Compounds and methods for treating protein aggregation diseases

Abstract

Described herein, inter alia, are compounds and methods for treating protein aggregation diseases.

Description

PATENT Attorney Docket No.: 062242-507001WO COMPOUNDS AND METHODS FOR TREATING PROTEIN AGGREGATION DISEASES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 737.161 filed December 20, 2024, U. S. Provisional Application No. 63 / 737,165 filed December 20, 2024, and U. S. Provisional Application No. 63 / 737,167 filed December 20, 2024, each of which is incorporated herein by reference in its entirety and for all purposes.BACKGROUND

[0002] Toxic protein aggregates spur neuronal degeneration and are a pathologic hallmark of multiple neurodegenerative diseases, such as Alzheimer’s disease, amyotrophic lateral sclerosis. Parkinson’s disease, and frontotemporal dementia. These toxic aggregates can be present both inside and outside of the cell. Across each of these diseases, there are many protein species that can develop toxic aggregates, such as P amyloid, alpha synuclein, tau, and TDP-43. A large percentage of patients have toxic aggregates from greater than one of these toxic protein aggregate species in the brain upon postmortem autopsy. Patients are usually diagnosed well after a large amount of these toxic aggregates have built up in the brain. Current FDA approved therapies for protein aggregates, such as recently approved anti- amyloid antibody therapies, fail to fully treat these protein aggregate diseases in several ways: they have poor cell penetrance and they do not physically break up existing protein aggregates. Disclosed herein, inter alia, are solutions to these and other problems in the art.BRIEF SUMMARY

[0003] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula:R1I

[0004] R1and R2are independently hydrogen, -CCl₃, -CBr3, -CF₃, -CI₃, -CHCl₂, -CHBr2, -CHF2. -CHb, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl₃, -OCF₃, -OCBr3, -OCI3, -OCHCl₂, -OCHBr2, -OCHI2, -OCHF2, -OCH2CL -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1and R2substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0005] R3is independently oxo, halogen, -CCI3, -CBr₃, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H. -OSO3H. -SO2NH2, -NHNH2. -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroar l.

[0006] The symbol z3 is an integer from 0 to 8.

[0007] R4is independently halogen, -CX43, -CHX42, -CH2X4, -OCX63, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOV4NR4AR4B, -NR4CNR4AR4B, -ONR4AR4B, -NR4CC(O)NR4AR4B. -N(O)m4. -NR4AR4B, -C(O)R4C, -C(O)OR4C. -OC(O)R4C, -OC(O)OR4C. -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0008] The symbol z4 is an integer from 0 to 5.

[0009] R5is independently halogen. -CX53, -CHX52, -CH2X5. -OCX53, -OCH2X5, -OCHX52, -CN, -SOn5R5D, -SOv5NR5AR5B, -NR5CNR5AR5B, -ONR5AR5B, -NR5CC(O)NR5AR5B, -N(O)m5, -NR5AR5B, -C(O)R5C, -C(O)OR5C, -OC(O)R5C, -OC(O)OR5C, -C(O)NR5AR5B, -OC(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -NR5AOR5C, -SF5, -N3, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0010] The symbol z5 is an integer from 0 to 3.

[0011] R4A, R4B, R4C, R4D, R5A, R5B, R5C, and R5Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCC13, -OCF3, -OCBr3, -OCI3, -OCHCl₂, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5Aand R5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0012] Each X4and X5is independently -F, -Cl, -Br, or -I. The symbols n4 and n5 are independently an integer from 0 to 4. The symbols m4, m5, v4, and v5 are independently 1 or 2.

[0013] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula:(IV). R1, R2, R3, z3, R4, and R5are as described herein, including in embodiments. The symbol z4 is an integer from 0 to 4. The symbol z5 is an integer from 0 to 5.

[0014] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula:(R3)Z3rmRXXr7(VIII). R3and z3 are as described herein, including in embodiments.

[0015] R6is hydrogen, halogen, -CX63, -CHX62, -CH2X6, -OCX6:,, -OCH2X6. -OCHX62, -CN, -SOn6R6D, -SOv6NR6AR6B, -NR6CNR6AR6B, -ONR6AR6B, -NR6CC(O)NR6AR6B, -N(O)m6, -NR6AR6B, -C(O)R6C, -C(O)OR6C, -OC(O)R6C, -OC(O)OR6C, -C(O)NR6AR6B, -OC(O)NR6AR6B, -OR6D, -SR6D, -NR6ASO2R6D, -NR6AC(O)R6C, -NR6AC(O)OR6C, -NR6AOR6C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0016] R7is halogen, -CX73, -CHX72, -CH2X7, -OCX73, -OCH2X7, -OCHX72, -CN, -SOn7R7D, -SOV7NR7AR7B, -NR7CNR7AR7B, -ONR7AR7B, -NR7CC(O)NR7AR7B, -N(O)m7, -NR7AR7B, -C(O)R7C, -C(O)OR7C, -OC(O)R7C, -OC(O)OR7C, -C(O)NR7AR7B, -OC(O)NR7AR7B, -OR7D, -SR7D, -NR7ASO2R7D, -NR7AC(O)R7C, -NR7AC(O)OR7C, -NR7AOR7C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0017] R6A, R6B, R6C, R6D, R7A, R7D. R7C, and R7Dare independently hydrogen. -CCI3, -CBr3, -CF3, -CI3, -CHC12, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCC13, -OCF3, -OCBr3, -OCI3, -OCHCl₂, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R7Aand R7Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0018] Each X6and X7is independently -F, -Cl, -Br, or -I. The symbols n6 and n7 are independently an integer from 0 to 4. The symbols m6. m7, v6, and v7 are independently 1 or 2.

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

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

[0021] In an aspect is provided a method of reducing formation of a protein aggregate or disrupting a protein aggregate, the method including contacting the protein aggregate with an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.DETAILED DESCRIPTIONI. Definitions

[0022] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0023] Where substituent groups are specified by their conventional chemical formulae, w ritten from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e g., -CH2O- is equivalent to -OCH2-.

[0024] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di-, and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons). In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl,homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkenyl includes one or more double bonds. An alkynyl includes one or more triple bonds.

[0025] 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 alkyd (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term “alkenylene,” by itself or as part of another substituent, means, unless otherw ise stated, a divalent radical derived from an alkene. The term “alkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne. In embodiments, the alkylene is fully saturated. In embodiments, the alkylene is monounsaturated. In embodiments, the alkydene is polyunsaturated. An alkenylene includes one or more double bonds. An alkynylene includes one or more triple bonds.

[0026] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized. 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 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, -0-CH3.-O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. A heteroalkyd moiety' may include oneheteroatom (e.g., O, N. S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). The term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and / or one or more triple bonds in additional to the one or more double bonds. The term “heteroalkynyl.” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and / or one or more double bonds in additional to the one or more triple bonds. In embodiments, the heteroalkyl is fully saturated. In embodiments, the heteroalkyl is monounsaturated. In embodiments, the heteroalkyl is polyunsaturated.

[0027] Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R", -OR', -SR', and / or -SO2R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like. 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, theheteroalkylene 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.

[0028] The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cyclohept l, and the like. Examples of heterocycloalk l include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl. tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. In embodiments, the cycloalkyl is fully saturated. In embodiments, the cycloalkyl is monounsaturated. In embodiments, the cycloalkyl is polyunsaturated. In embodiments, the heterocycloalkyl is fully saturated. In embodiments, the heterocycloalkyl is monounsaturated. In embodiments, the heterocycloalkyl is polyunsaturated.

[0029] In embodiments, the term “cy cloalky 1” means a monocy clic, bicyclic, or a multicyclic cycloalkyl ring system. In embodiments, monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In embodiments, cycloalkyl groups are fully saturated. A bicyclic or multicyclic cycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkyl ring of the multiple rings.

[0030] 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 acycloalkenyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkenyl ring of the multiple rings.

[0031] In embodiments, the term “heterocycloalkyl” means a monocyclic, bicyclic, or a multicyclic heterocycloalkyl ring system. In embodiments, heterocycloalkyl groups are fully saturated. A bicyclic or multicyclic heterocycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a heterocycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heterocycloalkyl ring of the multiple rings.

[0032] 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(Ci-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyL trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0033] The term “acyl” means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0034] The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within an aryl ring of the multiple rings. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heteroaromatic ring of the multiple rings). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1 -naphthyl, 2 -naphthyl, 4-biphenyl, 1 -pyrrolyl. 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, puriny l, 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 heteroaiyl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.

[0035] Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e g., substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g., all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is aheterocyclic 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.

[0036] The symbol ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

[0037] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.

[0038] 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:3or3

[0039] An alkylarylene moiety may be substituted (e.g., with a substituent group) on the alkylene moiety or the arylene linker (e.g., at carbons 2. 3, 4, or 6) with halogen, oxo, -N3. -CF3, -CCl₃, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.

[0040] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,” “heterocycloalkyd,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0041] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalky dene, heteroalkenyl, alkynyl, cycloalkyd, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =0, =NR', =N-0R', -NR'R", -SR', halogen, -SiR'R'R'". -OC(O)R', -C(O)R', -CO2R'. -CONR'R", -OC(O)NR’R", -NR" C(O)R', -NR'C(O)NR" R'", -NR" C(O)2R', -NRC(NR'R" R"')=NR"", -NRC(NR'R")=NR"', -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -NR'NR" R'", -ONR'R", -NR'C(O)NR" NR'" R"", -CN, -NO2, -NR'SO2R", -NR'C(O)R", -NR'C(O)OR", -NR'OR", in a number ranging from zero to(2m'+l), where m' is the total number of carbon atoms in such radical. R, R', R", R'", and R"" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'", and R"" group when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" includes, but is not limited to, 1 -pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term ’‘alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0042] Similar to the substituents described for the alkyl radical, substituents for the aiyl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R". -SR', halogen, -SiR'R" R"', -OC(O)R’, -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR" C(O)R', -NR'C(O)NR" R"', -NR" C(O)2R', -NR-C(NR'R" R'")=NR"", -NR-C(NR'R")=NR'", -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -NR’NR" R"', -ONR'R", -NR'C(O)NR" NR"'R"", -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(Ci-C4)alkoxy, and fluoro(Ci-C4)alkyl. -NR'SO2R", -NR'C(O)R", -NR'C(O)OR", -NR'OR", in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R", R'", and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyd, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'", and R"" groups when more than one of these groups is present.

[0043] Substituents for rings (e.g.. cycloalkyd, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms(obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown w ith 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 wi th the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.

[0044] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, tw o ringforming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0045] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')q-U-, wherein T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer of from 0 to 3.Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR’)s-X'- (C" R" R"')d-, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR1-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R", and R"' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0046] As used herein, the terms “heteroatom’’ or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0047] A “substituent group,” as used herein, means a group selected from the following moieties:(A) oxo, halogen, -CC13, -CBr₃, -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -OCCl₃, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CL -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -C0NH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., Ce-Cio aryl, C10 and, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and(B) alkyl (e.g., Ci-Cs alkyl, Ci-Ce 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-Cs cycloalkyl, C3-Ce cycloalk d, or C5-C6cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., Ce-Cio aryl, Cio aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from:(i) oxo, halogen, -CC13, -CBr3, -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I. -OCC13, -OCF3, -OCBr3, -OCI3. -OCHC12, -OCHBr2.-0CHI2, -OCHF2, -OCH2CI, -OCH2Br, -0CH2I, -0CH2F, -CN, -OH, -NH2, -C00H, -CONH2, -NO2, -SH, -SO3H, OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2. -NHS02H, -NHC(0)H, -NHC(0)0H, -NHOH, -N3, -SF5, unsubstituted alkyd (e.g., Ci-Cs alkyl, Ci -Co alkyl, or C1-C4 alky 1), 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-Cs cycloalkyl, or Cs-Ce cycloalkyl), unsubstituted heterocycloalkyd (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyd, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., Ce- C10 aryl, Cio aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (ii) alkyl (e.g., Ci-Cs alkyd. Ci-Ce alkyl, or C1-C4 alkyl), heteroalkyl (e.g.. 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8cycloalkyl, C3-Ce cycloalkyl, or Cs-Ce cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocy cloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., Ce- C10 aryl, Cio 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:(a) oxo, halogen, -CC13, -CBr3, -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -OCC13. -OCF3. -OCBr3, -OCI3, -OCHCl₂, -OCHBr2, -OCHh. -OCHF2, -OCH2Cl, -OCH2Br, -0CH2I, -OCH2F, -CN, -OH, -NH2, -C00H, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -N3. -SF5, unsubstituted alkyl (e.g.. Ci-C8alkyl, Ci-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 heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl. 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and(b) alkyl (e.g., Ci-Cs alkyl, Ci-Ce 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 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., Ce- C10 aryl, 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: oxo. halogen, -CCI3, -CBr?. -CF3. -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCI3, -OCFs, -OCBr3, -OCI3, -OCHCl₂, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted ary l (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).

[0048] A “size-limited substituent’’ or “size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl,each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heleroalkyl. 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 Ce-Cio aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0049] 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 Ci-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroar l is a substituted or unsubstituted 5 to 6 membered heteroaryl.

[0050] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.

[0051] In other embodiments of the compounds herein, each substituted or unsubstituted 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 cycloalkyd is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyd is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted Ce-C10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substitutedor unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkydene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted Cs-Cio arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

[0052] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted Ce-Cio aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted Ci-Cs alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted Ce-Cio arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.

[0053] In embodiments, a substituted or unsubstituted moiety (e.g.. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, substituted or unsubstituted heteroary 1, substituted or unsubstituted alky dene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalky dene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyd, unsubstituted heterocycloalkyl, unsubstituted ary 1,unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and / or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is substituted (e.g., is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene, respectively).

[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 substituted with at least one substituent group, wherein if the substituted moiety7is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety7is substituted with a plurality of substituent groups, each substituent group is different.

[0055] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalky7!, substituted cycloalky7!, substituted heterocycloalkyl, substituted ary7!, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one size-limited substituent group, wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different.

[0056] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substitutedheteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one lower substituent group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted w ith a plurality of lower substituent groups, each lower substituent group is different.

[0057] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted w ith a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group is different.

[0058] In a recited claim or chemical formula description herein, each R substituent or L linker that is described as being ‘‘substituted” without reference as to the identity of any chemical moiety that composes the “substituted” group (also referred to herein as an “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.

[0059] The first substituent group is denoted with a corresponding first decimal point numbering system such that, for example. R1may be substituted with one or more first substituent groups denoted by R1 1, R2may be substituted with one or more first substituent groups denoted by R2 1, R3may be substituted with one or more first substituent groups denoted by R3R4may be substituted with one or more first substituent groups denoted by R4R5may be substituted with one or more first substituent groups denoted by R; |. and the like up to or exceeding an R100that may be substituted with one or more first substituent groups denoted by R100 1. As a further example, R1Amay be substituted with one or morefirst 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\ R4Amay be substituted with one or more first substituent groups denoted by R4A1, 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 4. As a further example, L1may be substituted with one or more first substituent groups denoted by RLL1, L2may be substituted with one or more first substituent groups denoted by RL21, L3may be substituted with one or more first substituent groups denoted by RL3L4may be substituted with one or more first substituent groups denoted by RT 4L5may be substituted with one or more first substituent groups denoted by RL5 1and the like up to or exceeding an L100which may be substituted with one or more first substituent groups denoted by RL100 1. Thus, each numbered R group or L group (alternatively referred to herein as Rwwor Lwwwherein “WW” represents the stated superscript number of the subject R group or L group) described herein may be substituted with one or more first substituent groups referred to herein generally as Rw w 1or RLWW4, respectively. In turn, each first substituent group (e.g., R1 1, R2 1, R3 1, R41, 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 RLIOO.1)MAY BEfurther substituted with one or more second substituent groups (e.g., R1 2, R22, R3 2, R42, p 5.2 TJ IOO.2. plA.2 T? 2A.2 T>3A.2 p4 \,2 p 5A.2 p lOOA.2. T> L1.2 pL2.2 pL3.2 pL4.2 pL5 2RLIOO2reSpectively). Thus, each first substituent group, which may alternatively be represented herein as Rww 1as described above, may be further substituted with one or more second substituent groups, which may alternatively be represented herein as Rww-2.

[0060] Finally, each second substituent group (e.g., R1 2, R22, R3 2, R42, R52... R100'2; R1A 2, R2A 2. R:',R4A.2,R5A.2R100A.2.RL1.2RL2.2RL3.2R1 4.2RL5.2RL100.2)MAY BG FURTHERsubstituted with one or more third substituent groups (e.g., R1 3, R23, R3 3, R43, R5 3... R100'3;R1A.3R2A.3R3A.3R4A.3R5A.3R100A.3.RL1.3RL2.3RL3.3RL4.3RL5 3RL100.3. respectively). Thus, each second substituent group, which may alternatively be represented herein as Rww 2as described above, may be further substituted with one or more third substituent groups, which may alternatively be represented herein as Rww-3. Each of the first substituent groups may be optionally different. Each of the second substituent groups may be optionally different. Each of the third substituent groups may be optionally different.

[0061] 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, 1 A, 2A, 3A, IB, 2B, 3B, etc.). Likewise, Lwwis a linker recited in a claim or chemical formula description herein which is openly substituted. Again, ‘" WW” represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, IB, 2B, 3B, etc.). As stated above, in embodiments, each Rwwmay be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RWW 1; each first substituent group, Rwwmay be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as Rww-2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as Rww'3. Similarly, each Lwwlinker may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RLWW 1; each first substituent group, RLWW 1;may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RLWW.2.anjeachseconcj substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RLWW 3. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. For example, if Rwwis phenyl, the said phenyl group is optionally substituted by one or more RWW 1groups as defined herein below, e.g., when R1is 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-2which Rww-2is optionally substituted by one or more RWW 3. By way of example when the Rwwgroup is phenyl substituted by RWW, which is methyl, the methyl group may be further substituted to form groups including but not limited to:

[0062] RWW 1is independently oxo, halogen, -CXWW 13, -CHXWW 12, -CH2XWW-1, -OCXWW 13, -OCH2XWW 1, -OCHXWW 12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H. -OSO3H. -SO2NH2, -NHNH2. -0NH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, Rww^-substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, 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 Cs-Cs), RWW 2-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RWW 2-substituted or unsubstituted aryl (e.g., C6-C12, Ce-Cio, 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, RWW 1is independently oxo, halogen, -CXWW 13, -CHXWW J2, -CH2XWW-1, -OCXWW■13, -OCH2XWW-1, -OCHXWW-'2. -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H. -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH2, -NHC(O)NH2. -NHC(NH)NH2. -NHSO2H. -NHC(O)H, -NHC(O)OH. -NHOH. -N3, unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, 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 Cs-Ce), unsubstituted heterocy cloalkyl (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, Ce-Cio, 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.

[0063] RWW-2is independently oxo, halogen, -CXWW 23. -CHXWVv 22, -CH2XWVv'2.-OCXWW 23, -OCH2XWW2, -OCHXWW 22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3. RWW3-substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), RWW 3-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW 3-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or Cs-Ce), Rww^-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^-substituted or unsubstituted aryl (e.g., Ce-Ci2, Ce-Cio, or phenyl), or RWW 3-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RWW 2is independently oxo, halogen, -CXWW-CHXWW 22, -CH2XWW 2, -OCXWW 23, -OCH2XWW 2, -OCHXWW 22, -CN, -OH, -NH2. -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(0)0H, -NHOH, -N3, unsubstituted alkyl (e.g.. Ci-Cs, Ci-Ce, 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., Cs-Cs, Cs-Ce, C4-C6, or Cs-Ce), unsubstituted heterocycloalkyd (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, Ce-Cio, or phenyl), or unsubstituted heteroaryl (e.g.. 5 to 12 membered. 5 to 10 membered. 5 to 9 membered, or 5 to 6 membered). xWW 2is independently -F, -Cl, -Br, or -I.

[0064] RWW 3is independently oxo, halogen, -CXWW 33, -CHXWW 32, -CH2XWW 3, -OCXWW33, -OCH2XWW3, -OCHXWW32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H. -OSO3H. -SO2NH2, -NHNH2. -0NH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(0)H, -NHC(O)OH, -NHOH, -Ns, unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or Ci-C2), unsubstituted heteroalkyd (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., Cs-Cs, C3-C6, C4-C6, or Cs-Ce). 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, Ce-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered. 5 to 10 membered. 5 to 9 membered, or 5 to 6 membered). xW W 3is independently -F, -Cl, -Br, or -I.

[0065] Where two different Rwwsubstituents are joined together to form an openly substituted ring (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted ary l or substituted heteroaryl), in embodiments the openly substituted ring may be independently substituted with one or more first substituent groups, referred to herein as Rww-1: each first substituent group, R'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 be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as Rww 3; and each third substituent group, Rww-3, is unsubstituted. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. In the context of two different Rwwsubstituents joined together to form an openly substituted ring, the “WW” symbol in the RWW 1, R% w2and RWW jrefers to the designated number of one of the two different Rwwsubstituents. For example, in embodiments where R100Aand R100Bare optionally joined together to form an openly substituted ring, RWW 1is R100A 1, R^-2jsR100A2, and Rw w 3is R100A 3Alternatively, in embodiments where R100Aand R100Bare optionally joined together to form an openly substituted ring, Rww 1is R100B 1, RWW-2-SR100B 2, and RWW3is R100B 3RWW 1, ^WW.2anc| pww.s jnt|q|Sparagrapharedefined in the preceding paragraphs.

[0066] RLWW1is independently oxo, halogen, -CXLWW 13, -CHXLWW 12, -CH2XLWW 1, -ocxLWW-, -OCH2XLWW 1, -OCHXLWW12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H. -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2. -NHSO2H. -NHC(O)H, -NHC(O)OH. -NHOH, -N3, RLWW^-substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or Ci-C2), RLWW 2-substituted or unsubstituted heteroalkyd (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RI WW^-substituted or unsubstituted cycloalkyl (e.g., C3-Cs, C3-Ce, C4-C6, or Cs-Ce). RLWW 2-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RL^-substituted or unsubstituted ary l (e.g., Ce-Ci2, Ce-Cio, or phenyl), or RLWW 2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). In embodiments, RLWW 1is independently oxo, halogen, -CXLWW J3, -CHX^' - -CH2XLWW1, -ocx^-^, -OCH2XLWW-1. -OCHXLWW■12. -CN, -OH, -NH2. -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or Ci-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 Cs-Ce), 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, Cs-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLW W 1is independently -F, -Cl, -Br, or -I.

[0067] RLWW'2is independently oxo, halogen, -CXLWW 23, -CHXLWW 22, -CH2XLWW 2, -OCXLWW 23, -OCH2XLWW 2, -OCHXLWW 22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H. -OSO3H. -SO2NH2, -NHNH2. -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RLWW 3-substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), RLWW^-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW 3-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW 3-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW 3-substituted or unsubstituted ary l (e.g., C6-C12, Ce-Cio, or phenyl), or RLWW 3-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RLWW 2is independently oxo, halogen. -CXLWW 23.-CHXLWW'22, -CH2XLWW'2, -OCXLWW'23, -OCH2XLWW'2, -OCHXLWW'22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2. -NHC(O)NH2. -NHC(NH)NH2, -NHSO2H. -NHC(O)H, -NHC(0)0H. -NHOH, -N3, unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), unsubstituted heteroalkyd (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-Cs, C3-C6, C4-C6, or Cs-Ce), 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, Ce-Cio, 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.

[0068] RLWW 3is independently oxo. halogen, -CXLWW 33, -CHXLWW 32, -CH2XLWW 3, -OCXLWW 33. -OCH2XLWW3, -OCHXLWW32, -CN, -OH, -NH2. -COOH, -CONH2. -NO2, -SH. -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, 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., Cs-Cs, C3-C6, C4-C6, or Cs-Cg), 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., Ce-Ci2, Cg-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered. 5 to 10 membered. 5 to 9 membered, or 5 to 6 membered). xLWW3is independently -F, -CL -Br, or -I.

[0069] In the event that any R group recited in a claim or chemical formula description set forth herein (Rwwsubstituent) is not specifically defined in this disclosure, then that R group (Rwwgroup) is hereby defined as independently oxo, halogen, -CXWW3, -CHXWW2, -CH2XWW, -OCXWW3, -OCH2XWW, -OCHXWW2, -CN. -OH. -NH2, -COOH. -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH2, -NHC(0)NH2, NHC(NH)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -N3, RWW 1-substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), RWW 1-substituted or unsubstituted heteroalkyl (e.g.. 2 to 8 membered, 2 to 6 membered, 4 to 6 membered. 2 to 3 membered, or 4 to 5 membered), RWW 1-substituted or unsubstituted cycloalkyl (e.g., Cs-Cs, C3-C6, C4-C6, or Cs-Cg), Rww^-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RWW 1-substituted or unsubstituted aryl (e.g., C6-C12, Cg-Cio, or phenyl), or Rww 1-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). xwwis independently -F, -Cl, -Br, or -I. Again, ‘‘WW” represents the stated superscript number of the subject R group (e.g., 1, 2, 3, 1A, 2A, 3A, IB, 2B, 3B, etc.).RWW 1,RWW andRWW3are asdefined above.

[0070] In the event that any L linker group recited in a claim or chemical formula description set forth herein (i.e., an Lwwsubstituent) is not explicitly defined, then that L group (Lwwgroup) is herein defined as independently a bond, -O-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(NH)NH-, -C(O)O-, -OC(O)-, -S-, -SO2-, -SO2NH-, RLWW 1- substituted or unsubstituted alkylene (e.g.. Ci-Cs, Ci-Ce, C1-C4, or C1-C2), RLW W^-substitutedor unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RLW W 1-substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or Cs-Ce), RLWW 1-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW i_substituted or unsubstituted arylene (e g., C6-C12, Ce-Cio, or phenyl), or RLWW 1-substituted or unsubstituted heteroaiylene (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, IB, 2B, 3B, etc ).LWW 1Jas well as RLWW 2and RLWW.3are asdegne(iabove.

[0071] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and / or isolate. The present disclosure is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0072] 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.

[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.

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

[0079] As used herein, the terms “bioconjugate'’ and “bioconjugate linker’" refer to the resulting association between atoms or molecules of bioconjugate reactive groups or bioconjugate reactive moieties. The association can be direct or indirect. For example, a conjugate between a first bioconjugate reactive group (e.g., -NH2, -COOH, -billy droxysuccinimide, or -mal eimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate) provided herein can be direct, e.g., by covalent bond or linker (e.g., a first linker of second linker), or indirect, e.g., by non-covalent bond (e.g., electrostatic interactions (e.g., ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups)including, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g.. enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, for example, March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New- York, 1985; Hermanson. BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198, American Chemical Society, Washington, D C., 1982. In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., -N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., -sulfo-N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine).

[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-hydroxybenztri azole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters; (b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.; (c) haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom; (d) dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido or maleimide groups; (e) aldehyde or ketone groups such that subsequent derivatization is possible via formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition; (f) sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides; (g) thiol groups, which can be converted todisulfides, reacted with acyl halides, or bonded to metals such as gold, or react with maleimides; (h) amine or sulfhydryl groups (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized; (i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc.; (j) epoxides, which can react with, for example, amines and hydroxyl compounds; (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis; (1) 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 avidinbiotin complex or streptavidin-biotin complex.

[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 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 similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound.

[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 alkyl or heteroaryl group, is “substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl”, the group may contain one or more unsubstituted C1-C20 alkyls, and / or one or more unsubstituted 2 to 20 membered heteroalkyls.

[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 with at least one R substituent and each R substituent is optionally different. Where aparticular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R13substituents are present, each R13substituent may be distinguished as R13 A, R13 B, R13 C, R13 D, etc., wherein each of R13 A, R13 B, R13 C, R13 D, etc. is defined within the scope of the definition of R13and optionally differently. Where an R moiety, group, or substituent as disclosed herein is attached through the representation of a single bond and the R moiety, group, or substituent is oxo, a person having ordinary skill in the art will immediately recognize that the oxo is attached through a double bond in accordance with the normal rules of chemical valency.

[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 unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a hetero cycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding know n 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 particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as thesalts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts'’, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[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, 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.

[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.

[0089] In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds descnbed herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.

[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 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’7when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-natural or not wild ty pe). For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Likewise, a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is recombinant.

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

[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 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. Prokary otic cells include but are not limited to bacteria. Eukary otic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g.. spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.

[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 subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate ofdegeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation. The term ’‘treating” and conjugations thereof, include prevention of an injury', pathology', condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. In embodiments, the treating or treatment is no prophylactic treatment.

[0095] An ’‘effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzy me activity', increase enzyme activity, reduce signaling pathway, reduce one or more symptoms of a disease or condition. An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount” when referred to in this context. A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity- or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury', disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. An “activity increasing amount,” as used herein, refers to an amount of agonist required to increase the activity of an enzyme relative to the absence of the agonist. A “function increasing amount,” as used herein, refers to the amount of agonist required to increase the function of an enzyme or protein relative to the absence of the agonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3. 1992); Lloyd, The Art, Science and Technology ofPharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003. Gennaro. Ed., Lippincott, Williams & Wilkins).

[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 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 biomolecules, or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

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

[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 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 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 activity7is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity7in the absence of the agonist.

[0101] As defined herein, the term “inhibition,” “inhibit,” “inhibiting” and the like in reference to a cellular component-inhibitor interaction means negatively affecting (e.g., decreasing) the activity' or function of the cellular component (e.g., decreasing the signaling pathway stimulated by a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)), relative to the activity' or function of the cellular component in the absence of the inhibitor. In embodiments inhibition means negatively affecting (e.g., decreasing) the concentration or levels of the cellular component relative to the concentration or level of the cellular component in the absence of the inhibitor. In some embodiments, inhibition refers to reduction of a disease or symptoms of disease. In some embodiments, inhibition refers to a reduction in the activity' of a signal transduction pathway or signaling pathway (e.g., reduction of a pathway involving the cellular component). Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating the signaling pathway or enzymatic activity or the amount of a cellular component.

[0102] The terms “inhibitor,” “repressor,” “antagonist,” or “downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein. The antagonist can decrease expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist.

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

[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, 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 property or function of the target molecule or the amount of the target molecule.

[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, 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 embodiments, the disease is a disease related to (e.g., caused by) a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In embodiments, the disease is a protein aggregation disease. In embodiments, the disease is a neurodegenerative disease. In embodiments, the disease is diabetes. In embodiments, the disease is a p53 mutant cancer.

[0108] As used herein, the term '‘protein aggregation disease” refers to a disease or condition characterized by protein aggregation. In embodiments, the protein aggregation disease includes diseases outside the nervous system, such as primary systemic amyloidosis(AL amyloidosis), reactive systemic amyloidosis (AA amyloidosis), type II diabetes, injection-localized amyloidosis, beta-2 microglobulin amyloidosis, hereditary non-neuropathic amyloidosis, and Finnish hereditary systemic amyloidosis. In embodiments, the protein aggregation disease is a neurodegenerative disease. In embodiments, the protein aggregation disease is diabetes. In embodiments, the protein aggregation disease is a p53 mutant cancer.

[0109] As used herein, the term “neurodegenerative disease" refers to a disease or condition in which the function of a subject’s nervous system becomes impaired. Examples of neurodegenerative diseases that may be treated with a compound, pharmaceutical composition, or method described herein include, but are not limited to, Alexander’s disease, Alper’s disease, Alzheimer’s disease, amyloidosis, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis and frontotemporal lobar degeneration, antibody light chain amyloidosis, Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), C9orf72 amyotrophic lateral sclerosis, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, dementia with Lewy bodies, diffuse Lewy body disease, facial onset sensory and motor neuropathy, familial amyloid polyneuropathy, frontotemporal dementia, frontotemporal lobar degeneration, frontotemporal lobar degeneration tau predominant pathology, frontotemporal lobar degeneration TDP-43 predominant pathology, genetic human prion disease, Gerstmann-Straussler-Scheinker syndrome, hereditary cerebral amyloid angiopathy, Huntington’s disease, HIV-associated dementia, Kennedy’s disease, Krabbe’s disease, kuru, Lewy body dementia, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, multiple system proteinopathy, myotonic disorder, narcolepsy, Neuroborreliosis, Parkinson’s disease, Parkinson's disease-associated dementia, Pelizaeus-Merzbacher Disease. Perry syndrome, Pick’s disease, poly-Q disease, primary lateral sclerosis, primary progressive aphasia, prion diseases, progressive supranuclear palsy, Refsum’s disease, Sandhoff s disease, Schilder’s disease, scrapie, semantic dementia, spinocerebellar ataxias and other Poly-Q diseases, sporadic amyotrophic lateral sclerosis, inclusion body myositis, subacute combined degeneration of spinal cord secondary to Pernicious Anaemia, schizophrenia, spinocerebellar ataxia (multiple types with varying characteristics), spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson-Olszewski disease, Tabes dorsalis, transthyretin amyloidosis, and variant Creutzfeldt-Jakob disease.

[0110] As used herein, the term “cancer” refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus medulloblastoma, colorectal cancer, or pancreatic cancer. Additional examples include Hodgkin’s Disease, Non-Hodgkin’s Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary' macroglobulinemia, primary' brain tumors, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, esophageal cancer, genitourinary’ tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary' thyroid cancer, medullary' thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0111] The term "leukemia" refers broadly to progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary' leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embry onal leukemia, eosinophilic leukemia, Gross' leukemia, hairy -cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia.plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0112] As used herein, the term ’‘lymphoma” refers to a group of cancers affecting hematopoietic and lymphoid tissues. It begins in lymphocytes, the blood cells that are found primarily in lymph nodes, spleen, thymus, and bone marrow. Two main types of lymphoma are non-Hodgkin lymphoma and Hodgkin's disease. Hodgkin’s disease represents approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed-Sternberg malignant B lymphocytes. Non-Hodgkin’s lymphomas (NHL) can be classified based on the rate at which cancer grows and the type of cells involved. There are aggressive (high grade) and indolent (low grade) types of NHL. Based on the type of cells involved, there are B-cell and T-cell NHLs. Exemplary B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt’s lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.

[0113] The term "sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma,leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0114] The term "melanoma" is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.

[0115] The term "carcinoma" refers to a malignant new grow th made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary' carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides. exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatinifomi carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypemephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasophary ngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasivecarcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum. carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

[0116] As used herein, the terms "metastasis," "metastatic," and "metastatic cancer" can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part. “Metastatic cancer” is also called “Stage IV cancer.” Cancer occurs at an originating site, e g., breast, which site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or originating site acquire the ability to penetrate and infiltrate surrounding normal tissue in the local area and / or the ability7to penetrate the walls of the lymphatic system or vascular system circulating through the system to other sites and tissues in the body. A second clinically detectable tumor formed from cancer cells of a primary tumor is referred to as a metastatic or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor at the site of the breast consists of abnormal lung cells and not abnormal breast cells. The secondary tumor in the breast is referred to a metastatic lung cancer. Thus, the phrase metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors. The phrases non-metastatic cancer or subjects with cancer that is not metastatic refers to diseases in which subjects have a primary tumor but not one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject with or with a history of a primary lung tumor and with one or more secondary7tumors at a second location or multiple locations, e.g., in the breast.

[0117] The terms “cutaneous metastasis” or “skin metastasis” refer to secondary malignant cell growths in the skin, wherein the malignant cells originate from a primary cancer site (e.g., breast). In cutaneous metastasis, cancerous cells from a primary cancer site may migrate to the skin where they divide and cause lesions. Cutaneous metastasis may result from the migration of cancer cells from breast cancer tumors to the skin.

[0118] The term “visceral metastasis’" refer to secondary' malignant cell grow ths in the interal organs (e.g., heart, lungs, liver, pancreas, intestines) or body cavities (e.g., pleura, peritoneum), wherein the malignant cells originate from a primary cancer site (e.g., head and neck, liver, breast). In visceral metastasis, cancerous cells from a primary cancer site may migrate to the internal organs where they divide and cause lesions. Visceral metastasis may result from the migration of cancer cells from liver cancer tumors or head and neck tumors to internal organs.

[0119] The term “p53 mutant cancer” as used herein refers to a cancer expressing a mutant p53 protein. p53 mutant cancers include, but are not limited to, small cell lung cancer, squamous cell lung cancer, triple-negative breast cancer, and high-grade serous ovarian cancer.

[0120] 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.

[0121] 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, " Mo,105Pd,105Rh,111Ag,111In,123I,124I,125I,131I,142Pr,143Pr,149Pm,153Sm,154’1581Gd,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, Tm, Yb, Lu,32P, fluorophore (e.g., fluorescent dyes), modified oligonucleotides (e.g., moieties described in PCT / US2015 / 022063, which is incorporated herein by reference), electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide (" USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide (" SPIO") nanoparticles, SPIO nanoparticle aggregates, monochrystalline iron oxide nanoparticles, monochrystalline iron oxide, nanoparticle contrast agents, liposomes or other delivery vehicles containing Gadolinium chelate (" Gd-chelate") molecules. Gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxy gen-15, fluorine-18, rubidium-82), fluorodeoxy glucose (e.g., fluorine-18 labeled), any gamma ray emitting radionuclides, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g., including microbubble shells including albumin, galactose, lipid, and / or polymers; microbubble gas core including air, heavy gas(es), perfluorcarbon, nitrogen, octafluoropropane, perflexane lipid microsphere, perflutren, etc.), iodinated contrast agents (e.g., iohexol, iodixanol. ioversol, iopamidol, ioxilan, iopromide, diatrizoate, metrizoate, loxaglate), 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.

[0122] 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, " Mo,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,199Au,211At,211Pb.212Bi.212Pb,213Bi,223Ra. and225Ac. Paramagnetic ions that may be used as additional imaging agents in accordance with the embodiments of the disclosure include, but are not limited to, ions of transition and lanthanide metals (e.g., metals having atomic numbers of 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu. La. Ce, Pr, Nd, Pm, Sm, Eu. Gd, Tb, Dy, Ho, Er, Tm. Yb, and Lu.

[0123] “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 disclosed herein without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water. NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds disclosed herein.One of skill in the art will recognize that other pharmaceutical excipients are useful in the presently disclosed pharmaceutical compositions.

[0124] The term "preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0125] As used herein, the term "about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about includes the specified value.

[0126] As used herein, the term "administering” is used in accordance with its plain and ordinary meaning and includes oral administration, administration as a suppository', topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g.. a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intraarteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By "co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds disclosed herein can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The compositions disclosed herein can be delivered by transdermally. by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0127] 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.

[0128] 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. Coadministration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and / or adjunctive agents may be linked or conjugated to one another.

[0129] In therapeutic use for the treatment of a disease, compound(s) utilized in the pharmaceutical compositions disclosed herein may be administered at the initial dosage of about 0.001 mg / kg to about 1000 mg / kg daily. A daily dose range of about 0.01 mg / kg to about 500 mg / kg, or about 0.1 mg / kg to about 200 mg / kg, or about 1 mg / kg to about 100 mg / kg, or about 10 mg / kg to about 50 mg / kg, can be used. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound or drug being employed. For example, dosages can be empirically determined considering the type and stage of disease (e.g., cancer) diagnosed in a particular patient. The dose administered to a patient, in the context of the presently disclosed methods of therapeutic treatment, should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration of a compound in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

[0130] The term "associated" or “associated with’?in the context of a substance or substance activity or function associated with a disease (e.g., a protein associated disease, disease associated with a cellular component) means that the disease (e.g., cancer) is causedby (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function or the disease or a symptom of the disease may be treated by modulating (e.g., inhibiting or activating) the substance (e.g., cellular component). As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease.

[0131] 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, yvherein returning the aberrant activity to a normal or non-disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.

[0132] The term “electrophilic” as used herein refers to a chemical group that is capable of accepting electron density. An “electrophilic substituent,” “electrophilic chemical moiety,” or “electrophilic moiety” refers to an electron-poor chemical group, substituent, or moiety (monovalent chemical group), which may react with an electron-donating group, such as a nucleophile, by accepting an electron pair or electron density to form a bond.

[0133] ■‘Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density.

[0134] The term “isolated,” when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be. for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined 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.

[0135] 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, y-carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that havethe same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms “non-naturally occurring amino acid” and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.

[0136] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0137] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may in embodiments be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.

[0138] An amino acid or nucleotide base “position” is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end). Due to deletions, insertions, truncations, fusions, and the like that must be taken into account when determining an optimal alignment, in general the amino acid residue number in a test sequence determined by simply 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 relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence.

[0139] 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.

[0140] The term “protein complex” is used in accordance with its plain ordinary meaning and refers to a protein which is associated with an additional substance (e.g., another protein, protein subunit, or a compound). Protein complexes typically have defined quaternary structure. The association between the protein and the additional substance may be a covalent bond. In embodiments, the association between the protein and the additional substance (e.g., compound) is via non-covalent interactions. In embodiments, a protein complex refers to a group of two or more polypeptide chains. Proteins in a protein complex are linked by non-covalent protein-protein interactions. A non-limiting example of a protein complex is the proteasome.

[0141] The term “protein aggregate” is used in accordance with its plain ordinary meaning and refers to an aberrant collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are often associated with diseases (e.g., amyloidosis). In embodiments, when a protein misfolds as a result of a change in the amino acid sequence or a change in the native environment which disrupts normal non-covalent interactions, and the misfolded protein is not corrected or degraded, the unfolded / misfolded protein may aggregate. There are three main types of protein aggregates that may form: amorphous aggregates (also referred to herein as amorphous protein aggregates), oligomers (also referred to herein as protein oligomers), and amyloid fibrils.

[0142] The terms “oligomer” and “protein oligomer” as used herein refer to a protein aggregate that has a size range of from a trimer to a 20-mer. In embodiments, the oligomer has a size range of from 40 kD to 500 kD.

[0143] The term “reducing formation of a protein aggregate” as used herein refers to decreasing formation of a protein aggregate relative to the absence of administration of a compound provided herein.

[0144] The term “disrupting a protein aggregate” as used herein refers to reducing or preventing formation of a protein aggregate relative to the absence of administration of a compound provided herein.

[0145] The term “amyloid beta’' or “beta amyloid” is used in accordance with its plain ordinary meaning and refers to a mixture of peptides of 36 to 43 amino acids in length that are formed by sequential cleavage of the amyloid precursor protein (APP) by [3- and y-secretase. Amyloid beta is the main component of amyloid plaques found in the brains of people with Alzheimer’s disease.

[0146] The term “amyloid beta peptide 42” or “Ap42” or “A 1-42” as used herein refers to a 42-amino acid isoform of amyloid beta.

[0147] The term “TAR DNA-binding protein 43” or “TDP-43” as used herein refers to a protein encoded by the TARDBP gene. In embodiments, TDP-43 has the amino acid sequence set forth in or corresponding to Entrez 23435, UniProt Q13148, or RefSeq (protein) NP_031401.1. In embodiments, the amino acid sequence sequence is the sequence known at the time of filing of the present application.

[0148] The term “alpha-sy nuclein” or “aSyn” as used herein refers to a protein encoded by the SNCA gene. In embodiments, aSyn has the amino acid sequence set forth in or corresponding to Entrez 6622, UniProt P37840, RefSeq (protein) NP_000336.1, RefSeq (protein) NP_001139526.1, RefSeq (protein) NP_001139527.1, RefSeq (protein)NP 009292.1, or RefSeq (protein) NP_001362214. In embodiments, the amino acid sequence sequence is the sequence known at the time of filing of the present application.II. Compounds

[0149] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula:R1l

[0150] R1and R2are independently hydrogen, -CCl₃, -CBrs, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHE, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl₃, -OCF₃, -OCBr3, -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or Ci-C2), substitutedor 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., Cs-Cs. C3-C6, C4-C6, or Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R1and R2substituents 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).

[0151] R3is independently oxo, halogen, -CCI3. -CBr₃, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2. -CHI2, -CN, -OH, -NH2. -COOH, -CONH2, -NO2. -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2. -OCHBr2, -OCHF2, -OCHI2, -SF5. -N3, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, 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 Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0152] The symbol z3 is an integer from 0 to 8.

[0153] R4is independently halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D. -SOV4NR4AR4B, -NR4CNR4AR4B. -ONR4AR4B.-NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, 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 cycloalkyd (e.g., C3-C8, Cs-Ce, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered. 5 to 9 membered, or 5 to 6 membered).

[0154] The symbol z4 is an integer from 0 to 5.

[0155] R5is independently halogen, -CX53, -CHX52, -CH2X5, -OCX53, -OCH2X5, -OCHX52, -CN, -SOn5R5D, -SOV5NR5AR5B, -NR5CNR5AR5B, -ONR5AR5B, -NR5CC(O)NR5AR5B. -N(O)m5. -NR5AR5B, -C(O)R5C, -C(O)OR5C. -OC(O)R5C, -OC(O)OR5C. -C(O)NR5AR5B, -OC(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -NR5AOR5C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, 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, Cs-Ce, C4-C6, or Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0156] The symbol z5 is an integer from 0 to 3.

[0157] R4A, R4B, R4C, R4D, R5A, R5B, R5C, and R5Dare independently hydrogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, 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 cycloalkyd (e.g., C3-C8, C3-C6, C4-C6, or Cs-Ce), 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.. Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R4Aand R4Bsubstituents 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); R5Aand R5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form asubstituted 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).

[0158] Each X4and X5is independently -F, -Cl, -Br, or -I.

[0159] The symbols n4 and n5 are independently an integer from 0 to 4.

[0160] The symbols m4, m5, v4, and v5 are independently 1 or 2.

[0161] In embodiments, the compound has the formula:(II). R1, R2, R3, z3, R4, z4, R5, and z5 are as described herein, including in embodiments.

[0162] In embodiments, the compound has the formula:(Ila). R1, R2, and R4are as described herein, including in embodiments.

[0163] In embodiments, the compound has the formula:R1(III). R1, R2, R3, z3. R4. z4. R5. and z5 are as described herein, including in embodiments.

[0164] In embodiments, the compound has the formula:(Illa). R1, R2, and R4are as described herein, including in embodiments.

[0165] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula:

[0166] R1and R2are independently hydrogen, -CCI3, -CBrs, -CF3, -CI3, -CHCI2, -CHB, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F. substituted or unsubstituted alkyl (e.g., Ci-Cs. Ci-Cg, 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 Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R1and R2substituents 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).

[0167] R3is independently oxo, halogen, -CCI3, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH,-SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3. -OCBn, -OCF3, -OCI3. -OCH2Cl, -OCH2Br. -OCH2F. -OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Cg, 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 Cs-Cg), 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., Cg-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0168] The symbol z3 is an integer from 0 to 8.

[0169] R4is independently halogen. -CX43, -CHX42, -CH2X4. -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOV4NR4AR4B, -NR4CNR4AR4B, -ONR4AR4B, -NR4CC(O)NR4AR4B. -N(0)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Cg, 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 Cs-Cg), 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., Cg-C'io or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0170] The symbol z4 is an integer from 0 to 4.

[0171] R5is independently halogen. -CX53, -CHX52, -CH2X5. -OCX53, -OCH2X5, -OCHX52, -CN, -SOn5R5U, -SOV5NR5AR5B, -NR5CNR5AR5B, -ONR5AR5B, -NR5CC(O)NR5AR5B, -N(O)m5, -NR5AR5B, -C(O)R5C, -C(O)OR5C, -OC(O)R5C, -OC(O)OR5C, -C(O)NR5AR5B, -OC(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -NR5AOR5C. -SF5. -N3, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Cg, 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 Cs-Cg), substituted or unsubstitutedheterocycloalkyl (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.. Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0172] The symbol z5 is an integer from 0 to 5.

[0173] R4A, R4B, R4C, R4D, R5A, R5B, R5C, and R5Dare independently hydrogen, -CCl₃, -CBr3, -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN. -OH. -NH2, -COOH. -CONH2. -OCC13, -OCF3, -OCBr3, -OCI3. -OCHC12, -OCHBr2. -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e g., Ci-Cs, Ci-Ce, C1-C4, or Ci-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-Cs, C3-Ce. C4-C6, or Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R4Aand R4Bsubstituents 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); R5Aand R5Bsubstituents 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).

[0174] Each X4and X5is independently -F, -Cl, -Br, or -I.

[0175] The symbols n4 and n5 are independently an integer from 0 to 4.

[0176] The symbols m4, m5, v4, and v5 are independently 1 or 2.

[0177] In embodiments, the compound has the formula:(Va). R1, R2, R3, z3, R4, R5, and z5 are as described herein, including in embodiments.

[0178] In embodiments, the compound has the formula:(Vb). R1, R2, R3, z3, R5, and z5 are as described herein, including in embodiments. R41and R42are independently any value of R4as described herein, including in embodiments.

[0179] In embodiments, the compound has the formula:(Vc). R1, R2, R', z3, R4, R5, and z5 are as described herein, including in embodiments. R41and R42are independently any value of R4as described herein, including in embodiments.

[0180] In embodiments, the compound has the formula:(VI). R1, R2, R3, z3, R4, R5, and z5 are as described herein, including in embodiments. The symbol z4 is an integer from 0 to 3.

[0181] In embodiments, the compound has the formula:and z5 are as described herein, including in embodiments.

[0182] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula:

[0183] R6is hydrogen, halogen, -CX63, -CHX62, -CH2X6, -OCX63, -OCH2X6, -OCHX62, -CN, -SOn6R6D, -SOv6NR6AR6B, -NR6CNR6AR6B, -ONR6AR6B, -NR6CC(O)NR6AR6B, -N(0)m6, -NR6AR6B, -C(O)R6C, -C(O)OR6C, -OC(O)R6C, -OC(O)OR6C, -C(O)NR6AR6B, -OC(O)NR6AR6B, -OR6D, -SR6D, -NR6ASO2R6D, -NR6AC(O)R6C, -NR6AC(O)OR6C, -NR6AOR6C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or Ci-C ), 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-Cs, C3-C6, C4-C6, or Cs-Ce), 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 ary l (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.

[0184] R7is halogen, -CX73. -CHX72, -CH2X7, -OCX73. -OCH2X7, -OCHX72, -CN.-SOn7R7D, -SOv7NR7AR7B, -NR7CNR7AR7B, -ONR7AR7B, -NR7CC(O)NR7AR7B, -N(O)m7, -NR7AR7B. -C(O)R7C, -C(O)OR7C, -OC(O)R7C, -OC(O)OR7C, -C(O)NR7AR7B, -OC(O)NR7AR7B, -OR7D, -SR7D, -NR7ASO2R7D, -NR7AC(O)R7C, -NR7AC(O)OR7C, -NR7AOR7C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or Ci-C ), 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-Cs, C3-C6, C4-C6, or Cs-Cs), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.

[0185] R3is independently oxo, halogen, -CC13, -CBr3, -CF3, -CI3, -CH2CL -CH2Br, -CH2F, -CH2I, -CHC12. -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -OCC13, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, 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-Cs, C3-Ce, C4-C6, or Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g.. 5 to 10 membered. 5 to 9 membered, or 5 to 6 membered).

[0186] The symbol z3 is an integer from 0 to 8.

[0187] R6A, R6B, R6C, R6D, R7A, R7B, R7C, and R7Dare independently hydrogen, -CC13, -CBr3, -CF3, -CI3, -CHC12, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2. -OCC13, -OCF3, -OCBr3, -OCI3. -OCHC12, -OCHBr2. -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Cg, C1-C4, or Ci-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 orunsubstituted cycloalkyl (e.g., Cs-Cs, C3-C6, C4-C6, or Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R6Aand R6Bsubstituents 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); R7Aand R7Bsubstituents 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).

[0188] Each X6and X7is independently -F, -Cl, -Br, or -I.

[0189] The symbols n6 and n7 are independently an integer from 0 to 4.

[0190] The symbols m6, m7, v6, and v7 are independently 1 or 2.

[0191] In embodiments, the compound has the formula:CCOUR (IX). R6and R7are as described herein, including in embodiments.

[0192] In embodiments, the compound has the formula:ccd-aR7(X). R6and R7are as described herein, including in embodiments.

[0193] In embodiments, a substituted R1(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, orlower substituent group; wherein if the substituted R1is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R1is substituted, it is substituted with at least one substituent group. In embodiments, when R1is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1is substituted, it is substituted with at least one lower substituent group.

[0194] In embodiments, R1is hydrogen, -CCl₃, -CBr₃, -CF₃, -CI₃, -CHCl₂, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCl₂, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0195] In embodiments, R1is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted 3 to 6 membered heterocycloalkyl.

[0196] In embodiments, R1is hydrogen. In embodiments, R1is -CCI3. In embodiments, R1is -CBr₃. In embodiments, R1is -CF3. In embodiments, R1is -CI3. In embodiments, R1is -CH2CI. In embodiments, R1is -CH2Br. In embodiments, R1is -CH2F. In embodiments, R1is -CH2I. In embodiments, R1is -CHCI2. In embodiments, R1is -CHBr2, In embodiments, R1is -CHF2. In embodiments, R1is -CHI2. In embodiments, R1is -CN. In embodiments, R1is -OH. In embodiments, R1is -NH2. In embodiments, R1is -COOH. In embodiments, R1is -CONH2. In embodiments, R1is -OCCI3. In embodiments, R1is -OCBr₃. In embodiments, R1is -OCF3. In embodiments, R1is -OCI3. In embodiments, R1is -OCH2CI. In embodiments, R1is -OCH₂Br. In embodiments, R1is -OCH2F. In embodiments, R1is -OCH2I. In embodiments, R1is -OCHCh. In embodiments. R1is -OCHBr2. In embodiments, R1is -OCHF2. In embodiments, R1is -OCHI2. In embodiments, R1is unsubstituted C1-C4 alkyl. In embodiments, R1is unsubstituted methyl. In embodiments, R1is unsubstituted ethyl. In embodiments, R1is unsubstituted propyl. In embodiments, R1is unsubstituted n-propyl. In embodiments. R1is unsubstituted isopropyl. In embodiments, R1is unsubstituted butyl. In embodiments, R1is unsubstituted n-butyl. In embodiments, R1is unsubstituted isobutyl. In embodiments, R1is unsubstituted tert-butyl.

[0197] In embodiments, a substituted R2(e.g.. substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R2is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R2is substituted, it is substituted with at least one substituent group. In embodiments, when R2is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2is substituted, it is substituted with at least one lower substituent group.

[0198] In embodiments, R2is hydrogen. -CCl₃, -CBrs, -CF₃, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2CI, -CH2Br. -CH2F. -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl₃, -OCF₃, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0199] In embodiments, R2is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted Cs-Ce cycloalkyl, or substituted or unsubstituted 3 to 6 membered heterocycloalkyl.

[0200] In embodiments, R2is hydrogen. In embodiments, R2is -CCI3. In embodiments, R2is -CBr₃. In embodiments. R2is -CF3. In embodiments, R2is -CI3. In embodiments, R2is -CH2C1. In embodiments, R2is -CH2Br. In embodiments. R2is -CH2F. In embodiments, R2is -CH2I. In embodiments, R2is -CHC12. In embodiments, R2is -CHBr2. In embodiments, R2is -CHF2. In embodiments, R2is -CHI2. In embodiments, R2is -CN. In embodiments, R2is-OH. In embodiments, R2is -NH2. In embodiments. R2is -COOH. In embodiments. R2is -CONH2. In embodiments, R2is -OCCI3. In embodiments, R2is -OCBr₃. In embodiments, R2is -OCF3. In embodiments, R2is -OCI3. In embodiments, R2is -OCH2C1. In embodiments, R2is -OCH2Br. In embodiments, R2is -OCH2F. In embodiments, R2is -OCH2I. In embodiments. R2is -OCHC12. In embodiments, R2is -OCHBr2. In embodiments, R2is -OCHF2. In embodiments, R2is -OCHI2. 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 isobutyl. In embodiments, R2is unsubstituted tert-butyl.

[0201] In embodiments, R1and R2are unsubstituted methyl.

[0202] In embodiments, a substituted ring formed when R1and R2substituents 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 R1and R2substituents 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 R1and R2substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R1and R2substituents 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 R1and R2substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0203] In embodiments, R1and R2substituents, together with the nitrogen atom to which they are bonded, are joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R1and R2substituents, together with the nitrogen atom to which they are bonded, are joined to form a substituted or unsubstituted pyrrolidinyl.

[0204] In embodiments, a substituted R3(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R3is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R3is substituted, it is substituted with at least one substituent group. In embodiments, when R3is substituted, it is substituted with atleast one size-limited substituent group. In embodiments, when R3is substituted, it is substituted with at least one lower substituent group.

[0205] In embodiments, R3is independently oxo. In embodiments. R3is independently halogen. In embodiments, R3is independently -F. In embodiments, R3is independently -Cl. In embodiments, R3is independently -Br. In embodiments, R3is independently -I. In embodiments, R3is independently -CCl₃. In embodiments, R3is independently -CBr₃. In embodiments, R3is independently -CF3. In embodiments, R3is independently -CI3. In embodiments, R3is independently -CH2CI. In embodiments, R3is independently -CH₂Br In embodiments, R3is independently -CH2F. In embodiments, R3is independently -CH2I. In embodiments, R3is independently -CHCl₂. In embodiments, R3is independently -CHBr2. In embodiments, R3is independently -CHF2. In embodiments, R3is independently -CHI2. In embodiments, R3is independently -CN. In embodiments, R3is independently -OH. In embodiments, R3is independently -NH2. In embodiments, R3is independently -COOH. In embodiments, R3is independently -CONH2. In embodiments, R3is independently -NO2. In embodiments, R3is independently -SH. In embodiments, R3is independently -SO3H. In embodiments, R3is independently -OSO3H. In embodiments, R3is independently -SO2NH2. In embodiments, R3is independently -NHNH2. In embodiments, R3is independently -ONH2. In embodiments, R3is independently -NHC(O)NH2. In embodiments, R3is independently -NHSO2H. In embodiments, R3is independently -NHC(O)H. In embodiments, R3is independently -NHC(O)OH. In embodiments, R3is independently -NHOH. In embodiments, R3is independently -OCCI3. In embodiments, R3is independently -OCBr3. In embodiments, R3is independently -OCF3. In embodiments, R3is independently -OCI3. In embodiments, R3is independently -OCH2CI. In embodiments, R3is independently -OCH2Br. In embodiments, R3is independently -OCH2F. In embodiments, R3is independently -OCH2I. In embodiments, R3is independently -OCHCh. In embodiments, R3is independently -OCHBr₂. In embodiments, R3is independently -OCHF2. In embodiments, R3is independently -OCHI₂. In embodiments, R3is independently -SF5. In embodiments, R3is independently -N3. In embodiments, R3is independently unsubstituted C1-C4 alkyl. In embodiments, R3is independently unsubstituted methyl. In embodiments, R3is independently unsubstituted ethyl. In embodiments, R3is independently unsubstituted propyl. In embodiments, R3is independently unsubstituted n-propyl. In embodiments, R3is independently unsubstituted isopropyl. In embodiments, R3is independently unsubstituted butyl. In embodiments, R3is independently unsubstituted n-butyl. In embodiments, R3isindependently unsubstituted isobutyl. In embodiments, R3is independently unsubstituted tert-butyl.

[0206] In embodiments, z3 is 0. In embodiments. z3 is 1. In embodiments, z3 is 2. In embodiments, z3 is 3. In embodiments, z3 is 4. In embodiments, z3 is 5. In embodiments, z3 is 6. In embodiments, z3 is 7. In embodiments, z3 is 8.

[0207] In embodiments, a substituted R4(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R4is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4is substituted, it is substituted with at least one substituent group. In embodiments, when R4is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4is substituted, it is substituted with at least one lower substituent group.

[0208] In embodiments, a substituted R4A(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 R4Ais 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 R4Ais substituted, it is substituted with at least one substituent group. In embodiments, when R4Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4Ais substituted, it is substituted with at least one lower substituent group.

[0209] In embodiments, a substituted R4B(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 R4Bis 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 R4Bis substituted, it issubstituted with at least one substituent group. In embodiments, when R4Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4Bis substituted, it is substituted with at least one lower substituent group.

[0210] In embodiments, a substituted ring formed when R4Aand R4Bsubstituents 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 R4Aand R4Bsubstituents 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 R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R4Aand R4Bsubstituents 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 R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0211] In embodiments, a substituted R4C(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 R4Cis 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 R4Cis substituted, it is substituted with at least one substituent group. In embodiments, when R4Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4Cis substituted, it is substituted with at least one lower substituent group.

[0212] In embodiments, a substituted R4D(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 R4Dis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lowersubstituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4Dis substituted, it is substituted with at least one substituent group. In embodiments, when R4Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4Dis substituted, it is substituted with at least one lower substituent group.

[0213] In embodiments, R4Ais independently hydrogen. In embodiments, R4Ais independently unsubstituted C1-C4 alkyl. In embodiments, R4Ais independently unsubstituted methyl. In embodiments, R4Ais independently unsubstituted ethyl. In embodiments, R4Ais independently unsubstituted propyl. In embodiments, R4Ais independently unsubstituted n-propyl. In embodiments, R4Ais independently unsubstituted isopropyl. In embodiments, R4Ais independently unsubstituted butyl. In embodiments, R4Ais independently unsubstituted n-butyl. In embodiments, R4Ais independently unsubstituted isobutyl. In embodiments, R4Ais independently unsubstituted tert-butyl.

[0214] In embodiments, R4Bis independently hydrogen. In embodiments, R4Bis independently unsubstituted C1-C4 alkyl. In embodiments, R4Bis independently unsubstituted methyl. In embodiments, R4Bis independently unsubstituted ethyl. In embodiments, R4Bis independently unsubstituted propyl. In embodiments, R4Bis independently unsubstituted n-propyl. In embodiments, R4Bis independently unsubstituted isopropyl. In embodiments, R4Bis independently unsubstituted butyl. In embodiments, R4Bis independently unsubstituted n-butyl. In embodiments, R4Bis independently unsubstituted isobutyl. In embodiments. R4Bis independently unsubstituted tert-butyl.

[0215] In embodiments, R4Cis independently hydrogen. In embodiments, R4Cis independently unsubstituted C1-C4 alkyl. In embodiments, R4Cis independently unsubstituted methyl. In embodiments, R4Cis independently unsubstituted ethyl. In embodiments, R4Cis independently unsubstituted propyl. In embodiments. R4Cis independently unsubstituted n-propyl. In embodiments, R4Cis independently unsubstituted isopropyl. In embodiments, R4Cis independently unsubstituted butyl. In embodiments, R4Cis independently unsubstituted n-butyl. In embodiments, R4Cis independently unsubstituted isobutyl. In embodiments, R4Cis independently unsubstituted tert-butyl.

[0216] In embodiments, R4Dis independently hydrogen. In embodiments, R4Dis independently unsubstituted C1-C4 alkyl. In embodiments, R4Dis independently unsubstituted methyl. In embodiments, R4Dis independently unsubstituted ethyl. Inembodiments, R4Dis independently unsubstituted propyl. In embodiments. R4Dis independently unsubstituted n-propyl. In embodiments, R4Dis independently unsubstituted isopropyl. In embodiments, R4Dis independently unsubstituted butyl. In embodiments, R4Dis independently unsubstituted n-butyl. In embodiments, R4Dis independently unsubstituted isobutyl. In embodiments, R4Dis independently unsubstituted tert-butyl.

[0217] In embodiments, R4is independently halogen, -CCl₃, -CBr₃, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2. -CN. -OH. -NH2, -COOH. -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCl₃, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2. -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0218] In embodiments, R4is independently halogen. In embodiments, R4is independently -F. In embodiments, R4is independently -Cl. In embodiments, R4is independently -Br. In embodiments, R4is independently -I. In embodiments. R4is independently -CCI3. In embodiments, R4is independently -CBr₃. In embodiments, R4is independently -CF3. In embodiments, R4is independently -CI3. In embodiments, R4is independently -CH2C1. In embodiments, R4is independently -CH2Br. In embodiments, R4is independently -CH2F. In embodiments, R4is independently -CH2I. In embodiments. R4is independently -CHC12. In embodiments, R4is independently -CHBr2. In embodiments, R4is independently -CHF2. In embodiments, R4is independently -CHI2. In embodiments, R4is independently -CN. In embodiments, R4is independently -OH. In embodiments, R4is independently -NH2. In embodiments, R4is independently -COOH. In embodiments, R4is independently -CONH2. In embodiments, R4is independently -NO2. In embodiments, R4is independently -SH. In embodiments, R4is independently -SO3H. In embodiments, R4is independently -OSO3H. In embodiments, R4is independently -SO2NH2. In embodiments, R4is independently -NHNH2. In embodiments, R4is independently -ONH2. In embodiments. R4is independently -NHC(O)NH2. In embodiments, R4is independently -NHSO2H. In embodiments, R4is independently -NHC(O)H. In embodiments, R4is independently -NHC(O)OH. In embodiments, R4is independently -NHOH. In embodiments, R4is independently -OCCI3. In embodiments, R4is independently -OCBr₃. In embodiments, R4is independently -OCF3. In embodiments, R4is independently -OCI3. In embodiments, R4is independently -OCH₂Cl. In embodiments, R4is independently -OCH₂Br In embodiments, R4is independently -OCH2F. In embodiments, R4is independently -OCH2I. In embodiments, R4is independently -OCHCI2. In embodiments, R4is independently -OCHBr2. In embodiments, R4is independently -OCHF2. In embodiments, R4is independently -OCHI2. In embodiments, R4is independently -SF5. In embodiments, R4is independently -N3. In embodiments, R4is independently unsubstituted C1-C4 alkyl. In embodiments, R4is independently unsubstituted methyl. In embodiments, R4is independently unsubstituted ethyl. In embodiments, R4is independently unsubstituted propyl. In embodiments, R4is independently unsubstituted n-propyl. In embodiments, R4is independently unsubstituted isopropyl. In embodiments, R4is independently unsubstituted butyl. In embodiments. R4is independently unsubstituted n-butyl. In embodiments, R4is independently unsubstituted isobutyl. In embodiments, R4is independently unsubstituted tert-butyl. In embodiments, R4is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R4is independently unsubstituted methoxy. In embodiments, R4is independently unsubstituted ethoxy. In embodiments, R4is independently unsubstituted propoxy. In embodiments, R4is independently unsubstituted n-propoxy. In embodiments, R4is independently unsubstituted isopropoxy. In embodiments, R4is independently unsubstituted butoxy.

[0219] In embodiments, R4is independently halogen, -CN, -OH, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R4is independently halogen, -OH, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl. Inembodiments, R4is independently -Cl, -CN, -OH, -CH3, or^'0'^'0'^ inembodiments, R4is independently^0'^'0^.

[0220] In embodiments, z4 is 0. In embodiments, z4 is 1. In embodiments, z4 is 2. In embodiments, z4 is 3. In embodiments, z4 is 4. In embodiments, z4 is 5.

[0221] In embodiments, a substituted R41(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 R41is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lowersubstituent group may optionally be different. In embodiments, when R41is substituted, it is substituted with at least one substituent group. In embodiments, when R41is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R41is substituted, it is substituted with at least one lower substituent group.

[0222] In embodiments, R41is halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOV4NR4AR4B, -NR4CNR4AR4B. -ONR4AR4B.-NR4CC(O)NR4AR4B, -N(0)m4. -NR4AR4B. -C(O)R4C, -C(O)OR4C. -OC(O)R4C, -OC(O)OR4C. -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SFJ. -N3, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Cs, C1-C4, or Ci-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-Cs, C3-Ce, C4-C6, or Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0223] In embodiments, R41is halogen, -CC13, -CBr3, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCC13. -OCBr3, -OCF3, -OCI3. -OCH2Cl, -OCH2Br. -OCH2F.-OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroar l.

[0224] In embodiments, R41is halogen. In embodiments, R41is -F. In embodiments, R41is -Cl. In embodiments, R41is -Br. In embodiments, R41is -I. In embodiments, R41is -CCI3. In embodiments, R41is -CBr3. In embodiments, R41is -CF3. In embodiments, R41is — CI3. In embodiments, R41is -CH2C1. In embodiments, R41is -CH2Br. In embodiments, R41is -CH2F. In embodiments, R41is -CH2I. In embodiments, R41is -CHC12. In embodiments, R41is -CHBr2. In embodiments, R41is -CHF2. In embodiments, R41is -CHI2. In embodiments, R41is -CN. In embodiments, R41is -OH. In embodiments, R41is -NH2. In embodiments, R41is -COOH. In embodiments, R41is -CONH2. Inembodiments, R41is -NO2. In embodiments, R41is -SH. In embodiments, R41is -SO3H. In embodiments, R41is -OSO3H. In embodiments. R41is -SO2NH2. In embodiments, R41is -NHNH2. In embodiments, R41is -ONH2. In embodiments, R41is -NHC(O)NH2. In embodiments, R41is -NHSO2H. In embodiments, R41is -NHC(O)H. In embodiments, R41is -NHC(O)OH. In embodiments, R41is -NHOH. In embodiments, R41is -OCCI3. In embodiments, R41is -OCB. In embodiments. R41is -OCF3. In embodiments. R41is -OCR. In embodiments, R41is -OCH2CI. In embodiments, R41is -OQtyBr. In embodiments, R41is -OCH2F. In embodiments, R41is -OCH2I. In embodiments, R41is -OCHCh. In embodiments, R41is -OCHBr2. In embodiments, R41is -OCHF2. In embodiments, R41is -OCHI2. In embodiments. R41is -SF5. In embodiments, R41is -N3. In embodiments, R41is unsubstituted C1-C4 alkyl. In embodiments, R41is unsubstituted methyl. In embodiments, R41is unsubstituted ethyl. In embodiments, R41is unsubstituted propyl. In embodiments, R41is unsubstituted n-propyl. In embodiments, R41is unsubstituted isopropyl. In embodiments, R41is unsubstituted butyl. In embodiments, R41is unsubstituted n-butyl. In embodiments, R41is unsubstituted isobutyl. In embodiments, R41is unsubstituted tert-butyl. In embodiments, R41is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R41is unsubstituted methoxy. In embodiments, R41is unsubstituted ethoxy. In embodiments, R41is unsubstituted propoxy. In embodiments, R41is unsubstituted n-propoxy. In embodiments, R41is unsubstituted isopropoxy. In embodiments, R41is unsubstituted butoxy.

[0225] In embodiments, R41is halogen, -CN, -OH, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R41is -Cl, -CN, -OH, -CH3,or In embodiments, R41isS^O'Z^O / .

[0226] In embodiments, a substituted R42(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 R42is 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 R42is substituted, it is substituted with at least one substituent group. In embodiments, when R42is substituted, it issubstituted with at least one size-limited substituent group. In embodiments, when R42is substituted, it is substituted with at least one lower substituent group.

[0227] In embodiments, R42is halogen. -CX43, -CHX42, -CH2X4. -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOv4NR4AR4B, -NR4CNR4AR4B, -ONR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SFS, -N3, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, 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-Cs, C3-Ce, C4-C6, or Cs-Ce), 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., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0228] In embodiments, R42is halogen, -CC13, -CBr3, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHC12. -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NH2, -NHSO2H, -NHC(O)H, -NHC(0)0H, -NHOH, -OCC13, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHC12. -OCHBr2, -OCHF2, -OCHI2, -SF5. -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0229] In embodiments, R42is halogen. In embodiments, R42is -F. In embodiments, R42is -Cl. In embodiments, R42is -Br. In embodiments, R42is -I. In embodiments, R42is -CC13. In embodiments, R42is -CBr3. In embodiments, R42is -CF3. In embodiments, R42is -CI3. In embodiments, R42is -CH2CI. In embodiments, R42is -CH2Br. In embodiments, R42is -CH2F. In embodiments, R42is -CH2I. In embodiments, R42is -CHCI2. In embodiments, R42is -CHB. In embodiments, R42is -CHF2. In embodiments, R42is -CHI2. In embodiments, R42is -CN. In embodiments. R42is -OH. In embodiments. R42is -NH2. In embodiments, R42is -COOH. In embodiments, R42is -CONH2. In embodiments, R42is -NO2. In embodiments, R42is -SH. In embodiments, R42is -SO3H. In embodiments, R42is -OSO3H. In embodiments, R42is -SO2NH2. In embodiments, R42is-NHNH2. In embodiments, R42is -ONH2. In embodiments. R42is -NHC(O)NH2. In embodiments, R42is -NHSO2H. In embodiments, R42is -NHC(O)H. In embodiments, R42is -NHC(O)OH. In embodiments, R42is -NHOH. In embodiments, R42is -OCCI3. In embodiments, R42is OCB. In embodiments, R42is -OCF3. In embodiments, R42is -OCI3. In embodiments, R42is -OCH2CI. In embodiments, R42is -OCH₂Br. In embodiments, R42is -OCH2F. In embodiments, R42is -OCH2I. In embodiments, R42is -OCHCk. In embodiments, R42is -OCHBft. In embodiments, R42is -OCHF2. In embodiments, R42is -OCHI2. In embodiments, R42is -SF5. In embodiments, R42is -N3. In embodiments, R42is unsubstituted C1-C4 alkyl. In embodiments, R42is unsubstituted methyl. In embodiments, R42is unsubstituted ethyl. In embodiments, R42is unsubstituted propyl. In embodiments, R42is unsubstituted n-propyl. In embodiments, R42is unsubstituted isopropyl. In embodiments, R42is unsubstituted but l. In embodiments, R42is unsubstituted n-butyl. In embodiments, R42is unsubstituted isobutyl. In embodiments, R42is unsubstituted tert-butyl. In embodiments. R42is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R42is unsubstituted methoxy. In embodiments, R42is unsubstituted ethoxy. In embodiments, R42is unsubstituted propoxy. In embodiments, R42is unsubstituted n-propoxy. In embodiments, R42is unsubstituted isopropoxy. In embodiments, R42is unsubstituted butoxy.

[0230] In embodiments, R42is halogen, -CN. -OH, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R42is -CL -CN, -OH. -CH3,or ^0^0^ in embodiments, R42is.

[0231] 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 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.

[0232] In embodiments, a substituted R5A(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 R5Ais 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 R5Ais substituted, it is substituted with at least one substituent group. In embodiments, when R5Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5Ais substituted, it is substituted with at least one lower substituent group.

[0233] In embodiments, a substituted R5B(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 R5Bis 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 R5Bis substituted, it is substituted with at least one substituent group. In embodiments, when R5Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5Bis substituted, it is substituted with at least one lower substituent group.

[0234] In embodiments, a substituted ring formed when R5Aand R5Bsubstituents 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 R5Aand R5Bsubstituents 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 R5Aand R5Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R5Aand R5Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when thesubstituted ring formed when R5Aand R5Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0235] In embodiments, a substituted R5C(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 R5Cis 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 R5Cis substituted, it is substituted with at least one substituent group. In embodiments, when R5Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5Cis substituted, it is substituted with at least one lower substituent group.

[0236] In embodiments, a substituted R5D(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 R5Dis 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 R5Dis substituted, it is substituted with at least one substituent group. In embodiments, when R5Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5Dis substituted, it is substituted with at least one lower substituent group.

[0237] In embodiments, R5Ais independently hydrogen. In embodiments, R5Ais independently unsubstituted C1-C4 alkyl. In embodiments, R5Ais independently unsubstituted methyl. In embodiments, R5Ais independently unsubstituted ethyl. In embodiments, R5Ais independently unsubstituted propyl. In embodiments, R5Ais independently unsubstituted n-propyl. In embodiments, R5Ais independently unsubstituted isopropyl. In embodiments, R5Ais independently unsubstituted butyl. In embodiments, R5Ais independently unsubstituted n-butyl. In embodiments, R5Ais independently unsubstituted isobutyl. In embodiments. R5Ais independently unsubstituted tert-butyl.

[0238] In embodiments, R5Bis independently hydrogen. In embodiments, R5Bis independently unsubstituted C1-C4 alkyl. In embodiments, R5Bis independentlyunsubstituted methyl. In embodiments, R5Bis independently unsubstituted ethyl. In embodiments, R5Bis independently unsubstituted propyl. In embodiments. R5Bis independently unsubstituted n-propyl. In embodiments, R5Bis independently unsubstituted isopropyl. In embodiments, R5Bis independently unsubstituted butyl. In embodiments, R5Bis independently unsubstituted n-butyl. In embodiments, R5Bis independently unsubstituted isobutyl. In embodiments. R5Bis independently unsubstituted tert-butyl.

[0239] In embodiments, R5Cis independently hydrogen. In embodiments, R5Cis independently unsubstituted C1-C4 alkyl. In embodiments, R5Cis independently unsubstituted methyl. In embodiments, R5Cis independently unsubstituted ethyl. In embodiments, R5Cis independently unsubstituted propyl. In embodiments, R5Cis independently unsubstituted n-propyl. In embodiments, R5Cis independently unsubstituted isopropyl. In embodiments, R5Cis independently unsubstituted butyl. In embodiments, R5Cis independently unsubstituted n-butyl. In embodiments, R5Cis independently unsubstituted isobutyl. In embodiments, R5Cis independently unsubstituted tert-butyl.

[0240] In embodiments, R5Dis independently hydrogen. In embodiments, R5Dis independently unsubstituted C1-C4 alkyl. In embodiments, R5Dis independently unsubstituted methyl. In embodiments, R5Dis independently unsubstituted ethyl. In embodiments, R5Dis independently unsubstituted propyl. In embodiments, R5Dis independently unsubstituted n-propyl. In embodiments, R5Dis independently unsubstituted isopropyl. In embodiments, R5Dis independently unsubstituted butyl. In embodiments, R5Dis independently unsubstituted n-butyl. In embodiments, R5Dis independently unsubstituted isobutyl. In embodiments, R5Dis independently unsubstituted tert-but l.

[0241] In embodiments, R5is independently halogen, -CCl₃, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br. -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH. -SO3H. -OSO3H. -SO2NH2, -NHNH2. -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -NS, 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.

[0242] In embodiments, R5is independently halogen, -CCI3, -CBr₃, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCh, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2,substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.

[0243] In embodiments, R5is independently halogen. In embodiments, R5is independently -F. In embodiments, R5is independently -Cl. In embodiments, R5is independently -Br. In embodiments, R5is independently -I. In embodiments, R5is independently -CCI3. In embodiments, R3is independently -CBr₃. In embodiments, R5is independently -CF3. In embodiments, R5is independently -CI3. In embodiments, R5is independently -CH2CI. In embodiments, R5is independently -CFhBr In embodiments, R5is independently -CH2F. In embodiments, R5is independently -CH2I. In embodiments, R5is independently -CHCI2. In embodiments, R3is independently -CHBr2. In embodiments, R5is independently -CHF2. In embodiments, R5is independently -CHI2. In embodiments. R5is independently -CN. In embodiments, R5is independently -OH. In embodiments, R5is independently -NH2. In embodiments, R5is independently -COOH. In embodiments, R5is independently -CONH2. In embodiments, R5is independently -NO2. In embodiments, R5is independently -SH. In embodiments, R5is independently -SO3H. In embodiments, R3is independently -OSO3H. In embodiments. R5is independently -SO2NH2. In embodiments, R5is independently -NHNH2. In embodiments, R5is independently -ONH2. In embodiments, R5is independently -NHC(O)NH2. In embodiments, R5is independently -NHSO2H. In embodiments, R3is independently -NHC(O)H. In embodiments, R5is independently -NHC(O)OH. In embodiments, R5is independently -NHOH. In embodiments, R5is independently -OCCI3. In embodiments, R5is independently -OCBr?. In embodiments, R5is independently -OCF3. In embodiments, R5is independently -OCI3. In embodiments, R5is independently -OCH2CI. In embodiments, R5is independently -OCH2Br. In embodiments, R5is independently -OCH2F. In embodiments, R3is independently -OCH2I. In embodiments, R3is independently -OCHCh. In embodiments, R3is independently -OCHBr?. In embodiments, R3is independently -OCHF2. In embodiments, R3is independently -OCHI2. In embodiments, R3is independently -SF5. In embodiments, R3is independently -N3. In embodiments, R3is independently unsubstituted C1-C4 alkyl. In embodiments. R3is independently unsubstituted methyl. In embodiments, R3is independently unsubstituted ethyl. In embodiments, R3is independently unsubstituted propyl. In embodiments, R3is independently unsubstituted n-propyl. In embodiments, R3is independently unsubstituted isopropyl. In embodiments, R3is independently unsubstituted butyl. In embodiments. R3is independently unsubstituted n-butyl. In embodiments, R3is independently unsubstitutedisobutyl. In embodiments, R5is independently unsubstituted tert-butyl. In embodiments, R5is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R5is independently unsubstituted methoxy. In embodiments, R5is independently unsubstituted ethoxy. In embodiments, R5is independently' unsubstituted propoxy. In embodiments, R5is independently unsubstituted n-propoxy. In embodiments, R5is independently unsubstituted isopropoxy. In embodiments, R5is independently unsubstituted butoxy.

[0244] In embodiments, z5 is 0. In embodiments. z5 is 1. In embodiments, z5 is 2. In embodiments, z5 is 3. In embodiments, z5 is 4. In embodiments, z5 is 5.

[0245] In embodiments, a substituted R6(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 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 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.

[0246] In embodiments, a substituted R6A(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 R6Ais 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 R6Ais substituted, it is substituted with at least one substituent group. In embodiments, when R6Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R6Ais substituted, it is substituted with at least one lower substituent group.

[0247] In embodiments, a substituted R6B(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 R6Bis substituted with a plurality ofgroups 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 R6Bis substituted, it is substituted with at least one substituent group. In embodiments, when R6Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R6Bis substituted, it is substituted with at least one lower substituent group.

[0248] In embodiments, a substituted ring formed when R6Aand R6Bsubstituents 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 R6Aand R6Bsubstituents 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 R6Aand R6Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R6Aand R6Bsubstituents 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 R6Aand R6Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0249] In embodiments, a substituted R6C(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 R6Cis 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 R6Cis substituted, it is substituted with at least one substituent group. In embodiments, when R6Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R6Cis substituted, it is substituted with at least one lower substituent group.

[0250] In embodiments, a substituted R6D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substitutedheteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R6Dis 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 R6Dis substituted, it is substituted with at least one substituent group. In embodiments, when R6Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R6Dis substituted, it is substituted with at least one lower substituent group.

[0251] In embodiments, R6Ais hydrogen. In embodiments, R6Ais unsubstituted C1-C4 alkyl. In embodiments, R6Ais unsubstituted methyl. In embodiments, R6Ais unsubstituted ethyl. In embodiments, R6Ais unsubstituted propyl. In embodiments, R6Ais unsubstituted n-propyl In embodiments, R6Ais unsubstituted isopropyl. In embodiments, R6Ais unsubstituted butyl. In embodiments, R6Ais unsubstituted n-butyl. In embodiments, R6Ais unsubstituted isobutyl. In embodiments, R6Ais unsubstituted tert-butyl.

[0252] In embodiments, R6Bis hydrogen. In embodiments, R6Bis unsubstituted C1-C4 alkyl. In embodiments, R6Bis unsubstituted methyl. In embodiments, R6Bis unsubstituted ethyl. In embodiments, R6Bis unsubstituted propyl. In embodiments, R6Bis unsubstituted n-propyl. In embodiments, R6Bis unsubstituted isopropyl. In embodiments, R6Bis unsubstituted butyl. In embodiments, R6Bis unsubstituted n-butyl. In embodiments, R6Bis unsubstituted isobutyl. In embodiments, R6Bis unsubstituted tert-butyl.

[0253] In embodiments, R6Cis hydrogen. In embodiments, R6Cis unsubstituted C1-C4 alkyl. In embodiments, R6Cis unsubstituted methyl. In embodiments, R6Cis unsubstituted ethyl. In embodiments, R6Cis unsubstituted propyl. In embodiments, R6Cis unsubstituted n-propyl. In embodiments, R6Cis unsubstituted isopropyl. In embodiments, R6Cis unsubstituted butyl. In embodiments, R6Cis unsubstituted n-butyl. In embodiments. R6Cis unsubstituted isobutyl. In embodiments, R6Cis unsubstituted tert-butyl.

[0254] In embodiments, R6Dis hydrogen. In embodiments, R6Dis unsubstituted C1-C4 alkyl. In embodiments, R6Dis unsubstituted methyl. In embodiments, R6Dis unsubstituted ethyl. In embodiments, R6Dis unsubstituted propyl. In embodiments, R6Dis unsubstituted n-propyl. In embodiments, R6Dis unsubstituted isopropyl. In embodiments, R6Dis unsubstituted butyl. In embodiments, R6Dis unsubstituted n-butyl. In embodiments. R6Dis unsubstituted isobutyl. In embodiments, R6Dis unsubstituted tert-butyl.

[0255] In embodiments, R6is halogen, -CCl₃, -CBr₃,, -CF3, -CI3, -CH2CI, -CH₂Br, -CH2F, -CH2I, -CHCI2. -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl₃, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2, -OCHBr₂, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0256] In embodiments, R6is substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0257] In embodiments, R6is hydrogen. In embodiments, R6is halogen. In embodiments, R6is F. In embodiments, R6is -Cl. In embodiments, R6is -Br. In embodiments, R6is -I. In embodiments, R6is -CC13. In embodiments, R6is -CBr3. In embodiments, R6is -CF3. In embodiments, R6is -CI3. In embodiments, R6is -CH2CI. In embodiments. R6is -CH2Br. In embodiments, R6is -CH2F. In embodiments, R6is -CH2I. In embodiments, R6is -CHCI2. In embodiments, R6is -CHBr2. In embodiments, R6is -CHF2. In embodiments, R6is -CHI2. In embodiments, R6is -CN. In embodiments, R6is -OH. In embodiments, R6is -NH2. In embodiments, R6is -COOH. In embodiments, R6is -CONH2. In embodiments, R6is -NO2. In embodiments, R6is -SH. In embodiments, R6is -SO3H. In embodiments, R6is -OSO3H. In embodiments, R6is -SO2NH2. In embodiments, R6is -NHNH2. In embodiments, R6is -ONH2. In embodiments, R6is -NHC(O)NH2. In embodiments. R6is -NHSO2H. In embodiments, R6is -NHC(O)H. In embodiments, R6is -NHC(O)OH. In embodiments, R6is -NHOH. In embodiments, R6is -OCCI3. In embodiments, R6is -OCBr3. In embodiments, R6is -OCF3. In embodiments, R6is -OCI3. In embodiments, R6is -OCH2CI. In embodiments, R6is -OCH₂Br. In embodiments, R6is -OCH2F. In embodiments, R6is -OCH2I. In embodiments, R6is -OCHCI2. In embodiments, R6is -OCHBr2. In embodiments, R6is -OCHF2. In embodiments, R6is -OCHI2. In embodiments, R6is -SF5. In embodiments, R6is -N3. In embodiments, R6is unsubstituted C1-C4 alkyl. In embodiments, R6is unsubstituted methyl. In embodiments, R6is unsubstituted ethyl. In embodiments, R6is unsubstituted propyl. In embodiments, R6is unsubstituted n-propyl. Inembodiments, R6is unsubstituted isopropyl. In embodiments, R6is unsubstituted butyl. In embodiments, R6is unsubstituted n-butyl. In embodiments, R6is unsubstituted isobutyl. In embodiments, R6is unsubstituted tert-butyl. In embodiments, R6is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R6is unsubstituted methoxy. In embodiments, R6is unsubstituted ethoxy. In embodiments, R6is unsubstituted propoxy. In embodiments, R6is unsubstituted n-propoxy. In embodiments, R6is unsubstituted isopropoxy. In embodiments, R6is unsubstituted butoxy.

[0258] In embodiments, a substituted R7(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 R7is 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 R7is substituted, it is substituted with at least one substituent group. In embodiments, when R7is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R7is substituted, it is substituted with at least one lower substituent group.

[0259] In embodiments, a substituted R7A(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 R7Ais 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 R7Ais substituted, it is substituted with at least one substituent group. In embodiments, when R7Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R7Ais substituted, it is substituted with at least one lower substituent group.

[0260] In embodiments, a substituted R7B(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 R7Bis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lowersubstituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R7Bis substituted, it is substituted with at least one substituent group. In embodiments, when R7Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R7Bis substituted, it is substituted with at least one lower substituent group.

[0261] In embodiments, a substituted ring formed when R7Aand R7Bsubstituents 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 R7Aand R7Bsubstituents 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 R7Aand R7Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R7Aand R7Bsubstituents 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 R7Aand R7Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0262] In embodiments, a substituted R7C(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 R7Cis 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 R7Cis substituted, it is substituted with at least one substituent group. In embodiments, when R7Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R7Cis substituted, it is substituted with at least one lower substituent group.

[0263] In embodiments, a substituted R7D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, orlower substituent group; wherein if the substituted R7Dis 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 R7Dis substituted, it is substituted with at least one substituent group. In embodiments, when R7Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R7Dis substituted, it is substituted with at least one lower substituent group.

[0264] In embodiments, R7Ais hydrogen. In embodiments, R7Ais unsubstituted C1-C4 alkyl. In embodiments, R7Ais unsubstituted methyl. In embodiments, R7Ais unsubstituted ethyl. In embodiments, R7Ais unsubstituted propyl. In embodiments, R7Ais unsubstituted n-propyl. In embodiments, R7Ais unsubstituted isopropyl. In embodiments, R7Ais unsubstituted butyl. In embodiments, R7Ais unsubstituted n-butyl. In embodiments, R7Ais unsubstituted isobutyl. In embodiments, R7Ais unsubstituted tert-butyl.

[0265] In embodiments, R7Bis hydrogen. In embodiments, R7Bis unsubstituted C1-C4 alkyl. In embodiments, R7Bis unsubstituted methyl. In embodiments, R7Bis unsubstituted ethyl. In embodiments, R7Bis unsubstituted propyl. In embodiments, R7Bis unsubstituted n-propyl In embodiments, R7Bis unsubstituted isopropyl. In embodiments, R7Bis unsubstituted butyl. In embodiments, R7Bis unsubstituted n-butyl. In embodiments, R7Bis unsubstituted isobutyl. In embodiments, R7Bis unsubstituted tert-butyl.

[0266] In embodiments, R7Cis hydrogen. In embodiments, R7Cis unsubstituted C1-C4 alkyl. In embodiments, R7Cis unsubstituted methyl. In embodiments, R7Cis unsubstituted ethyl. In embodiments, R7Cis unsubstituted propyl. In embodiments, R7Cis unsubstituted n-propyl. In embodiments, R7Cis unsubstituted isopropyl. In embodiments, R7Cis unsubstituted butyl. In embodiments, R7Cis unsubstituted n-butyl. In embodiments, R7Cis unsubstituted isobutyl. In embodiments, R7Cis unsubstituted tert-butyl.

[0267] In embodiments, R7Dis hydrogen. In embodiments. R7Dis unsubstituted C1-C4 alkyl. In embodiments, R7Dis unsubstituted methyl. In embodiments, R7Dis unsubstituted ethyl. In embodiments, R7Dis unsubstituted propyl. In embodiments, R7Dis unsubstituted n-propyl. In embodiments, R7Dis unsubstituted isopropyl. In embodiments, R7Dis unsubstituted butyl. In embodiments, R7Dis unsubstituted n-butyl. In embodiments. R7Dis unsubstituted isobutyl. In embodiments, R7Dis unsubstituted tert-butyl.

[0268] In embodiments, R7is halogen, -CCl₃, -CBr₃,, -CF3, -CI3, -CH2CI, -CH₂Br, -CH2F, -CH2I, -CHCI2. -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl₃, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2, -OCHBr₂, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0269] In embodiments, R7is substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0270] In embodiments, R7is halogen. In embodiments, R7is -F. In embodiments, R7is -Cl. In embodiments, R7is -Br. In embodiments, R7is -I. In embodiments, R7is -CCI3. In embodiments, R7is -CBr₃. In embodiments, R7is -CF3. In embodiments, R7is -CI3. In embodiments, R7is -CH2CI. In embodiments, R7is -CH2Br. In embodiments. R7is -CH2F. In embodiments, R7is -CH2I. In embodiments, R7is -CHCI2. In embodiments, R7is -CHBr2. In embodiments, R7is -CHF2. In embodiments, R7is -CHI2. In embodiments, R7is -CN. In embodiments, R7is -OR7D, wherein R7Dis as described herein, including in embodiments. In embodiments, R7is -OH. In embodiments, R7is -NH2. In embodiments, R7is -COOH. In embodiments, R7is -CONH2. In embodiments, R7is -NO2. In embodiments, R7is -SH. In embodiments, R7is -SO3H. In embodiments, R7is -OSO3H. In embodiments, R7is -SO2NH2. In embodiments, R7is -NHNH2. In embodiments, R7is -ONH2. In embodiments, R7is -NHC(O)NH2. In embodiments, R7is -NHSO2H. In embodiments, R7is -NHC(O)H. In embodiments, R7is -NHC(O)OH. In embodiments, R7is -NHOH. In embodiments, R7is -OCCI3. In embodiments, R7is -OCBr3. In embodiments, R7is -OCF3. In embodiments, R7is -OCI3. In embodiments, R7is -OCH2CI. In embodiments, R7is -OCH2Br. In embodiments, R7is -OCH2F. In embodiments, R7is -OCH2I. In embodiments, R7is -OCHCI2. In embodiments, R7is -OCHBr2. In embodiments, R7is -OCHF2. In embodiments, R7is -OCHI2. In embodiments, R7is -SF5. In embodiments, R7is -N3. In embodiments, R7is unsubstituted C1-C4 alkyl. In embodiments, R7is unsubstituted methyl. In embodiments, R7is unsubstituted ethyl. In embodiments, R7isunsubstituted propyl. In embodiments, R7is unsubstituted n-propyl. In embodiments, R7is unsubstituted isopropyl. In embodiments. R7is unsubstituted butyl. In embodiments, R7is unsubstituted n-butyl. In embodiments, R7is unsubstituted isobutyl. In embodiments, R7is unsubstituted tert-butyl. In embodiments, R7is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R7is unsubstituted methoxy. In embodiments, R7is unsubstituted ethoxy. In embodiments, R7is unsubstituted propoxy. In embodiments, R7is unsubstituted n-propoxy. In embodiments, R7is unsubstituted isopropoxy. In embodiments, R7is unsubstituted butoxy.

[0271] In embodiments, when R1is substituted, R1is substituted with one or more first substituent groups denoted by R1 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1 1substituent group is substituted, the R1 1substituent group is substituted with one or more second substituent groups denoted by R1 2as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R1 2substituent group is substituted, the R1 2substituent group is substituted with one or more third substituent groups denoted by R1 3as explained in the definitions section above in the description of “first substituent group(s)’’. In the above embodiments, R1, R1 1, R1 2, and R13have values corresponding to the values of Rww, RWW I. Rww-2. and Rww-5. respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, RWW 1, RWW.2, and RWW3correspond to R1, R1 1, R1 2. and R1 3, respectively.

[0272] In embodiments, when R2is substituted. R2is substituted with one or more first substituent groups denoted by R2 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2 1substituent group is substituted, the R2 1substituent group is substituted with one or more second substituent groups denoted by R22as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R22substituent group is substituted, the R22substituent group is substituted with one or more third substituent groups denoted by R2 1as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2. R2-1, R22, and R23have values corresponding to the values of Rww. RWW 1RWW.2ANC[ RWW.3reSpectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww, RWW 13RWW.2 and RWW 3correspond to R2, R2 1, R22, and R23, respectively.

[0273] In embodiments, when R1and R2substituents 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 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)7’. In embodiments, when an R1 2substituent group is substituted, the R1 2substituent group is substituted with one or more third substituent groups denoted by R1 3as explained in the definitions section above in the description of “first substituent group(s)’'. In the above embodiments, R1-1, R1 2, and R1 3have values corresponding to the values of RWW 1, RW 2. and Rww 3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW3. Rww'2, and Rww?correspond to R1 1. R1 2, and R1respectively.

[0274] In embodiments, when R1and R2substituents 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 R2 1as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R21substituent group is substituted, the R21substituent group is substituted with one or more second substituent groups denoted by R22as explained in the definitions section above in the description of “first substituent group(s)’’. In embodiments, when an R22substituent group is substituted, the R22substituent group is substituted with one or more third substituent groups denoted by R23as explained in the definitions section above in the description of “first substituent group(s)" In the above embodiments, R21, R22, and R23have 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. Rww'2, and Rww-?correspond to R2 1. R22, and R2', respectively.

[0275] In embodiments, when R3is substituted, R3is substituted with one or more first substituent groups denoted by R3 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3 1substituent group is substituted, the R3 1substituent group is substituted with one or more second substituentgroups denoted by R3 2as explained in the definitions section above in the description of “first substituent group(s)” In embodiments, when an R32substituent 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. R32, and R33have values corresponding to the values of Rww, RwwRww-2, and Rww-3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”. wherein RWVv, RwRWW2and RWW 3correspond to R3, R3 1, R32, and R33, respectively.

[0276] In embodiments, when R4is substituted, R4is substituted with one or more first substituent groups denoted by R41as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R41substituent group is substituted, the R41substituent group is substituted with one or more second substituent groups denoted by R42as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R42substituent group is substituted, the R42substituent group is substituted with one or more third substituent groups denoted by R43as explained in the definitions section above in the description of “first substituent group(s)’’. In the above embodiments, R4, R41, R42, and R43have values corresponding to the values of Rww, RWW I. Rww-2. and Rww'5. respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, RWW 1, RWW.2, and RWW3correspond to R4, R41, R42. and R43, respectively.

[0277] In embodiments, when R41is substituted, R41is substituted with one or more first substituent groups denoted by R4 1 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4 1 1substituent group is substituted, the R41 1substituent group is substituted with one or more second substituent groups denoted by R4 1 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R41 2substituent group is substituted, the R41-2substituent group is substituted with one or more third substituent groups denoted by R41 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R44, R41 1, R4 1 2and R41 3have values corresponding to the values of Rww,RWW 1. RWW2_ANC| respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww, RWW 13RWW.2 and RWW 3correspond to R41, R41 1, R4 1 2, and R4 1?, respectively.

[0278] In embodiments, when R42is substituted, R42is substituted with one or more first substituent groups denoted by R421as explained in the definitions section above in the description of ‘’first substituent group(s)’’. In embodiments, when an R421substituent group is substituted, the R421substituent group is substituted with one or more second substituent groups denoted by R422as explained in the definitions section above in the description of “first substituent group(s)". In embodiments, when an R422substituent group is substituted, the R422substituent group is substituted with one or more third substituent groups denoted by R4'2'3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R42, R4-21, R4-22, and R423have values corresponding to the values of Rww, RWW4, Rww25 anc| RWW.1, respectively, as explained in the definitions section above in the description of “first substituent group(s)’; wherein Rww. R1.RW.2 and RWW 3correspond to R42, R421, R4-22, and R423, respectively.

[0279] In embodiments, when R4Ais substituted, R4Ais substituted with one or more first substituent groups denoted by R4A 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A 1substituent group is substituted, the R4A 1substituent group is substituted with one or more second substituent groups denoted by R4A2as explained in the definitions section above in the description of “first substituent group(s)’:. In embodiments, when an R4A 2substituent group is substituted, the R4A 2substituent group is substituted with one or more third substituent groups denoted by R4A 3as explained in the definitions section above in the description of “first substituent group(s)’’. In the above embodiments, R4A, R4A I. R4A 2, and R4A3have values corresponding to the values of Rww, Rww'1, RWW-2,anc| ^ww.-. respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, RWW 1, RWW.2, and Rw W3correspond to R4A, R4A 1, R4A 2, and R4A3, respectively.

[0280] In embodiments, when R4Bis substituted, R4Bis substituted with one or more first substituent groups denoted by R4B 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B 1substituent group is substituted, the R4B 1substituent group is substituted with one or more second substituent groups denoted by R4B 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B 2substituent group is substituted, the R4B 2substituent group is substituted with one or more third substituent groups denoted by R4B 3as explained in the definitions section above in the description of “first substituentgroup(s)'’. In the above embodiments, R4B, R4B 1, R4B 2, and R4B 3have values corresponding to the values of Rw, Rww\ Rww-2, and Rww-3, respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww, RwwRW.2 and RWW 3correspond to R4B, R4B 1, R4B 2, and R4B 3, respectively.

[0281] In embodiments, when R4Aand R4Bsubstituents 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 R4A 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A 1substituent group is substituted, the R4A 1substituent group is substituted with one or more second substituent groups denoted by R4A 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A2substituent group is substituted, the R4A 2substituent group is substituted with one or more third substituent groups denoted by R4A3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4A 1, R4A 2, and R4A 3have values corresponding to the values of RW 1,RWW2anjRWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rw v, 1;RWW 2,anc|Rww,3C0rreSp0nd to R4A 1, R4A-2, and R4A3, respectively.

[0282] In embodiments, when R4Aand R4Bsubstituents 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 R4B 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B 1substituent group is substituted, the R4B 1substituent group is substituted with one or more second substituent groups denoted by R4B 2as explained in the definitions section above in the description of “first substituent group(s)’’. In embodiments, when an R4B 2substituent group is substituted, the R4B 2substituent group is substituted with one or more third substituent groups denoted by R4B 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4B 1, R4B 2, and R4B Jhave values corresponding to the values of RWW4,RWW.2ANC|RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW 1, RWW 2and RWW 3correspond to R4B 4, R4B 2, and R4B 3, respectively.

[0283] In embodiments, when R4Cis substituted, R4Cis substituted with one or more first substituent groups denoted by R4C 1as explained in the definitions section above in the description of ‘’first substituent group(s)’’. In embodiments, when an R4C 1substituent group is substituted, the R4C 1substituent group is substituted with one or more second substituent groups denoted by R4C 2as explained in the definitions section above in the description of “first substituent group(s)". In embodiments, when an R4C 2substituent group is substituted, the R4C 2substituent group is substituted with one or more third substituent groups denoted by R4C 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4C, R4C4, R4C 2, and R4C 3have values corresponding to the values of Rww, RWW4, Rww25 anc| RWWJ, respectively, as explained in the definitions section above in the description of “first substituent group(s)’; wherein Rww. R1.RW.2 and RWW 3correspond to R4C, R4C 1, R4C 2, and R4C3, respectively.

[0284] In embodiments, when R4Dis substituted, R4Uis substituted with one or more first substituent groups denoted by R4D 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4D 1substituent group is substituted, the R4D 1substituent group is substituted with one or more second substituent groups denoted by R4D2as explained in the definitions section above in the description of “first substituent group(s)’:. In embodiments, when an R4D 2substituent group is substituted, the R4D 2substituent group is substituted with one or more third substituent groups denoted by R4D 3as explained in the definitions section above in the description of “first substituent group(s)’’. In the above embodiments, R4D, R4D 1, R4D 2, and R4D 3have values corresponding to the values of Rww, Rww'1, RWW-2,anc| ^ww.-. respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, RWW 1, RWW.2, and Rw W3correspond to R4D, R4D 1, R4D 2, and R4D 3, respectively.

[0285] 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 substituted, 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 R52substituent group is substituted, the R5 2substituent group is substituted with one or more third substituent groups denoted by R5 3as explained in the definitions section above in the description of “first substituentgroup(s)'’. In the above embodiments, R5, R5R52, and R53have values corresponding to the values of Rww. Rww-1, Rww'2, and RWW2’, respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww, RwwRW.2 and RWW 3correspond to R5, R5 1, R52, and R53, respectively.

[0286] In embodiments, when R5Ais substituted, R5Ais substituted with one or more first substituent groups denoted by R5A 1as explained in the definitions section above in the description of “first substituent group(s)". In embodiments, when an R5A 1substituent group is substituted, the R5A 1substituent group is substituted with one or more second substituent groups denoted by R5A2as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R5A 2substituent group is substituted, the R5A 2substituent group is substituted with one or more third substituent groups denoted by R5A3as explained in the definitions section above in the description of “first substituent group(s)’’. In the above embodiments, R5A, R5A J, R5A2, and R5A3have values corresponding to the values of Rw w, Rww-1, Rww-2, and RWW3. respectively, as explained in the definitions section above in the description of “first substituent group(s)'’, wherein Rww. RWW 15RWW2, and R3correspond to R5A, R5 A1, R5A 2. and R5A3, respectively.

[0287] In embodiments, when R5Bis substituted, R5Bis substituted with one or more first substituent groups denoted by R5B 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5B 1substituent group is substituted, the R5B 1substituent group is substituted with one or more second substituent groups denoted by R5B 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5B 2substituent group is substituted, the R5B 2substituent group is substituted with one or more third substituent groups denoted by R5B 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5B, R5B l, R5B 2. and R5B 3have values corresponding to the values of Rww, RWWA, Rww-2;and Rww-3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, RwwRWW.2 and RWW3correspond to R5B, R5B-1, R5B 2, and R5B 3, respectively.

[0288] In embodiments, when R5Aand R5Bsubstituents 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 R5A1as explained in the definitions section above in the description of “firstsubstituent group(s)’'. In embodiments, when an R5A 1substituent group is substituted, the R5A 1substituent group is substituted with one or more second substituent groups denoted by R5A2as explained in the definitions section above in the description of '‘first substituent group(s)”. In embodiments, when an R5A 2substituent group is substituted, the R5A 2substituent group is substituted with one or more third substituent groups denoted by R5A3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5A-1, R5A 2, and R5A3have values corresponding to the values ofRWWJ,ANC| 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 R5A 1. R5A 2, and R5A\ respectively.

[0289] In embodiments, when R5Aand R5Bsubstituents 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 R5B 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5B 1substituent group is substituted, the R5B 1substituent group is substituted with one or more second substituent groups denoted by R5B 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5B 2substituent group is substituted, the R5B 2substituent group is substituted with one or more third substituent groups denoted by R5B 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5B-1, R5B 2, and R5B 3have values corresponding to the values of RWW 1, ^WW2anc[ RW\V.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 R5B 1. R5B 2, and R5B 3, respectively.

[0290] In embodiments, when R5Cis substituted, R5Cis substituted with one or more first substituent groups denoted by R5C 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5C 1substituent group is substituted, the R5C 1substituent group is substituted with one or more second substituent groups denoted by R5C 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5C 2substituent group is substituted, the R5C 2substituent group is substituted with one or more third substituent groups denoted by R5C 3as explained in the definitions section above in the description of “first substituentgroup(s)'’. In the above embodiments, R5C, R5C, R5C 2, and R5C 3have values corresponding to the values of Rw, Rww\ Rww-2, and Rww-3, respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww, RwwRW.2 and RWW 3correspond to R5C, R5C 1, R5C 2, and R5C3, respectively.

[0291] In embodiments, when R5Dis substituted, R5Dis substituted with one or more first substituent groups denoted by R5D 1as explained in the definitions section above in the description of “first substituent group(s)". In embodiments, when an R5D 1substituent group is substituted, the R5D 1substituent group is substituted with one or more second substituent groups denoted by R5D 2as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R5D 2substituent group is substituted, the R5E> 2substituent group is substituted with one or more third substituent groups denoted by R5D 3as explained in the definitions section above in the description of “first substituent group(s)’’. In the above embodiments, R5U, R5U J, R5U 2, and R5U 3have values corresponding to the values of Rw w, Rww-1, Rww-2, and RWW3. respectively, as explained in the definitions section above in the description of “first substituent group(s)'’, wherein Rww. RWW 15RWW2, and R3correspond to R5D, R5D, R5D 2. and R5D 3, respectively.

[0292] 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 R62as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R62substituent group is substituted, the R62substituent group is substituted with one or more third substituent groups denoted by R6as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R6. R6 A, R62, and R63have values corresponding to the values of Rww, RWW. I, ^WW.2ANC| RWW.3 respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, RwwRWW.2 and RWW3correspond to R6, R6 1, R62, and R63, respectively.

[0293] In embodiments, when R6Ais substituted, R6Ais substituted with one or more first substituent groups denoted by R6A 1as explained in the definitions section above in the description of “first substituent group(s)’’. In embodiments, when an R6A 1substituent group is substituted, the R6A 1substituent group is substituted with one or more second substituentgroups denoted by R6A2as explained in the definitions section above in the description of “first substituent group(s)” In embodiments, when an R6A 2substituent group is substituted, the R6A 2substituent group is substituted with one or more third substituent groups denoted by R6A 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R6A, R6A I. R6A 2, and R6A 3have values corresponding to the values of Rww, Rww-1, Rww-2, and Rww- respectively, as explained in the definitions section above in the description of “first substituent group(s)”. wherein RWVv, RwRWW2and RWW 3correspond to R6A, R6A 1, R6A2, and R6A3, respectively.

[0294] In embodiments, when R6Bis substituted, R6Bis substituted with one or more first substituent groups denoted by R6B 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6B 1substituent group is substituted, the R6B 1substituent group is substituted with one or more second substituent groups denoted by R6B 2as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R6B 2substituent group is substituted, the R6B 2substituent group is substituted with one or more third substituent groups denoted by R6B 3as explained in the definitions section above in the description of “first substituent group(s)’’. In the above embodiments, R6B, R6B-1, R6B 2, and R6B 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, R""-2. and RWW3correspond to R6B, R6B-1, R6B 2, and R6B 3. respectively.

[0295] In embodiments, when R6Aand R6Bsubstituents 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 R6A 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6A 1substituent group is substituted, the R6A 1substituent group is substituted with one or more second substituent groups denoted by R6A 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6A 2substituent group is substituted, the R6A 2substituent group is substituted with one or more third substituent groups denoted by R6A 3as explained in the definitions section above in the description of “first substituent group(s)7’. In the above embodiments, R6A 1, R6A 2, and R6A 3have values corresponding to the values of RWW 1, RWW2anj RWW.?,reSpectively;as explained in the definitions section above in thedescription of “first substituent group(s)”, wherein RwwRww2,anc| RW.3correSpOncito R6AI. R6A2and R6A3, respectively.

[0296] In embodiments, when R6Aand R6Bsubstituents 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 R6B 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6B 1substituent group is substituted, the R6B 1substituent group is substituted with one or more second substituent groups denoted by R6B 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6B 2substituent group is substituted, the R6B 2substituent group is substituted with one or more third substituent groups denoted by R6B 3as explained in the definitions section above in the description of “first substituent group(s)7’. In the above embodiments, R6B 1, R6B 2, and R6B 3have values corresponding to the values of RWW 1, ^WW.2anj RWW.3,reSpectively;as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW 1, RWW2,anc| R*®correSpOncito R6B-i. R6B 2, and R6B 3, respectively.

[0297] In embodiments, when R6Cis substituted, R6Cis substituted with one or more first substituent groups denoted by R6C 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6C 1substituent group is substituted, the R6C 1substituent group is substituted with one or more second substituent groups denoted by R6C 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6C 2substituent group is substituted, the R6C 2substituent group is substituted with one or more third substituent groups denoted by R6C 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R6C, R6C l, R6C 2. and R6C 3have values corresponding to the values of Rww, RWWA, RWW-2ANC| WW.3,reSpecpVely, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, RwwRWW.2 and RWW3correspond to R6C, R6C-1, R6C 2, and R6C 3, respectively.

[0298] In embodiments, when R6Dis substituted, R6Dis substituted with one or more first substituent groups denoted by R6D 1as explained in the definitions section above in the description of “first substituent group(s)’’. In embodiments, when an R6D 1substituent group is substituted, the R6D 1substituent group is substituted with one or more second substituentgroups denoted by R6D 2as explained in the definitions section above in the description of “first substituent group(s)” In embodiments, when an R6D 2substituent group is substituted, the R6E> 2substituent group is substituted with one or more third substituent groups denoted by R6D 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R6D, R6I) I. R6D 2, and R6D 3have values corresponding to the values of Rww, Rww-1, Rww-2, and Rww- respectively, as explained in the definitions section above in the description of “first substituent group(s)”. wherein RWVv, RwRWW2and RWW 3correspond to R6U, R6U 1, R6U 2, and R6U 3, respectively.

[0299] In embodiments, when R7is substituted, R7is substituted with one or more first substituent groups denoted by R7 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7 1substituent group is substituted, the R7 1substituent group is substituted with one or more second substituent groups denoted by R72as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R72substituent group is substituted, the R72substituent group is substituted with one or more third substituent groups denoted by R73as explained in the definitions section above in the description of “first substituent group(s)’’. In the above embodiments, R7, R71, R72, and R73have values corresponding to the values of Rww, RWW I. Rww-2. and Rww-5. respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, RWW 1, RWW.2, and RWW3correspond to R7, R7 1, R72. and R73, respectively.

[0300] In embodiments, when R7Ais substituted, R7Ais substituted with one or more first substituent groups denoted by R7A1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7A 1substituent group is substituted, the R7A 1substituent group is substituted with one or more second substituent groups denoted by R7A 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7A 2substituent group is substituted, the R7A 2substituent group is substituted with one or more third substituent groups denoted by R7A 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R7A, R7 I. R7A 2. and R7A 3have values corresponding to the values of Rww, RWW 1. RWW2_ and RWW3. respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww, RWW 13Rww-2_ and RWW 3correspond to R7A, R7A l, R7A 2, and R7 3. respectively.

[0301] In embodiments, when R7Bis substituted, R7Bis substituted with one or more first substituent groups denoted by R7B 1as explained in the definitions section above in the description of ‘’first substituent group(s)’’. In embodiments, when an R7B 1substituent group is substituted, the R7B 1substituent group is substituted with one or more second substituent groups denoted by R7B 2as explained in the definitions section above in the description of “first substituent group(s)". In embodiments, when an R7B 2substituent group is substituted, the R7B 2substituent group is substituted with one or more third substituent groups denoted by R7B 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R7B, R7B-1, R7B 2, and R7B'3have values corresponding to the values of Rww, RwwRww2,anc| RWWJ, respectively, as explained in the definitions section above in the description of “first substituent group(s)". wherein Rww. R1.RW.2 and RWW 3correspond to R7B, R7B 1, R7B 2, and R7, 5_ respectively.

[0302] In embodiments, when R7Aand R7Bsubstituents 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 R7A 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7A 1substituent group is substituted, the R7A 1substituent group is substituted with one or more second substituent groups denoted by R7A 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7A 2substituent group is substituted, the R7A 2substituent group is substituted with one or more third substituent groups denoted by R7A3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R7A I. R7A 2, and R7A3have values corresponding to the values of RWW 1,RWW2anjRwwreSpectivety;as explained in the definitions section above in the description of “first substituent group(s)7’, wherein RWW 1, RWW2anc|RW. Jcorrespond to R7A 1, R7A'2, and R7A J, respectively.

[0303] In embodiments, when R7Aand R7Bsubstituents 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 R7B 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7B 1substituent group is substituted, the R7B 1substituent group is substituted with one or more second substituent groups denoted byR7B 2as explained in the definitions section above in the description of “first substituent group(s)’; In embodiments, when an R7B 2substituent group is substituted, the R7B 2substituent group is substituted with one or more third substituent groups denoted by R7B 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R7B I. R7B 2, and R7B 3have values corresponding to the values of RWW 1, RWW2anj RWW. S,reSpectively, as explained in the definitions section above in the description of “first substituent group(s)". wherein RWWJ, RW 2;and RWW 3correspond to R7B 1, R7B'2, and R7B J, respectively.

[0304] In embodiments, when R7Cis substituted, R7Cis substituted with one or more first substituent groups denoted by R7C 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7C 1substituent group is substituted, the R7C 1substituent group is substituted with one or more second substituent groups denoted by R7C 2as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R7C 2substituent group is substituted, the R7C 2substituent group is substituted with one or more third substituent groups denoted by R7C 3as explained in the definitions section above in the description of “first substituent group(s)’’. In the above embodiments, R7C, R7C-1, R7C 2, and R7C 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 RWW3correspond to R7C, R7C-1, R7C 2, and R7C 3. respectively.

[0305] In embodiments, when R7Dis substituted, R7Dis substituted with one or more first substituent groups denoted by R7D 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7D 1substituent group is substituted, the R7D 1substituent group is substituted with one or more second substituent groups denoted by R7D 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7D 2substituent group is substituted, the R7D 2substituent group is substituted with one or more third substituent groups denoted by R7D 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R7D, R7I) I. R7D 2. and R7D 3have values corresponding to the values of Rww, RWW 1. RWW 2_ and RWW3. respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww, RWW 13RWW.2 and RWW 3correspond to R7D, R7D-1, R7D 2, and R7D 3, respectively.

[0306] In embodiments, the compound has the formula:(compound 1). In embodiments, the compound has the formula:

[0307] (compound 3). In embodiments, the compound has the formula:(compound 4). In embodiments, the compound has the(compound 5). In embodiments, the compound hasccon

[0308] In embodiments, the compound has the formula: OH (compound 8). In embodiments, the compound has the formula:cr"^"'a OH (compound 9). In embodiments, the compound has theformula: OH (compound 10).

[0309] In embodiments, the compound is useful as a comparator compound. In embodiments, the comparator compound can be used to assess the activity of a test compound as set forth in an assay described herein (e.g., in the examples section, figures, or tables).

[0310] In embodiments, the compound is a compound as described herein, including in embodiments. In embodiments the compound is a compound described herein (e.g., in the examples section, figures, tables, or claims).

[0311] In embodiments, when the compound has the formula (III), then R4is not substituted 1.2.4-oxadiazolyl.

[0312] In embodiments, the compound is not:

[0313] In embodiments, R4is not -OH. In embodiments, R4is not -CN.III. Pharmaceutical compositions

[0314] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0315] 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.

[0316] In embodiments, the compound is a compound of formula (I). (II), (Ila), (III), or (Illa), including all embodiments thereof. In embodiments, the compound is a compound of formula (IV), (Va), (Vb), (Vc), (VI), or (VII), including all embodiments thereof. In embodiments, the compound is a compound of formula (IV), (Va), (VI), or (VII), including all embodiments thereof. In embodiments, the compound is a compound of formula (VIII), (IX), or (X), including all embodiments thereof. In embodiments, the compound is a compound as described herein, including in embodiments. In embodiments the compound is a compound described herein (e.g., in the examples section, figures, tables, or claims).

[0317] In embodiments, the pharmaceutical composition is an oral dosage form. In embodiments, the pharmaceutical composition is a tablet dosage form. In embodiments, the pharmaceutical composition is a capsule dosage form. In embodiments, the pharmaceutical composition is an intranasal dosage form. In embodiments, the pharmaceutical composition is an intravenous dosage form. In embodiments, the pharmaceutical composition is an injectable dosage form.IV. Methods of use

[0318] In an aspect is provided a method of treating a protein aggregation disease in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0319] In embodiments, the compound is a compound of formula (I), (II), (Ila), (III), or (Illa), including all embodiments thereof. In embodiments, the compound is a compound of formula (IV), (Va), (Vb), (Vc), (VI), or (VII), including all embodiments thereof. In embodiments, the compound is a compound of formula (IV), (Va), (VI), or (VII), including all embodiments thereof. In embodiments, the compound is a compound of formula (VIII), (IX), or (X), including all embodiments thereof. In embodiments, the compound is a compound as described herein, including in embodiments. In embodiments the compound is a compound described herein (e.g., in the examples section, figures, tables, or claims).

[0320] In embodiments, the protein aggregation disease is a neurodegenerative disease. In embodiments, the neurodegenerative disease is frontotemporal dementia. In embodiments, the neurodegenerative disease is a synucleinopathy. In embodiments, the neurodegenerative disease is a tauopathy. In embodiments, the neurodegenerative disease is sporadic amyotrophic lateral sclerosis. In embodiments, the neurodegenerative disease is TDP-43 mutated amyotrophic lateral sclerosis. In embodiments, the neurodegenerative disease is amyotrophic lateral sclerosis and frontotemporal lobar degeneration. In embodiments, the neurodegenerative disease is frontotemporal lobar degeneration. In embodiments, the neurodegenerative disease is Pick’s disease. In embodiments, the neurodegenerative disease is frontotemporal lobar degeneration TDP-43 predominant pathology. In embodiments, the neurodegenerative disease is frontotemporal lobar degeneration tau predominant pathology. In embodiments, the neurodegenerative disease is semantic dementia. In embodiments, the neurodegenerative disease is primary progressive aphasia. In embodiments, the neurodegenerative disease is multiple system proteinopathy. In embodiments, the neurodegenerative disease is Perry syndrome. In embodiments, the neurodegenerative disease is facial onset sensory and motor neuropathy. In embodiments, the neurodegenerative disease is inclusion body myositis. In embodiments, the neurodegenerative disease is valosin containing protein (VCP) disease. In embodiments, the neurodegenerative disease is myotonic disorder. In embodiments, the neurodegenerative disease is Alzheimer’s disease.In embodiments, the neurodegenerative disease is Parkinson’s disease. In embodiments, the neurodegenerative disease is dementia with Lewy bodies. In embodiments, the neurodegenerative disease is Parkinson’s disease-associated dementia. In embodiments, the neurodegenerative disease is multiple system atrophy. In embodiments, the neurodegenerative disease is corticobasal degeneration. In embodiments, the neurodegenerative disease is progressive supranuclear palsy. In embodiments, the neurodegenerative disease is Huntington’s disease. In embodiments, the neurodegenerative disease is C9orf72 amyotrophic lateral sclerosis. In embodiments, the neurodegenerative disease is amyloidosis. In embodiments, the neurodegenerative disease is antibody light chain amyloidosis. In embodiments, the neurodegenerative disease is transthyretin amyloidosis. In embodiments, the neurodegenerative disease is prion disease. In embodiments, the prion disease is Creutzfeldt- Jakob disease. In embodiments, the prion disease is variant Creutzfeldt-Jakob disease. In embodiments, the prion disease is genetic human prion disease. In embodiments, the prion disease is bovine spongiform encephalopathy. In embodiments, the prion disease is scrapie. In embodiments, the neurodegenerative disease is diffuse Lewy body disease. In embodiments, the neurodegenerative disease is spinocerebellar ataxia. In embodiments, the neurodegenerative disease is poly-Q disease. In embodiments, the neurodegenerative disease is hereditary cerebral amyloid angiopathy. In embodiments, the neurodegenerative disease is familial amyloid polyneuropathy. In embodiments, the neurodegenerative disease is C9orf72 frontotemporal dementia. In embodiments, the neurodegenerative disease is FUS ALS and FUS frontotemporal dementia. In embodiments, the neurodegenerative disease is TMEM106b Parkinson’s disease. In embodiments, the neurodegenerative disease is TMEM106b Alzheimer’s disease. In embodiments, the neurodegenerative disease is TMEM106b ALS. In embodiments, the neurodegenerative disease is TMEM175 Parkinson’s disease. In embodiments, the neurodegenerative disease is TMEM175 Alzheimer’s disease. In embodiments, the neurodegenerative disease is TMEM175 Alzheimer’s disease.

[0321] In embodiments, the protein aggregation disease is diabetes. In embodiments, the protein aggregation disease is type II diabetes. In embodiments, the protein aggregation disease is type I diabetes. In embodiments, the protein aggregation disease is a p53 mutant cancer. In embodiments, the protein aggregation disease is an influenza A virus infection. In embodiments, the protein aggregation disease is a herpesvirus infection. In embodiments, the herpesvirus is an M45 herpesvirus infection. In embodiments, the protein aggregationdisease is primary' systemic amyloidosis. In embodiments, the protein aggregation disease is reactive systemic amyloidosis. In embodiments, the protein aggregation disease is injection-localized amyloidosis. In embodiments, the protein aggregation disease is beta-2 microglobulin amyloidosis. In embodiments, the protein aggregation disease is hereditary non-neuropathic amyloidosis. In embodiments, the protein aggregation disease is Finnish hereditary systemic amyloidosis.

[0322] In embodiments, the compound is administered orally. In embodiments, the compound is administered intranasally. In embodiments, the compound is administered intravenously. In embodiments, the compound is administered by injection.

[0323] In an aspect is provided a method of reducing formation of a protein aggregate or disrupting a protein aggregate, the method including contacting the protein aggregate with an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0324] In embodiments, the compound is a compound of formula (I), (II), (Ila), (III), or (Illa), including all embodiments thereof. In embodiments, the compound is a compound of formula (IV), (Va), (Vb), (Vc), (VI), or (VII), including all embodiments thereof. In embodiments, the compound is a compound of formula (IV), (Va), (VI), or (VII), including all embodiments thereof. In embodiments, the compound is a compound of formula (VIII), (IX), or (X), including all embodiments thereof. In embodiments, the compound is a compound as described herein, including in embodiments. In embodiments the compound is a compound described herein (e.g., in the examples section, figures, tables, or claims).

[0325] In embodiments, the protein aggregate is a prion protein aggregate. In embodiments, the protein aggregate is an amyloid precursor protein aggregate. In embodiments, the protein aggregate is a beta amyloid aggregate. In embodiments, the protein aggregate is an alpha synuclein aggregate. In embodiments, the protein aggregate is a superoxide dismutase aggregate. In embodiments, the protein aggregate is a tau aggregate. In embodiments, the protein aggregate is an immunoglobulin aggregate. In embodiments, the protein aggregate is an amyloid-A aggregate. In embodiments, the protein aggregate is a transthyretin aggregate. In embodiments, the protein aggregate is a beta-2 microglobulin aggregate. In embodiments, the protein aggregate is a cystatin C aggregate. In embodiments, the protein aggregate is an apolipoprotein Al aggregate. In embodiments, the protein aggregate is a TDP-43 aggregate. In embodiments, the protein aggregate is an islet amyloidpolypeptide aggregate. In embodiments, the protein aggregate is an ANF aggregate. In embodiments, the protein aggregate is a gelsolin aggregate. In embodiments, the protein aggregate is an insulin aggregate. In embodiments, the protein aggregate is a lysozyme aggregate. In embodiments, the protein aggregate is a fibrinogen aggregate. In embodiments, the protein aggregate is a huntingtin aggregate. In embodiments, the protein aggregate is an ataxin aggregate. In embodiments, the protein aggregate is an aggregate of a protein with a Poly-Q stretch. In embodiments, the protein with a Poly-Q stretch is a protein having at least 36 consecutive glutamine residues.

[0326] In embodiments, the protein aggregate is an oligomer. In embodiments, the oligomer is a trimer. In embodiments, the oligomer is a tetramer. In embodiments, the oligomer is a pentamer. In embodiments, the oligomer is a hexamer. In embodiments, the oligomer is a heptamer. In embodiments, the oligomer is an octamer. In embodiments, the oligomer is a nonamer. In embodiments, the oligomer is a decamer. In embodiments, the oligomer is an 11-mer. In embodiments, the oligomer is a 12-mer. In embodiments, the oligomer is a 13-mer. In embodiments, the oligomer is a 14-mer. In embodiments, the oligomer is a 15-mer. In embodiments, the oligomer is a 16-mer. In embodiments, the oligomer is a 17-mer. In embodiments, the oligomer is an 18-mer. In embodiments, the oligomer is a 19-mer. In embodiments, the oligomer is a 20-mer.

[0327] In embodiments, the protein aggregate is an oligomer, In embodiments, the oligomer has a size range of from about 40 kD to about 500 kD. In embodiments, the oligomer has a size range of from about 50 kD to about 400 kD. In embodiments, the oligomer has a size range of from about 65 kD to about 150 kD. In embodiments, the oligomer has a size range of from about 100 kD to about 300 kD. In embodiments, the oligomer has a size range of from about 45 kD to about 200 kD. In embodiments, the oligomer has a size range of from about 80 kD to about 500 kD. In embodiments, the oligomer is about 40 kD. In embodiments, the oligomer is about 50 kD. In embodiments, the oligomer is about 60 kD. In embodiments, the oligomer is about 70 kD. In embodiments, the oligomer is about 80 kD. In embodiments, the oligomer is about 90 kD. In embodiments, the oligomer is about 100 kD. In embodiments, the oligomer is about 120 kD. In embodiments, the oligomer is about 140 kD. In embodiments, the oligomer is about 160 kD. In embodiments, the oligomer is about 180 kD. In embodiments, the oligomer is about 200 kD. In embodiments, the oligomer is about 220 kD. In embodiments, the oligomer is about 240kD. In embodiments, the oligomer is about 260 kD. In embodiments, the oligomer is about 280 kD. In embodiments, the oligomer is about 300 kD. In embodiments, the oligomer is about 320 kD. In embodiments, the oligomer is about 340 kD. In embodiments, the oligomer is about 360 kD. In embodiments, the oligomer is about 380 kD. In embodiments, the oligomer is about 400 kD. In embodiments, the oligomer is about 420 kD. In embodiments, the oligomer is about 440 kD. In embodiments, the oligomer is about 460 kD. In embodiments, the oligomer is about 480 kD. In embodiments, the oligomer is about 500 kD.

[0328] In embodiments, the protein aggregate is an oligomer. In embodiments, the oligomer has a size range of from 40 kD to 500 kD. In embodiments, the oligomer has a size range of from 50 kD to 400 kD. In embodiments, the oligomer has a size range of from 65 kD to 150 kD. In embodiments, the oligomer has a size range of from 100 kD to 300 kD. In embodiments, the oligomer has a size range of from 45 kD to 200 kD. In embodiments, the oligomer has a size range of from 80 kD to 500 kD. In embodiments, the oligomer is 40 kD. In embodiments, the oligomer is 50 kD. In embodiments, the oligomer is 60 kD. In embodiments, the oligomer is 70 kD. In embodiments, the oligomer is 80 kD. In embodiments, the oligomer is 90 kD. In embodiments, the oligomer is 100 kD. In embodiments, the oligomer is 120 kD. In embodiments, the oligomer is 140 kD. In embodiments, the oligomer is 160 kD. In embodiments, the oligomer is 180 kD. In embodiments, the oligomer is 200 kD. In embodiments, the oligomer is 220 kD. In embodiments, the oligomer is 240 kD. In embodiments, the oligomer is 260 kD. In embodiments, the oligomer is 280 kD. In embodiments, the oligomer is 300 kD. In embodiments, the oligomer is 320 kD. In embodiments, the oligomer is 340 kD. In embodiments, the oligomer is 360 kD. In embodiments, the oligomer is 380 kD. In embodiments, the oligomer is 400 kD. In embodiments, the oligomer is 420 kD. In embodiments, the oligomer is 440 kD. In embodiments, the oligomer is 460 kD. In embodiments, the oligomer is 480 kD. In embodiments, the oligomer is 500 kD.

[0329] In embodiments, the contacting occurs in vivo. In embodiments, the contacting occurs in a subj ect. wherein an effective amount of the compound is administered to the subject. In embodiments, the subject has a protein aggregation disease. In embodiments, the contacting occurs in vitro. In embodiments, the contacting occurs ex vivo.

[0330] In embodiments, the amount of the protein aggregate is decreased by about 1.5-, 2-, 3-, 4-, 5-. 6-, 7-, 8-, 9-. 10-, 15-, 20-. 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-. 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the protein aggregate is decreased by about 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the protein aggregate is decreased by about 2-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the protein aggregate is decreased by about 5-fold relative to a control (e g., absence of the compound). In embodiments, the amount of the protein aggregate is decreased by about 10-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the protein aggregate is decreased by about 25-fold relative to a control (e.g.. absence of the compound). In embodiments, the amount of the protein aggregate is decreased by about 50-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the protein aggregate is decreased by about 100-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the protein aggregate is decreased by about 250-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the protein aggregate is decreased by about 500-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the protein aggregate is decreased by about 1000-fold relative to a control (e.g., absence of the compound).

[0331] In embodiments, the amount of the protein aggregate is decreased by at least 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the protein aggregate is decreased by at least 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the protein aggregate is decreased by at least 2-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the protein aggregate is decreased by at least 5-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the protein aggregate is decreased by at least 10-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the protein aggregate is decreased by at least 25-fold relative to a control (e g., absence of the compound). In embodiments, the amount of the protein aggregate is decreased by at least 50-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the protein aggregate is decreased by at least 100-fold relative to a control (e.g., absence of thecompound). In embodiments, the amount of the protein aggregate is decreased by at least 250-fold relative to a control (e.g.. absence of the compound). In embodiments, the amount of the protein aggregate is decreased by at least 500-fold relative to a control (e.g., absence of the compound). In embodiments, the amount of the protein aggregate is decreased by at least 1000-fold relative to a control (e.g., absence of the compound).V. Embodiments

[0332] Embodiment Pl. A method of treating a protein aggregation disease in a subj ect in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula:R1I(I); yvhereinR1and R2are independently hydrogen, -CCl₃, -CBr₃, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHE, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3. -OCF3. -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2. -OCHF2. -OCH2Cl, -OCH2Br. -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1and R2substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R3is independently oxo, halogen, -CCI3, -CBr₃, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H. -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl₃, -OCBr3, -OCF3, -OCI3. -OCH2CI, -OCH2Br. -OCH2F.-OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z3 is an integer from 0 to 8;R4is independently halogen. -CX43, -CHX42, -CH2X4. -OCX63, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOV4NR4AR4B, -NR4CNR4AR4B, -ONR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z4 is an integer from 0 to 5;R5is independently halogen, -CX53, -CHX52, -CH2X5, -OCX53, -OCH2X5, -OCHX52, -CN, -SOn5R5D, -SOV5NR5AR5B, -NR5CNR5AR5B, -ONR5AR5B, -NR5CC(O)NR5AR5B, -N(O)m5, -NR5AR5B, -C(O)R5C, -C(O)OR5C, -OC(O)R5C, -OC(O)OR5C, -C(O)NR5AR5B, -OC(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -NR5AOR5C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 3;R4AR4B, R4< J^4|)_ R5ARSBANC| R5Darejnc|epenc|ently hydrogen, -CCI3, -CBr₃, -CF3, -CI3, -CHC12, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl₃, -OCF3, -OCBr3, -OCI3, -OCHCl₂, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted hctcroaryl: R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5Aand R5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;each X4and X5is independently -F, -Cl, -Br, or -I;n4 and n5 are independently an integer from 0 to 4; andm4, m5, v4, and v5 are independently 1 or 2.

[0333] Embodiment P2. The method of embodiment Pl, wherein the protein aggregation disease is a neurodegenerative disease.

[0334] Embodiment P3. The method of embodiment P2, wherein the neurodegenerative disease is frontotemporal dementia, a synucleinopathy, or a tauopathy.

[0335] Embodiment P4. The method of embodiment P2, wherein the neurodegenerative disease is sporadic amyotrophic lateral sclerosis, TDP-43 mutated amyotrophic lateral sclerosis, amyotrophic lateral sclerosis and frontotemporal lobar degeneration, frontotemporal lobar degeneration, Pick's disease, frontotemporal lobar degeneration TDP-43 predominant pathology, frontotemporal lobar degeneration tau predominant pathology, semantic dementia, primary progressive aphasia, multiple system proteinopathy, Perry syndrome, facial onset sensory and motor neuropathy, inclusion body myositis, valosin-containing protein disease, myotonic disorder. Alzheimer’s disease. Parkinson’s disease, dementia with Lewy bodies, Parkinson’s disease-associated dementia, multiple system atrophy, corticobasal degeneration, progressive supranuclear palsy, Huntington’s disease, C9orf72 amyotrophic lateral sclerosis, amyloidosis, antibody light chain amyloidosis, transthyretin amyloidosis, prion disease, diffuse Lewy body disease, spinocerebellar ataxia, poly-Q disease, hereditary cerebral amyloid angiopathy, familial amyloid polyneuropathy, C9orf72 frontotemporal dementia, FUS ALS and FUS frontotemporal dementia, TMEM106b Parkinson’s disease, TMEM106b Alzheimer's disease, TMEM106b ALS, TMEM175 Parkinson’s disease, TMEM175 Alzheimer’s disease, or TMEM175 Alzheimer’s disease.

[0336] Embodiment P5. The method of embodiment P4, wherein the prion disease is Creutzfeldt-Jakob disease, variant Creutzfeldt- Jakob disease, genetic human prion disease, bovine spongiform encephalopathy, or scrapie.

[0337] Embodiment P6. The method of embodiment Pl, wherein the protein aggregation disease is diabetes.

[0338] Embodiment P7. The method of embodiment Pl, wherein the protein aggregation disease is a p53 mutant cancer.

[0339] Embodiment P8. The method of embodiment P 1, wherein the protein aggregation disease is an influenza A virus infection or a herpesvirus infection.

[0340] Embodiment P9. The method of embodiment P8. wherein the herpesvirus is an M45 herpesvirus infection.

[0341] Embodiment PIO. The method of embodiment P 1, wherein the protein aggregation disease is primary systemic amyloidosis, reactive systemic amyloidosis, type II diabetes, type I diabetes, injection-localized amyloidosis, beta-2 microglobulin amyloidosis, hereditary non-neuropathic amyloidosis, or Finnish hereditary systemic amyloidosis.

[0342] Embodiment PH. The method of one of embodiments Pl to P 10, wherein the compound is administered orally, intranasally, intravenously, or by injection.

[0343] Embodiment P12. The method of one of embodiments Pl to Pl 1, wherein the compound has the formula:R1I

[0344] Embodiment Pl 3. The method of one of embodiments Pl to Pl 1, wherein the compound has the formula:R1

[0345] Embodiment P 14. The method of one of embodiments Pl to P 11, wherein the compound has the formula:

[0346] Embodiment Pl 5. The method of one of embodiments Pl to Pl 1, wherein the compound has the formula:

[0347] Embodiment P16. The method of one of embodiments Pl to P15. wherein R1is hydrogen or unsubstituted C1-C4 alkyl.

[0348] Embodiment P17. The method of one of embodiments Pl to P15, wherein R1is unsubstituted methyl.

[0349] Embodiment Pl 8. The method of one of embodiments Pl to Pl 7, wherein R2is hydrogen or unsubstituted C1-C4 alkyl.

[0350] Embodiment Pl 9. The method of one of embodiments Pl to Pl 7. wherein R2is unsubstituted methyl.

[0351] Embodiment P20. The method of one of embodiments Pl to Pl 9, wherein R4is independently halogen, -CC13, -CBr3, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHC12, -CHB12. -CHF2, -CHE, -CN. -OH, -NH2, -COOH. -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2. -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCC13, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0352] Embodiment P21. The method of one of embodiments Pl to P19, wherein R4is independently halogen, -OH, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

[0353] Embodiment P22. The method of one of embodiments Pl to Pl 9, wherein R4is independently -OH.

[0354] Embodiment P23. The method of one of embodiments Pl to Pl 1, wherein the compound has the formula:

[0355] Embodiment P24. The method of one of embodiments Pl to Pl 1, wherein the compound has the formula:

[0356] Embodiment P25. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound, or a pharmaceutically acceptable salt thereof, having the formula:R1and R2are independently hydrogen, -CCl₃, -CBrs, -CF3, -CI3, -CHCI2, -CH B.-CHF2. -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl₃, -OCF₃, -OCBr3, -OCI3, -OCHCl₂, -OCHBr2, -OCHI2, -OCHF2, -OCH2CL -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1and R2substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R3is independently oxo, halogen, -CCI3, -CBr₃, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H. -OSO3H. -SO2NH2, -NHNH2. -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z3 is an integer from 0 to 8;R4is independently halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOv4NR4AR4B, -NR4CNR4AR4B, -ONR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z4 is an integer from 0 to 5;R5is independently halogen. -CX53. -CHX52, -CH2X5. -OCX53, -OCH2X5, -OCHX52.-CN, -S0nsR5D, -SOv5NR5AR5B, -NR5CNR5AR5B, -ONR5AR5B, -NR5CC(O)NR5AR5B, -N(O)m5, -NR5AR5B, -C(O)R5C, -C(O)OR5C, -OC(O)R5C, -OC(O)OR5C, -C(O)NR5AR5B, -OC(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -NR5AOR5C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 3;R4A, R4B, R4C, R4D, R5A, R5B, R5C, and R5Dare independently hydrogen, -CCI3, -CBr₃.-CF3, -CI3, -CHCk, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCk, -OCF3, -OCBr₃. -OCI3, -OCHCl₂, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5Aand R5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;each X4and X5is independently -F, -Cl, -Br, or -I;n4 and n5 are independently an integer from 0 to 4; andm4, m5, v4, and v5 are independently 1 or 2.

[0357] Embodiment P26. The pharmaceutical composition of embodiment P25, wherein the compound has the formula:R1

[0358] Embodiment P27. The pharmaceutical composition of embodiment P25, wherein the compound has the formula:

[0359] Embodiment P28. The pharmaceutical composition of embodiment P25, wherein the compound has the formula:

[0360] Embodiment P29. The pharmaceutical composition of embodiment P25, wherein the compound has the formula:

[0361] Embodiment P30. The pharmaceutical composition of one of embodiments P25 to P29, wherein the pharmaceutical composition is an oral dosage form, an intranasal dosage form, an intravenous dosage form, or an inj ectable dosage form.

[0362] Embodiment P31. A compound, or a pharmaceutically acceptable salt thereof, having the formula:(III); wherein R1and R2are independently hydrogen, -CCI3, -CBr3. -CF3, -CI3, -CHCI2, -CHBrz, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3. -OCF3. -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2. -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1and R2substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R3is independently oxo, halogen, -CCI3, -CBr₃, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H. -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3. -OCH2CI, -OCH2Br. -OCH2F.-OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z3 is an integer from 0 to 8;R4is independently halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOv4NR4AR4B, -NR4CNR4AR4B, -ONR4AR4B, -NR4CC(O)NR4AR4B, -N(0)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D. -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z4 is an integer from 0 to 5;R5is independently halogen, -CX53, -CHX52, -CH2X5, -OCX53, -OCH2X5, -OCHX52, -CN, -SOn5R5D, -SOV5NR5AR5D, -NR5CNR5AR5B, -ONR5AR5B, -NR5CC(O)NR5AR5B, -N(O)m5, -NR5AR5B, -C(O)R5C, -C(O)OR5C, -OC(O)R5C, -OC(O)OR5C, -C(O)NR5AR5B, -OC(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -NR5AOR5C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 3;R4A, R4B, R4C, R4D, R5A, R5B, R5C, and R5Dare independently hydrogen, -CCI3, -CBrs, -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH. -CONH2, -OCCI3, -OCF3, -OCBr3, -OCI3. -OCHCl₂, -OCHBr2. -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5Aand R5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;each X4and X5is independently -F, -Cl, -Br, or -I;n4 and n5 are independently an integer from 0 to 4; andm4, m5, v4, and v5 are independently 1 or 2;wherein when the compound has the formula (III), then R4is not substituted 1,2,4-oxadiazolyl; andwherein the compound is not:

[0363] Embodiment P32. The compound of embodiment P31, having the formula:

[0364] Embodiment P33. The compound of embodiment P31, having the formula:R1

[0365] Embodiment P34. The compound of embodiment P31, having the formula:R1

[0366] Embodiment P35. The compound of embodiment P31, having the formula:

[0367] Embodiment P36. The compound of one of embodiments P31 to P35. wherein R1is hydrogen or unsubstituted C1-C4 alkyl.

[0368] Embodiment P37. The compound of one of embodiments P31 to P35, wherein R1is unsubstituted methyl.

[0369] Embodiment P38. The compound of one of embodiments P31 to P37, wherein R2is hydrogen or unsubstituted C1-C4 alkyl.

[0370] Embodiment P39. The compound of one of embodiments P31 to P37. wherein R2is unsubstituted methyl.

[0371] Embodiment P40. The compound of one of embodiments P31 to P37, wherein R4is independently halogen, -CCI3, -CBr3, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H. -NHC(O)OH, -NHOH, -OCC13, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0372] Embodiment P41. The compound of one of embodiments P31 to P37. wherein R4is independently halogen, -OH, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

[0373] Embodiment P42. The compound of one of embodiments P31 to P37, wherein R4is independently -OH.

[0374] Embodiment P43. The compound of embodiment P31, having the formula:

[0375] Embodiment QI. A method of treating a protein aggregation disease in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula:R1and R2are independently hydrogen, -CCl₃, -CBrs, -CF3, -CI3, -CHCI2, -CHB, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl₃, -OCF₃, -OCBr₃. -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1and R2substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R3is independently oxo, halogen, -CCI3, -CBr2, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H. -OSO3H. -SO2NH2, -NHNH2. -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z3 is an integer from 0 to 8;R4is independently halogen. -CX43, -CHX42, -CH2X4. -OCX63, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOV4NR4AR4B, -NR4CNR4AR4B, -ONR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z4 is an integer from 0 to 4;R5is independently halogen, -CX53, -CHX52, -CH2X5, -OCX53, -OCH2X5, -OCHX52, -CN, -SOn5R5D, -SOV5NR5AR5B, -NR5CNR5AR5B, -ONR5AR5B, -NR5CC(O)NR5AR5B, -N(O)m5, -NR5AR5B, -C(O)R5C, -C(O)OR5C, -OC(O)R5C, -OC(O)OR5C, -C(O)NR5AR5B, -OC(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -NR5AOR5C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z5 is an integer from 0 to 5;R4AR4B, R4< J^4|)_ R5ARSBANC| R5Darejnc|epenc|ently hydrogen, -CCI3, -CBr₃, -CF3, -CI3, -CHC12, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl₃, -OCF3, -OCBr3, -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted hctcroaryl: R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5Aand R5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;each X4and X5is independently -F, -Cl, -Br, or -I;n4 and n5 are independently an integer from 0 to 4; andm4, m5, v4, and v5 are independently 1 or 2.

[0376] Embodiment Q2. The method of embodiment QI, wherein the protein aggregation disease is a neurodegenerative disease.

[0377] Embodiment Q3. The method of embodiment Q2, wherein the neurodegenerative disease is frontotemporal dementia, a synucleinopathy, or a tauopathy.

[0378] Embodiment Q4. The method of embodiment Q2, wherein the neurodegenerative disease is sporadic amyotrophic lateral sclerosis, TDP-43 mutated amyotrophic lateral sclerosis, amyotrophic lateral sclerosis and frontotemporal lobar degeneration, frontotemporal lobar degeneration, Pick's disease, frontotemporal lobar degeneration TDP-43 predominant pathology, frontotemporal lobar degeneration tau predominant pathology, semantic dementia, primary progressive aphasia, multiple system proteinopathy, Perry syndrome, facial onset sensory and motor neuropathy, inclusion body myositis, valosin-containing protein disease, myotonic disorder. Alzheimer’s disease. Parkinson’s disease, dementia with Lewy bodies, Parkinson’s disease-associated dementia, multiple system atrophy, corticobasal degeneration, progressive supranuclear palsy, Huntington’s disease, C9orf72 amyotrophic lateral sclerosis, amyloidosis, antibody light chain amyloidosis, transthyretin amyloidosis, prion disease, diffuse Lewy body disease, spinocerebellar ataxia, poly-Q disease, hereditary cerebral amyloid angiopathy, familial amyloid polyneuropathy, C9orf72 frontotemporal dementia, FUS ALS and FUS frontotemporal dementia, TMEM106b Parkinson’s disease, TMEM106b Alzheimer's disease, TMEM106b ALS, TMEM175 Parkinson’s disease, TMEM175 Alzheimer’s disease, or TMEM175 Alzheimer’s disease.

[0379] Embodiment Q5. The method of embodiment Q4, wherein the prion disease is Creutzfeldt-Jakob disease, variant Creutzfeldt- Jakob disease, genetic human prion disease, bovine spongiform encephalopathy, or scrapie.

[0380] Embodiment Q6. The method of embodiment QI, wherein the protein aggregation disease is diabetes.

[0381] Embodiment Q7. The method of embodiment QI, wherein the protein aggregation disease is a p53 mutant cancer.

[0382] Embodiment Q8. The method of embodiment QI, wherein the protein aggregation disease is an influenza A virus infection or a herpesvirus infection.

[0383] Embodiment Q9. The method of embodiment Q8, wherein the herpesvirus is an M45 herpesvirus infection.

[0384] Embodiment QI 0. The method of embodiment QI, wherein the protein aggregation disease is primary systemic amyloidosis, reactive systemic amyloidosis, type II diabetes, type I diabetes, injection-localized amyloidosis, beta-2 microglobulin amyloidosis, hereditary non-neuropathic amyloidosis, or Finnish hereditary systemic amyloidosis.

[0385] Embodiment QI 1. The method of one of embodiments QI to Q10, wherein the compound is administered orally, intranasally, intravenously, or by injection.

[0386] Embodime...

Claims

WHAT IS CLAIMED IS:

1. A method of treating a protein aggregation disease in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula:whereinR1and R2are independently hydrogen, -CCl₃, -CBrs, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl₃, -OCF3, -OCBr3, -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1and R2substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R3is independently oxo, halogen, -CCh. -CBrs, -CFs, -CI3, -CH2C1. -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl₃, -OCBr3, -OCF3, -OCl₃, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCh. -OCHBr2, -OCHF2, -OCHI2, -SF5. -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z3 is an integer from 0 to 8;R4is independently halogen, -CX4s. -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOV4NR4AR4B, -NR4CNR4AR4B, -ONR4AR4B, -NR4CC(O)NR4AR4B-N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z4 is an integer from 0 to 5;R5is independently halogen, -CX53, -CHX52, -CH2X5, -OCX53, -OCH2X5, -OCHX52, -CN, -SOn5R5D, -SOV5NR5AR5B, -NR5CNR5AR5B, -ONR5AR5B, -NR5CC(O)NR5AR5B. -N(O)m5. -NR5AR5B, -C(O)R5C, -C(O)OR5C. -OC(O)R5C, -OC(O)OR5C. -C(O)NR5AR5B, -OC(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -NR5AOR5C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z5 is an integer from 0 to 3;R4A, R4B, R4C, R4D, R5A, R5B, R5C, and R5Dare independently hydrogen, -CCI3, -CBrs, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2. -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCHsBr, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5Aand R5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;each X4and X5is independently -F, -Cl. -Br, or -I;n4 and n5 are independently an integer from 0 to 4; andm4, m5, v4, and v5 are independently 1 or 2.

2. The method of claim 1, wherein the compound has the formula;3. The method of claim 1. wherein the compound has the formula:

4. The method of claim 1, wherein the compound has the formula:

5. The method of claim 1, wherein the compound has the formula:

6. The method of claim 1, wherein R1is hydrogen or unsubstituted C1-C4 alkyl.

7. The method of claim 1, wherein R1is unsubstituted methyl.

8. The method of claim 1, wherein R2is hydrogen or unsubstituted C1-C4 alkyl.

9. The method of claim 1, wherein R2is unsubstituted methyl.

10. The method of claim 1, wherein R4is independently halogen, -CCI3, -CBr3, -CF3, -CI3, -CH2CI. -CH2Br, -CH2F, -CH2I, -CHCh, -CHBr2, -CHF2, -CHI2, -CN.-OH, -NH2, -COOH, -CONH2. -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCl₂, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

11. The method of claim 1, wherein R4is independently halogen, -OH, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

12. The method of claim 1, wherein R4is independently -OH.

13. The method of claim 1, wherein the compound has the formula:

14. The method of claim 1. wherein the compound has the formula:

15. A method of treating a protein aggregation disease in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula:R1and R2are independently hydrogen. -CCl₃, -CBr₃, -CF₃, -CI₃, -CHCl₂, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryk R1and R2substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R3is independently oxo, halogen, -CCI3, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F. -CH2I, -CHCh, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2, -OCHBr₂. -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z3 is an integer from 0 to 8;R4is independently halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4U, -SOV4NR4AR4B, -NR4CNR4AR4B, -ONR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C. -SF5. -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z4 is an integer from 0 to 4;R5is independently halogen, -CX53, -CHX52, -CH2X5, -OCX53, -OCH2X5, -OCHX52, -CN, -SOn5R5D. -SOV5NR5AR5B, -NR5CNR5AR5B. -ONR5AR5B.-NR5CC(O)NR5AR5B, -N(O)m5, -NR5AR5B, -C(O)R5C, -C(O)OR5C, -OC(O)R5C, -OC(O)OR5C, -C(O)NR5AR5B, -OC(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -NR5AOR5C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z5 is an integer from 0 to 5;R4A, R4B, R4C, R4D, R5A, R5B, R5C, and R5Dare independently hy drogen, -CCI3, -CBr3, -CF3, -CI3, -CHCl₂. -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN. -OH, -NH2, -COOH, -CONH2, -OCCI3, -OCF3, -OCBr, -OCI3, -OCHCl₂, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5Aand R5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;each X4and X5is independently -F, -Cl, -Br, or -I;n4 and n5 are independently an integer from 0 to 4; andm4, m5, v4, and v5 are independently 1 or 2.

16. The method of claim 15, wherein the compound has the formula:

17. The method of claim 15, wherein R1is hydrogen or unsubstituted Ci- C4 alkyl.

18. The method of claim 15, wherein R1is unsubstituted methyl.

19. The method of claim 15, wherein R2is hydrogen or unsubstituted Ci-C4alkyl.

20. The method of claim 15, wherein R2is unsubstituted methyl.

21. The method of claim 15, wherein R4is independently halogen, -CCI3, -CBr3, -CF3, -CI3, -CH2CI. -CH2Br, -CH2F, -CH2I, -CHC12. -CHBr2, -CHF2, -CHI2, -CN. -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCC13, -OCBr3, -OCF3, -OCI3, -OCH2C1. -OCH2Br, -OCH2F, -OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

22. The method of claim 15, wherein R4is independently halogen, -CN, -OH, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 6 membered heteroalkyl.

23. The method of claim 15, wherein R4is independently -Cl. -CN, -OH,-CH3, or A)'.

24. The method of claim 15, wherein R5is independently halogen, -CC13, -CBr3, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCh, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2. -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCC13, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCl₂, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

25. The method of claim 15, wherein z5 is 0.

26. The method of claim 15, wherein the compound has the formula:

27. A method of treating a protein aggregation disease in a subject in need thereof, said method compnsing administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula:(R3)Z3R7(VIII);whereinR6is hydrogen, halogen, -CX6?, -CHX62. -CH2X6, -OCX63, -OCH2X6, -OCHX62, -CN, -SOn6R6D. -SOv6NR6AR6B, -NR6CNR6AR6B. -ONR6AR6B-NR6CC(O)NR6AR6B, -N(O)m6, -NR6AR6B, -C(O)R6C, -C(O)OR6C, -OC(O)R6C, -OC(O)OR6C, -C(O)NR6AR6B, -OC(O)NR6AR6B, -OR6D, -SR6D, -NR6ASO2R6D, -NR6AC(O)R6C, -NR6AC(O)OR6C, -NR6AOR6C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R7is halogen, -CX73, -CHX72, -CH2X7, -OCX73, -OCH2X7, -OCHX72, -CN, -SOn7R7D, -SOV7NR7AR7B, -NR7CNR7AR7D, -ONR7AR7D, -NR7CC(O)NR7AR7D. -N(O)m7, -NR7AR7B, -C(O)R7C, -C(O)OR7C, -OC(O)R7C, -OC(O)OR7C, -C(O)NR7AR7B-OC(O)NR7AR7B, -OR7D, -SR7D, -NR7ASO2R7D, -NR7AC(O)R7C, -NR7AC(O)OR7C, -NR7AOR7C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R3is independently oxo, halogen, -CC13, -CBr3, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H. -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z3 is an integer from 0 to 8;R6A, R6B. R6C. R6D. R7A. R7B. R7C. and R7Dare independently hydrogen, -CC13, -CBr3, -CF3, -CI3, -CHC12. -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN. -OH, -NH2, -COOH, -CONH2, -OCC13, -OCF3, -OCBr3, -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R7Aand R7Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;each X6and X7is independently -F, -Cl, -Br, or -I;n6 and n7 are independently an integer from 0 to 4; andm6, m7, v6, and v7 are independently 1 or 2.

28. The method of claim 27, wherein the compound has the formula:

29. The method of claim 27, wherein the compound has the formula:

30. The method of claim 27, wherein R6is hydrogen, halogen, -CCl₃, -CBr3, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2. -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

31. The method of claim 27, wherein R6is hydrogen or halogen.

32. The method of claim 27, wherein R6is hydrogen or -Cl.

33. The method of claim 27, wherein R7is halogen, -CCl₃, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHC12. -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCC13, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I. -OCHCl₂, -OCHBr2. -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

34. The method of claim 27, wherein R7is -OR2D.

35. The method of claim 34, wherein R7Dis hydrogen or unsubstituted Ci- C4 alkyl.

36. The method of claim 27, wherein R7is -OH.

37. The method of claim 27, wherein the compound has the formula:

38. The method of any one of claims 1 to 37, wherein the protein aggregation disease is a neurodegenerative disease.

39. The method of claim 38, wherein the neurodegenerative disease is frontotemporal dementia, a synucleinopathy, or atauopathy.

40. The method of claim 38, wherein the neurodegenerative disease is sporadic amyotrophic lateral sclerosis. TDP-43 mutated amyotrophic lateral sclerosis, amyotrophic lateral sclerosis and frontotemporal lobar degeneration, frontotemporal lobar degeneration, Pick’s disease, frontotemporal lobar degeneration TDP-43 predominant pathology7, frontotemporal lobar degeneration tau predominant pathology7, semantic dementia, primary7progressive aphasia, multiple system proteinopathy, Perry syndrome, facial onset sensory and motor neuropathy, inclusion body myositis, valosin-containing protein disease, myotonic disorder, Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, Parkinson’s disease-associated dementia, multiple system atrophy, corticobasal degeneration, progressive supranuclear palsy, Huntington's disease, C9orf72 amyotrophic lateral sclerosis, amyloidosis, antibody light chain amyloidosis, transthyretin amyloidosis, prion disease, diffuse Lewy body disease, spinocerebellar ataxia, poly-Q disease, hereditary cerebral amyloid angiopathy, familial amyloid polyneuropathy, C9orf72 frontotemporal dementia,FUS ALS and FUS frontotemporal dementia, TMEM106b Parkinson’s disease, TMEM106b Alzheimer’s disease. TMEM106b ALS, TMEM175 Parkinson’s disease, TMEM175 Alzheimer’s disease, or TMEM175 Alzheimer’s disease.

41. The method of claim 40, wherein the prion disease is Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, genetic human prion disease, bovine spongiform encephalopathy, or scrapie.

42. The method of any one of claims 1 to 37, wherein the protein aggregation disease is diabetes.

43. The method of any one of claims 1 to 37, wherein the protein aggregation disease is a p53 mutant cancer.

44. The method of any one of claims 1 to 37, wherein the protein aggregation disease is an influenza A virus infection or a herpesvirus infection.

45. The method of claim 44, wherein the herpesvirus is an M45 herpesvirus infection.

46. The method of any one of claims 1 to 37, wherein the protein aggregation disease is primary systemic amyloidosis, reactive systemic amyloidosis, type II diabetes, type I diabetes, injection-localized amyloidosis, beta-2 microglobulin amyloidosis, hereditary non-neuropathic amyloidosis, or Finnish hereditary systemic amyloidosis.

47. The method of any one of claims 1 to 37, wherein the compound is administered orally, intranasally, intravenously, or by injection.

48. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound, or a pharmaceutically acceptable salt thereof, having the formula:R1whereinR1and R2are independently hydrogen. -CCl₃, -CBr₃, -CF₃, -CI₃, -CHCl₂, -CHBn. -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1and R2substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R' is independently oxo, halogen, -CCI3, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F. -CH2I, -CHCh, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2. -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z3 is an integer from 0 to 8;R4is independently halogen, -CX43, -CHX42, -CH2X4. -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOv4NR4AR4B, -NR4CNR4AR4B, -ONR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -OC(O)R4C, -OC(O)OR4C, -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C. -SFs. -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl:z4 is an integer from 0 to 5;R5is independently halogen, -CX53, -CHX52, -CH2X5. -OCX53, -OCH2X5, -OCHX52, -CN, -SOn5R5U, -SOV5NR5AR5B, -NR5CNR5AR5B, -ONR5AR5B, -NR5CC(O)NR5AR5B, -N(O)m5, -NR5AR5B, -C(O)R5C, -C(O)OR5C, -OC(O)R5C, -OC(O)OR5C, -C(O)NR5AR5B, -OC(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -NR5AOR5C. -SFs. -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z5 is an integer from 0 to 3;R4AR4B, R4C R4D, R5.\ RSB R5C R5Dareindepencientiy hydrogen, -CCI3, -CBr3, -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCC13, -OCF3, -OCBr3, -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5Aand R5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;each X4and X5is independently -F, -Cl, -Br, or -I;n4 and n5 are independently an integer from 0 to 4; andm4. m5, v4, and v5 are independently 1 or 2.

49. The pharmaceutical composition of claim 48, wherein the compound has the formula:

50. The pharmaceutical composition of claim 48, wherein the compound has the formula:R1I51. The pharmaceutical composition of claim 48, wherein the compound has the formula:

52. The pharmaceutical composition of claim 48, wherein the compound has the formula:

53. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound, or a pharmaceutically acceptable salt thereof, having the formula:R1and R2are independently hydrogen, -CC13, -CBr3, -CF3, -CI3, -CHCk, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3, -OCF3, -OCBr3. -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1and R2substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R3is independently oxo, halogen, -CCl₃, -CBr₃, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBn, -OCF3, -OCI3. -OCH2Cl, -OCH2Br. -OCH2F.-OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z3 is an integer from 0 to 8;R4is independently halogen, -CX43, -CHX42, -CH2X4, -OCX63, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOV4NR4AR4B, -NR4CNR4AR4B, -ONR4AR4B, -NR4CC(O)NR4AR4B. -N(O)m4. -NR4AR4B, -C(O)R4C, -C(O)OR4C. -OC(O)R4C, -OC(O)OR4C. -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z4 is an integer from 0 to 4;R5is independently halogen, -CX5, -CHX52, -CH2X5, -OCX5, -OCH2X5, -OCHX52, -CN, -SOn5R5D, -SOV5NR5AR5B, -NR5CNR5AR5B, -ONR5AR5B, -NR5CC(O)NR5AR5B. -N(O)m5, -NR5AR5B, -C(O)R5C, -C(O)OR5C. -OC(O)R5C, -OC(O)OR5C. -C(O)NR5AR5B, -OC(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -NR5AOR5C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z5 is an integer from 0 to 5;R4A, R4B, R4C, R4D, R5A, R5B, R5C, and R5Dare independently hydrogen, -CCI3, -CBrs, -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2. -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2. -OCH2CI, -OCH2Br. -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5Aand R5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;each X4and X5is independently -F, -Cl. -Br, or -I;n4 and n5 are independently an integer from 0 to 4; andm4, m5, v4, and v5 are independently 1 or 2.

54. The pharmaceutical composition of claim 53, wherein the compound has the formula:

55. The pharmaceutical composition of claim 53, wherein the compound has the formula:

56. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound, or a pharmaceutically acceptable salt thereof, having the formula:(R3)Z3R7(VIII);whereinR6is halogen, -CX63, -CHX62, -CH2X6, -OCX63, -OCH2X6, -OCHX62. -CN, -SOn6R6D, -SOV6NR6AR6B. -NR6CNR6AR6B, -ONR6AR6B, -NR6CC(O)NR6AR6B. -N(0)m6. -NR6AR6B, -C(O)R6C, -C(O)OR6C, -OC(O)R6C, -OC(O)OR6C, -C(O)NR6AR6B, -OC(O)NR6AR6B, -OR6D, -SR6D, -NR6ASO2R6D, -NR6AC(O)R6C, -NR6AC(O)OR6C, -NR6AOR6C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R7is halogen, -CX73, -CHX72, -CH2X7, -OCX73, -OCH2X7, -OCHX72, -CN, -SOn7R7D, -SOV7NR7AR7B, -NR7CNR7AR7D, -ONR7AR7D, -NR7CC(O)NR7AR7D. -N(O)m7, -NR7AR7B, -C(O)R7C, -C(O)OR7C, -OC(O)R7C, -OC(O)OR7C, -C(O)NR7AR7B-OC(O)NR7AR7B, -OR7D, -SR7D, -NR7ASO2R7D, -NR7AC(O)R7C, -NR7AC(O)OR7C, -NR7AOR7C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R3is independently oxo, halogen, -CC13, -CBr3, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H. -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z3 is an integer from 0 to 8;R6A, R6B. R6C. R6D. R7A. R7B. R7C. and R7Dare independently hydrogen, -CC13, -CBr3, -CF3, -CI3, -CHC12. -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN. -OH, -NH2, -COOH, -CONH2, -OCC13, -OCF3, -OCBr3, -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R7Aand R7Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;each X6and X7is independently -F, -Cl, -Br, or -I;n6 and n7 are independently an integer from 0 to 4; andm6, m7, v6, and v7 are independently 1 or 2.

57. The pharmaceutical composition of claim 56, wherein the compound has the formula:

58. The pharmaceutical composition of claim 56, wherein the compound has the formula:

59. The pharmaceutical composition of any one of claims 48 to 58, wherein the pharmaceutical composition is an oral dosage form, an intranasal dosage form, an intravenous dosage form, or an injectable dosage form.

60. A compound, or a pharmaceutically acceptable salt thereof, having the formula:whereinR1and R2are independently hydrogen, -CCI3, -CBr₃. -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I. -CN. -OH, -NH2, -COOH. -CONH2, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2CL -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted ary 1. or substituted or unsubstituted heteroaryl; R1and R2substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R3is independently oxo, halogen, -CCI3, -CBr₃, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2,-SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBn, -OCF3, -OCI3. -OCH2Cl, -OCH2Br. -OCH2F.-OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z3 is an integer from 0 to 8;R4is independently halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOV4NR4AR4B, -NR4CNR4AR4B. -ONR4AR4B-NR4CC(O)NR4AR4B, -N(O)m4. -NR4AR4B. -C(O)R4C, -C(O)OR4C. -OC(O)R4C, -OC(O)OR4C. -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D-NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SFS. -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z4 is an integer from 0 to 5;R5is independently halogen, -CX53, -CHX52, -CH2X5, -OCX53, -OCH2X5, -OCHX52, -CN, -SOn5R5D, -SOV5NR5AR5B, -NR5CNR5AR5B. -ONR5AR5B.-NR5CC(O)NR5AR5B. -N(O)m5, -NR5AR5B. -C(O)R5C, -C(O)OR5C. -OC(O)R5C, -OC(O)OR5C. -C(O)NR5AR5B, -OC(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -NR5AOR5C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z5 is an integer from 0 to 3;R4A, R4B, R4C, R4D, R5A, R5B, R5C, and R5Dare independently hydrogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2. -OCCI3, -OCF3, -OCBr3, -OCI3. -OCHCl2, -OCHBr2. -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5Aand R5Bsubstituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;each X4and X3is independently -F, -Cl, -Br, or -I;n4 and n5 are independently an integer from 0 to 4; andm4, m5, v4, and v5 are independently 1 or 2;wherein when the compound has the formula (III), then R4is not substituted 1,2,4-oxadiazolyl; andwherein the compound is not:I61. The compound of claim 60, having the formula:

62. The compound of claim 60, having the formula:

63. The compound of claim 60, having the formula:

64. The compound of claim 60, having the formula:R165. The compound of claim 60, wherein R1is hydrogen or unsubstituted Ci-C4alkyl.

66. The compound of claim 60, wherein R1is unsubstituted methyl.

67. The compound of claim 60, wherein R2is hydrogen or unsubstituted C1-C4 alkyl.

68. The compound of claim 60, wherein R2is unsubstituted methy l.

69. The compound of any one of claims 60 to 68, wherein R4is independently halogen, -CC13, -CBr3, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN. -OH. -NH2, -COOH. -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCC13, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl. substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

70. The compound of any one of claims 60 to 68, wherein R4is independently halogen, -OH, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl.

71. The compound of any one of claims 60 to 68, wherein R4is independently -OH.

72. The compound of claim 60, having the formula:

73. A compound, or a pharmaceutically acceptable salt thereof, having the formula:R1and R2are independently hydrogen, -CCl₃, -CBrs, -CF3, -CI3, -CHCk, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3, -OCF3, -OCBr3. -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1and R2substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R3is independently oxo, halogen, -CCl₃, -CBr₃, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2,-SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBn, -OCF3, -OCI3. -OCH2Cl, -OCH2Br. -OCH2F.-OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z3 is an integer from 0 to 8;R4is independently halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOV4NR4AR4B, -NR4CNR4AR4B. -ONR4AR4B-NR4CC(O)NR4AR4B, -N(O)m4. -NR4AR4B. -C(O)R4C, -C(O)OR4C. -OC(O)R4C, -OC(O)OR4C. -C(O)NR4AR4B, -OC(O)NR4AR4B, -OR4D, -SR4D, -NR4ASO2R4D-NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SFS. -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z4 is an integer from 0 to 3;R5is independently halogen, -CX53, -CHX52, -CH2X5, -OCX53, -OCH2X5, -OCHX52, -CN, -SOn5R5D, -SOV5NR5AR5B, -NR5CNR5AR5B. -ONR5AR5B.-NR5CC(O)NR5AR5B. -N(O)m5, -NR5AR5B. -C(O)R5C, -C(O)OR5C. -OC(O)R5C, -OC(O)OR5C. -C(O)NR5AR5B, -OC(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -NR5AOR5C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z5 is an integer from 0 to 5;R4A, R4B, R4C, R4D, R5A, R5B, R5C, and R5Dare independently hydrogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2. -OCCI3, -OCF3, -OCBr3, -OCI3. -OCHCl2, -OCHBr2. -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5Aand R5Bsubstituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;each X4and X3is independently -F, -Cl, -Br, or -I;n4 and n5 are independently an integer from 0 to 4; andm4, m5, v4, and v5 are independently 1 or 2.

74. The compound of claim 73, having the formula:

75. The compound of claim 73, wherein R1is hydrogen or unsubstituted C1-C4 alkyl.

76. The compound of claim 73, wherein R1is unsubstituted methy l.

77. The compound of claim 73, wherein R2is hydrogen or unsubstituted C1-C4 alkyl.

78. The compound of claim 73, wherein R2is unsubstituted methyl.

79. The compound of any one of claims 73 to 78, wherein R3is independently halogen, -CCl₃, -CBr3, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN. -OH. -NH2, -COOH. -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2. -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

80. The compound of any one of claims 73 to 78, wherein z5 is 0.

81. The compound of claim 73, having the formula:

82. A compound, or a pharmaceutically acceptable salt thereof, having the formula:(Vc);whereinR1and R2are unsubstituted methyl;R3is independently oxo, halogen, -CCh. -CBr₃, -CF3, -CI3, -CH2CI. -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHT2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, NHNH2, ONH2, NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3. -OCH2Cl, -OCH2Br. -OCH2F, -OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, -SF5. -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z3 is an integer from 0 to 8;R4, R4-1, and R42are independently halogen, -CN, -OH, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 6 membered heteroalkyl;R5is independently halogen, -CX53, -CHX52, -CH2X5, -OCX53, -OCH2X5, -OCHX52, -CN, -SOn5R5D, -SOV5NR5AR5B, -NR5CNR5AR5B, -ONR5AR5B, -NR5CC(O)NR5AR5B-N(O)m5, -NR5AR5B, -C(O)R5C, -C(O)OR5C, -OC(O)R5C, -OC(O)OR5C, -C(O)NR5AR5B, -OC(O)NR5AR5B, -OR5D, -SR5D, -NR5ASO2R5D, -NR5AC(O)R5C, -NR5AC(O)OR5C, -NR5AOR5C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;z5 is an integer from 0 to 5;RSA RSB R5Canj R5D independently hydrogen, -CCIs, -CBr₃. -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3, -OCF3, -OCBr₃. -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I. -OCH2F. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5Aand R5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;each X4and X5is independently -F, -Cl, -Br, or -I;n4 and n5 are independently an integer from 0 to 4; andm4. m5, v4, and v5 are independently 1 or 2.

83. The compound of claim 82, having the formula:

84. The compound of claim 82, wherein R4is -Cl. -CN. -OH, -CH3, or85. The compound of claim 82, having the formula:

86. The compound of claim 82, having the formula:(Vc).

87. The compound of claim 82, wherein R41and R42are independently-Cl, -CN, -OH, -CH3, or O O'88. The compound of any one of claims 82 to 87, wherein R5is independently halogen, -CCl₃, -CBr₃. -CF3, -CI3, -CH2CI, -CfhBr. -CH2F, -CH2I, -CHCh, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl₃, -OCBr3, -OCF3, -OCI3, -OCH2C1. -OCH2Br, -OCH2F, -OCH2I. -OCHCl₂, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

89. The compound of any one of claims 82 to 87, wherein z5 is 0.

90. The compound of claim 82, having the formula:

91. A compound, or a pharmaceutically acceptable salt thereof, having the formula:whereinR6is hydrogen, halogen, -CX63, -CHX62, -CH2X6, -OCX63, -OCH2X6, -OCHX62, -CN, -SOn6R6D. -SOV6NR6AR6B, -NR6CNR6AR6B. -ONR6AR6B-NR6CC(O)NR6AR6B, -N(0)m6, -NR6AR6B, -C(O)R6C, -C(O)OR6C, -OC(O)R6C, -OC(O)OR6C, -C(O)NR6AR6B, -OC(O)NR6AR6B, -OR6D, -SR6D, -NR6ASO2R6D, -NR6AC(O)R6C, -NR6AC(O)OR6C, -NR6AOR6C, -SF5, -N3, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R7is halogen, -CX73, -CHX72, -CH2X7, -OCX73, -OCH2X7, -OCHX72, -CN, -SOn7R7D, -SOv7NR7AR7B, -NR7CNR7AR7B, -ONR7AR7B, -NR7CC(O)NR7AR7B, -N(O)m7, -NR7AR7,!. -C(O)R7C, -C(O)OR7C, -OC(O)R7C, -OC(O)OR7C, -C(O)NR7AR7B, -OC(O)NR7AR7B, -OR7D, -SR7D. -NR7ASO2R7D, -NR7AC(O)R7C, -NR7AC(O)OR7C, -NR7AOR7C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R6A, R6B, R6C, R6D, R7A, R7B, R7C, and R7Dare independently hydrogen, -CC13, -CBr3, -CF3, -CI3, -CHC12, -CHBr2, -CHF2, -CHI2, -CH2CL -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCC13, -OCF3, -OCBr3, -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R7Aand R7Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;each X6and X7is independently -F, -Cl, -Br, or -I;n6 and n7 are independently an integer from 0 to 4; andm6. m7, v6, and v7 are independently 1 or 2.

92. The compound of claim 91, wherein R6is hydrogen, halogen, -CC13, -CBr3, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH. -CONH2. -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2. -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCC13, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl₂, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

93. The compound of claim 91, wherein R6is hydrogen or halogen.

94. The compound of claim 91, wherein R6is hydrogen or -Cl.

95. The compound of any one of claims 91 to 94, wherein R7is halogen, -CC13, -CBr3, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2. -SH, -SO3H. -OSO3H. -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCC13, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

96. The compound of any one of claims 91 to 94, wherein R7is -OR7D.

97. The compound of claim 96, wherein R7Uis hydrogen or unsubstituted C1-C4 alkyl.

98. The compound of any one of claims 91 to 94, wherein R7is -OH.

99. The compound of claim 91, having the formula:

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