group. In embodiments, when R104Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R104Ais substituted, it is substituted with at least one lower substituent group. 30

[0216] In embodiments, R104Ais hydrogen. In embodiments, R104Ais unsubstituted C1-C4 alkyl. In embodiments, R104Ais unsubstituted methyl. In embodiments, R104Ais unsubstituted ethyl. In embodiments, R104Ais unsubstituted propyl. In embodiments, R104Ais 76unsubstituted n-propyl. In embodiments, R104Ais unsubstituted isopropyl. In embodiments, R104Ais unsubstituted butyl. In embodiments, R104Ais unsubstituted n-butyl. In embodiments, R104Ais unsubstituted isobutyl. In embodiments, R104Ais unsubstituted tert- butyl. 5

[0217] In embodiments, a substituted L105(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 L105is substituted with a plurality of groups selected from substituent groups, size-limited 10 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 L105is substituted, it is substituted with at least one substituent group. In embodiments, when L105is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L105is substituted, it is substituted with at least one 15 lower substituent group.

[0218] In embodiments, L105is a bond. In embodiments, L105is -C(O)-. In embodiments, L105is -C(O)O-. In embodiments, L105is -OC(O)-. In embodiments, L105is -O-. In embodiments, L105is -S-. In embodiments, L105is -NR105-. In embodiments, L105is -NH-. In embodiments, L105is -C(O)NR105-. In embodiments, L105is -C(O)NH-. In embodiments,20 L105is -NR105C(O)-. In embodiments, L105is -NHC(O)-. In embodiments, L105is -NR105C(O)O-. In embodiments, L105is -NHC(O)O-. In embodiments, L105is -OC(O)NR105-. In embodiments, L105is -OC(O)NH-. In embodiments, L105is -NR105C(O)NR105A-. In embodiments, L105is -NHC(O)NH-. In embodiments, L105is -S(O)2-. In embodiments, L105is -NR105S(O)2-. In embodiments, L105is -NHS(O)2-. In 25 embodiments, L105is -S(O)2NR105-. In embodiments, L105is -S(O)2NH-. In embodiments, L105is unsubstituted C1-C4alkylene. In embodiments, L105is unsubstituted methylene. In embodiments, L105is unsubstituted ethylene. In embodiments, L105is unsubstituted propylene. In embodiments, L105is unsubstituted n-propylene. In embodiments, L105is unsubstituted isopropylene. In embodiments, L105is unsubstituted butylene. In 30 embodiments, L105is unsubstituted n-butylene. In embodiments, L105is unsubstituted isobutylene. In embodiments, L105is unsubstituted tert-butylene. In embodiments, L105is substituted or unsubstituted phenylene. 77

[0219] In embodiments, a substituted R105(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 R105is substituted with a plurality of 5 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 R105is substituted, it is substituted with at least one substituent group. In embodiments, when R105is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R105is 10 substituted, it is substituted with at least one lower substituent group.

[0220] In embodiments, R105is hydrogen. In embodiments, R105is unsubstituted C1-C4 alkyl. In embodiments, R105is unsubstituted methyl. In embodiments, R105is unsubstituted ethyl. In embodiments, R105is unsubstituted propyl. In embodiments, R105is unsubstituted n-propyl. In embodiments, R105is unsubstituted isopropyl. In embodiments, R105is 15 unsubstituted butyl. In embodiments, R105is unsubstituted n-butyl. In embodiments, R105is unsubstituted isobutyl. In embodiments, R105is unsubstituted tert-butyl.

[0221] In embodiments, a substituted R105A(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 20 lower substituent group; wherein if the substituted R105Ais 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 R105Ais substituted, it is substituted with at least one substituent group. In embodiments, when R105Ais substituted,25 it is substituted with at least one size-limited substituent group. In embodiments, when R105Ais substituted, it is substituted with at least one lower substituent group.

[0222] In embodiments, R105Ais hydrogen. In embodiments, R105Ais unsubstituted C1-C4 alkyl. In embodiments, R105Ais unsubstituted methyl. In embodiments, R105Ais unsubstituted ethyl. In embodiments, R105Ais unsubstituted propyl. In embodiments, R105Ais 30 unsubstituted n-propyl. In embodiments, R105Ais unsubstituted isopropyl. In embodiments, R105Ais unsubstituted butyl. In embodiments, R105Ais unsubstituted n-butyl. In 78embodiments, R105Ais unsubstituted isobutyl. In embodiments, R105Ais unsubstituted tert- butyl.

[0223] In embodiments, a substituted R20(e.g., substituted aryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if 5 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 10 substituent group. In embodiments, when R20is substituted, it is substituted with at least one lower substituent group.

[0224] In embodiments, R20is a substituted or unsubstituted C6-C10 aryl. In embodiments, R20is a substituted or unsubstituted phenyl. In embodiments, R20is a monovalent form of a biomolecule. In embodiments, R20is a monovalent form of a nucleic acid (e.g., DNA or 15 RNA). In embodiments, R20is a monovalent form of a protein. In embodiments, R20is a monovalent form of a carbohydrate. In embodiments, R20is a monovalent form of a lipid. In embodiments, R20is a monovalent form of a primary metabolite. In embodiments, R20is a monovalent form of a secondary metabolite. In embodiments, R20is a monovalent form of a natural product. In embodiments, R20is a monovalent form of a peptide nucleic acid. In 20 embodiments, R20is a monovalent form of an antibody. In embodiments, R20is a monovalent form of an aptamer. In embodiments, R20is a monovalent form of a small molecule affinity ligands (e.g., inhibitor, biotin, or hapten). In embodiments, R20is a monovalent form of a drug.

[0225] In embodiments, a substituted R1(e.g., substituted alkyl, substituted heteroalkyl, 25 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 30 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 79least one size-limited substituent group. In embodiments, when R1is substituted, it is substituted with at least one lower substituent group.

[0226] In embodiments, R1is hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or 5 unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0227] In embodiments, R1is hydrogen. In embodiments, R1is deuterium. In embodiments, R1is unsubstituted C1-C4 alkyl. In embodiments, R1is unsubstituted methyl. In embodiments, R1is unsubstituted ethyl. In embodiments, R1is unsubstituted propyl. In 10 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.

[0228] In embodiments, a substituted R2(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted 15 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 20 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.

[0229] In embodiments, R2is hydrogen. In embodiments, R2is deuterium. In embodiments, R2is halogen. In embodiments, R2is –F. In embodiments, R2is –Cl. In25 embodiments, R2is –Br. In embodiments, R2is –I. In embodiments, R2is unsubstituted C1- C4 alkyl. In embodiments, R2is unsubstituted methyl. In embodiments, R2is unsubstituted ethyl. In embodiments, R2is unsubstituted propyl. In embodiments, R2is unsubstituted n- propyl. In embodiments, R2is unsubstituted isopropyl. In embodiments, R2is unsubstituted butyl. In embodiments, R2is unsubstituted n-butyl. In embodiments, R2is unsubstituted 30 isobutyl. In embodiments, R2is unsubstituted tert-butyl. 80

[0230] 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 5 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 10 substituted with at least one lower substituent group.

[0231] In embodiments, R3is hydrogen. In embodiments, R3is deuterium. In embodiments, R3is halogen. In embodiments, R3is –F. In embodiments, R3is –Cl. In embodiments, R3is –Br. In embodiments, R3is –I. In embodiments, R3is unsubstituted C1- C4alkyl. In embodiments, R3is unsubstituted methyl. In embodiments, R3is unsubstituted15 ethyl. In embodiments, R3is unsubstituted propyl. In embodiments, R3is unsubstituted n- propyl. In embodiments, R3is unsubstituted isopropyl. In embodiments, R3is unsubstituted butyl. In embodiments, R3is unsubstituted n-butyl. In embodiments, R3is unsubstituted isobutyl. In embodiments, R3is unsubstituted tert-butyl.

[0232] In embodiments, a substituted R4(e.g., substituted alkyl, substituted heteroalkyl, 20 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 25 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.

[0233] In embodiments, R4is hydrogen. In embodiments, R4is deuterium. In 30 embodiments, R4is halogen. In embodiments, R4is –F. In embodiments, R4is –Cl. In embodiments, R4is –Br. In embodiments, R4is –I. In embodiments, R4is unsubstituted C1- C4alkyl. In embodiments, R4is unsubstituted methyl. In embodiments, R4is unsubstituted 81ethyl. 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. 5

[0234] In embodiments, a substituted R5(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 R5is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent 10 groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R5is substituted, it is substituted with at least one substituent group. In embodiments, when R5is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5is substituted, it is substituted with at least one lower substituent group. 15

[0235] In embodiments, R5is hydrogen. In embodiments, R5is deuterium. In embodiments, R5is halogen. In embodiments, R5is –F. In embodiments, R5is –Cl. In embodiments, R5is –Br. In embodiments, R5is –I. In embodiments, R5is unsubstituted C1- C4 alkyl. In embodiments, R5is unsubstituted methyl. In embodiments, R5is unsubstituted ethyl. In embodiments, R5is unsubstituted propyl. In embodiments, R5is unsubstituted n- 20 propyl. In embodiments, R5is unsubstituted isopropyl. In embodiments, R5is unsubstituted butyl. In embodiments, R5is unsubstituted n-butyl. In embodiments, R5is unsubstituted isobutyl. In embodiments, R5is unsubstituted tert-butyl.

[0236] In embodiments, a substituted R6(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted 25 heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R6is 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 R6is substituted, it is substituted with at 30 least one substituent group. In embodiments, when R6is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R6is substituted, it is substituted with at least one lower substituent group. 82

[0237] In embodiments, R6is hydrogen, deuterium, 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. 5

[0238] In embodiments, R6is hydrogen. In embodiments, R6is deuterium. In embodiments, R6is unsubstituted C1-C4alkyl. In embodiments, R6is unsubstituted methyl. In embodiments, R6is unsubstituted ethyl. In embodiments, R6is unsubstituted propyl. In embodiments, R6is unsubstituted n-propyl. In embodiments, R6is unsubstituted isopropyl. In embodiments, R6is unsubstituted butyl. In embodiments, R6is unsubstituted n-butyl. In 10 embodiments, R6is unsubstituted isobutyl. In embodiments, R6is unsubstituted tert-butyl.

[0239] In embodiments, R7is hydrogen, deuterium, or halogen. In embodiments, R7is hydrogen. In embodiments, R7is deuterium. In embodiments, R7is halogen. In embodiments, R7is –F. In embodiments, R7is –Cl. In embodiments, R7is –Br. In embodiments, R7is –I. 15

[0240] In embodiments, R8is hydrogen, deuterium, or halogen. In embodiments, R8is hydrogen. In embodiments, R8is deuterium. In embodiments, R8is halogen. In embodiments, R8is –F. In embodiments, R8is –Cl. In embodiments, R8is –Br. In embodiments, R8is –I.

[0241] In embodiments, R9is hydrogen, deuterium, or halogen. In embodiments, R9is 20 hydrogen. In embodiments, R9is deuterium. In embodiments, R9is halogen. In embodiments, R9is –F. In embodiments, R9is –Cl. In embodiments, R9is –Br. In embodiments, R9is –I.

[0242] In embodiments, R10is hydrogen, deuterium, or halogen. In embodiments, R10is hydrogen. In embodiments, R10is deuterium. In embodiments, R10is halogen. In 25 embodiments, R10is –F. In embodiments, R10is –Cl. In embodiments, R10is –Br. In embodiments, R10is –I.

[0243] In embodiments, W1is N. In embodiments, W1is C(R11), wherein R11is as described herein, including in embodiments.

[0244] In embodiments, a substituted R11(e.g., substituted alkyl, substituted heteroalkyl, 30 substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or 83lower 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 5 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.

[0245] In embodiments, R11is hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or 10 unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0246] In embodiments, R11is hydrogen. In embodiments, R11is deuterium. In embodiments, R11is unsubstituted C1-C4alkyl. In embodiments, R11is unsubstituted methyl. In embodiments, R11is unsubstituted ethyl. In embodiments, R11is unsubstituted propyl. In 15 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. In embodiments, R11is substituted or unsubstituted phenyl.

[0247] In embodiments, R11is hydrogen, deuterium, R21-substituted or unsubstituted alkyl,20 R21-substituted or unsubstituted heteroalkyl, R21-substituted or unsubstituted cycloalkyl, R21- substituted or unsubstituted heterocycloalkyl, R21-substituted or unsubstituted aryl, or R21- substituted or unsubstituted heteroaryl. In embodiments, R11is R21-substituted or unsubstituted alkyl, R21-substituted or unsubstituted heteroalkyl, R21-substituted or unsubstituted cycloalkyl, R21-substituted or unsubstituted heterocycloalkyl, R21-substituted or25 unsubstituted aryl, or R21-substituted or unsubstituted heteroaryl. In embodiments, R11is R21- substituted or unsubstituted C1-C4alkyl. In embodiments, R11is R21-substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R11is R21-substituted or unsubstituted C3-C8cycloalkyl. In embodiments, R11is R21-substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R11is R21-substituted or unsubstituted 30 phenyl. In embodiments, R11is R21-substituted or unsubstituted 5 to 6 membered heteroaryl.

[0248] R21is independently oxo, halogen, -CX213, -CHX212, -CH2X21, -OCX213, -OCH2X21, --NR21CC(O)NR21AR21B, -N(O)m21, -NR21AR21B, -C(O)R21C, -C(O)OR21C, -OC(O)R21C, -OC(O)OR21C, -C(O)NR21AR21B, -C(NR21C)NR21AR21B, -OC(O)NR21AR21B, -OR21D, -SR21D, -NR21ASO2R21D, -NR21AC(O)R21C, 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 5 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 10 membered).

[0249] R21A, R21B, R21C, and R21Dare 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 15 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 unsubstituted20 heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R21Aand R21Bsubstituents 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). 25

[0250] Each X21is independently –F, -Cl, -Br, or –I.

[0251] The symbol n21 is independently an integer from 0 to 4.

[0252] The symbols m21 and v21 are independently 1 or 2.

[0253] The symbol z21 is an integer from 0 to 11.

[0254] In embodiments, a substituted R21(e.g., substituted alkyl, substituted heteroalkyl, 30 substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or 85lower substituent group; wherein if the substituted R21is 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 R21is substituted, it is substituted with at 5 least one substituent group. In embodiments, when R21is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R21is substituted, it is substituted with at least one lower substituent group.

[0255] In embodiments, a substituted R21A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted 10 heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R21Ais 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 R21Ais substituted, it is 15 substituted with at least one substituent group. In embodiments, when R21Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R21Ais substituted, it is substituted with at least one lower substituent group.

[0256] In embodiments, a substituted R21B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted 20 heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R21Bis 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 R21Bis substituted, it is 25 substituted with at least one substituent group. In embodiments, when R21Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R21Bis substituted, it is substituted with at least one lower substituent group.

[0257] In embodiments, a substituted ring formed when R21Aand R21Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and / or substituted 30 heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R21Aand R21Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of 86groups 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 R21Aand R21Bsubstituents bonded to the same nitrogen atom are joined is 5 substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R21Aand R21Bsubstituents 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 R21Aand R21Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower 10 substituent group.

[0258] In embodiments, a substituted R21C(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 R21Cis substituted with a plurality of 15 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 R21Cis substituted, it is substituted with at least one substituent group. In embodiments, when R21Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R21Cis 20 substituted, it is substituted with at least one lower substituent group.

[0259] In embodiments, a substituted R21D(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 R21Dis substituted with a plurality of 25 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 R21Dis substituted, it is substituted with at least one substituent group. In embodiments, when R21Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R21Dis 30 substituted, it is substituted with at least one lower substituent group.

[0260] In embodiments, R21Ais independently hydrogen. In embodiments, R21Ais independently unsubstituted C1-C4alkyl. In embodiments, R21Ais independently 87unsubstituted methyl. In embodiments, R21Ais independently unsubstituted ethyl. In embodiments, R21Ais independently unsubstituted propyl. In embodiments, R21Ais independently unsubstituted n-propyl. In embodiments, R21Ais independently unsubstituted isopropyl. In embodiments, R21Ais independently unsubstituted butyl. In embodiments, R21A5 is independently unsubstituted n-butyl. In embodiments, R21Ais independently unsubstituted isobutyl. In embodiments, R21Ais independently unsubstituted tert-butyl.

[0261] In embodiments, R21Bis independently hydrogen. In embodiments, R21Bis independently unsubstituted C1-C4alkyl. In embodiments, R21Bis independently unsubstituted methyl. In embodiments, R21Bis independently unsubstituted ethyl. In 10 embodiments, R21Bis independently unsubstituted propyl. In embodiments, R21Bis independently unsubstituted n-propyl. In embodiments, R21Bis independently unsubstituted isopropyl. In embodiments, R21Bis independently unsubstituted butyl. In embodiments, R21Bis independently unsubstituted n-butyl. In embodiments, R21Bis independently unsubstituted isobutyl. In embodiments, R21Bis independently unsubstituted tert-butyl. 15

[0262] In embodiments, R21Cis independently hydrogen. In embodiments, R21Cis independently unsubstituted C1-C4 alkyl. In embodiments, R21Cis independently unsubstituted methyl. In embodiments, R21Cis independently unsubstituted ethyl. In embodiments, R21Cis independently unsubstituted propyl. In embodiments, R21Cis independently unsubstituted n-propyl. In embodiments, R21Cis independently unsubstituted20 isopropyl. In embodiments, R21Cis independently unsubstituted butyl. In embodiments, R21Cis independently unsubstituted n-butyl. In embodiments, R21Cis independently unsubstituted isobutyl. In embodiments, R21Cis independently unsubstituted tert-butyl.

[0263] In embodiments, R21Dis independently hydrogen. In embodiments, R21Dis independently unsubstituted C1-C4alkyl. In embodiments, R21Dis independently 25 unsubstituted methyl. In embodiments, R21Dis independently unsubstituted ethyl. In embodiments, R21Dis independently unsubstituted propyl. In embodiments, R21Dis independently unsubstituted n-propyl. In embodiments, R21Dis independently unsubstituted isopropyl. In embodiments, R21Dis independently unsubstituted butyl. In embodiments, R21Dis independently unsubstituted n-butyl. In embodiments, R21Dis independently unsubstituted 30 isobutyl. In embodiments, R21Dis independently unsubstituted tert-butyl.

[0264] In embodiments, R21is independently halogen, -CX213, -CHX212, -CH2X21, -OCX213, --NR21CC(O)NR21AR21B, -N(O)m21, -NR21AR21B, -C(O)R21C, -C(O)OR21C, -OC(O)R21C, -OC(O)OR21C, -C(O)NR21AR21B, -C(NR21C)NR21AR21B, -OC(O)NR21AR21B, -OR21D, -SR21D, -NR21ASO2R21D, -NR21AC(O)R21C, 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 5 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 10 membered).

[0265] In embodiments, R21is independently oxo. In embodiments, R21is independently halogen. In embodiments, R21is independently –F. In embodiments, R21is independently –Cl. In embodiments, R21is independently –Br. In embodiments, R21is independently –I. In embodiments, R21is independently -CCl3. In embodiments, R21is independently -CBr3. 15 In embodiments, R21is independently -CF3. In embodiments, R21is independently -CI3. In embodiments, R21is independently -CH2Cl. In embodiments, R21is independently -CH2Br. In embodiments, R21is independently -CH2F. In embodiments, R21is independently -CH2I. In embodiments, R21is independently -CHCl2. In embodiments, R21is independently -CHBr2. In embodiments, R21is independently -CHF2. In embodiments, R21is 20 independently -CHI2. In embodiments, R21is independently –CN. In embodiments, R21is independently –OH. In embodiments, R21is independently -NH2. In embodiments, R21is independently –COOH. In embodiments, R21is independently -CONH2. In embodiments, R21is independently -NO2. In embodiments, R21is independently –SH. In embodiments, R21is independently -SO3H. In embodiments, R21is independently -OSO3H. In embodiments, 25 R21is independently -SO2NH2. In embodiments, R21is independently ^NHNH2. In embodiments, R21is independently ^ONH2. In embodiments, R21is independently ^NHC(O)NH2. In embodiments, R21is independently -NHSO2H. In embodiments, R21is independently -NHC(O)H. In embodiments, R21is independently -NHC(O)OH. In embodiments, R21is independently –NHOH. In embodiments, R21is independently -OCCl3. 30 In embodiments, R21is independently -OCBr3. In embodiments, R21is independently -OCF3. In embodiments, R21is independently -OCI3. In embodiments, R21is independently -OCH2Cl. In embodiments, R21is independently -OCH2Br. In embodiments, R21is independently -OCH2F. In embodiments, R21is independently -OCH2I. In embodiments, R2189is independently -OCHCl2. In embodiments, R21is independently -OCHBr2. In embodiments, R21is independently -OCHF2. In embodiments, R21is independently -OCHI2. In embodiments, R21is independently -SF5. In embodiments, R21is independently -N3. In embodiments, R21is independently unsubstituted C1-C4 alkyl. In embodiments, R21is 5 independently unsubstituted methyl. In embodiments, R21is independently unsubstituted ethyl. In embodiments, R21is independently unsubstituted propyl. In embodiments, R21is independently unsubstituted n-propyl. In embodiments, R21is independently unsubstituted isopropyl. In embodiments, R21is independently unsubstituted butyl. In embodiments, R21is independently unsubstituted n-butyl. In embodiments, R21is independently unsubstituted 10 isobutyl. In embodiments, R21is independently unsubstituted tert-butyl. In embodiments, R21is independently substituted or unsubstituted 2 to 6 membered heteroalkyl. In In embodiments, R21is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R21is independently unsubstituted methoxy. In embodiments, R21is independently unsubstituted ethoxy. In embodiments, R21is independently unsubstituted 15 propoxy. In embodiments, R21is independently unsubstituted n-propoxy. In embodiments, R21is independently unsubstituted isopropoxy. In embodiments, R21is independently unsubstituted butoxy.

[0266] In embodiments, z21 is 0. In embodiments, z21 is 1. In embodiments, z21 is 2. In embodiments, z21 is 3. In embodiments, z21 is 4. In embodiments, z21 is 5. In 20 embodiments, z21 is 6. In embodiments, z21 is 7. In embodiments, z21 is 8. In embodiments, z21 is 9. In embodiments, z21 is 10. In embodiments, z21 is 11.

[0267] In embodiments, Rmbodiments, R1embodiments, R

[0268] In embodiments, R11is 90. R21is as described herein, including in embodiments. The symbol z21 is an integer from 0 to 4.

[0269] R22is independently halogen, -CX223, -CHX222, -CH2X22, -OCX223, -OCH2X22, -OCHX222, -CN, -SOn22R22D, -SOv22NR22AR22B, ^NR22CNR22AR22B, ^ONR22AR22B, 5 -NR22CC(O)NR22AR22B, -N(O)m22, -NR22AR22B, -C(O)R22C, -C(O)OR22C, -OC(O)R22C, -OC(O)OR22C, -C(O)NR22AR22B, -C(NR22C)NR22AR22B, -OC(O)NR22AR22B, -OR22D, -SR22D, -NR22ASO2R22D, -NR22AC(O)R22C, 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 10 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). 15

[0270] R23is independently halogen, -CX233, -CHX232, -CH2X23, -OCX233, -OCH2X23, -OCHX232, -CN, -SOn23R23D, -SOv23NR23AR23B, ^NR23CNR23AR23B, ^ONR23AR23B, -NR23CC(O)NR23AR23B, -N(O)m23, -NR23AR23B, -C(O)R23C, -C(O)OR23C, -OC(O)R23C, -OC(O)OR23C, -C(O)NR23AR23B, -C(NR23C)NR23AR23B, -OC(O)NR23AR23B, -OR23D, -SR23D, -NR23ASO2R23D, -NR23AC(O)R23C, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1- 20 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 25 substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0271] R22A, R22B, R22C, R22D, R23A, R23B, R23C, and R23Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, 91-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), 5 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); R22Aand R22Bsubstituents bonded to the same nitrogen atom may 10 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); R23Aand R23Bsubstituents 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 15 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).

[0272] Each X22and X23is independently –F, -Cl, -Br, or –I.

[0273] The symbols n22 and n23 are independently an integer from 0 to 4.

[0274] The symbols m22, m23, v22, and v23 are independently 1 or 2. 20

[0275] The symbol z22 is an integer from 0 to 4.

[0276] The symbol z23 is an integer from 0 to 5.

[0277] The symbol n is an integer from 0 to 10.

[0278] In embodiments, a substituted R22(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted 25 heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R22is 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 R22is substituted, it is substituted with at 30 least one substituent group. In embodiments, when R22is substituted, it is substituted with at 92least one size-limited substituent group. In embodiments, when R22is substituted, it is substituted with at least one lower substituent group.

[0279] In embodiments, a substituted R22A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted 5 heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R22Ais 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 R22Ais substituted, it is 10 substituted with at least one substituent group. In embodiments, when R22Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R22Ais substituted, it is substituted with at least one lower substituent group.

[0280] In embodiments, a substituted R22B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted 15 heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R22Bis 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 R22Bis substituted, it is 20 substituted with at least one substituent group. In embodiments, when R22Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R22Bis substituted, it is substituted with at least one lower substituent group.

[0281] In embodiments, a substituted ring formed when R22Aand R22Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and / or substituted 25 heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R22Aand R22Bsubstituents 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 30 substituent group may optionally be different. In embodiments, when the substituted ring formed when R22Aand R22Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the 93substituted ring formed when R22Aand R22Bsubstituents 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 R22Aand R22Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower 5 substituent group.

[0282] In embodiments, a substituted R22C(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 R22Cis substituted with a plurality of 10 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 R22Cis substituted, it is substituted with at least one substituent group. In embodiments, when R22Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R22Cis 15 substituted, it is substituted with at least one lower substituent group.

[0283] In embodiments, a substituted R22D(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 R22Dis substituted with a plurality of 20 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 R22Dis substituted, it is substituted with at least one substituent group. In embodiments, when R22Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R22Dis 25 substituted, it is substituted with at least one lower substituent group.

[0284] In embodiments, R22Ais independently hydrogen. In embodiments, R22Ais independently unsubstituted C1-C4 alkyl. In embodiments, R22Ais independently unsubstituted methyl. In embodiments, R22Ais independently unsubstituted ethyl. In embodiments, R22Ais independently unsubstituted propyl. In embodiments, R22Ais 30 independently unsubstituted n-propyl. In embodiments, R22Ais independently unsubstituted isopropyl. In embodiments, R22Ais independently unsubstituted butyl. In embodiments, R22A94is independently unsubstituted n-butyl. In embodiments, R22Ais independently unsubstituted isobutyl. In embodiments, R22Ais independently unsubstituted tert-butyl.

[0285] In embodiments, R22Bis independently hydrogen. In embodiments, R22Bis independently unsubstituted C1-C4alkyl. In embodiments, R22Bis independently 5 unsubstituted methyl. In embodiments, R22Bis independently unsubstituted ethyl. In embodiments, R22Bis independently unsubstituted propyl. In embodiments, R22Bis independently unsubstituted n-propyl. In embodiments, R22Bis independently unsubstituted isopropyl. In embodiments, R22Bis independently unsubstituted butyl. In embodiments, R22Bis independently unsubstituted n-butyl. In embodiments, R22Bis independently unsubstituted 10 isobutyl. In embodiments, R22Bis independently unsubstituted tert-butyl.

[0286] In embodiments, R22Cis independently hydrogen. In embodiments, R22Cis independently unsubstituted C1-C4 alkyl. In embodiments, R22Cis independently unsubstituted methyl. In embodiments, R22Cis independently unsubstituted ethyl. In embodiments, R22Cis independently unsubstituted propyl. In embodiments, R22Cis 15 independently unsubstituted n-propyl. In embodiments, R22Cis independently unsubstituted isopropyl. In embodiments, R22Cis independently unsubstituted butyl. In embodiments, R22Cis independently unsubstituted n-butyl. In embodiments, R22Cis independently unsubstituted isobutyl. In embodiments, R22Cis independently unsubstituted tert-butyl.

[0287] In embodiments, R22Dis independently hydrogen. In embodiments, R22Dis 20 independently unsubstituted C1-C4alkyl. In embodiments, R22Dis independently unsubstituted methyl. In embodiments, R22Dis independently unsubstituted ethyl. In embodiments, R22Dis independently unsubstituted propyl. In embodiments, R22Dis independently unsubstituted n-propyl. In embodiments, R22Dis independently unsubstituted isopropyl. In embodiments, R22Dis independently unsubstituted butyl. In embodiments, R22D25 is independently unsubstituted n-butyl. In embodiments, R22Dis independently unsubstituted isobutyl. In embodiments, R22Dis independently unsubstituted tert-butyl.

[0288] In embodiments, R22is independently halogen. In embodiments, R22is independently –F. In embodiments, R22is independently –Cl. In embodiments, R22is independently –Br. In embodiments, R22is independently –I. In embodiments, R22is 30 independently -CCl3. In embodiments, R22is independently -CBr3. In embodiments, R22is independently -CF3. In embodiments, R22is independently -CI3. In embodiments, R22is independently -CH2Cl. In embodiments, R22is independently -CH2Br. In embodiments, R2295is independently -CH2F. In embodiments, R22is independently -CH2I. In embodiments, R22is independently -CHCl2. In embodiments, R22is independently -CHBr2. In embodiments, R22is independently -CHF2. In embodiments, R22is independently -CHI2. In embodiments, R22is independently –CN. In embodiments, R22is independently –OH. In embodiments, R225 is independently -NH2. In embodiments, R22is independently –COOH. In embodiments, R22is independently -CONH2. In embodiments, R22is independently -NO2. In embodiments, R22is independently –SH. In embodiments, R22is independently -SO3H. In embodiments, R22is independently -OSO3H. In embodiments, R22is independently -SO2NH2. In embodiments, R22is independently ^NHNH2. In embodiments, R22is independently ^ONH2. 10 In embodiments, R22is independently ^NHC(O)NH2. In embodiments, R22is independently -NHSO2H. In embodiments, R22is independently -NHC(O)H. In embodiments, R22is independently -NHC(O)OH. In embodiments, R22is independently –NHOH. In embodiments, R22is independently -OCCl3. In embodiments, R22is independently -OCBr3. In embodiments, R22is independently -OCF3. In embodiments, R2215 is independently -OCI3. In embodiments, R22is independently -OCH2Cl. In embodiments, R22is independently -OCH2Br. In embodiments, R22is independently -OCH2F. In embodiments, R22is independently -OCH2I. In embodiments, R22is independently -OCHCl2. In embodiments, R22is independently -OCHBr2. In embodiments, R22is independently -OCHF2. In embodiments, R22is independently -OCHI2. In embodiments, R22is 20 independently -SF5. In embodiments, R22is independently -N3. In embodiments, R22is independently unsubstituted C1-C4 alkyl. In embodiments, R22is independently unsubstituted methyl. In embodiments, R22is independently unsubstituted ethyl. In embodiments, R22is independently unsubstituted propyl. In embodiments, R22is independently unsubstituted n- propyl. In embodiments, R22is independently unsubstituted isopropyl. In embodiments, R2225 is independently unsubstituted butyl. In embodiments, R22is independently unsubstituted n- butyl. In embodiments, R22is independently unsubstituted isobutyl. In embodiments, R22is independently unsubstituted tert-butyl. In embodiments, R22is independently substituted or unsubstituted 2 to 6 membered heteroalkyl. In In embodiments, R22is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R22is independently 30 unsubstituted methoxy. In embodiments, R22is independently unsubstituted ethoxy. In embodiments, R22is independently unsubstituted propoxy. In embodiments, R22is independently unsubstituted n-propoxy. In embodiments, R22is independently unsubstituted isopropoxy. In embodiments, R22is independently unsubstituted butoxy. 96

[0289] In embodiments, z22 is 0. In embodiments, z22 is 1. In embodiments, z22 is 2. In embodiments, z22 is 3. In embodiments, z22 is 4.

[0290] In embodiments, a substituted R23(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted 5 heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R23is 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 R23is substituted, it is substituted with at 10 least one substituent group. In embodiments, when R23is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R23is substituted, it is substituted with at least one lower substituent group.

[0291] In embodiments, a substituted R23A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted 15 heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R23Ais 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 R23Ais substituted, it is 20 substituted with at least one substituent group. In embodiments, when R23Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R23Ais substituted, it is substituted with at least one lower substituent group.

[0292] In embodiments, a substituted R23B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted 25 heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R23Bis 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 R23Bis substituted, it is 30 substituted with at least one substituent group. In embodiments, when R23Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R23Bis substituted, it is substituted with at least one lower substituent group. 97

[0293] In embodiments, a substituted ring formed when R23Aand R23Bsubstituents 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 R23Aand R23B5 substituents 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 R23Aand R23Bsubstituents bonded to the same nitrogen atom are joined is 10 substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R23Aand R23Bsubstituents 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 R23Aand R23Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower 15 substituent group.

[0294] In embodiments, a substituted R23C(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 R23Cis substituted with a plurality of 20 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 R23Cis substituted, it is substituted with at least one substituent group. In embodiments, when R23Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R23Cis 25 substituted, it is substituted with at least one lower substituent group.

[0295] In embodiments, a substituted R23D(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 R23Dis substituted with a plurality of 30 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 R23Dis substituted, it is 98substituted with at least one substituent group. In embodiments, when R23Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R23Dis substituted, it is substituted with at least one lower substituent group.

[0296] In embodiments, R23Ais independently hydrogen. In embodiments, R23Ais 5 independently unsubstituted C1-C4 alkyl. In embodiments, R23Ais independently unsubstituted methyl. In embodiments, R23Ais independently unsubstituted ethyl. In embodiments, R23Ais independently unsubstituted propyl. In embodiments, R23Ais independently unsubstituted n-propyl. In embodiments, R23Ais independently unsubstituted isopropyl. In embodiments, R23Ais independently unsubstituted butyl. In embodiments, R23A10 is independently unsubstituted n-butyl. In embodiments, R23Ais independently unsubstituted isobutyl. In embodiments, R23Ais independently unsubstituted tert-butyl.

[0297] In embodiments, R23Bis independently hydrogen. In embodiments, R23Bis independently unsubstituted C1-C4alkyl. In embodiments, R23Bis independently unsubstituted methyl. In embodiments, R23Bis independently unsubstituted ethyl. In 15 embodiments, R23Bis independently unsubstituted propyl. In embodiments, R23Bis independently unsubstituted n-propyl. In embodiments, R23Bis independently unsubstituted isopropyl. In embodiments, R23Bis independently unsubstituted butyl. In embodiments, R23Bis independently unsubstituted n-butyl. In embodiments, R23Bis independently unsubstituted isobutyl. In embodiments, R23Bis independently unsubstituted tert-butyl. 20

[0298] In embodiments, R23Cis independently hydrogen. In embodiments, R23Cis independently unsubstituted C1-C4 alkyl. In embodiments, R23Cis independently unsubstituted methyl. In embodiments, R23Cis independently unsubstituted ethyl. In embodiments, R23Cis independently unsubstituted propyl. In embodiments, R23Cis independently unsubstituted n-propyl. In embodiments, R23Cis independently unsubstituted25 isopropyl. In embodiments, R23Cis independently unsubstituted butyl. In embodiments, R23Cis independently unsubstituted n-butyl. In embodiments, R23Cis independently unsubstituted isobutyl. In embodiments, R23Cis independently unsubstituted tert-butyl.

[0299] In embodiments, R23Dis independently hydrogen. In embodiments, R23Dis independently unsubstituted C1-C4alkyl. In embodiments, R23Dis independently 30 unsubstituted methyl. In embodiments, R23Dis independently unsubstituted ethyl. In embodiments, R23Dis independently unsubstituted propyl. In embodiments, R23Dis independently unsubstituted n-propyl. In embodiments, R23Dis independently unsubstituted 99isopropyl. In embodiments, R23Dis independently unsubstituted butyl. In embodiments, R23Dis independently unsubstituted n-butyl. In embodiments, R23Dis independently unsubstituted isobutyl. In embodiments, R23Dis independently unsubstituted tert-butyl.

[0300] In embodiments, R23is independently halogen. In embodiments, R23is 5 independently –F. In embodiments, R23is independently –Cl. In embodiments, R23is independently –Br. In embodiments, R23is independently –I. In embodiments, R23is independently -CCl3. In embodiments, R23is independently -CBr3. In embodiments, R23is independently -CF3. In embodiments, R23is independently -CI3. In embodiments, R23is independently -CH2Cl. In embodiments, R23is independently -CH2Br. In embodiments, R2310 is independently -CH2F. In embodiments, R23is independently -CH2I. In embodiments, R23is independently -CHCl2. In embodiments, R23is independently -CHBr2. In embodiments, R23is independently -CHF2. In embodiments, R23is independently -CHI2. In embodiments, R23is independently –CN. In embodiments, R23is independently –OH. In embodiments, R23is independently -NH2. In embodiments, R23is independently –COOH. In embodiments, R2315 is independently -CONH2. In embodiments, R23is independently -NO2. In embodiments, R23is independently –SH. In embodiments, R23is independently -SO3H. In embodiments, R23is independently -OSO3H. In embodiments, R23is independently -SO2NH2. In embodiments, R23is independently ^NHNH2. In embodiments, R23is independently ^ONH2. In embodiments, R23is independently ^NHC(O)NH2. In embodiments, R23is 20 independently -NHSO2H. In embodiments, R23is independently -NHC(O)H. In embodiments, R23is independently -NHC(O)OH. In embodiments, R23is independently –NHOH. In embodiments, R23is independently -OCCl3. In embodiments, R23is independently -OCBr3. In embodiments, R23is independently -OCF3. In embodiments, R23is independently -OCI3. In embodiments, R23is independently -OCH2Cl. In embodiments, 25 R23is independently -OCH2Br. In embodiments, R23is independently -OCH2F. In embodiments, R23is independently -OCH2I. In embodiments, R23is independently -OCHCl2. In embodiments, R23is independently -OCHBr2. In embodiments, R23is independently -OCHF2. In embodiments, R23is independently -OCHI2. In embodiments, R23is independently -SF5. In embodiments, R23is independently -N3. In embodiments, R23is 30 independently unsubstituted C1-C4 alkyl. In embodiments, R23is independently unsubstituted methyl. In embodiments, R23is independently unsubstituted ethyl. In embodiments, R23is independently unsubstituted propyl. In embodiments, R23is independently unsubstituted n- propyl. In embodiments, R23is independently unsubstituted isopropyl. In embodiments, R2310is independently unsubstituted butyl. In embodiments, R23is independently unsubstituted n- butyl. In embodiments, R23is independently unsubstituted isobutyl. In embodiments, R23is independently unsubstituted tert-butyl. In embodiments, R23is independently substituted or unsubstituted 2 to 6 membered heteroalkyl. In In embodiments, R23is independently 5 unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R23is independently unsubstituted methoxy. In embodiments, R23is independently unsubstituted ethoxy. In embodiments, R23is independently unsubstituted propoxy. In embodiments, R23is independently unsubstituted n-propoxy. In embodiments, R23is independently unsubstituted isopropoxy. In embodiments, R23is independently unsubstituted butoxy. 10

[0301] In embodiments, z23 is 0. In embodiments, z23 is 1. In embodiments, z23 is 2. In embodiments, z23 is 3. In embodiments, z23 is 4. In embodiments, z23 is 5.

[0302] 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. In embodiments, n is 5. In embodiments, n is 6. In embodiments, n is 7. In embodiments, n is 8. In embodiments, n is 9. In 15 embodiments, n is 10.

[0303] In embodiments, R11isR11is 20.

[0304] In embodiments, when R1is substituted, R1is substituted with one or more first 5 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, 10 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, 15 and RWW.3correspond to R1, R1.1, R1.2, and R1.3, respectively.

[0305] 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 20 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 10R2.3as 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, 5 and RWW.3correspond to R2, R2.1, R2.2, and R2.3, respectively.

[0306] 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 10 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 15 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.

[0307] 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 20 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 25 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. 30

[0308] In embodiments, when R5is substituted, R5is substituted with one or more first substituent groups denoted by R5.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5.1substituent group is 10substituted, the R5.1substituent group is substituted with one or more second substituent groups denoted by R5.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5.2substituent group is substituted, the R5.2substituent group is substituted with one or more third substituent groups denoted by 5 R5.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5, R5.1, R5.2, and R5.3have 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 R5, R5.1, R5.2, and R5.3, respectively. 10

[0309] In embodiments, when R6is substituted, R6is substituted with one or more first substituent groups denoted by R6.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6.1substituent group is substituted, the R6.1substituent group is substituted with one or more second substituent groups denoted by R6.2as explained in the definitions section above in the description of 15 “first substituent group(s)”. In embodiments, when an R6.2substituent group is substituted, the R6.2substituent group is substituted with one or more third substituent groups denoted by R6.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R6, R6.1, R6.2, and R6.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions 20 section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R6, R6.1, R6.2, and R6.3, respectively.

[0310] 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 25 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 substituent 30 group(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 10section 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.

[0311] 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 5 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 10 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. 15

[0312] 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 20 “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 25 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.

[0313] 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 30 is substituted, the R14.1substituent group is substituted with one or more second substituent groups 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, 10the 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 5 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.

[0314] In embodiments, when R15is substituted, R15is substituted with one or more first substituent groups denoted by R15.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R15.1substituent group 10 is substituted, the R15.1substituent group is substituted with one or more second substituent groups denoted by R15.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R15.2substituent group is substituted, the R15.2substituent group is substituted with one or more third substituent groups denoted by R15.3as explained in the definitions section above in the description of “first substituent 15 group(s)”. In the above embodiments, R15, R15.1, R15.2, and R15.3have 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 R15, R15.1, R15.2, and R15.3, respectively.

[0315] In embodiments, when R16is substituted, R16is substituted with one or more first 20 substituent groups denoted by R16.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R16.1substituent group is substituted, the R16.1substituent group is substituted with one or more second substituent groups denoted by R16.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R16.2substituent group is substituted, 25 the R16.2substituent group is substituted with one or more third substituent groups denoted by R16.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R16, R16.1, R16.2, and R16.3have 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, 30 and RWW.3correspond to R16, R16.1, R16.2, and R16.3, respectively.

[0316] In embodiments, when R17is substituted, R17is substituted with one or more first substituent groups denoted by R17.1as explained in the definitions section above in the 10description of “first substituent group(s)”. In embodiments, when an R17.1substituent group is substituted, the R17.1substituent group is substituted with one or more second substituent groups denoted by R17.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R17.2substituent group is substituted, 5 the R17.2substituent group is substituted with one or more third substituent groups denoted by R17.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R17, R17.1, R17.2, and R17.3have 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, 10 and RWW.3correspond to R17, R17.1, R17.2, and R17.3, respectively.

[0317] 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 15 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 20 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.

[0318] In embodiments, when R21is substituted, R21is substituted with one or more first substituent groups denoted by R21.1as explained in the definitions section above in the 25 description of “first substituent group(s)”. In embodiments, when an R21.1substituent group is substituted, the R21.1substituent group is substituted with one or more second substituent groups denoted by R21.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21.2substituent group is substituted, the R21.2substituent group is substituted with one or more third substituent groups denoted by 30 R21.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R21, R21.1, R21.2, and R21.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions 10section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R21, R21.1, R21.2, and R21.3, respectively.

[0319] In embodiments, when R21Ais substituted, R21Ais substituted with one or more first substituent groups denoted by R21A.1as explained in the definitions section above in the 5 description of “first substituent group(s)”. In embodiments, when an R21A.1substituent group is substituted, the R21A.1substituent group is substituted with one or more second substituent groups denoted by R21A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21A.2substituent group is substituted, the R21A.2substituent group is substituted with one or more third substituent groups denoted 10 by R21A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R21A, R21A.1, R21A.2, and R21A.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 R21A, R21A.1, R21A.2, and R21A.3, respectively. 15

[0320] In embodiments, when R21Bis substituted, R21Bis substituted with one or more first substituent groups denoted by R21B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21B.1substituent group is substituted, the R21B.1substituent group is substituted with one or more second substituent groups denoted by R21B.2as explained in the definitions section above in the description of 20 “first substituent group(s)”. In embodiments, when an R21B.2substituent group is substituted, the R21B.2substituent group is substituted with one or more third substituent groups denoted by R21B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R21B, R21B.1, R21B.2, and R21B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in 25 the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R21B, R21B.1, R21B.2, and R21B.3, respectively.

[0321] In embodiments, when R21Aand R21Bsubstituents 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 30 denoted by R21A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21A.1substituent group is substituted, the R21A.1substituent group is substituted with one or more second substituent groups denoted by 10R21A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21A.2substituent group is substituted, the R21A.2substituent group is substituted with one or more third substituent groups denoted by R21A.3as explained in the definitions section above in the description of “first substituent group(s)”. In 5 the above embodiments, R21A.1, R21A.2, and R21A.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 R21A.1, R21A.2, and R21A.3, respectively.

[0322] In embodiments, when R21Aand R21Bsubstituents bonded to the same nitrogen atom 10 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 R21B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21B.1substituent group is substituted, the R21B.1substituent group is substituted with one or more second substituent groups denoted by 15 R21B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21B.2substituent group is substituted, the R21B.2substituent group is substituted with one or more third substituent groups denoted by R21B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R21B.1, R21B.2, and R21B.3have values corresponding to the values of 20 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 R21B.1, R21B.2, and R21B.3, respectively.

[0323] In embodiments, when R21Cis substituted, R21Cis substituted with one or more first substituent groups denoted by R21C.1as explained in the definitions section above in the 25 description of “first substituent group(s)”. In embodiments, when an R21C.1substituent group is substituted, the R21C.1substituent group is substituted with one or more second substituent groups denoted by R21C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21C.2substituent group is substituted, the R21C.2substituent group is substituted with one or more third substituent groups denoted 30 by R21C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R21C, R21C.1, R21C.2, and R21C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in 10the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R21C, R21C.1, R21C.2, and R21C.3, respectively.

[0324] In embodiments, when R21Dis substituted, R21Dis substituted with one or more first substituent groups denoted by R21D.1as explained in the definitions section above in the 5 description of “first substituent group(s)”. In embodiments, when an R21D.1substituent group is substituted, the R21D.1substituent group is substituted with one or more second substituent groups denoted by R21D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21D.2substituent group is substituted, the R21D.2substituent group is substituted with one or more third substituent groups denoted 10 by R21D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R21D, R21D.1, R21D.2, and R21D.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 R21D, R21D.1, R21D.2, and R21D.3, respectively. 15

[0325] In embodiments, when R22is substituted, R22is substituted with one or more first substituent groups denoted by R22.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R22.1substituent group is substituted, the R22.1substituent group is substituted with one or more second substituent groups denoted by R22.2as explained in the definitions section above in the description of 20 “first substituent group(s)”. In embodiments, when an R22.2substituent group is substituted, the R22.2substituent group is substituted with one or more third substituent groups denoted by R22.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R22, R22.1, R22.2, and R22.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions 25 section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R22, R22.1, R22.2, and R22.3, respectively.

[0326] In embodiments, when R22Ais substituted, R22Ais substituted with one or more first substituent groups denoted by R22A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R22A.1substituent group 30 is substituted, the R22A.1substituent group is substituted with one or more second substituent groups denoted by R22A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R22A.2substituent group is substituted, 11the R22A.2substituent group is substituted with one or more third substituent groups denoted by R22A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R22A, R22A.1, R22A.2, and R22A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in 5 the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R22A, R22A.1, R22A.2, and R22A.3, respectively.

[0327] In embodiments, when R22Bis substituted, R22Bis substituted with one or more first substituent groups denoted by R22B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R22B.1substituent group 10 is substituted, the R22B.1substituent group is substituted with one or more second substituent groups denoted by R22B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R22B.2substituent group is substituted, the R22B.2substituent group is substituted with one or more third substituent groups denoted by R22B.3as explained in the definitions section above in the description of “first substituent 15 group(s)”. In the above embodiments, R22B, R22B.1, R22B.2, and R22B.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 R22B, R22B.1, R22B.2, and R22B.3, respectively.

[0328] In embodiments, when R22Aand R22Bsubstituents bonded to the same nitrogen atom 20 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 R22A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R22A.1substituent group is substituted, the R22A.1substituent group is substituted with one or more second substituent groups denoted by 25 R22A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R22A.2substituent group is substituted, the R22A.2substituent group is substituted with one or more third substituent groups denoted by R22A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R22A.1, R22A.2, and R22A.3have values corresponding to the values of 30 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 R22A.1, R22A.2, and R22A.3, respectively. 11

[0329] In embodiments, when R22Aand R22Bsubstituents 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 R22B.1as explained in the definitions section above in the description of “first 5 substituent group(s)”. In embodiments, when an R22B.1substituent group is substituted, the R22B.1substituent group is substituted with one or more second substituent groups denoted by R22B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R22B.2substituent group is substituted, the R22B.2substituent group is substituted with one or more third substituent groups denoted by R22B.3as 10 explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R22B.1, R22B.2, and R22B.3have values corresponding to the values ofRWW.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 R22B.1, R22B.2, and R22B.3, respectively. 15

[0330] In embodiments, when R22Cis substituted, R22Cis substituted with one or more first substituent groups denoted by R22C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R22C.1substituent group is substituted, the R22C.1substituent group is substituted with one or more second substituent groups denoted by R22C.2as explained in the definitions section above in the description of 20 “first substituent group(s)”. In embodiments, when an R22C.2substituent group is substituted, the R22C.2substituent group is substituted with one or more third substituent groups denoted by R22C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R22C, R22C.1, R22C.2, and R22C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in 25 the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R22C, R22C.1, R22C.2, and R22C.3, respectively.

[0331] In embodiments, when R22Dis substituted, R22Dis substituted with one or more first substituent groups denoted by R22D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R22D.1substituent group 30 is substituted, the R22D.1substituent group is substituted with one or more second substituent groups denoted by R22D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R22D.2substituent group is substituted, 11the R22D.2substituent group is substituted with one or more third substituent groups denoted by R22D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R22D, R22D.1, R22D.2, and R22D.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in 5 the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R22D, R22D.1, R22D.2, and R22D.3, respectively.

[0332] In embodiments, when R23is substituted, R23is substituted with one or more first substituent groups denoted by R23.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R23.1substituent group 10 is substituted, the R23.1substituent group is substituted with one or more second substituent groups denoted by R23.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R23.2substituent group is substituted, the R23.2substituent group is substituted with one or more third substituent groups denoted by R23.3as explained in the definitions section above in the description of “first substituent 15 group(s)”. In the above embodiments, R23, R23.1, R23.2, and R23.3have 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 R23, R23.1, R23.2, and R23.3, respectively.

[0333] In embodiments, when R23Ais substituted, R23Ais substituted with one or more first 20 substituent groups denoted by R23A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R23A.1substituent group is substituted, the R23A.1substituent group is substituted with one or more second substituent groups denoted by R23A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R23A.2substituent group is substituted, 25 the R23A.2substituent group is substituted with one or more third substituent groups denoted by R23A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R23A, R23A.1, R23A.2, and R23A.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, 30 RWW.1, RWW.2, and RWW.3correspond to R23A, R23A.1, R23A.2, and R23A.3, respectively.

[0334] In embodiments, when R23Bis substituted, R23Bis substituted with one or more first substituent groups denoted by R23B.1as explained in the definitions section above in the 11description of “first substituent group(s)”. In embodiments, when an R23B.1substituent group is substituted, the R23B.1substituent group is substituted with one or more second substituent groups denoted by R23B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R23B.2substituent group is substituted, 5 the R23B.2substituent group is substituted with one or more third substituent groups denoted by R23B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R23B, R23B.1, R23B.2, and R23B.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, 10 RWW.1, RWW.2, and RWW.3correspond to R23B, R23B.1, R23B.2, and R23B.3, respectively.

[0335] In embodiments, when R23Aand R23Bsubstituents 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 R23A.1as explained in the definitions section above in the description of “first 15 substituent group(s)”. In embodiments, when an R23A.1substituent group is substituted, the R23A.1substituent group is substituted with one or more second substituent groups denoted by R23A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R23A.2substituent group is substituted, the R23A.2substituent group is substituted with one or more third substituent groups denoted by R23A.3as 20 explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R23A.1, R23A.2, and R23A.3have values corresponding to the values ofespectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R23A.1, R23A.2, and R23A.3, respectively. 25

[0336] In embodiments, when R23Aand R23Bsubstituents 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 R23B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R23B.1substituent group is substituted, the 30 R23B.1substituent group is substituted with one or more second substituent groups denoted by R23B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R23B.2substituent group is substituted, the R23B.211substituent group is substituted with one or more third substituent groups denoted by R23B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R23B.1, R23B.2, and R23B.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 R23B.1, R23B.2, and R23B.3, respectively.

[0337] In embodiments, when R23Cis substituted, R23Cis substituted with one or more first substituent groups denoted by R23C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R23C.1substituent group is substituted, the R23C.1substituent group is substituted with one or more second substituent groups denoted by R23C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R23C.2substituent group is substituted, the R23C.2substituent group is substituted with one or more third substituent groups denoted by R23C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R23C, R23C.1, R23C.2, and R23C.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 R23C, R23C.1, R23C.2, and R23C.3, respectively.

[0338] In embodiments, when R23Dis substituted, R23Dis substituted with one or more first substituent groups denoted by R23D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R23D.1substituent group is substituted, the R23D.1substituent group is substituted with one or more second substituent groups denoted by R23D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R23D.2substituent group is substituted, the R23D.2substituent group is substituted with one or more third substituent groups denoted by R23D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R23D, R23D.1, R23D.2, and R23D.3have values corresponding to the values of RWW, RWW.1, RWW.2, andRWW.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 R23D, R23D.1, R23D.2, and R23D.3, respectively.

[0339] In embodiments, when R101is substituted, R101is substituted with one or more first substituent groups denoted by R101.1as explained in the definitions section above in thedescription of “first substituent group(s)”. In embodiments, when an R101.1substituent group is substituted, the R101.1substituent group is substituted with one or more second substituent groups denoted by R101.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R101.2substituent group is substituted, 5 the R101.2substituent group is substituted with one or more third substituent groups denoted by R101.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R101, R101.1, R101.2, and R101.3have values corresponding to the values of RWW, RWW.1, RW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, 10 RWW.1, RWW.2, and RWW.3correspond to R101, R101.1, R101.2, and R101.3, respectively.

[0340] In embodiments, when R101Ais substituted, R101Ais substituted with one or more first substituent groups denoted by R101A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R101A.1substituent group is substituted, the R101A.1substituent group is substituted with one or more second 15 substituent groups denoted by R101A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R101A.2substituent group is substituted, the R101A.2substituent group is substituted with one or more third substituent groups denoted by R101A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R101A, R101A.1, R101A.2, 20 and R101A.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 R101A, R101A.1, R101A.2, and R101A.3, respectively.

[0341] In embodiments, when R102is substituted, R102is substituted with one or more first 25 substituent groups denoted by R102.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R102.1substituent group is substituted, the R102.1substituent group is substituted with one or more second substituent groups denoted by R102.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R102.2substituent group is substituted, 30 the R102.2substituent group is substituted with one or more third substituent groups denoted by R102.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R102, R102.1, R102.2, and R102.3have values 11corresponding 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 R102, R102.1, R102.2, and R102.3, respectively.

[0342] In embodiments, when R102Ais substituted, R102Ais substituted with one or more 5 first substituent groups denoted by R102A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R102A.1substituent group is substituted, the R102A.1substituent group is substituted with one or more second substituent groups denoted by R102A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R102A.2substituent 10 group is substituted, the R102A.2substituent group is substituted with one or more third substituent groups denoted by R102A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R102A, R102A.1, R102A.2, and R102A.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 15 substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R102A, R102A.1, R102A.2, and R102A.3, respectively.

[0343] In embodiments, when R103is substituted, R103is substituted with one or more first substituent groups denoted by R103.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R103.1substituent group 20 is substituted, the R103.1substituent group is substituted with one or more second substituent groups denoted by R103.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R103.2substituent group is substituted, the R103.2substituent group is substituted with one or more third substituent groups denoted by R103.3as explained in the definitions section above in the description of “first substituent 25 group(s)”. In the above embodiments, R103, R103.1, R103.2, and R103.3have 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 R103, R103.1, R103.2, and R103.3, respectively.

[0344] In embodiments, when R103Ais substituted, R103Ais substituted with one or more 30 first substituent groups denoted by R103A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R103A.1substituent group is substituted, the R103A.1substituent group is substituted with one or more second 11substituent groups denoted by R103A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R103A.2substituent group is substituted, the R103A.2substituent group is substituted with one or more third substituent groups denoted by R103A.3as explained in the definitions section above in the 5 description of “first substituent group(s)”. In the above embodiments, R103A, R103A.1, R103A.2, and R103A.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 R103A, R103A.1, R103A.2, and R103A.3, respectively. 10

[0345] In embodiments, when R104is substituted, R104is substituted with one or more first substituent groups denoted by R104.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R104.1substituent group is substituted, the R104.1substituent group is substituted with one or more second substituent groups denoted by R104.2as explained in the definitions section above in the description of 15 “first substituent group(s)”. In embodiments, when an R104.2substituent group is substituted, the R104.2substituent group is substituted with one or more third substituent groups denoted by R104.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R104, R104.1, R104.2, and R104.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in 20 the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R104, R104.1, R104.2, and R104.3, respectively.

[0346] In embodiments, when R104Ais substituted, R104Ais substituted with one or more first substituent groups denoted by R104A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R104A.1substituent 25 group is substituted, the R104A.1substituent group is substituted with one or more second substituent groups denoted by R104A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R104A.2substituent group is substituted, the R104A.2substituent group is substituted with one or more third substituent groups denoted by R104A.3as explained in the definitions section above in the 30 description of “first substituent group(s)”. In the above embodiments, R104A, R104A.1, R104A.2, and R104A.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 11substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R104A, R104A.1, R104A.2, and R104A.3, respectively.

[0347] In embodiments, when R105is substituted, R105is substituted with one or more first substituent groups denoted by R105.1as explained in the definitions section above in the 5 description of “first substituent group(s)”. In embodiments, when an R105.1substituent group is substituted, the R105.1substituent group is substituted with one or more second substituent groups denoted by R105.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R105.2substituent group is substituted, the R105.2substituent group is substituted with one or more third substituent groups denoted 10 by R105.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R105, R105.1, R105.2, and R105.3have 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 R105, R105.1, R105.2, and R105.3, respectively. 15

[0348] In embodiments, when R105Ais substituted, R105Ais substituted with one or more first substituent groups denoted by R105A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R105A.1substituent group is substituted, the R105A.1substituent group is substituted with one or more second substituent groups denoted by R105A.2as explained in the definitions section above in the 20 description of “first substituent group(s)”. In embodiments, when an R105A.2substituent group is substituted, the R105A.2substituent group is substituted with one or more third substituent groups denoted by R105A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R105A, R105A.1, R105A.2, and R105A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, 25 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 R105A, R105A.1, R105A.2, and R105A.3, respectively.

[0349] In embodiments, when L101is substituted, L101is substituted with one or more first substituent groups denoted by RL101.1as explained in the definitions section above in the 30 description of “first substituent group(s)”. In embodiments, when an RL101.1substituent group is substituted, the RL101.1substituent group is substituted with one or more second substituent groups denoted by RL101.2as explained in the definitions section above in the description of 11“first substituent group(s)”. In embodiments, when an RL101.2substituent group is substituted, the RL101.2substituent group is substituted with one or more third substituent groups denoted by RL101.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L101, RL101.1, RL101.2, and RL101.3havalues 5 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

[0350] In embodiments, when L102is substituted, L102is substituted with one or more first substituent groups denoted by RL102.1as explained in the definitions section above in the 10 description of “first substituent group(s)”. In embodiments, when an RL102.1substituent group is substituted, the RL102.1substituent group is substituted with one or more second substituent groups denoted by RL102.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL102.2substituent group is substituted, the RL102.2substituent group is substituted with one or more third substituent groups denoted 15 by RL102.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L102, RL102.1, RL102.2, and RL102.3have 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 Lspectively. 20

[0351] In embodiments, when L103is substituted, L103is substituted with one or more first substituent groups denoted by RL103.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL103.1substituent group is substituted, the RL103.1substituent group is substituted with one or more second substituent groups denoted by RL103.2as explained in the definitions section above in the description of 25 “first substituent group(s)”. In embodiments, when an RL103.2substituent group is substituted, the RL103.2substituent group is substituted with one or more third substituent groups denoted by RL103.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L103, RL103.1, RL103.2, and RL103.3have values corresponding to the values of LWW, RLWW.1, RLWW.2, and RLWW.3, respectively, as explained 30 in the definitions section above in the description of “first substituent group(s)”, wherein

[0352] In embodiments, when L104is substituted, L104is substituted with one or more first substituent groups denoted by RL104.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL104.1substituent group is substituted, the RL104.1substituent group is substituted with one or more second substituent 5 groups denoted by RL104.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL104.2substituent group is substituted, the RL104.2substituent group is substituted with one or more third substituent groups denoted by RL104.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L104, RL104.1, RL104.2, and RL104.3have values 10 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 Lspectively.

[0353] In embodiments, when L105is substituted, L105is substituted with one or more first substituent groups denoted by RL105.1as explained in the definitions section above in the 15 description of “first substituent group(s)”. In embodiments, when an RL105.1substituent group is substituted, the RL105.1substituent group is substituted with one or more second substituent groups denoted by RL105.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL105.2substituent group is substituted, the RL105.2substituent group is substituted with one or more third substituent groups denoted 20 by RL105.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L105, RL105.1, RL105.2, and RL105.3have 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 L12[ 5embodiments, the compound has the formula:. n embodiments, the compound has the formula:. n embodiments, the compound has the formula:embodiments, the compound has the formula:5 embodiments, the compound has the fo12embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:

[0355] In embodiments, the compound is useful as a comparator compound. In 5 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).

[0356] 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 10 examples section, figures, tables, or claims). III. Pharmaceutical compositions

[0357] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 15

[0358] 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. In embodiments, the compound is a compound of formula (I), (II), or (III), including all embodiments thereof. 12IV. Methods of use

[0359] In an aspect is provided a method of detecting a target substance, the method including contacting a sample with a compound described herein, or a salt thereof; and detecting an emission light from the compound, the emission light indicating the presence of 5 the target substance. In embodiments, the compound is a compound of formula (I), (II), or (III), including all embodiments thereof.

[0360] In embodiments, the sample is a biological sample. In embodiments, the detecting step is performed with a microscope.

[0361] In embodiments, the method further includes exposing the compound to an 10 absorption light including a wavelength of about 100 nm to about 2,500 nm. In embodiments, the absorption light includes a wavelength of about 100 nm to about 1,000 nm. In embodiments, the absorption light includes a wavelength of about 100 nm to about 900 nm. In embodiments, the absorption light includes a wavelength of about 100 nm to about 800 nm. In embodiments, the absorption light includes a wavelength of about 100 nm to 15 about 700 nm. In embodiments, the absorption light includes a wavelength of about 100 nm to about 600 nm. In embodiments, the absorption light includes a wavelength of about 100 nm to about 500 nm. In embodiments, the absorption light includes a wavelength of about 200 nm to about 2,500 nm. In embodiments, the absorption light includes a wavelength of about 300 nm to about 2,500 nm. In embodiments, the absorption light includes a 20 wavelength of about 400 nm to about 2,500 nm. In embodiments, the absorption light includes a wavelength of about 500 nm to about 2,500 nm. In embodiments, the absorption light includes a wavelength of about 600 nm to about 2,500 nm. In embodiments, the absorption light includes a wavelength of about 700 nm to about 2,500 nm. In embodiments, the absorption light includes a wavelength of about 800 nm to about 2,500 nm. 25

[0362] In embodiments, the contacting step and the detecting step are performed in a live cell. In embodiments, the contacting step and the detecting step are performed in vivo.

[0363] In an aspect is provided a method of imaging a cell, the method including: (i) contacting the cell with a compound described herein, or a salt thereof, including in embodiments; (ii) illuminating the cell with a first wavelength of light; and (iii) imaging the 30 cell by detecting a second wavelength of light; wherein the first wavelength of light and the second wavelength of light are different. In embodiments, the compound is a compound of formula (I), (II), or (III), including all embodiments thereof. 12

[0364] In embodiments, the second wavelength of light is in the far red to near infrared region.

[0365] In embodiments, the method further includes: (iv) contacting the cell with one or more optogenetic tools; and (v) imaging the cell by detecting light emissions at one or more 5 additional wavelengths. In embodiments, the one or more optogenetic tools are selected from GFP, Ca2+indicators, fluorescent voltage sensors, and ChannelRhodopsin2 (ChR2).

[0366] In an aspect is provided a method of measuring changes in membrane potential in an excitable cell, the method including: (i) contacting the excitable cell with a compound described herein, or a salt thereof; (ii) stimulating the excitable cell to evoke action 10 potentials; and (iii) measuring action potential firing by optical or electrical sampling. In embodiments, the compound is a compound of formula (I), (II), or (III), including all embodiments thereof.

[0367] In embodiments, the optical sampling is measured using a camera. In embodiments, the camera is a charge-coupled device. In embodiments, the camera is an active-pixel sensor. 15 In embodiments, the charge-coupled device is an electron multiplying charge-coupled device. In embodiments, the charge-coupled device is a complementary metal-oxide-semiconductor (CMOS). In embodiments, the complementary metal-oxide-semiconductor is a Scientific CMOS (sCMOS). In embodiments, the optical sampling is measured using confocal microscopy. 20

[0368] In embodiments, the excitable cell is stimulated using a whole-cell current clamp or by field stimulation. In embodiments, the excitable cell is a neuron, cardiomyocyte, myocyte, or a secretory cell. V. Embodiments

[0369] Embodiment P1. A compound, or a salt thereof, having the formula: 25D1and D2are independently an electron donating moiety; 12A1and A2are independently an electron accepting moiety; n1 and n2 are independently 0 or 1; W1is N or C(R11); R11is hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted 5 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -L1-R20; L1is a bond or a divalent linker; R20is a substituted or unsubstituted aryl, a monovalent form of a biomolecule, or a 10 monovalent form of a drug; R1and R6are independently hydrogen, deuterium, 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; 15 R2, R3, R4, and R5are independently hydrogen, deuterium, halogen, 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 R7, R8, R9, and R10are independently hydrogen, deuterium, or halogen. 20

[0370] Embodiment P2. The compound of embodiment P1, having the formula:

[0371] Embodiment P3. The compound of embodiment P1, having the formula:

[0372] Embodiment P4. The compound of one of embodiments P1 to P3, wherein D1and D2are independentlyherein 5 R12and R13are independently hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0373] Embodiment P5. The compound of one of embodiments P1 to P3, wherein D1and D2are.

[0374] Embodiment P6. The compound of one of embodiments P1 to P3, having the 10 f

[0375] Embodiment P7. The compound of one of embodiments P1 to P6, wherein A1a,R14, R15, R16, and R17are independently hydrogen, -ORA, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or 5 unsubstituted heteroaryl; and RAis independently hydrogen or unsubstituted alkyl.

[0376] Embodiment P8. The compound of one of embodiments P1 to P6, wherein A1a10

[0377] Embodiment P9. The compound of one of embodiments P1 to P8, wherein L1is -L101-L102-L103-L104-L105-; L101is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR101, -C(O)NR101-, -NR101C(O)-, -NR101C(O)O-, -OC(O)NR101-, -NR101C(O)NR101A-, -S(O)2-, -NR101S(O)2-, -S(O)2NR101-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted 15 or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L102is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR102, -C(O)NR102-, -NR102C(O)-, -NR102C(O)O-, -OC(O)NR102-, -NR102C(O)NR102A-, -S(O)2-, -N...

Claims

WHAT IS CLAIMED IS: 1 1. A compound, or a salt thereof, having the formula: 23 wherein 4 D1and D2are independently an electron donating moiety; 5 A1and A2are independently an electron accepting moiety; 6 n1 and n2 are independently 0 or 1; 7 W1is N or C(R11); 8 R11is hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or 9 unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted 10 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, 11 or -L1-R20; 12 L1is a bond or a divalent linker; 13 R20is a substituted or unsubstituted aryl, a monovalent form of a biomolecule, 14 or a monovalent form of a drug; 15 R1and R6are independently hydrogen, deuterium, substituted or unsubstituted 16 alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, 17 substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted 18 or unsubstituted heteroaryl; 19 R2, R3, R4, and R5are independently hydrogen, deuterium, halogen, 20 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or 21 unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or 22 unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 23 R7, R8, R9, and R10are independently hydrogen, deuterium, or halogen. 1 2. The compound of claim 1, having the formula: 172 1 3 21 4. The compound of claim 1, wherein D1and D2are independently 2herein 3 R12and R13are independently hydrogen, deuterium, halogen, substituted or 4 unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted 5 heteroaryl. 1 5The compound of claim 1, wherein D1and D2are. 1 6. The compound of claim 1, having the formula: 2 1 72 3 4 5 , 67 R14, R15, R16, and R17are independently hydrogen, -ORA, substituted or 8 unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, 9 or substituted or unsubstituted heteroaryl; and 10 RAis independently hydrogen or unsubstituted alkyl. 1 8. The compound of claim 1, wherein A1and A2are independently 2 31 9. The compound of claim 1, wherein L1is -L101-L102-L103-L104-L105-; 2 L101is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR101, -C(O)NR101-, 3 -NR101C(O)-, -NR101C(O)O-, -OC(O)NR101-, -NR101C(O)NR101A-, -S(O)2-, -NR101S(O)2-, 4 -S(O)2NR101-, substituted or unsubstituted alkylene, substituted or unsubstituted 5 heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted 176 heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted 7 heteroarylene; 8 L102is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR102, -C(O)NR102-, 9 -NR102C(O)-, -NR102C(O)O-, -OC(O)NR102-, -NR102C(O)NR102A-, -S(O)2-, -NR102S(O)2-, 10 -S(O)2NR102-, substituted or unsubstituted alkylene, substituted or unsubstituted 11 heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted 12 heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted 13 heteroarylene; 14 L103is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR103, -C(O)NR103-, 15 -NR103C(O)-, -NR103C(O)O-, -OC(O)NR103-, -NR103C(O)NR103A-, -S(O)2-, -NR103S(O)2-, 16 -S(O)2NR103-, substituted or unsubstituted alkylene, substituted or unsubstituted 17 heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted 18 heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted 19 heteroarylene; 20 L104is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR104, -C(O)NR104-, 21 -NR104C(O)-, -NR104C(O)O-, -OC(O)NR104-, -NR104C(O)NR104A-, -S(O)2-, -NR104S(O)2-, 22 -S(O)2NR104-, substituted or unsubstituted alkylene, substituted or unsubstituted 23 heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted 24 heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted 25 heteroarylene; 26 L105is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR105, -C(O)NR105-, 27 -NR105C(O)-, -NR105C(O)O-, -OC(O)NR105-, -NR105C(O)NR105A-, -S(O)2-, -NR105S(O)2-, 28 -S(O)2NR105-, substituted or unsubstituted alkylene, substituted or unsubstituted 29 heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted 30 heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted 31 heteroarylene; and 32 R33 independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, 34 -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCBr3, -OCF3, -OCI3, 35 -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or 36 unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 37 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or 38 substituted or unsubstituted heteroaryl. 171 10. The compound of claim 1, wherein R20is a monovalent form of a 2 nucleic acid or a monovalent form of a protein. 1 11. The compound of claim 1, wherein R11is R21-substituted or 2 unsubstituted alkyl, R21-substituted or unsubstituted heteroalkyl, R21-substituted or 3 unsubstituted cycloalkyl, R21-substituted or unsubstituted heterocycloalkyl, R21-substituted or 4 unsubstituted aryl, or R21-substituted or unsubstituted heteroaryl; 5 R21is independently oxo, halogen, -CX213, -CHX212, -CH2X21, -OCX213, 6 -OCH2X21, -OCHX212, -CN, -SOn21R21D, -SOv21NR21AR21B, ^NR21CNR21AR21B, 7 ^ONR21AR21B, -NR21CC(O)NR21AR21B, -N(O)m21, -NR21AR21B, -C(O)R21C, -C(O)OR21C, 8 -OC(O)R21C, -OC(O)OR21C, -C(O)NR21AR21B, -C(NR21C)NR21AR21B, -OC(O)NR21AR21B, 9 -OR21D, -SR21D, -NR21ASO2R21D, -NR21AC(O)R21C, substituted or unsubstituted alkyl, 10 substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or 11 unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or 12 unsubstituted heteroaryl; 13 R21A, R21B, R21C, and R21Dare independently hydrogen, -CCl3, -CBr3, -CF3, 14 -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, 15 -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, 16 -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or 17 unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted 18 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 19 R21Aand R21Bsubstituents bonded to the same nitrogen atom may optionally be joined to 20 form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted 21 heteroaryl; 22 each X21is independently –F, -Cl, -Br, or –I; 23 n21 is independently an integer from 0 to 4; 24 m21 and v21 are independently 1 or 2; and 25 z21 is an integer from 0 to 11. 1 12. The compound of claim 11, wherein R11is R21-substituted or 2 unsubstituted phenyl. 171 13. The compound of claim 1, wherein R11 14. The compound of claim 1, wherein R11is 21 15. The compound of claim 1, wherein R11is 23 R21is independently halogen, -CX213, -CHX212, -CH2X21, -OCX213, -OCH2X21, 4 -OCHX212, -CN, -SOn21R21D, -SOv21NR21AR21B, ^NR21CNR21AR21B, ^ONR21AR21B, 5 -NR21CC(O)NR21AR21B, -N(O)m21, -NR21AR21B, -C(O)R21C, -C(O)OR21C, -OC(O)R21C, 6 -OC(O)OR21C, -C(O)NR21AR21B, -C(NR21C)NR21AR21B, -OC(O)NR21AR21B, -OR21D, -SR21D, 7 -NR21ASO2R21D, -NR21AC(O)R21C, substituted or unsubstituted alkyl, substituted or 8 unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted 9 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 10 R22is independently halogen, -CX223, -CHX222, -CH2X22, -OCX223, -OCH2X22, 11 -OCHX222, -CN, -SOn22R22D, -SOv22NR22AR22B, ^NR22CNR22AR22B, ^ONR22AR22B, 12 -NR22CC(O)NR22AR22B, -N(O)m22, -NR22AR22B, -C(O)R22C, -C(O)OR22C, -OC(O)R22C, 13 -OC(O)OR22C, -C(O)NR22AR22B, -C(NR22C)NR22AR22B, -OC(O)NR22AR22B, -OR22D, -SR22D, 14 -NR22ASO2R22D, -NR22AC(O)R22C, substituted or unsubstituted alkyl, substituted or 15 unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted 16 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 17 R23is independently halogen, -CX233, -CHX232, -CH2X23, -OCX233, -OCH2X23, 18 -OCHX232, -CN, -SOn23R23D, -SOv23NR23AR23B, ^NR23CNR23AR23B, ^ONR23AR23B, 19 -NR23CC(O)NR23AR23B, -N(O)m23, -NR23AR23B, -C(O)R23C, -C(O)OR23C, -OC(O)R23C, 20 -OC(O)OR23C, -C(O)NR23AR23B, -C(NR23C)NR23AR23B, -OC(O)NR23AR23B, -OR23D, -SR23D, 17721 -NR23ASO2R23D, -NR23AC(O)R23C, substituted or unsubstituted alkyl, substituted or 22 unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted 23 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 24 R25 independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, 26 -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, 27 -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or 28 unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 29 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or 30 substituted or unsubstituted heteroaryl; R21Aand R21Bsubstituents bonded to the same 31 nitrogen atom may optionally be joined to form a substituted or unsubstituted 32 heterocycloalkyl or substituted or unsubstituted heteroaryl; R22Aand R22Bsubstituents bonded 33 to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted 34 heterocycloalkyl or substituted or unsubstituted heteroaryl; R23Aand R23Bsubstituents bonded 35 to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted 36 heterocycloalkyl or substituted or unsubstituted heteroaryl; 37 each X21, X22, and X23is independently –F, -Cl, -Br, or –I; 38 n21, n22, and n23 are independently an integer from 0 to 4; 39 m21, m22, m23, v21, v22, and v23 are independently 1 or 2; 40 z21 is an integer from 0 to 4; 41 z22 is an integer from 0 to 4; 42 z23 is an integer from 0 to 5; and 43 n is an integer from 0 to 10. 1 16. The compound of claim 15, wherein R11is 172 3 4 1 2 34 5 61 18. A pharmaceutical composition comprising the compound of one of 2 claims 1 to 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically 3 acceptable excipient. 1 19. A method of detecting a target substance, said method comprising 2 contacting a sample with the compound of one of claims 1 to 17, or a salt thereof; and 3 detecting an emission light from the compound, the emission light indicating the presence of 4 the target substance. 1 20. The method of claim 19, wherein the sample is a biological sample. 1 21. The method of claim 19, wherein the detecting step is performed with 2 a microscope. 1 22. The method of claim 19, further comprising exposing the compound to 2 an absorption light comprising a wavelength of about 100 nm to about 2,500 nm. 181 23. The method of claim 19, wherein the contacting step and the detecting 2 step are performed in a live cell. 1 24. The method of claim 19, wherein the contacting step and the detecting 2 step are performed in vivo. 1 25. A method of imaging a cell, said method comprising:2 (i) contacting the cell with the compound of one of claims 1 to 17, or a3 salt thereof;4 (ii) illuminating the cell with a first wavelength of light; and5 (iii) imaging the cell by detecting a second wavelength of light;6 wherein the first wavelength of light and the second wavelength of light are 7 different. 1 26. The method of claim 25, wherein the second wavelength of light is in 2 the far red to near infrared region. 1 27. The method of claim 25, further comprising: 2 (iv) contacting the cell with one or more optogenetic tools; and 3 (v) imaging the cell by detecting light emissions at one or more additional 4 wavelengths. 1 28. The method of claim 27, wherein the one or more optogenetic tools are 2 selected from GFP, Ca2+indicators, fluorescent voltage sensors, and ChannelRhodopsin2 3 (ChR2). 1 29. A method of measuring changes in membrane potential in an excitable 2 cell, said method comprising:3 (i) contacting the excitable cell with the compound of one of claims 1 to4 17, or a salt thereof;5 (ii) stimulating the excitable cell to evoke action potentials; and6 (iii) measuring action potential firing by optical or electrical sampling.1 30. The method of claim 29, wherein the optical sampling is measured 2 using a camera or confocal microscopy. 181 31. The method of claim 30, wherein the camera is a charge-coupled 2 device or an active-pixel sensor. 1 32. The method of claim 31, wherein the charge-coupled device is an 2 electron multiplying charge-coupled device or a complementary metal-oxide-semiconductor 3 (CMOS). 1 33. The method of claim 32, wherein the complementary metal-oxide- 2 semiconductor is a Scientific CMOS (sCMOS). 1 34. The method of claim 29, wherein the excitable cell is stimulated using 2 a whole-cell current clamp or by field stimulation. 1 35. The method of claim 29, wherein the excitable cell is a neuron, 2 cardiomyocyte, myocyte, or a secretory cell. 18

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