EP4750758A1 - Ire1alpha inhibitors and uses thereof - Google Patents

Abstract

Described herein, inter alia, are compounds for inhibiting IRE1α and uses thereof.

Description

IRE1 ALPHA INHIBITORS AND USES THEREOF

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63/528,802, filed July 25, 2023, which is incorporated herein by reference in its entirety and for all purposes.

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

[0002] This invention was made with government support under grant nos. U01 DK123609 and R01 DK100623 awarded by The National Institutes of Health. The government has certain rights in the invention.

BACKGROUND

[0003] During mammalian cell growth and differentiation, the unfolded protein response (UPR) homeostatically adjusts endoplasmic reticulum (ER) protein-folding capacity to match changing cellular secretory demands. However, under high/chronic ER stress conditions the UPR triggers apoptosis. This dichotomy is promoted by differential activation levels of the ER transmembrane kinase/endoribonuclease (RNase) IREla. IREla kinase auto- phosphorylation operates as a rheostat to control downstream RNase-induced outputs that either sustain adaptive ER protein-folding or cause apoptosis. The IREla RNase can be controlled allosterically by kinase inhibitors that at maximal occupancy either fully inactivate or activate the RNAse. Overwhelming of protein folding and structural maturation in the early secretory pathw ay leads to accumulation of misfolded and immature secretory proteins in the endoplasmic reticulum (ER) (PMIDs: 22116877). Eukaryotic cells evolved intracellular signaling pathways to respond to such ‘'ER stress”. These “Unfolded Protein Response” (UPR) pathways maintain cellular secretory function and physiological health in the face of remediable ER stress (PMIDs: 29107536). First discovered in unicellular eukaryotes. UPR pathways promote homeostatic/ adaptive outputs through transcriptional upregulation of ER protein-folding and quality-control factors that extract terminally misfolded proteins back to the cytosol for degradation. However, in mammalian cells experiencing ER stress levels that cannot be mitigated by these adaptive arms, the UPR triggers programmed cell death (PCD), typically through mitochondrial apoptosis (PMIDs: 29107536). Multi-cellular organisms may benefit from culling irreversibly ER-stressed cells because the protein cargo that surviving cells continue to secrete is more likely to be pristine. However, in chronic states of such '’terminal" UPR activation, the large-scale decrement of cells through unchecked PCD may actively promote cell degenerative diseases, such as diabetes mellitus (PMCID 5568783). One critical life-death switch in the UPR is governed by the ER transmembrane multi-domain sensor protein, IREla. IREla is activated upon ER stress elevation, causing this sensor to self-associate in the ER membrane. This event causes IRElot’s cytosolic Ser/Thr kinase to trans auto-phosphorylate, which results in subsequent activation of its C-terminal endoribonuclease (RNase) catalytic domain. The range of available IREla RNase activation states runs a gamut from the inactive, the active, to the hyperactive, with the level of activity controlled rheostatically by the upstream kinase module. From its inactive monomeric state, low-level kinase/RNase activation (caused by dimerization) initiates (adaptive) XBP1 mRNA transcription factor frame-shift splicing, while high-level kinase/RNase hyperactivation (due to homo-oligomerization) expands the RNase substrate repertoire to myriad ER-localized mRNAs that become endonucleolytically cleaved (in a process termed RIDD), (PMCIDs: 2762408. 4244221), thus initiating apoptosis. Thus, for maintaining cellular homeostasis, a priori, the “sweet spot” for IREla RNase activation may lie at a level wherein XBP1 mRNA splicing remains permissible, but without the initiation of RIDD. The cellular effects of such a meta-stable activation state have even been demonstrated with IREla mutants (some found naturally as somatic mutations in cancers that act as RNase hypomorphs) and chemical-genetic (“bumped inhibitor/holed kinase”) systems (PMIDs: 25018104 and 19665977). But while it has been established that ATP-competitive inhibitors can control endogenous IREla's RNase activity through the kinase domain, these allosteric modulators have largely been shown to enforce opposite extremes of activation states (PMID 23086298). Disclosed herein, inter alia, are solutions to these and other problems in the art.

BRIEF SUMMARY

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

[0005] Ring A is substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene.

[0006] L¹ is a bond, -O-. -S-, -S(O)-, -S(O)₂-, -NR¹⁰-, -C(O)-. -C(O)NR¹⁰-, -NR¹⁰C(O)-, -C(O)O-. -OC(O)-. -NR¹⁰S(O)-. -S(O)NR¹⁰-, -NR¹⁰S(O)₂-, -S(O)₂NR¹⁰-, -NR¹⁰C(O)O-, -OC(O)NR¹⁰-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0007] L² is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0008] R¹ is hydrogen, halogen, -CC1₃, -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, -OCC1₃, -OCBr₃, -OCF₃, -OCI₃, -OCH₂C1, -OCH₂Br, -OCH₂F, -OCH₂I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N₃, unsubstituted alkyl, or unsubstituted heteroalkyl.

[0009] R² is -N(R^2A)(R^2B) or a substituted or unsubstituted nitrogen-containing heterocycloalkyl.

[0010] R^2A and R^2B are independently hydrogen, -CCI3. -CBr,. -CF3, -CI3, -CHCI2. -CHBr₂, -CHF₂, -CHI2, -CH₂C1, -CH₂Br, -CH₂F, -CH₂I, -CN, -OH, -NH₂, -COOH, -CONH₂, -OCCI3, -OCF₃, -OCBr₃, -OCI3, -OCHCh, -OCHBr₂, -OCHI₂, -OCHF₂, -OCH₂C1, -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. [0011] R³, R^3A, and R^3B are independently hydrogen, halogen, -CCh, -CBn, -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, -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.

[0012] R⁴ is independently 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, -OCH₂C1, -OCH₂Br, -OCH₂F, -OCH2I, -OCHCh, -OCHBr₂, -OCHF₂, -OCHh, -SF5, -N3, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0013] The symbol z4 is an integer from 0 to 2.

[0014] R¹⁰ is hydrogen, -CCI3, -CBr₃, -CF₃, -CI3, -CHCh, -CHBr₂, -CHF₂, -CHI₂, -CH₂C1, -CH₂Br, -CH₂F, -CH2I, -CN. -OH, -NH₂, -COOH. -CONH₂, -OCCh, -OCF₃, -OCBr₃, -OCI3, -OCHCh, -OCHBr₂, -OCHI₂, -OCHF₂, -OCH₂C1. -OCH₂Br, -OCH₂I. -OCH₂F. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary 1, or substituted or unsubstituted heteroaryl.

[0015] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0016] In an aspect is provided a method of treating a cancer, neurodegenerative disorder, inflammatory' disease, fibrosing disorder, demyelinating disorder, dermatologic disorder, rheumatic disease, autoimmune disease, metabolic disorder, or eye disease in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0017] In an aspect is provided a method of treating a disease associated with IREl a activity in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0018] In an aspect is provided a method of decreasing the level of IRE la protein activity in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

I. Definitions

[0019] 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.

[0020] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0021] 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. [0022] The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. The term “alkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne. In embodiments, the alkylene is fully saturated. In embodiments, the alkylene is monounsaturated. In embodiments, the alkylene is polyunsaturated. An alkenylene includes one or more double bonds. An alkynylene includes one or more triple bonds. [0023] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group 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, -O-CH₃, -O-CH₂-CH₃, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH₂-NH-OCH₃ and -CH₂-O-Si(CH₃)₃. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O. N, S, Si, or P). The term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in additional to the one or more double bonds. The term “heteroalkynyl.” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds. In embodiments, the heteroalkyl is fully saturated. In embodiments, the heteroalky l is monounsaturated. In embodiments, the heteroalkyl is polyunsaturated.

[0024] 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 heteroalkyd groups, such as -NR'R" or the like, it will be understood that the terms heteroalky I 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, the heteroalkylene is fully saturated. In embodiments, the heteroalkydene is monounsaturated. In embodiments, the heteroalkydene is polyunsaturated. A heteroalkenylene includes one or more double bonds. A heteroalkynylene includes one or more triple bonds. [0025] The terms “cycloalkyl” and “heterocycloalkyl.” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. In embodiments, the cycloalkyl is fully saturated. In embodiments, the cycloalkyl is monounsaturated. In embodiments, the cycloalkyl is polyunsaturated. In embodiments, the heterocycloalkyl is fully saturated. In embodiments, the heterocycloalkyl is monounsaturated. In embodiments, the heterocycloalkyl is polyunsaturated.

[0026] In embodiments, the term “cycloalkyl” means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system. In embodiments, monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In embodiments, cycloalkyl groups are fully saturated. A bicyclic or multicyclic cycloalkyd 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 cycloalky l ring of the multiple rings.

[0027] In embodiments, a cycloalkyl is a cycloalkenyl. The term “cycloalkenyl” is used in accordance with its plain ordinary meaning. In embodiments, a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system. A bicyclic or multicyclic cycloalkenyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkenyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkenyl ring of the multiple rings.

[0028] 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 heterocycloalkyd ring of the multiple rings.

[0029] 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.

[0030] 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.

[0031] 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 “heteroary l” 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 heteroaiyl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be atached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyL pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1 -naphthyl, 2-naphthyl, 4-biphenyl, 1 -pyrrolyl. 2- pyrrolyl. 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4- oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5 -benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1 -isoquinolyl, 5-isoquinolyl. 2-quinoxalinyl, 5 -quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.

[0032] Spirocyclic rings are two or more rings wherein adjacent rings are atached 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 cycloalkyd, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g., all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different. [0033] The symbol “ ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula. [0034] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom. [0035] 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: , 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. [0037] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below. [0038] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR', =N-OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'C(O)NR''R''', -NR''C(O)₂R', -NRC(NR'R''R''')=NR'''', -NRC(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO₂, -NR'SO₂R'', -NR'C(O)R'', -NR'C(O)OR'', -NR'OR'', in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH₃, -C(O)CF₃, -C(O)CH₂OCH₃, and the like). [0039] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO₂R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)₂R', -S(O)₂NR'R'', -NRSO₂R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)OR'', -NR'OR'', in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R'', R''', and R'''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or 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. [0040] Substituents for rings (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency. [0041] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring- forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure. [0042] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')_q-U-, wherein T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH₂)_r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)₂-, -S(O)₂NR'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR')s-X'- (C''R''R''')d-, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)₂-, or -S(O)₂NR'-. The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. [0043] As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si). In embodiments, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si). [0044] A “substituent group,” as used herein, means a group selected from the following moieties: (A) oxo, halogen, -CCl₃, -CBr₃, -CF₃, -CI₃, -CHCl₂, -CHBr₂, -CHF₂, -CHI₂, -CH₂Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF₂, -OCH₂Cl, -OCH₂Br, -OCH₂I, -OCH₂F, -CN, -OH, -NH₂, -COOH, -CONH₂, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH₂, –NHC(NH)NH₂, -NHSO₂H, -NHC(O)H, -NHC(O)OH, -NHOH, -N₃, -SF₅, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (B) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C₆-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: (i) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH₂Br, -CH₂F, -CH₂I, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃, -OCHCl₂, -OCHBr₂, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆- C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (ii) alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C₆- 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: (a) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH₂Cl, -CH₂Br, -CH₂F, -CH₂I, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃, -OCHCl₂, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (b) alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C₆- 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, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr₂, -CHF₂, -CHI₂, -CH₂Cl, -CH₂Br, -CH₂F, -CH₂I, -OCCl₃, -OCF₃, -OCBr₃, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH₂F, -CN, -OH, -NH₂, -COOH, -CONH₂, -NO₂, -SH, -SO₃H, –OSO₃H, -SO₂NH₂, ^NHNH₂, ^ONH₂, ^NHC(O)NHNH₂, ^NHC(O)NH₂, –NHC(NH)NH₂, -NHSO₂H, -NHC(O)H, -NHC(O)OH, -NHOH, -N₃, -SF₅, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0045] A “size-limited substituent” or “size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. [0046] A “lower substituent” or “lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₈ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃- C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 6 membered heteroaryl. [0047] 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. [0048] 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 cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6- C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈ cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene. [0049] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇ cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 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. [0050] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and/or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is substituted (e.g., is a substituted alkyd, substituted heteroalkyl, substituted cycloalkyd, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene, respectively).

[0051] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyd, substituted cycloalkyd, substituted heterocycloalky 1, substituted ary 1, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted moiety is substituted with a plurality⁷ of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety' is substituted with a plurality of substituent groups, each substituent group is different.

[0052] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroary l, 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 moiety⁷ is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different.

[0053] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroary l, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one lower substituent group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different. [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, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group is different. [0055] 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. [0056] The first substituent group is denoted with a corresponding first decimal point numbering system such that, for example, R¹ may be substituted with one or more first substituent groups denoted by R^1.1, R² may be substituted with one or more first substituent groups denoted by R^2.1, R³ may be substituted with one or more first substituent groups denoted by R^3.1, R⁴ may be substituted with one or more first substituent groups denoted by R^4.1, R⁵ may be substituted with one or more first substituent groups denoted by R^5.1, and the like up to or exceeding an R¹⁰⁰ that may be substituted with one or more first substituent groups denoted by R^100.1. As a further example, R^1A may be substituted with one or more first substituent groups denoted by R^1A.1, R^2A may be substituted with one or more first substituent groups denoted by R^{2A 1}, R^3A may be substituted with one or more first substituent groups denoted by R^3A \ R^4A may be substituted with one or more first substituent groups denoted by R^{4A I}. R^5A may be substituted with one or more first substituent groups denoted by R^{5A 1} and the like up to or exceeding an R^100A may be substituted with one or more first substituent groups denoted by R^l00A4. As a further example, L¹ may be substituted with one or more first substituent groups denoted by R^L1 -¹, L² may be substituted with one or more first substituent groups denoted by R¹'^{2 1}. L³ may be substituted with one or more first substituent groups denoted by R^{L3 I}_ L⁴ may be substituted with one or more first substituent groups denoted by R^L4J. L⁵ may be substituted with one or more first substituent groups denoted by R^{1 5 1} and the like up to or exceeding an L¹⁰⁰ which may be substituted with one or more first substituent groups denoted by R^{L100 1}. Thus, each numbered R group or L group (alternatively referred to herein as R^ww or L^ww wherein "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 R^{ww 1} or R^{LWW J}. respectively. In turn, each first substituent group (e.g., R¹ \ R²⁴, R^{3 1}, R⁴¹, R^{5 1} ... R^{100 1}; _R1A.1 _R2A.l _R3A.1 _R4A.1 R^{5A 1} _R100A.l. _RL1.1 _RL2.1 _RL3.1 _RL4.1 _RL5 1 _RL100.1) _{MAY BG} further substituted with one or more second substituent groups (e.g., R^{1 2}, R²², R^{3 2}, R⁴², _R5.2 _R1002. _R1A.2 _R2A.2 _R3A.2 _R4A.2 _R5A.2 _R100A.2. _RL1.2 _RL2.2 _RL3.2 _RL4.2 _RL52

R^{1 1002}. respectively). Thus, each first substituent group, which may alternatively be represented herein as R^{ww 1} as described above, may be further substituted with one or more second substituent groups, which may alternatively be represented herein as R°²

[0057] Finally, each second substituent group (e.g., R^{1 2}, R²², R^{3 2}, R⁴², R⁵² ... R¹⁰⁰²; R^1A2, R^2A'², R3A.2 _R4A.2, _R5A.2 _R100A.2. _RL12 _RL2.2, _RL3.2 _RL42 _RL5.2 _RL100.2) _{may bg} f_urlbcr substituted with one or more third substituent groups (e.g., R^{1 3}. R²³, R^{3 3}, R⁴³, R^{5 3} ... R¹⁰⁰³; _R1A.3 _R2A.3 _R3A.3 _R4A.3 _R5A 3 _R100A.3. _RL1.3 _RL2.3 _RL3.3 _RL4.3 _RL5 3 _RL100.3. respectively). Thus, each second substituent group, which may alternatively be represented herein as R^{WW 2} as described above, may be further substituted with one or more third substituent groups, which may alternatively be represented herein as R^{ww 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.

[0058] Thus, as used herein, R^ww represents 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, L^ww is 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 R^{w w} may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as R^ww -¹; each first substituent group, R^ww \ may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R^ww'²; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R^W'^A'-³. Similarly, each L^ww linker may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as R^{LWW 1}; each first substituent group, R^LWW \ may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RLWW.2. _anc| _each _secon(j substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R^LWW-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 R" ^w is phenyl, the said phenyl group is optionally substituted by one or more R^{ww 1} groups as defined herein below, e.g., when R^{ww 1} is R^{WW 2}-substituted or unsubstituted alkyl, examples of groups so formed include but are not limited to itself optionally substituted by 1 or more R^ww-², which R^{ww 2} is optionally substituted by one or more R^{WW 3}. By way of example when the R^ww group is phenyl substituted by R^{WW 1}, which is methyl, the methyl group may be further substituted to form groups including but not limited to:

[0059] R^{WW 1} is independently oxo, halogen, -CX^{WW 1} ₃, -CHX^WW ■¹ ₂, -CH₂X^WWJ, -ocx^ww \ -OCH₂X^WW -¹, -OCHX^{WW 1} ₂, -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, R^WW ^-substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), R^{WW 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), R^{WW 2}-substi luted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or Cs-Cs), R^{WW 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), R^{WW 2}-substituted or unsubstituted aryl (e.g., C6-C12, Ce-Cio, or phenyl), or R^ww ^-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^{ww 1} is independently oxo, halogen, -CX^{WW 1}3, -CHX^{WW J} ₂, -CH₂X^WW -¹, -OCX^WW ’₃, -OCH₂X^WW -¹, -OCHX^WW ’₂, -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, 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-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). X^WW.1 is independently –F, -Cl, -Br, or –I. [0060] R^WW.2 is independently oxo, halogen, -CX^WW.23, -CHX^WW.22, -CH2X^WW.2, -OCX^WW.2 ₃, -OCH₂X^WW.2, -OCHX^WW.2 ₂, -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, R^WW.3-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R^WW.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), R^WW.3-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C₅-C₆), R^WW.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), R^WW.3-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^WW.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, R^WW.2 is independently oxo, halogen, -CX^WW.2 ₃, -CHX^WW.2 ₂, -CH2X^WW.2, -OCX^WW.23, -OCH2X^WW.2, -OCHX^WW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO₂, -SH, -SO₃H, -OSO₃H, -SO₂NH₂, ^NHNH₂, ^ONH₂, ^NHC(O)NHNH₂, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X^WW.2 is independently –F, -Cl, -Br, or –I. [0061] R^WW.3 is independently oxo, halogen, -CX^WW.33, -CHX^WW.32, -CH2X^WW.3, -OCX^WW.3 ₃, -OCH₂X^WW.3, -OCHX^WW.3 ₂, -CN, -OH, -NH₂, -COOH, -CONH₂, -NO₂, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X^WW.3 is independently –F, -Cl, -Br, or –I. [0062] Where two different R^WW substituents are joined together to form an openly substituted ring (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl), in embodiments the openly substituted ring may be independently substituted with one or more first substituent groups, referred to herein as R^WW.1; each first substituent group, R^WW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R^WW.2; and each second substituent group, R^WW.2, may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R^WW.3; and each third substituent group, R^WW.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 R^WW substituents joined together to form an openly substituted ring, the “WW” symbol in the R^WW.1, R^WW.2 and R^WW.3 refers to the designated number of one of the two different R^WW substituents. For example, in embodiments where R^100A and R^100B are optionally joined together to form an openly substituted ring, R^WW.1 is R^100A.1, R^WW.2 is R^100A.2, and R^WW.3 is R^100A.3. Alternatively, in embodiments where R^100A and R^100B are optionally joined together to form an openly substituted ring, R^WW.1 is R^100B.1, R^WW.2 is R^100B.2, and R^WW.3 is R^100B.3. R^WW.1, R^WW.2 and R^WW.3 in this paragraph are as defined in the preceding paragraphs. [0063] R^LWW.1 is independently oxo, halogen, -CX^LWW.13, -CHX^LWW.12, -CH2X^LWW.1, -OCX^LWW.1 ₃, -OCH₂X^LWW.1, -OCHX^LWW.1 ₂, -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, R^LWW.2-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R^LWW.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), R^LWW.2-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C₅-C₆), R^LWW.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), R^LWW.2-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^LWW.2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^LWW.1 is independently oxo, halogen, -CX^LWW.1 ₃, -CHX^LWW.12, -CH2X^LWW.1, -OCX^LWW.13, -OCH2X^LWW.1, -OCHX^LWW.12, -CN, -OH, -NH2, -COOH, -CONH₂, -NO₂, -SH, -SO₃H, -OSO₃H, -SO₂NH₂, ^NHNH₂, ^ONH₂, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X^LWW.1 is independently –F, -Cl, -Br, or –I. [0064] R^LWW.2 is independently oxo, halogen, -CX^LWW.23, -CHX^LWW.22, -CH2X^LWW.2, -OCX^LWW.2 ₃, -OCH₂X^LWW.2, -OCHX^LWW.2 ₂, -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, R^LWW.3-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R^LWW.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), R^WW.3-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C₅-C₆), R^LWW.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), R^LWW.3-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^LWW.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, R^LWW.2 is independently oxo, halogen, -CX^LWW.2 ₃, -CHX^LWW.22, -CH2X^LWW.2, -OCX^LWW.23, -OCH2X^LWW.2, -OCHX^LWW.22, -CN, -OH, -NH2, -COOH, -CONH₂, -NO₂, -SH, -SO₃H, -OSO₃H, -SO₂NH₂, ^NHNH₂, ^ONH₂, ^NHC(O)NHNH₂, ^NHC(O)NH₂, –NHC(NH)NH₂, -NHSO₂H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X^LWW.2 is independently –F, -Cl, -Br, or –I. [0065] R^LWW.3 is independently oxo, halogen, -CX^LWW.3 ₃, -CHX^LWW.3 ₂, -CH₂X^LWW.3, -OCX^LWW.33, -OCH2X^LWW.3, -OCHX^LWW.32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO₃H, -OSO₃H, -SO₂NH₂, ^NHNH₂, ^ONH₂, ^NHC(O)NHNH₂, ^NHC(O)NH₂, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X^LWW.3 is independently –F, -Cl, -Br, or –I. [0066] In the event that any R group recited in a claim or chemical formula description set forth herein (R^WW substituent) is not specifically defined in this disclosure, then that R group (R^WW group) is hereby defined as independently oxo, halogen, -CX^WW ₃, -CHX^WW ₂, -CH2X^WW, -OCX^WW3, -OCH2X^WW, -OCHX^WW2, -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, R^WW.1-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R^WW.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), R^WW.1-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C₅-C₆), R^WW.1-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R^WW.1-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^WW.1-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X^WW is independently –F, -Cl, -Br, or –I. Again, “WW” represents the stated superscript number of the subject R group (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). R^WW.1, R^WW.2, and R^WW.3 are as defined above. [0067] In the event that any L linker group recited in a claim or chemical formula description set forth herein (i.e., an L^WW substituent) is not explicitly defined, then that L group (L^WW group) is herein defined as independently a bond, –O-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, –NHC(NH)NH-, -C(O)O-, -OC(O)-, -S-, -SO2-, -SO2NH-, R^LWW.1- substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R^LWW.1-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R^LWW.1-substituted or unsubstituted cycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^LWW.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), R^LWW.1-substituted or unsubstituted arylene (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^LWW.1- substituted or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Again, “WW” represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). R^LWW.1, as well as R^LWW.2 and R^LWW.3 are as defined above. [0068] 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. [0069] 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. [0070] 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. [0071] 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. [0072] 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.

[0073] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon are within the scope of this disclosure.

[0074] 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.

[0075] 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.

[0076] 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., -NFL, -COOH, -N- hydroxysuccinimide, or -maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate) provided herein can be direct, e.g.. by covalent bond or linker (e.g.. a first linker of second linker), or indirect, e.g., by non-covalent bond (e.g., electrostatic interactions (e.g., ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups) including, but are not limited to nucleophilic substitutions (e.g.. reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g.. enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, for example, March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New- York, 1985; Hermanson. BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198, American Chemical Society, Washington, D C., 1982. In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety') is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., pyridyl moiety') is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., -N- hydroxy succinimide 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).

[0077] Useful bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example: (a) carboxyl groups and various derivatives thereof including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters; (b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.; (c) haloalky 1 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 to disulfides, reacted with acyl halides, or bonded to metals such as gold, or react with maleimides; (h) amine or sulfhydryl groups (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized; (i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc.; (j) epoxides, which can react with, for example, amines and hydroxyl compounds; (k) phosphoramidites and other standard 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 avidin- biotin complex or streptavidin-biotin complex.

[0078] 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.

[0079] “Analog,” “analogue,” or “derivative” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.

[0080] 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 alkyd 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.

[0081] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R¹³ substituents are present, each R¹³ substituent may be distinguished as R^{13 A}, R^{13 B}, R^{1? c}, R^{13 D}, etc., wherein each of R^{13 A}, R^{13 B}, R^{13 c}, R^{13 D}, etc. is defined within the scope of the definition of R¹³ and 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.

[0082] Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary' skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

[0083] 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 w ith a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al.. ‘"Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977. 66. 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0084] 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.

[0085] 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.

[0086] In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.

[0087] Certain compounds of the present disclosure can exist in unsolvated forms as w ell 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.

[0088] A polypeptide, or a cell is ‘'recombinant’⁷ when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-natural or not wild type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Likewise, a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is recombinant.

[0089] “Co-administer” is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).

[0090] A “cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaroytic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g.. spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.

[0091] 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 of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. The term ’‘treating” and conjugations thereof, include prevention of an injury', pathology', condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. In embodiments, the treating or treatment is not prophylactic treatment.

[0092] 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 of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003. Gennaro. Ed., Lippincott, Williams & Wilkins).

[0093] '‘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).

[0094] “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.

[0095] 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.

[0096] 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. [0097] 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 activity⁷ is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity⁷ in the absence of the agonist.

[0098] 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.

[0099] 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.

[0100] The term “modulator” refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule (e.g., a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) relative to the absence of the composition.

[0101] 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.).

[0102] 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.

[0103] '‘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.

[0104] “Disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. In some embodiments, the disease is a disease related to (e.g., caused by) a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In embodiments, the disease is a cancer (e.g., breast cancer, ovarian cancer, colon adenocarcinoma, lung adenocarcinoma, lung small cell carcinoma, pancreatic adenocarcinoma, pancreatic neuroendocrine tumors, glioblastoma, prostate cancer, hepatocellular carcinoma, myeloma, leukemia, or lymphoma). In embodiments, the disease is a neurodegenerative disorder. In embodiments, the disease is an inflammatory disease (e.g., gastrointestinal disease or chronic inflammatory lung disease). In embodiments, the disease is a fibrosing disorder (e g., pulmonary fibrosis). In embodiments, the disease is a demyelinating disorder. In embodiments, the disease is a dermatologic disorder. In embodiments, the disease is a rheumatic disease. In embodiments, the disease is an autoimmune disease (e.g., peripheral neuropathy). In embodiments, the disease is a metabolic disorder (e.g., diabetes mellitus). In embodiments, the disease is an eye disease.

[0105] 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, urinary⁷ 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.

[0106] The term "leukemia" refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood- leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross’ leukemia, hairy -cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0107] 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. Exemplar}' 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.

[0108] 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, embry onal 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.

[0109] 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 melanomajuvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.

[0110] The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplar}' 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, medullar}' carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum. carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

[0111] As used herein, the terms "metastasis," "metastatic," and "metastatic cancer" can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part. “Metastatic cancer” is also called “Stage IV cancer.” Cancer occurs at an originating site, e g., breast, which site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or originating site acquire the ability to penetrate and infiltrate surrounding normal tissue in the local area and/or the ability to penetrate the walls of the lymphatic system or vascular system circulating through the system to other sites and tissues in the body. A second clinically detectable tumor formed from cancer cells of a primary tumor is referred to as a metastatic or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary' tumor at the site of the breast consists of abnormal lung cells and not abnormal breast cells. The secondary tumor in the breast is referred to a metastatic lung cancer. Thus, the phrase metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors. The phrases non- metastatic cancer or subjects with cancer that is not metastatic refers to diseases in which subjects have a primary' tumor but not one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject with or with a history of a primary lung tumor and with one or more secondary' tumors at a second location or multiple locations, e.g., in the breast.

[0112] 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.

[0113] 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.

[0114] As used herein, the term “neurodegenerative disorder” or “neurodegenerative disease” refers to a disease or condition in which the function of a subject’s nervous system becomes impaired. Examples of neurodegenerative diseases that may be treated with a compound, pharmaceutical composition, or method described herein include Alexander’s disease, Alper’s disease, Alzheimer’s disease, Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, chronic fatigue syndrome, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann- Straus si er- Scheinker syndrome, Huntington’s disease, HIV-associated dementia, Kennedy’s disease, Krabbe's disease, kuru, Lewy' body dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple sclerosis, Multiple System Atrophy, myalgic encephalomyelitis. Narcolepsy, Neuroborreliosis, Parkinson’s disease, Pelizaeus-Merzbacher Disease, Pick’s disease, Primary lateral sclerosis, Prion diseases, Refsum's disease, Sandhoffs disease, Schilder’s disease, Subacute combined degeneration of spinal cord secondary' to Pernicious Anaemia, Schizophrenia, Spinocerebellar ataxia (multiple types with varying characteristics), Spinal muscular atrophy. Steele-Richardson-Olszewski disease, progressive supranuclear palsy, or Tabes dorsalis.

[0115] As used herein, the terms “posterior eye indication” or “anterior eye indication” refer to eye conditions caused by changes in the anterior hyaloid membrane of the eye and the optical structures behind it. In embodiments, posterior eye indication is retinal degeneration represented by retinitis pigmentosa, Stargardt's disease, wet AMD, and dry AMD. In embodiments, anterior eye indication is glaucoma and Fuch's dystrophy.

[0116] As used herein, the term "inflammatory disease’⁷ refers to a disease or condition characterized by aberrant inflammation (e g., an increased level of inflammation compared to a control such as a healthy person not suffering from a disease). Examples of inflammatory diseases include autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, ankylosing spondylitis, psoriasis, Sjogren’s syndrome, vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet's disease, Crohn’s disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison’s disease, Vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, ischemia reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis.

[0117] As used herein, the term "chronic inflammatory lung disease” is used in accordance with its plain ordinary meaning and refers to chronic inflammation of lung tissue. Exemplary disorders include, but are not limited to, bronchial asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis or cystic fibrosis (CF).

[0118] As used herein, the term “fibrosing disorder” refers to a condition characterizied bylesions of circumscribed fibrotic areas involving different levels of the dermis, subcutis, and sometimes, underlying soft tissue and bone. In embodiments, the fibrosing disorder is idiopathic pulmonary fibrosis (IPF), familial pulmonary- fibrosis (FPF), scleroderma (systemic sclerosis), renal finrosis, and hepatic fibrosis.

[0119] As used herein, the term “demyelinating disorder” refers to a disorder of the nervous system in which the myelin sheath of neurons is damaged. In embodiments, the demyelinating disorder is multiple sclerosis (MS), Guillan-Barre syndrome, adrenoleukodystrophy, adrenomyeloneuropathy, optic neuritis, and transverse myelitis.

[0120] As used herein, the term “dermatologic disorder” refers to a disease or condition that affects the integumentary system, i.e.. the organ system that encloses the bosy and includes skin, nails, and related myscle and glands. Examples of dermatologic disorders include, but are not limited to, acne, alopecia areata, atopic dermatitis, psoriasis, Raynaud’s phenomenon, rosacea, skin cancer, vitiligo, actinic prurigo, argyria, chromhidrosis, epidermolysis bullosa, harlequin ichthyosis, lamellar ichthyosis, and necrobiosis lipoidica.

[0121] As used herein, the term “rheumatic disease” refers to a disease or condition that affects joints, tendons, muscle, ligaments, bones, and muscles. Examples of dermatologic disorders include, but are not limited to, rheumatoid arthritis, palindromic rheumatism, juvenile arthritis, systemic lupus erythematosus, Sjogren syndrome, scleroderma, polymyositis, dermatomyositis, Behcet’s disease, relapsing polychondritis, ankylosing spondylitis, reactive arthritis, psoriatic arthritis, osteoarthritis, gout, neoplasms, neurovascular disorders, bone and cartilage disorders, bursitis, tendinitis, and capsulitis.

[0122] As used herein, the term “autoimmune disease” refers to a disease or condition in which a subject’s immune system has an aberrant immune response against a substance that does not normally elicit an immune response in a healthy subject. Examples of autoimmune diseases that may be treated with a compound, pharmaceutical composition, or method described herein include Acute Disseminated Encephalomyelitis (ADEM), Acute necrotizing hemorrhagic leukoencephalitis, Addison’s disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome (APS), Autoimmune angioedema, Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmune hepatitis, Autoimmune hyperlipidemia, Autoimmune immunodeficiency, Autoimmune inner ear disease (AIED). Autoimmune myocarditis. Autoimmune oophoritis, Autoimmune pancreatitis, Autoimmune retinopathy. Autoimmune thrombocytopenic purpura (ATP), Autoimmune thyroid disease, Autoimmune urticaria, Axonal or neuronal neuropathies, Balo disease, Behcet’s disease, Bullous pemphigoid, Cardiomyopathy, Castleman disease, Celiac disease, Chagas disease, Chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal ostomyelitis (CRMO), Churg-Strauss syndrome, Cicatricial pemphigoid/benign mucosal pemphigoid, Crohn’s disease, Cogans syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST disease, Essential mixed cryoglobulinemia, Demyelinating neuropathies. Dermatitis herpetiformis, Dermatomyositis. Devic’s disease (neuromyelitis optica). Discoid lupus. Dressier’s syndrome, Endometriosis, Eosinophilic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Experimental allergic encephalomyelitis, Evans syndrome, Fibromyalgia , Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture's syndrome, Granulomatosis with Polyangiitis (GPA) (formerly called Wegener s Granulomatosis), Graves’ disease, Guillain-Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura, Herpes gestationis, Hypogammaglobulinemia. Idiopathic thrombocytopenic purpura (ITP). IgA nephropathy, IgG4-related sclerosing disease, Immunoregulatory lipoproteins, Inclusion body myositis, Interstitial cystitis, Juvenile arthritis. Juvenile diabetes (Type 1 diabetes), Juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus (SLE), Lyme disease, chronic, Meniere’s disease, Microscopic polyangiitis, Mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha-Habermann disease. Multiple sclerosis. Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica (Devic’s), Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus), Paraneoplastic cerebellar degeneration, Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Parsonnage-Tumer syndrome, Pars planitis (peripheral uveitis), Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia, POEMS syndrome, Polyarteritis nodosa, Type I, II, & III autoimmune polyglandular syndromes, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome. Postpericardiotomy syndrome, Progesterone dermatitis, Primary biliary cirrhosis, Primary sclerosing cholangitis. Psoriasis, Psoriatic arthritis, Idiopathic pulmonary' fibrosis, Pyoderma gangrenosum, Pure red cell aplasia, Raynauds phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Reiter’s syndrome. Relapsing polychondritis, Restless legs syndrome, Retroperitoneal fibrosis. Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren’s syndrome, Sperm & testicular autoimmunity, Stiff person syndrome, Subacute bacterial endocarditis (SBE), Susac’s syndrome, Sympathetic ophthalmia, Takayasu’s arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, Transverse myelitis, Type 1 diabetes. Ulcerative colitis, Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vesiculobullous dermatosis, Vitiligo, or Wegener’s granulomatosis (i.e., Granulomatosis with Polyangiitis (GPA). In embodiments, the autoimmune disease is rheumamtoid arthritis, Grave's disease, Hashimoto disease, Addison's disease, lupus, ankylosing spondylitis, and sarcoidosis. [0123] As used herein, the term “peripheral neuropathy” refers to a damaged neuron, a condition caused by trauma, injury, local compression, prolonged pressure, or inflammation of a nerve or group of nen es. Peripheral neuropathy can be primary, such as Charcot-Marie Tooth (CMT), or secondary, caused by diabetes mellitus.

[0124] The term “metabolic disorder” refers to a disorder characterized by one or more abnormal metabolic processes in a subject. In embodiments, a metabolic disorder may be associated with, related to. or may be diabetes (e.g.. type 1 diabetes or type 2 diabetes), insulin resistance, metabolic syndrome, obesity, hyperlipidemia, hyperglycemia, high serum triglycerides, and/or high blood pressure. In embodiments, a metabolic disorder may be associated with, related to, or may be a diabetes associated disease selected from nephropathy, retinopathy, neuropathy, cardiovascular disease, or inflammation. In embodiments, a metabolic disorder may be associated with, related to, or may be nephropathy, retinopathy, neuropathy, cardiovascular disease, or inflammation.

[0125] As used herein, the term “diabetes mellitus” refers to a group of metabolic discorders characterized by high blood sugar levels over a prolonged period of time. In embodiments, diabetes mellitus is represented by type 1 diabetes, type 2 diabetes, monogenic (MODY) syndrome, and recessive genetic disorders (Wolcott Rallisson syndrome and Wolfram syndrome).

[0126] As used herein, the term “eye disease” refers to a disease or condition characterized by eye problems (e.g., an increased level of eye problems compared to a control such as a healthy person not suffering from a disease). Examples of eye diseases include, but are not limited to, cataract (e.g.. congenital cataract), optic nerve disorders (e.g., glaucoma), retinal disorders, macular degeneration, diabetic eye problems, and conjunctivitis.

[0127] 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.

[0128] 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 include ¹⁸F, ³²P, ³³P, ⁴⁵Ti, ⁴⁷Sc, ⁵²Fe, ⁵⁹Fe, ⁶²Cu, ⁶⁴Cu, ⁶⁷Cu, ⁶⁷Ga, ⁶⁸Ga, ⁷⁷ As, ⁸⁶Y, ⁹⁰Y, ⁸⁹Sr, ⁸⁹Zr, ⁹⁴Tc, ⁹⁴Tc, ^99mTc, "Mo, ¹⁰⁵Pd, ¹⁰⁵Rh, ^{i n}Ag, ^mIn, ¹²³I, ¹²⁴I, ¹²⁵I. ¹³¹I, ¹⁴²Pr, ¹⁴³Pr, ¹⁴⁹Pm, ¹⁵³Sm, ¹⁵⁴-¹⁵⁸¹Gd, ¹⁶¹Tb, ¹⁶⁶Dy, ¹⁶⁶Ho, ¹⁶⁹Er, ¹⁷⁵LU, ¹⁷⁷LU, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁸⁹Re, ¹⁹⁴Ir, ¹⁹⁸ Au, ¹⁹⁹Au, ²¹¹At, ²¹¹Pb, ²¹²BI, ²¹²Pb, ²¹³BI, ²²³Ra, ²²⁵ Ac, Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, ³²P, fluorophore (e.g., fluorescent dyes), modified oligonucleotides (e.g., moieties described in PCT/US2015/022063. which is incorporated herein by reference), electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide ("SPIO") nanoparticles, SPIO nanoparticle aggregates, monochrystalline iron oxide nanoparticles, monochrystalline iron oxide, nanoparticle contrast agents, liposomes or other delivery vehicles containing Gadolinium chelate ("Gd-chelate") molecules, Gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium- 82), 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. ioxaglate). barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide.

[0129] 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, ⁷⁷ As, ⁸⁶Y, ⁹⁰Y, ⁸⁹Sr, ⁸⁹Zr, ⁹⁴TC, ⁹⁴TC, "^mTc, "Mo, ¹⁰⁵Pd, ¹⁰⁵Rh, ^mAg, ^{n i}In, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ¹⁴²Pr, ¹⁴³Pr, ¹⁴⁹Pm, ¹⁵³Sm, ¹⁵⁴'¹⁵⁸Gd, ¹⁶¹Tb, ¹⁶⁶Dy, ¹⁶⁶Ho. ¹⁶⁹Er, ¹⁷⁵Lu, ¹⁷⁷Lu, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁸⁹Re. ¹⁹⁴Ir, ¹⁹⁸ Au, ¹⁹⁹ Au, ²¹¹At, ²¹¹Pb. ²¹²Bi. ²¹²Pb, ²¹³Bi, ²²³Ra. and ²²⁵ Ac. 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. [0130] “Pharmaceutically acceptable excipient’' and “pharmaceutically acceptable carrier’" refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary' agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0131] 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.

[0132] 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.

[0133] As used herein, the term “administering” is used in accordance with its plain and ordinary meaning and includes oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini- osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra- arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By ‘'co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0134] 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.

[0135] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co- administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1. 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and/or adjunctive agents may be linked or conjugated to one another.

[0136] In therapeutic use for the treatment of a disease, compound utilized in the pharmaceutical compositions of the present invention may be administered at the initial dosage of about 0.001 mg/kg to about 1000 mg/kg daily. A daily dose range of about 0.01 mg/kg to about 500 mg/kg, or about 0.1 mg/kg to about 200 mg/kg, or about 1 mg/kg to about 100 mg/kg, or about 10 mg/kg to about 50 mg/kg, can be used. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound or drug being employed. For example, dosages can be empirically determined considering the type and stage of disease (e.g., a cancer, neurodegenerative disorder, inflammatory disease, fibrosing disorder, demyelinating disorder, dermatologic disorder, rheumatic disease, autoimmune disease, metabolic disorder, or eye disease) diagnosed in a particular patient. The dose administered to a patient, in the context of the present invention, should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the 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 w hich 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.

[0137] The term '‘associated” or “associated with” in the context of a substance or substance activity⁷ or function associated with a disease (e.g., a protein associated disease, disease associated with a cellular component) means that the disease (e g., a cancer, neurodegenerative disorder, inflammatory disease, fibrosing disorder, demyelinating disorder, dermatologic disorder, rheumatic disease, autoimmune disease, metabolic disorder, or eye disease) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function or the disease or a symptom of the disease may be treated by modulating (e.g., inhibiting or activating) the substance (e.g., cellular component). As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease.

[0138] The term “aberrant” as used herein refers to different from normal. When used to describe enzy matic activity⁷, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity⁷ 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.

[0139] 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.

[0140] "Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density.

[0141] 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.

[0142] 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., hydroxy proline, y- carboxy glutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] The term “protein aggregate” is used in accordance with its plain ordinary meaning and refers to an aberrant collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are often associated with diseases (e.g., amyloidosis). Typically, when a protein misfolds as a result of a change in the amino acid sequence or a change in the native environment which disrupts normal non-covalent interactions, and the misfolded protein is not corrected or degraded, the unfolded/misfolded protein may aggregate. There are three main types of protein aggregates that may form: amorphous aggregates, oligomers, and amyloid fibrils. In embodiments, protein aggregates are termed aggresomes. [0149] The term “IRE1” or “IRE1α” or “ERN1” or “inositol-requiring enzyme 1 α” refers to a serine/threonine protein kinase and endoribonuclease. The term includes any recombinant or naturally-occurring form of IRE1α, including variants thereof that maintain IRE1α function or activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% function or activity compared to wildtype). In embodiments, IRE1α is encoded by the ERN1 gene. In embodiments, IRE1α has the amino acid sequence set forth in or corresponding to Entrez 2081, UniProt O75460, or RefSeq (protein) NP_001424.3. II. Compounds [0150] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: (I) or (II). [0151] Ring A is substituted or unsubstituted arylene (e.g., C₆-C₁₀ or phenylene) or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0152] L¹ is a bond, -O-, -S-, -S(O)-, -S(O)₂-, -NR¹⁰-, -C(O)-, -C(O)NR¹⁰-, -NR¹⁰C(O)-, -C(O)O-, -OC(O)-, -NR¹⁰S(O)-, -S(O)NR¹⁰-, -NR¹⁰S(O)2-, -S(O)2NR¹⁰-, -NR¹⁰C(O)O-, -OC(O)NR¹⁰-, substituted or unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), or substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). [0153] L² is a bond, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1- C₂), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C₆-C₁₀ or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0154] R¹ is hydrogen, halogen, -CCl₃, -CBr₃, -CF₃, -CI₃, -CH₂Cl, -CH₂Br, -CH₂F, -CH₂I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr₂, -OCHF₂, -OCHI₂, -SF₅, -N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁- C2), 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). [0155] R² is –N(R^2A)(R^2B) or a substituted or unsubstituted nitrogen-containing heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). [0156] R^2A and R^2B are independently hydrogen, -CCl₃, -CBr₃, -CF₃, -CI₃, -CHCl₂, -CHBr₂, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF₃, -OCBr₃, -OCI₃, -OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, -OCH₂Cl, -OCH₂Br, -OCH₂I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0157] R³, R^3A, and R^3B are independently hydrogen, halogen, -CCl₃, -CBr₃, -CF₃, -CI₃, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH₂, -NO₂, -SH, -SO₃H, -OSO₃H, -SO₂NH₂, ^NHNH₂, ^ONH₂, ^NHC(O)NH₂, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH₂Br, -OCH₂F, -OCH₂I, -OCHCl₂, -OCHBr₂, -OCHF₂, -OCHI₂, -SF₅, -N₃, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6- C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0158] R⁴ is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH₂I, -CHCl₂, -CHBr₂, -CHF₂, -CHI₂, -CN, -OH, -NH₂, -COOH, -CONH₂, -NO₂, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH₂I, -OCHCl₂, -OCHBr₂, -OCHF₂, -OCHI₂, -SF₅, -N₃, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0159] The symbol z4 is an integer from 0 to 2. [0160] R¹⁰ is hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH₂Br, -CH₂F, -CH₂I, -CN, -OH, -NH₂, -COOH, -CONH₂, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C₆- C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0161] In embodiments, the compound has the formula: (I). Ring A, L¹, L², R¹, R², R³, R⁴, and z4 are as described herein, including in embodiments. [0162] In embodiments, the compound has the formula: (II). Ring A, L¹, L², R¹, R², R^3A, R^3B, R⁴, and z4 are as described herein, including in embodiments. [0163] In embodiments, the compound has the formula:

(III) or (IV). L¹, L², R¹, R², R³, R^3A, R^3B, R⁴, and z4 are as described herein, including in embodiments. [0164] R⁵ is independently halogen, -CX⁵ ₃, -CHX⁵ ₂, -CH₂X⁵, -OCX⁵ ₃, -OCH₂X⁵, -OCHX⁵2, -CN, -SOn5R^5D, -SOv5NR^5AR^5B, ^NR^5CNR^5AR^5B, ^ONR^5AR^5B, -NR^5CC(O)NR^5AR^5B, -N(O)_m5, -NR^5AR^5B, -C(O)R^5C, -C(O)OR^5C, -OC(O)R^5C, -OC(O)OR^5C, -C(O)NR^5AR^5B, -OC(O)NR^5AR^5B, -OR^5D, -SR^5D, -NR^5ASO2R^5D, -NR^5AC(O)R^5C, -NR^5AC(O)OR^5C, -NR^5AOR^5C, -SF₅, -N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁- C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0165] R^5A, R^5B, R^5C, and R^5D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl₂, -CHBr₂, -CHF₂, -CHI₂, -CH₂Cl, -CH₂Br, -CH₂F, -CH₂I, -CN, -OH, -NH₂, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH₂Br, -OCH₂I, -OCH₂F, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R^5A and R^5B substituents 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).

[0166] Each X’ is independently -F, -Cl, -Br, or -I. [0167] The symbol n5 is an integer from 0 to 4.

[0168] The symbols m5 and v5 are independently 1 or 2.

[0169] The symbol z5 is an integer from 0 to 6.

[0170] In embodiments, the compound has the formula:

(III). L¹, L², R¹, R², R³, R⁴, z4, R⁵, and z5 are as described herein, including in embodiments.

[0171] In embodiments, the compound has the formula:

(IV). L¹, L², R¹, R², R^3A, R^3B, R⁴, Z4, R⁵, and z5 are as described herein, including in embodiments.

[0172] In embodiments, the compound has the formula:

HN_X _

L I²

R² (V). L¹, L², R¹, R², R³, R⁴, z4. R⁵, and z5 are as described herein, including in embodiments.

[0173] In embodiments, the compound has the formula:

^HN _X2 I R² (VI). L¹, L², R¹, R², R^3A, R^3B, R⁴, Z4, R⁵, and z5 are as described herein, including in embodiments.

[0174] In embodiments, a substituted Ring A (e.g., 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 Ring A 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 Ring A is substituted, it is substituted with at least one substituent group. In embodiments, when Ring A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when Ring A is substituted, it is substituted with at least one lower substituent group. [0175] In embodiments, Ring A is a substituted or unsubstituted ary lene. In embodiments, Ring A is a substituted or unsubstituted Ce-Cio ary lene. In embodiments, Ring A is a substituted or unsubstituted naphthylene. In embodiments, Ring A is a substituted or unsubstituted 1 -naphthylene. In embodiments, Ring A is a substituted or unsubstituted 2- naphthylene. In embodiments, Ring A is a substituted or unsubstituted heteroary lene. In embodiments, Ring A is a substituted or unsubstituted 5 to 10 membered heteroarylene.

[0177] In embodiments, a substituted L¹ (e.g., substituted alkylene and/or substituted heteroalkylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L¹ 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 L¹ is substituted, it is substituted with at least one substituent group. In embodiments, when L¹ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L¹ is substituted, it is substituted with at least one lower substituent group.

[0178] In embodiments, when L¹ is a substituted alkylene or substituted heteroalky lene, then the substituted alkylene or substituted heteroalkylene is substituted with a substituent group; wherein the substituent group is selected from the following moieties: (A) oxo, halogen, -CCh, -CBr₃, -CF₃, -CI₃, -CHCh, -CHBr₂, -CHF₂, -CHI₂, -CH₂C1, -CH₂Br, -CH₂F, -CH₂I. -OCC1₃, -OCF₃, -OCBr₃, -OCI₃. -OCHCh, -OCHBr₂. -0CHI₂, -OCHF₂, -OCH2CL -OCH₂Br, -OCH₂I, -OCH₂F, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -SO₃H, -OSO₃H, -SO₂NH₂, -NHNH₂, -ONH2, -NHC(0)NHNH₂, -NHC(0)NH₂, -NHC(NH)NH₂. -NHSO2H, -NHC(0)H, -NHC(0)0H, -NH0H, -N₃, -SF5, unsubstituted alkyl, or unsubstituted heteroalkyl, and

(B) alkyl or heteroalkyl, substituted with at least one substituent selected from:

(1) oxo, halogen, -CC1₃, -CBr₃, -CF₃, -CI₃, -CHCh, -CHBr₂, -CHF₂, -CHI₂, -CH₂C1, -CH₂Br, -CH₂F, -CH2I, -OCC1₃, -OCF₃, -OCBr₃, -OCI3, -OCHC1₂, -OCHBr₂, -OCHI₂, -OCHF₂, -OCH₂C1, -OCH₂Br, -0CH₂I, -OCH₂F, -CN, -OH, -NH₂, -COOH, -CONH2, -NO2. -SH, -SO3H, -OSO3H. -SO2NH2, -NHNH2. -ONH2, -NHC(0)NHNH₂, -NHC(0)NH₂, -NHC(NH)NH₂, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -N₃, -SF5, unsubstituted alky l, or unsubstituted heteroalkyl, and

(ii) alkyl or heteroalkyl, substituted with at least one substituent selected from:

(a) oxo. halogen, -CC1₃, -CBr₃. -CF₃, -CI₃. -CHCh, -CHBr₂. -CHF₂. -CHI₂, -CH2CL -CH₂Br, -CH₂F, -CH2I, -OCCh, -OCF₃, -OCBr₃, -OCI₃, -OCHCh, -OCHBr₂, -OCHh, -OCHF2, -OCH₂C1, -OCH₂Br, -OCH₂I, -OCH₂F, -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, -SF₅, unsubstituted alkyl, or unsubstituted heteroalkyl, and

(b) alkyl or heteroalkyl, substituted with at least one substituent selected from: oxo, halogen. -CCh, -CBr₃, -CF₃, -CI₃, -CHCh, -CHBr₂, -CHF₂, -CHh. -CH2CI, -CH₂Br, -CH2F, -CH2I, -OCCh, -OCF₃, -OCBr₃, -OCh, -OCHCh, -OCHBn, -OCHh, -OCHF₂, -OCH₂C1, -OCH₂Br, -OCH₂I, -OCH₂F, -CN, -OH, -NH₂, -COOH, -C0NH₂, -NO2, -SH, -SO₃H, -OSO₃H, -SO₂NH₂, -NHNH₂. -ONH₂, -NHC(0)NHNH₂, -NHC(0)NH₂, -NHC(NH)NH₂, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -N₃, -SF5, unsubstituted alky l, or unsubstituted heteroalkyl. [0179] In embodiments, L¹ is a bond. In embodiments, L¹ is -O-. In embodiments, L¹ is -S-. In embodiments, L¹ is -S(O)-. In embodiments, L¹ is -S(O)2-. In embodiments, L¹ is -NR¹⁰-. In embodiments, L¹ is -NH-. In embodiments, L¹ is -C(O)-. In embodiments, L¹ is -C(O)NR¹⁰-. In embodiments, L¹ is -C(O)NH-. In embodiments, L¹ is -NR¹⁰C(O)-. In embodiments, L¹ is -NHC(O)-. In embodiments, L¹ is -C(O)O-. In embodiments, L¹ is -OC(O)-. In embodiments, L¹ is -NR¹⁰S(O)-. In embodiments, L¹ is -NHS(O)-. In embodiments, L¹ is -S(O)NR¹⁰-. In embodiments, L¹ is -S(O)NH-. In embodiments, L¹ is -NR¹⁰S(O)2-. In embodiments, L¹ is -NHS(O)2-. In embodiments, L¹ is -S(O)2NR¹⁰-. In embodiments, L¹ is -S(O)₂NH-. In embodiments, L¹ is -NR¹⁰C(O)O-. In embodiments, L¹ is -NHC(O)O-. In embodiments, L¹ is -OC(O)NR¹⁰-. In embodiments, L¹ is -OC(O)NH-. In embodiments, L¹ is unsubstituted C₁-C₄ alkylene. In embodiments, L¹ is unsubstituted methylene. In embodiments, L¹ is unsubstituted ethylene. In embodiments, L¹ is unsubstituted propylene. In embodiments, L¹ is unsubstituted n-propylene. In embodiments, L¹ is unsubstituted isopropylene. In embodiments, L¹ is unsubstituted butylene. In embodiments, L¹ is unsubstituted n-butylene. In embodiments, L¹ is unsubstituted isobutylene. In embodiments, L¹ is unsubstituted tert-butylene. In embodiments, L¹ is substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L¹ is oxo- substituted 2 to 6 membered heteroalkylene. In embodiments, L¹ is unsubstituted 2 to 6 membered heteroalkylene. [0180] In embodiments, L¹ is -NR¹⁰S(O)₂- or substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L¹ is -NR¹⁰S(O)2- or -NR¹⁰S(O)2-(unsubstituted C1-C6 alkylene)-. [0181] In embodiments, L¹ is -NHS(O)2-, , , , or . In embodiments, L¹ is -NHS(O)₂-. In embodiments, L¹ is . In embodiments, L¹ is . In embodiments, L¹ is . In embodiments, L¹ is . [0182] In embodiments, a substituted R¹⁰ (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R¹⁰ 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 R¹⁰ is substituted, it is substituted with at least one substituent group. In embodiments, when R¹⁰ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R¹⁰ is substituted, it is substituted with at least one lower substituent group. [0183] In embodiments, when R¹⁰ is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl, then the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with a substituent group as described herein. [0184] In embodiments, R¹⁰ is hydrogen. In embodiments, R¹⁰ is -CCl3. In embodiments, R¹⁰ is -CBr₃. In embodiments, R¹⁰ is -CF₃. In embodiments, R¹⁰ is -CI₃. In embodiments, R¹⁰ is -CHCl2. In embodiments, R¹⁰ is -CHBr2. In embodiments, R¹⁰ is -CHF2. In embodiments, R¹⁰ is -CHI₂. In embodiments, R¹⁰ is -CH₂Cl. In embodiments, R¹⁰ is -CH₂Br. In embodiments, R¹⁰ is -CH2F. In embodiments, R¹⁰ is -CH2I. In embodiments, R¹⁰ is –CN. In embodiments, R¹⁰ is –OH. In embodiments, R¹⁰ is -NH₂. In embodiments, R¹⁰ is –COOH. In embodiments, R¹⁰ is -CONH2. In embodiments, R¹⁰ is -OCCl3. In embodiments, R¹⁰ is -OCF₃. In embodiments, R¹⁰ is -OCBr₃. In embodiments, R¹⁰ is -OCI₃. In embodiments, R¹⁰ is -OCHCl₂. In embodiments, R¹⁰ is -OCHBr₂. In embodiments, R¹⁰ is -OCHI₂. In embodiments, R¹⁰ is -OCHF₂. In embodiments, R¹⁰ is -OCH₂Cl. In embodiments, R¹⁰ is -OCH₂Br. In embodiments, R¹⁰ is -OCH₂I. In embodiments, R¹⁰ is -OCH₂F. In embodiments, R¹⁰ is unsubstituted C₁-C₄ alkyl. In embodiments, R¹⁰ is unsubstituted methyl. In embodiments, R¹⁰ is unsubstituted ethyl. In embodiments, R¹⁰ is unsubstituted propyl. In embodiments, R¹⁰ is unsubstituted n-propyl. In embodiments, R¹⁰ is unsubstituted isopropyl. In embodiments, R¹⁰ is unsubstituted butyl. In embodiments, R¹⁰ is unsubstituted n-butyl. In embodiments, R¹⁰ is unsubstituted isobutyl. In embodiments, R¹⁰ is unsubstituted tert-butyl. [0185] In embodiments, R¹⁰ is hydrogen, -CCl₃, -CBr₃, -CF₃, -CI₃, -CHCl₂, -CHBr₂, -CHF₂, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr₃, -OCI₃, -OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, -OCH₂Cl, -OCH₂Br, -OCH₂I, -OCH₂ F, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In embodiments, R¹⁰ is hydrogen or unsubstituted C₁-C₄ alkyl. [0186] In embodiments, R¹ is hydrogen. In embodiments, R¹ is halogen. In embodiments, R¹ is –F. In embodiments, R¹ is –Cl. In embodiments, R¹ is –Br. In embodiments, R¹ is –I. In embodiments, R¹ is -CCl₃. In embodiments, R¹ is -CBr₃. In embodiments, R¹ is -CF₃. In embodiments, R¹ is -CI3. In embodiments, R¹ is -CH2Cl. In embodiments, R¹ is -CH2Br. In embodiments, R¹ is -CH₂F. In embodiments, R¹ is -CH₂I. In embodiments, R¹ is -CHCl₂. In embodiments, R¹ is -CHBr2. In embodiments, R¹ is -CHF2. In embodiments, R¹ is -CHI2. In embodiments, R¹ is –CN. In embodiments, R¹ is –OH. In embodiments, R¹ is -NH₂. In embodiments, R¹ is –COOH. In embodiments, R¹ is -CONH2. In embodiments, R¹ is -NO2. In embodiments, R¹ is –SH. In embodiments, R¹ is -SO₃H. In embodiments, R¹ is -OSO₃H. In embodiments, R¹ is -SO₂NH₂. In embodiments, R¹ is ^NHNH₂. In embodiments, R¹ is ^ONH₂. In embodiments, R¹ is ^NHC(O)NH₂. In embodiments, R¹ is -NHSO₂H. In embodiments, R¹ is -NHC(O)H. In embodiments, R¹ is -NHC(O)OH. In embodiments, R¹ is –NHOH. In embodiments, R¹ is -OCCl3. In embodiments, R¹ is -OCBr3. In embodiments, R¹ is -OCF₃. In embodiments, R¹ is -OCI₃. In embodiments, R¹ is -OCH₂Cl. In embodiments, R¹ is -OCH2Br. In embodiments, R¹ is -OCH2F. In embodiments, R¹ is -OCH₂I. In embodiments, R¹ is -OCHCl₂. In embodiments, R¹ is -OCHBr₂. In embodiments, R¹ is -OCHF2. In embodiments, R¹ is -OCHI2. In embodiments, R¹ is -SF5. In embodiments, R¹ is -N₃. In embodiments, R¹ is unsubstituted C₁-C₄ alkyl. In embodiments, R¹ is unsubstituted methyl. In embodiments, R¹ is unsubstituted ethyl. In embodiments, R¹ is unsubstituted propyl. In embodiments, R¹ is unsubstituted n-propyl. In embodiments, R¹ is unsubstituted isopropyl. In embodiments, R¹ is unsubstituted butyl. In embodiments, R¹ is unsubstituted n-butyl. In embodiments, R¹ is unsubstituted isobutyl. In embodiments, R¹ is unsubstituted tert-butyl. [0187] In embodiments, R¹ is –CF3 or unsubstituted C1-C6 alkyl. In embodiments, R¹ is –CF3, unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, or unsubstituted tert-butyl. [0188] In embodiments, -L¹-R¹ is , , , , , , , or . In embodiments, -L¹-R¹ is . In embodiments, -L¹-R¹ is . In embodiments, -L¹-R¹ is . In embodiments, -L¹-R¹ is . In embodiments, -L¹-R¹ is . In embodiments, -L¹-R¹ is . In embodiments, -L¹-R¹ is . In embodiments, -L¹-R¹ is . [0189] In embodiments, a substituted L² (e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L² 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 L² is substituted, it is substituted with at least one substituent group. In embodiments, when L² is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L² is substituted, it is substituted with at least one lower substituent group. [0190] In embodiments, L² is a bond. In embodiments, L² is unsubstituted C1-C4 alkylene. In embodiments, L² is unsubstituted methylene. In embodiments, L² is unsubstituted ethylene. In embodiments, L² is unsubstituted propylene. In embodiments, L² is unsubstituted n-propylene. In embodiments, L² is unsubstituted isopropylene. In embodiments, L² is unsubstituted butylene. In embodiments, L² is unsubstituted n-butylene. In embodiments, L² is unsubstituted isobutylene. In embodiments, L² is unsubstituted tert- butylene.

[0191] In embodiments, a substituted R² (e.g., substituted nitrogen-containing heterocycloalkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R² 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 R² is substituted, it is substituted with at least one substituent group. In embodiments, when R² is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R² is substituted, it is substituted with at least one lower substituent group.

[0192] In embodiments, R² is a substituted or unsubstituted nitrogen-containing heterocycloalkyl. In embodiments, R² is a substituted or unsubstituted nitrogen-containing 3 to 8 membered heterocycloalkyl. In embodiments, R² is a substituted or unsubstituted piperidinyl. In embodiments, R² is an unsubstituted piperidinyl. In embodiments, R² is a piperidinyl substituted with a halogen. In embodiments, R² is a piperidinyl substituted with -F. In embodiments, R² is a piperidinyl substituted with -Cl. In embodiments, R² is a piperidinyl substituted with -Br. In embodiments, R² is a piperidinyl substituted with -I. In embodiments, R² is H . In embodiments, R² is

[0193] In embodiments, R² is -N(R^2A)(R^2B); R^2A and R^2B are as described herein, including in embodiments.

[0194] In embodiments, a substituted R^2A (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 R^2A 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 R^2A is substituted, it is substituted with at least one substituent group. In embodiments, when R^2A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^2A is substituted, it is substituted with at least one lower substituent group. [0195] In embodiments, R^2A is hydrogen. In embodiments, R^2A is -CCl3. In embodiments, R^2A is -CBr₃. In embodiments, R^2A is -CF₃. In embodiments, R^2A is -CI₃. In embodiments, R^2A is -CHCl2. In embodiments, R^2A is -CHBr2. In embodiments, R^2A is -CHF2. In embodiments, R^2A is -CHI₂. In embodiments, R^2A is -CH₂Cl. In embodiments, R^2A is -CH2Br. In embodiments, R^2A is -CH2F. In embodiments, R^2A is -CH2I. In embodiments, R^2A is –CN. In embodiments, R^2A is –OH. In embodiments, R^2A is -NH₂. In embodiments, R^2A is –COOH. In embodiments, R^2A is -CONH2. In embodiments, R^2A is -OCCl3. In embodiments, R^2A is -OCF₃. In embodiments, R^2A is -OCBr₃. In embodiments, R^2A is -OCI₃. In embodiments, R^2A is -OCHCl2. In embodiments, R^2A is -OCHBr2. In embodiments, R^2A is -OCHI₂. In embodiments, R^2A is -OCHF₂. In embodiments, R^2A is -OCH₂Cl. In embodiments, R^2A is -OCH2Br. In embodiments, R^2A is -OCH2I. In embodiments, R^2A is -OCH₂F. In embodiments, R^2A is substituted or unsubstituted C₁-C₄ alkyl. In embodiments, R^2A is unsubstituted methyl. In embodiments, R^2A is unsubstituted ethyl. In embodiments, R^2A is unsubstituted propyl. In embodiments, R^2A is unsubstituted n-propyl. In embodiments, R^2A is unsubstituted isopropyl. In embodiments, R^2A is unsubstituted butyl. In embodiments, R^2A is unsubstituted n-butyl. In embodiments, R^2A is unsubstituted isobutyl. In embodiments, R^2A is unsubstituted tert-butyl. In embodiments, R^2A is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R^2A is substituted or unsubstituted C3-C8 cycloalkyl. In embodiments, R^2A is substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R^2A is substituted or unsubstituted phenyl. In embodiments, R^2A is substituted or unsubstituted 5 to 6 membered heteroaryl. [0196] In embodiments, a substituted R^2B (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 R^2B 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 R^2B is substituted, it is substituted with at least one substituent group. In embodiments, when R^2B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^2B is substituted, it is substituted with at least one lower substituent group. [0197] In embodiments, R^2B is hydrogen. In embodiments, R^2B is -CCl3. In embodiments, R^2B is -CBr₃. In embodiments, R^2B is -CF₃. In embodiments, R^2B is -CI₃. In embodiments, R^2B is -CHCl2. In embodiments, R^2B is -CHBr2. In embodiments, R^2B is -CHF2. In embodiments, R^2B is -CHI₂. In embodiments, R^2B is -CH₂Cl. In embodiments, R^2B is -CH2Br. In embodiments, R^2B is -CH2F. In embodiments, R^2B is -CH2I. In embodiments, R^2B is –CN. In embodiments, R^2B is –OH. In embodiments, R^2B is -NH₂. In embodiments, R^2B is –COOH. In embodiments, R^2B is -CONH2. In embodiments, R^2B is -OCCl3. In embodiments, R^2B is -OCF₃. In embodiments, R^2B is -OCBr₃. In embodiments, R^2B is -OCI₃. In embodiments, R^2B is -OCHCl2. In embodiments, R^2B is -OCHBr2. In embodiments, R^2B is -OCHI₂. In embodiments, R^2B is -OCHF₂. In embodiments, R^2B is -OCH₂Cl. In embodiments, R^2B is -OCH2Br. In embodiments, R^2B is -OCH2I. In embodiments, R^2B is -OCH₂F. In embodiments, R^2B is substituted or unsubstituted C₁-C₄ alkyl. In embodiments, R^2B is unsubstituted methyl. In embodiments, R^2B is unsubstituted ethyl. In embodiments, R^2B is unsubstituted propyl. In embodiments, R^2B is unsubstituted n-propyl. In embodiments, R^2B is unsubstituted isopropyl. In embodiments, R^2B is unsubstituted butyl. In embodiments, R^2B is unsubstituted n-butyl. In embodiments, R^2B is unsubstituted isobutyl. In embodiments, R^2B is unsubstituted tert-butyl. In embodiments, R^2B is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R^2B is substituted or unsubstituted C3-C8 cycloalkyl. In embodiments, R^2B is substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R^2B is substituted or unsubstituted phenyl. In embodiments, R^2B is substituted or unsubstituted 5 to 6 membered heteroaryl. [0198] 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 R³ 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 R³ is substituted, it is substituted with at least one substituent group. In embodiments, when R³ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R³ is substituted, it is substituted with at least one lower substituent group.

[0199] In embodiments, R³ is hydrogen. In embodiments, R³ is halogen. In embodiments, R³ is -F. In embodiments, R³ is -Cl. In embodiments, R’ is -Br. In embodiments, R³ is -I. In embodiments, R³ is -CCI3. In embodiments, R' is -CBrs. In embodiments, R³ is -CF3. In embodiments, R' is -CI3. In embodiments, R³ is -CH2CI. In embodiments, R³ is -CFhBr. In embodiments, R³ is -CH2F. In embodiments, R³ is -CH2I. In embodiments, R³ is -CHCh. In embodiments, R³ is -CHBr? In embodiments, R³ is -CHF2. In embodiments, R³ is -CHI2. In embodiments, R³ is -CN. In embodiments, R³ is -OH. In embodiments, R³ is -NH2. In embodiments, R³ is -COOH. In embodiments, R³ is -CONH2. In embodiments, R³ is -NO2. In embodiments, R³ is -SH. In embodiments, R³ is -SO3H. In embodiments, R³ is -OSO3H. In embodiments, R³ is -SO2NH2. In embodiments, R³ is -NHNH2. In embodiments, R³ is -ONH2. In embodiments, R³ is -NHC(O)NH2. In embodiments, R³ is -NHSO2H. In embodiments, R³ is -NHC(O)H. In embodiments, R³ is -NHC(O)OH. In embodiments, R³ is -NHOH. In embodiments, R³ is -OCCI3. In embodiments. R³ is -OCBrs. In embodiments, R³ is -OCF3. In embodiments, R³ is -OCI3. In embodiments, R³ is -OCH2CI. In embodiments, R³ is -OCH2BE In embodiments, R³ is -OCH2F. In embodiments, R³ is -OCH2I. In embodiments. R³ is -OCHCh. In embodiments, R³ is -OCHBr2. In embodiments, R³ is -OCHF2. In embodiments, R³ is -OCHI2. In embodiments, R³ is -SF5. In embodiments, R³ is -N3. In embodiments, R³ is unsubstituted C1-C4 alkyl. In embodiments, R³ is unsubstituted methyl. In embodiments, R³ is unsubstituted ethyl. In embodiments, R' is unsubstituted propyl. In embodiments, R³ is unsubstituted n-propyl. In embodiments, R³ is unsubstituted isopropyl. In embodiments, R³ is unsubstituted butyl. In embodiments, R³ is unsubstituted n-butyl. In embodiments, R³ is unsubstituted isobutyl. In embodiments, R³ is unsubstituted lert-butyl.

[0200] In embodiments, R³ is hydrogen or unsubstituted C1-C4 alky l. In embodiments, R³ is hydrogen or unsubstituted methyl.

[0201] In embodiments, a substituted R^3A (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 R^{3 A} 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 R^3A is substituted, it is substituted with at least one substituent group. In embodiments, when R^3A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^3A is substituted, it is substituted with at least one lower substituent group.

[0202] In embodiments, R^3A is hydrogen. In embodiments, R^3A is halogen. In embodiments, R^3A is -F. In embodiments, R^3A is -Cl. In embodiments, R^3A is -Br. In embodiments, R^3A is -I. In embodiments, R^3A is -CCI3. In embodiments, R^3A is -CBn In embodiments, R^3A is -CF3. In embodiments, R^3A is -CI3. In embodiments, R^3A is -CH2CI. In embodiments, R^3A is -CFBBr. In embodiments, R^3A is -CH2F. In embodiments, R^3A is -CH2I. In embodiments, R^3A is -CHCh. In embodiments, R^3A is -CHBr2. In embodiments, R^3A is -CHF2. In embodiments, R^3A is -CHI2. In embodiments. R^3A is -CN. In embodiments. R^3A is -OH. In embodiments, R’^A is -NH2. In embodiments, R^3A is -COOH. In embodiments, R^3A is -CONH2. In embodiments, R^3A is -NO2. In embodiments, R^3A is -SH. In embodiments, R^3A is -SO3H. In embodiments, R^3A is -OSO3H. In embodiments, R^JA is -SO2NH2. In embodiments, R^3A is -NHNH2. In embodiments, R^3A is -ONH2. In embodiments, R^3A is -NHC(O)NH2. In embodiments, R^3A is -NHSO2H. In embodiments, R^3A is -NHC(O)H. In embodiments, R^3A is -NHC(O)OH. In embodiments, R^3A is -NHOH. In embodiments. R^3A is -OCCI3. In embodiments, R^3A is -OCBrs. In embodiments, R^3A is -OCF3. In embodiments, R^3A is -OCI3. In embodiments, R^3A is -OCH2CI. In embodiments, R^3A is -OCH2Br. In embodiments, R^3A is -OCH2F. In embodiments, R^3A is -OCH2I. In embodiments, R^3A is -OCHCI2. In embodiments, R^3A is -OCHBr2. In embodiments, R^3A is -OCHF2. In embodiments, R^3A is -OCHI2. In embodiments, R^3A is -SF5. In embodiments, R^3A is -N3. In embodiments, R^3A is unsubstituted C1-C4 alkyl. In embodiments, R^3A is unsubstituted methyl. In embodiments, R^3A is unsubstituted ethyl. In embodiments, R^3A is unsubstituted propyl. In embodiments, R^3A is unsubstituted n-propyl. In embodiments, R^3A is unsubstituted isopropyl. In embodiments, R^3A is unsubstituted butyl. In embodiments. R^3A is unsubstituted n-butyl. In embodiments, R^3A is unsubstituted isobutyl. In embodiments, R^3A is unsubstituted tert -butyl.

[0203] In embodiments, a substituted R^3B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyd, 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 R^3B 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 R^3B is substituted, it is substituted with at least one substituent group. In embodiments, when R^3B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^3B is substituted, it is substituted with at least one lower substituent group.

[0204] In embodiments, R^3B is hydrogen. In embodiments, R^3B is halogen. In embodiments, R^3B is -F. In embodiments, R^3B is -Cl. In embodiments, R^3B is -Br. In embodiments, R^3B is -I. In embodiments, R^3B is -CCI3. In embodiments, R^3B is -CBrs. In embodiments, R^3B is -CF3. In embodiments, R^3B is -CI3. In embodiments, R^3B is -CH2CI. In embodiments, R^3B is -Cl-hBr. In embodiments. R^3B is -CH2F. In embodiments, R^3B is -CH2I. In embodiments, R^3B is -CHCh. In embodiments, R^3B is -CHBr2. In embodiments, R^3B is -CHF2. In embodiments, R^3B is -CHI2. In embodiments, R^3B is -CN. In embodiments, R^3B is -OH. In embodiments, R^3B is -NH2. In embodiments, R^3B is -COOH. In embodiments, R^3B is -CONH2. In embodiments, R^3B is -NO2. In embodiments, R^3B is -SH. In embodiments, R^3B is -SO3H. In embodiments, R^3B is -OSO3H. In embodiments, R^3B is -SO2NH2. In embodiments, R^3B is -NHNH2. In embodiments, R^3B is -ONH2. In embodiments, R^3B is -NHC(O)NH2. In embodiments, R^3B is -NHSO2H. In embodiments. R^3B is -NHC(O)H. In embodiments, R^3B is -NHC(O)OH. In embodiments, R^3B is -NHOH. In embodiments, R^3B is -OCCI3. In embodiments, R^3B is -OCBrs. In embodiments, R^3B is -OCF3. In embodiments, R^3B is -OCI3. In embodiments, R^3B is -OCH2CI. In embodiments, R^3B is -OCH2Br. In embodiments, R^3B is -OCH2F. In embodiments, R^3B is -OCH2I. In embodiments, R^3B is -OCHCI2. In embodiments, R^3B is -OCHBr2. In embodiments, R^3B is -OCHF2. In embodiments, R^3B is -OCHI2. In embodiments, R^3B is -SF5. In embodiments, R^3B is -N3. In embodiments, R^3B is unsubstituted C1-C4 alkyl. In embodiments, R'^B is unsubstituted methyl. In embodiments, R^3B is unsubstituted ethyl. In embodiments, R^3B is unsubstituted propyl. In embodiments, R^3B is unsubstituted n-propyl. In embodiments, R^3B is unsubstituted isopropyl. In embodiments, R^3B is unsubstituted butyl. In embodiments, R^3B is unsubstituted n-butyl. In embodiments, R^3B is unsubstituted isobutyl. In embodiments, R^3B is unsubstituted tert-butyl. [0205] In embodiments, a substituted R⁴ (e.g.. substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyd, 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 R⁴ is substituted with a plurality⁷ 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 R⁴ is substituted, it is substituted with at least one substituent group. In embodiments, when R⁴ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R⁴ is substituted, it is substituted with at least one lower substituent group.

[0206] In embodiments, R⁴ is independently halogen. In embodiments, R⁴ is independently -F. In embodiments, R⁴ is independently -Cl. In embodiments, R⁴ is independently -Br. In embodiments, R⁴ is independently -I. In embodiments, R⁴ is independently -CCI3. In embodiments, R⁴ is independently CBn. In embodiments, R⁴ is independently -CF3. In embodiments, R⁴ is independently -CI3. In embodiments, R⁴ is independently -CH2CI. In embodiments, R⁴ is independently -CkhBr. In embodiments. R⁴ is independently -CH2F. In embodiments, R⁴ is independently -CH2I. In embodiments, R⁴ is independently -CHCI2. In embodiments, R⁴ is independently -CHBn. In embodiments, R⁴ is independently -CHF2. In embodiments, R⁴ is independently -CHI2. In embodiments, R⁴ is independently -CN. In embodiments, R⁴ is independently -OH. In embodiments, R⁴ is independently -NH2. In embodiments, R⁴ is independently -COOH. In embodiments, R⁴ is independently -CONH2. In embodiments, R⁴ is independently -NO2. In embodiments, R⁴ is independently -SH. In embodiments, R⁴ is independently -SO3H. In embodiments, R⁴ is independently -OSO3H. In embodiments, R⁴ is independently -SO2NH2. In embodiments, R⁴ is independently -NHNH2. In embodiments, R⁴ is independently -ONH2. In embodiments, R⁴ is independently -NHC(O)NH2. In embodiments, R⁴ is independently -NHSO2H. In embodiments, R⁴ is independently -NHC(O)H. In embodiments, R⁴ is independently -NHC(O)OH. In embodiments, R⁴ is independently -NHOH. In embodiments, R⁴ is independently -OCCI3. In embodiments, R⁴ is independently -OCBr.3. In embodiments, R⁴ is independently -OCF3. In embodiments, R⁴ is independently -OCI3. In embodiments, R⁴ is independently -OCH2CI. In embodiments, R⁴ is independently -OCH2Br. In embodiments, R⁴ is independently -OCH2F. In embodiments, R⁴ is independently -OCH2I. In embodiments, R⁴ is independently -OCHCI2. In embodiments, R⁴ is independently -OCHBr2. In embodiments, R⁴ is independently -OCHF2. In embodiments, R⁴ is independently -OCHI2. In embodiments, R⁴ is independently -SF5. In embodiments, R⁴ is independently -N3. In embodiments, R⁴ is independently unsubstituted C1-C4 alkyl. In embodiments, R⁴ is independently unsubstituted methyl. In embodiments, R⁴ is independently unsubstituted ethyl. In embodiments, R⁴ is independently unsubstituted propyl. In embodiments, R⁴ is independently unsubstituted n-propyl. In embodiments, R⁴ is independently unsubstituted isopropyl. In embodiments. R⁴ is independently unsubstituted butyl. In embodiments. R⁴ is independently unsubstituted n-butyl. In embodiments, R⁴ is independently unsubstituted isobutyl. In embodiments, R⁴ is independently unsubstituted tert-butyl. In embodiments, R⁴ is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R⁴ is independently unsubstituted methoxy. In embodiments, R⁴ is independently unsubstituted ethoxy. In embodiments, R⁴ is independently unsubstituted propoxy. In embodiments, R⁴ is independently unsubstituted n-propoxy. In embodiments, R⁴ is independently unsubstituted isopropoxy . In embodiments, R⁴ is independently unsubstituted butoxy.

[0207] In embodiments, z4 is 0. In embodiments. z4 is 1. In embodiments, z4 is 2.

[0208] In embodiments, a substituted R⁵ (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyd, 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 R⁵ 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 R³ is substituted, it is substituted with at least one substituent group. In embodiments, when R³ is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R⁵ is substituted, it is substituted with at least one lower substituent group.

[0209] In embodiments, a substituted R^5A (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 R^5A 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 R^5A is substituted, it is substituted with at least one substituent group. In embodiments, when R^5A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^5A is substituted, it is substituted with at least one lower substituent group.

[0210] In embodiments, a substituted R^5B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyd, 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 R^5B 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 R^5B is substituted, it is substituted with at least one substituent group. In embodiments, when R^5B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^5B is substituted, it is substituted with at least one lower substituent group.

[0211] In embodiments, a substituted ring formed when R^5A and R^5B substituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalky l 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 R^5A and R^5B substituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R^5A and R^5B substituents 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 R^5A and R^5B substituents 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 R^5A and R^5B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0212] In embodiments, a substituted R^5C (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 low er substituent group; wherein if the substituted R^3C 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 R^5C is substituted, it is substituted with at least one substituent group. In embodiments, when R^3C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^5C is substituted, it is substituted with at least one lower substituent group.

[0213] In embodiments, a substituted R^5D (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyd, 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 R^5D 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 R^5D is substituted, it is substituted with at least one substituent group. In embodiments, when R^5U is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^5D is substituted, it is substituted with at least one lower substituent group.

[0214] In embodiments, R^3A is independently hydrogen. In embodiments, R^3A is independently unsubstituted C1-C4 alkyl. In embodiments, R^3A is independently unsubstituted methyl. In embodiments, R^3A is independently unsubstituted ethyl. In embodiments, R^3A is independently unsubstituted propyl. In embodiments, R^5A is independently unsubstituted n-propyl. In embodiments, R^3A is independently unsubstituted isopropyl. In embodiments, R^3A is independently unsubstituted butyl. In embodiments, R^3A is independently unsubstituted n-butyl. In embodiments, R^3A is independently unsubstituted isobutyl. In embodiments, R^5A is independently unsubstituted tert-buty l.

[0215] In embodiments, R^3B is independently hydrogen. In embodiments, R^3B is independently unsubstituted C1-C4 alkyl. In embodiments, R^3B is independently unsubstituted methyl. In embodiments, R^3B is independently unsubstituted ethyl. In embodiments, R^3B is independently unsubstituted propyl. In embodiments, R^3B is independently unsubstituted n-propyl. In embodiments, R^5B is independently unsubstituted isopropyl. In embodiments, R^5B is independently unsubstituted butyl. In embodiments, R^3B is independently unsubstituted n-butyl. In embodiments, R^3B is independently unsubstituted isobutyl. In embodiments, R^3B is independently unsubstituted tert-butyl. [0216] In embodiments, R^5C is independently hydrogen. In embodiments, R^5C is independently unsubstituted C1-C4 alkyl. In embodiments, R^5C is independently unsubstituted methyl. In embodiments, R^5C is independently unsubstituted ethyl. In embodiments, R^5C is independently unsubstituted propyl. In embodiments, R^5C is independently unsubstituted n-propyl. In embodiments, R^5C is independently unsubstituted isopropyl. In embodiments, R^5C is independently unsubstituted butyl. In embodiments, R^5C is independently unsubstituted n-butyl. In embodiments, R^5C is independently unsubstituted isobutyl. In embodiments, R^3C is independently unsubstituted tert-butyl.

[0217] In embodiments, R^5D is independently hydrogen. In embodiments, R^5D is independently unsubstituted C1-C4 alkyl. In embodiments, R^5D is independently unsubstituted methyl. In embodiments, R^5D is independently unsubstituted ethyl. In embodiments, R^5D is independently unsubstituted propyl. In embodiments. R^5D is independently unsubstituted n-propyl. In embodiments, R^3D is independently unsubstituted isopropyl. In embodiments, R^3D is independently unsubstituted butyl. In embodiments, R^5D is independently unsubstituted n-butyl. In embodiments, R^5D is independently unsubstituted isobutyl. In embodiments. R^5D is independently unsubstituted tert-butyl.

[0218] In embodiments, R⁵ is independently halogen, -CCh, -CBr?, -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, -OCH₂C1. -OCH₂Br, -OCH₂F, -OCH₂I, -OCHCb, -OCHBn, -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.

[0219] In embodiments, R⁵ is independently halogen. In embodiments, R⁵ is independently -F. In embodiments, R³ is independently -Cl. In embodiments, R³ is independently -Br. In embodiments, R³ is independently -I. In embodiments, R³ is independently -CCh. In embodiments, R³ is independently -CBrs. In embodiments, R³ is independently -CF3. In embodiments, R³ is independently -CI3. In embodiments, R³ is independently -CH₂C1. In embodiments, R³ is independently -CH₂Br. In embodiments. R³ is independently -CH₂F. In embodiments, R³ is independently -CH₂I. In embodiments, R³ is independently -CHC1₂. In embodiments, R³ is independently -CHBr₂. In embodiments, R³ is independently -CHF₂. In embodiments, R³ is independently -CHI2. In embodiments, R⁵ is independently -CN. In embodiments, R⁵ is independently -OH. In embodiments, R⁵ is independently -NH2. In embodiments, R⁵ is independently -COOH. In embodiments, R³ is independently -CONH2. In embodiments, R³ is independently -NO2. In embodiments, R⁵ is independently -SH. In embodiments, R⁵ is independently -SO3H. In embodiments, R⁵ is independently -OSO3H. In embodiments, R⁵ is independently -SO2NH2. In embodiments, R³ is independently -NHNH2. In embodiments, R³ is independently -ONH2. In embodiments, R³ is independently -NHC(O)NH2. In embodiments, R³ is independently -NHSO2H. In embodiments, R³ is independently -NHC(O)H. In embodiments, R³ is independently -NHC(O)OH. In embodiments, R³ is independently -NHOH. In embodiments, R³ is independently -OCCI3. In embodiments, R³ is independently -OCBr3. In embodiments, R³ is independently -OCF3. In embodiments, R³ is independently -OCI3. In embodiments, R³ is independently -OCH2CI. In embodiments, R³ is independently -OCH2Br. In embodiments, R³ is independently -OCH2F. In embodiments, R³ is independently -OCH2I. In embodiments, R³ is independently -OCHCI2. In embodiments, R³ is independently -OCHBr2. In embodiments, R³ is independently -OCHF2. In embodiments, R⁵ is independently -OCHI2. In embodiments, R³ is independently -SF5. In embodiments, R³ is independently -N3. In embodiments, R³ is independently unsubstituted C1-C4 alkyl. In embodiments. R³ is independently unsubstituted methyl. In embodiments, R³ is independently unsubstituted ethyl. In embodiments, R³ is independently unsubstituted propyl. In embodiments, R³ is independently unsubstituted n-propyl. In embodiments, R³ is independently unsubstituted isopropyl. In embodiments, R³ is independently unsubstituted butyl. In embodiments. R³ is independently unsubstituted n-butyl. In embodiments, R³ is independently unsubstituted isobutyl. In embodiments, R³ is independently unsubstituted tert-butyl. In embodiments, R³ is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R³ is independently unsubstituted methoxy. In embodiments, R³ is independently unsubstituted ethoxy. In embodiments, R³ is independently unsubstituted propoxy. In embodiments, R³ is independently unsubstituted n-propoxy. In embodiments, R³ is independently unsubstituted isopropoxy. In embodiments, R³ is independently unsubstituted butoxy.

[0220] In embodiments, R³ is independently halogen or unsubstituted C1-C4 alkyl. In embodiments, R³ is independently -F or unsubstituted methyl. [0221] 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. In embodiments, z5 is 6.

[0222] In embodiments, when Ring A is substituted. Ring A is substituted with one or more first substituent groups denoted by R^{A 1} as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^{A 1} substituent group is substituted, the R^{A 1} substituent group is substituted with one or more second substituent groups denoted by R^{A 2} as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^A2 substituent group is substituted, the R^{A 2} substituent group is substituted with one or more third substituent groups denoted by R^{A 3} as explained in the definitions section above in the description of “first substituent group(s)’; In the above embodiments. R^A, R^A -¹, R^A2. and R^A3 have values corresponding to the values of R^ww, R^ww \ R^ww-², and RWW.3 respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^ww, R^ww \ R^ww-², and R^{WW 3} correspond to R^A. R^A \ R^A2, and R^A3, respectively.

[0223] In embodiments, when R² is substituted, R² is substituted with one or more first substituent groups denoted by R^{2 1} as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^{2 1} substituent group is substituted, the R^{2 1} substituent group is substituted with one or more second substituent groups denoted by R²² as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R²² substituent group is substituted, the R²² substituent group is substituted with one or more third substituent groups denoted by R²³ as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments. R². R^{2 1}. R²², and R²³ have values corresponding to the values of R^ww. R^{WW 1}, R^WW2 _anj _Rww.3 _reSp_ectively , as explained in the definitions section above in the description of “first substituent group(s)’’, wherein R^ww, R^w \ R^WW2 and R^{WW 3} correspond to R², R^{2 1}, R²², and R²³, respectively.

[0224] In embodiments, when R^2A is substituted, R^2A is substituted with one or more first substituent groups denoted by R^{2A 1} as explained in the definitions section above in the description of “first substituent group(s)". In embodiments, when an R^{2A 1} substituent group is substituted, the R^{2A 1} substituent group is substituted with one or more second substituent groups denoted by R^2A2 as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R^{2A 2} substituent group is substituted, the R^{2A 2} substituent group is substituted with one or more third substituent groups denoted by R^{2A 3} as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^2A, R^{2A I}. R^{2A 2}, and R^{2A 3} have values corresponding to the values of R"^w, R^ww -¹, R^ww-², and R^WW3 _? respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^ww. R^{WW 1}, R^{WW 2}, and R^{WW 3} correspond to R^2A, R^{2A 1}, R^{2A 2}. and R^{2A 3}, respectively.

[0225] In embodiments, when R^2B is substituted, R^2B is substituted with one or more first substituent groups denoted by R^{2B 1} as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^{2B 1} substituent group is substituted, the R^{2B 1} substituent group is substituted with one or more second substituent groups denoted by R^{2B 2} as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^{2B 2} substituent group is substituted, the R^{2B 2} substituent group is substituted with one or more third substituent groups denoted by R^{2B 3} as explained in the definitions section above in the description of “first substituent group(s)’; In the above embodiments, R^2B, R^2B -¹, R^{2B 2}. and R^{2B 3} have values corresponding to the values of R^ww, R" ^WA, R^WW22, and R^{WW 3} _? respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^ww, R^ww -¹, R^ww-², and R^{WW 3} correspond to R^2B, R^2B \ R^{2B 2}, and R^{2B 3}. respectively.

[0226] In embodiments, when R³ is substituted, R³ is substituted with one or more first substituent groups denoted by R^{3 1} as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^{3 1} substituent group is substituted, the R^{3 1} substituent group is substituted with one or more second substituent groups denoted by R^{3 2} as explained in the definitions section above in the description of “first substituent group(s)". In embodiments, when an R³² substituent group is substituted, the R^{3 2} substituent group is substituted with one or more third substituent groups denoted by R^{5 3} as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R³, R^{3 1}. R^{3 2}, and R³³ have values corresponding to the values of R^ww, R^ww \ R^ww;2. and R^ww-³, respectively, as explained in the definitions section above in the description of “first substituent group(s)”. wherein R^ww. R^{WW 1}. _RWW2 and R^{WW 3} correspond to R³, R³ R³², and R^{3 3}, respectively. [0227] In embodiments, when R^3A is substituted, R' ^A is substituted with one or more first substituent groups denoted by R^{3A 1} as explained in the definitions section above in the description of ‘’first substituent group(s)’’. In embodiments, when an R^{3A 1} substituent group is substituted, the R^{3A 1} substituent group is substituted with one or more second substituent groups denoted by R^3A2 as explained in the definitions section above in the description of “first substituent group(s)". In embodiments, when an R^{3A 2} substituent group is substituted, the R^{3A 2} substituent group is substituted with one or more third substituent groups denoted by R^{3A 3} as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^3A, R^3A -¹, R^{3A 2}, and R^3A3 have values corresponding to the values of R^ww, R^w% R^{ww 2}, _ancj RWW.3, _reSp_ectively, as explained in the definitions section above in the description of “first substituent group(s)’; wherein R^{A w}. R^ww \ R^WW-², and R^{WW 3} correspond to R^3A, R^{3A 1}, R^{3A 2}, and R^3A3, respectively.

[0228] In embodiments, when R^3B is substituted, R^3B is substituted with one or more first substituent groups denoted by R^{3B 1} as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^{3B 1} substituent group is substituted, the R^{3B 1} substituent group is substituted with one or more second substituent groups denoted by R^{3B 2} as explained in the definitions section above in the description of “first substituent group(s)’^:. In embodiments, when an R^{3B 2} substituent group is substituted, the R^{3B 2} substituent group is substituted with one or more third substituent groups denoted by R^{3B 3} as explained in the definitions section above in the description of “first substituent group(s)’’. In the above embodiments, R^3B, R^3B -¹, R^{3B 2}, and R^{3B 3} have values corresponding to the values of R^ww, R^ww \ R^ww-², _ancj RWW.3, _reSp_ectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^ww, R^TO\ R^ww-², and R^WW3 correspond to R^3B, R^3B -¹, R^{3B 2}, and R^{3B 3}. respectively.

[0229] In embodiments, when R⁴ is substituted, R⁴ is substituted with one or more first substituent groups denoted by R^{4 1} as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^{4 1} substituent group is substituted, the R^{4 1} substituent group is substituted with one or more second substituent groups denoted by R⁴² as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R⁴² substituent group is substituted, the R⁴² substituent group is substituted with one or more third substituent groups denoted by R⁴³ as explained in the definitions section above in the description of “first substituent group(s)'’. In the above embodiments, R⁴. R^{4 1}. R⁴², and R⁴³ have values corresponding to the values of R^ww. R^uw -¹, R^WW-², and R^WW3, respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein R^ww, R™*, R^WW2 and R^{WW 3} correspond to R⁴, R^{4 1}, R⁴², and R⁴³, respectively.

[0230] In embodiments, when R⁵ is substituted, R⁵ is substituted with one or more first substituent groups denoted by R^{5 1} as explained in the definitions section above in the description of “first substituent group(s)". In embodiments, when an R^{5 1} substituent group is substituted, the R^{5 1} substituent group is substituted with one or more second substituent groups denoted by R^{5 2} as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R⁵² substituent group is substituted, the R^{5 2} substituent group is substituted with one or more third substituent groups denoted by R⁵³ as explained in the definitions section above in the description of “first substituent group(s)’’. In the above embodiments, R⁵, R^{5 1}, R^{5 2}, and R⁵³ have values corresponding to the values of R^ww, R^{ww l}, R^ww'², and R^ww'³, respectively, as explained in the definitions section above in the description of “first substituent group(s)'’, wherein R^ww. R*^w \ R^W2 and R^{ww 3} correspond to R⁵. R^{5 J}, R⁵². and R^{5 3}, respectively.

[0231] In embodiments, when R^5A is substituted, R^5A is substituted with one or more first substituent groups denoted by R^{5A 1} as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^{5A 1} substituent group is substituted, the R^{5A 1} substituent group is substituted with one or more second substituent groups denoted by R^{5A 2} as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^{5A 2} substituent group is substituted, the R^{5A 2} substituent group is substituted with one or more third substituent groups denoted by R^{5A 3} as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^5A, R’^A \ R^{5A 2}. and R^{5A 3} have values corresponding to the values of R^ww, R^{WW 1} R^W2 and R^ww-³, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^ww, R^ww \ R^ww-², and R^{WW 3} correspond to R^5A, R^5A -¹, R^{5A 2}, and R^5A?, respectively.

[0232] In embodiments, when R^5B is substituted, R^5B is substituted with one or more first substituent groups denoted by R^{5B 1} as explained in the definitions section above in the description of “first substituent group(s)’’. In embodiments, when an R^{5B 1} substituent group is substituted, the R^{5B 1} substituent group is substituted with one or more second substituent groups denoted by R^{5B 2} as explained in the definitions section above in the description of “first substituent group(s)” In embodiments, when an R^{5B 2} substituent group is substituted, the R^{5B 2} substituent group is substituted with one or more third substituent groups denoted by R^{5B 3} as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^5B, R^5B \ R^{5B 2}, and R^{5B 3} have values corresponding to the values of R^ww, R^ww -¹, R^WW2, and R^WW3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”. wherein R^ww. R^w \ R^ww \ and R^{WW 3} correspond to R^5B, R^{5B 1}, R^{5B 2}, and R^{5B 3}, respectively.

[0233] In embodiments, when R^5A and R^5B substituents 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 R^{5A 1} as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^{5A 1} substituent group is substituted, the R^{5A 1} substituent group is substituted with one or more second substituent groups denoted by R^{5A 2} as explained in the definitions section above in the description of “first substituent group(s)". In embodiments, when an R^{5A 2} substituent group is substituted, the R^{5A 2} substituent group is substituted with one or more third substituent groups denoted by R^{5A 3} as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^5A ', R^{5A 2}, and R^{5A 3} have values corresponding to the values of RWW.I, _RWW2 _anj _Rww.s, respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein R^UAV -¹, R^^{W 2}, and R^WW3 correspond to R^{5A 1}, R^{5A 2}, and R^{5A 3}, respectively.

[0234] In embodiments, when R^3A and R^5B substituents 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 R^{5B 1} as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^{5B 1} substituent group is substituted, the R^{5B 1} substituent group is substituted with one or more second substituent groups denoted by R^{5B 2} as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^{5B 2} substituent group is substituted, the R^{5B 2} substituent group is substituted with one or more third substituent groups denoted by R^{3B 3} as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^{5B 1}, R^{5B 2}, and R^5B have values corresponding to the values of RWW.I, _RWW2 _anj _RWW.3, respectively, as explained in the definitions section above in the description of ‘’first substituent group(s)’’, wherein R'^A"'-¹, R^^{W 2}, and R^WW3 correspond to R^{5B 1}, R^{5B 2}, and R^5B respectively.

[0235] In embodiments, when R^5C is substituted, R^5C is substituted with one or more first substituent groups denoted by R^{5C 1} as explained in the definitions section above in the description of “first substituent group(s)". In embodiments, when an R^{5C 1} substituent group is substituted, the R^{5C 1} substituent group is substituted with one or more second substituent groups denoted by R^{5C 2} as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R^{5C 2} substituent group is substituted, the R^{5C 2} substituent group is substituted with one or more third substituent groups denoted by R^{5C 3} as explained in the definitions section above in the description of “first substituent group(s)’’. In the above embodiments, R^5C, R^{5C J}, R^{5C 2}, and R^{5C 3} have values corresponding to the values of R¹'^vw, R^WW -¹, R^ww-², and R^ww-³, respectively, as explained in the definitions section above in the description of “first substituent group(s)'’, wherein R^ww. R^{% w} \ R^W2 and R^{ww 3} correspond to R^5C, R^{5C 1}, R^{5C 2}, and R^{5C 3}. respectively.

[0236] In embodiments, when R^5D is substituted, R^5D is substituted with one or more first substituent groups denoted by R^{5D 1} as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, w hen an R^{5D 1} substituent group is substituted, the R^{5D 1} substituent group is substituted with one or more second substituent groups denoted by R^{5D 2} as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^{5D 2} substituent group is substituted, the R^{5D 2} substituent group is substituted with one or more third substituent groups denoted by R^{5D 3} as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^5D, R?¹’ -¹, R^{5D 2}. and R^{5D 3} have values corresponding to the values of R^ww, R^{WW 1} RWW.2 _ancj _Rwwa, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^ww, R^ww \ R^WW2, and R^{WW 3} correspond to R^5D, R^5D -¹, R^{5D 2}, and R^{5D 3}, respectively.

[0237] In embodiments, when R¹⁰ is substituted, R¹⁰ is substituted with one or more first substituent groups denoted by R^{10 1} as explained in the definitions section above in the description of “first substituent group(s)’’. In embodiments, when an R^{10 1} substituent group is substituted, the R^{10 1} substituent group is substituted with one or more second substituent groups denoted by R¹⁰² as explained in the definitions section above in the description of “first substituent group(s)” In embodiments, when an R^{10 2} substituent group is substituted, the R¹⁰² substituent group is substituted with one or more third substituent groups denoted by R¹⁰³ as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R¹⁰, R^{10 1}, R¹⁰², and R^{10 3} have values corresponding to the values of R^ww, R^ww -¹, R^WW2, and R^WW3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”. wherein R^ww. R^w \ R^ww \ and R^{WW 3} correspond to R¹⁰, R^{10 1}, R^{10 2}, and R¹⁰ -’, respectively.

[0238] In embodiments, when L¹ is substituted, L¹ is substituted with one or more first substituent groups denoted by R^{L1 1} as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^{L1 1} substituent group is substituted, the R^{L1 1} substituent group is substituted with one or more second substituent groups denoted by R^{L1 2} as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R^LL2 substituent group is substituted, the R^{L1 2} substituent group is substituted with one or more third substituent groups denoted by R^{L1 3} as explained in the definitions section above in the description of “first substituent group(s)’’. In the above embodiments, L¹, R^LL1, R^LL2, and R^L13 have values corresponding to the values of L^ww, R^LW1, RLWW.2, _anj RLWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein L^ww, R^{LWW 1} _? RLWW.2, and R^LWW-³ are L¹, R^L1 -¹, R^{L1 2}. and R^{L1 3}, respectively.

[0239] In embodiments, when L² is substituted. L² is substituted with one or more first substituent groups denoted by R^{L2 1} as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^{L2 1} substituent group is substituted, the R^{L2 1} substituent group is substituted with one or more second substituent groups denoted by R^L22 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^L22 substituent group is substituted, the R^L22 substituent group is substituted with one or more third substituent groups denoted by R^L23 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L². R^{L2 1}, R^L22, and R^L23 have values corresponding to the values of L^ww. R^{LWW 1}, RLWW.2, _ANC[ RLWW.3 _reSp_ectively. as explained in the definitions section above in the description of “first substituent group(s)’’, wherein L^ww, R^{LWW 1} RLWW.2 and R^{LWW ?} are L², R^{L2 1}. R^L22, and R^{L2 ?}, respectively.

[0240] In embodiments, the compound has the formula: embodiments, the compound has the formula: In embodiments, the

compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula: In embodiments, the

compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

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compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

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compound has the formula: In embodiments, the compound has the formula: . In embodiments, the compound has the formula:

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compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

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compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

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compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:

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compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:

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compound has the formula: . In embodiments, the compound has the formula: In embodiments, the compound has the formula:

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compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:

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compound has the formula: In embodiments, the compound has the formula. . In embodiments, the compound has the formula.

In embodiments, the compound has the formula: embodiments, the compound has the formula: In embodiments, the

compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:

H . In embodiments, the compound has the formula: H . In embodiments, the compound has the formula: In embodiments, the

compound has the formula: . In embodiments, the compound has the formula: In embodiments, the compound has the formula:

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compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:

HN

In embodiments, the compound has the formula: H . In embodiments, the compound has the formula: . In embodiments, the

compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:

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compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:

In embodiments, the compound has the formula: H . In embodiments, the compound has the formula: In embodiments, the

compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula:

embodiments, the compound has the formula: In embodiments, the

compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:

In embodiments, the compound has the formula: embodiments, the compound has the formula: In embodiments, the

compound has the formula: . In embodiments, the compound has the

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[0241] In embodiments, the compound has the formula: embodiments, the compound has the formula: In embodiments, the

compound has the formula: formula: In embodiments, the compound has the formula:

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compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

N

S

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compound has the formula: In embodiments, the compound has the

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compound has the formula: . In embodiments, the compound has the formula: In embodiments, the compound has the formula:

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compound has the formula: H . In embodiments, the compound has the formula: In embodiments, the compound has the formula:

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compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:

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compound has the formula: . In embodiments, the compound has the formula: . In embodiments, the compound has the formula:

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compound has the formula: . In embodiments, the compound has the formula: In embodiments, the compound has the formula:

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compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:

In embodiments, the compound has the formula: . In embodiments, the compound has the formula: In embodiments, the

compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:

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compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

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In embodiments, the compound has the formula: . In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula:

In embodiments, the compound has the formula: embodiments, the compound has the formula: In embodiments, the

compound has the formula: . In embodiments, the compound has the formula: In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

[0242] In embodiments, the compound is useful as a comparator compound. In embodiments, the comparator compound can be used to assess the activity⁷ of a test compound as set forth in an assay described herein (e.g., in the examples section, figures, or tables).

[0243] In embodiments, the compound is a compound as described herein, including in embodiments. In embodiments the compound is a compound described herein (e.g., in the examples section, figures, tables, or claims).

III. Pharmaceutical compositions

[0244] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0245] 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.

[0246] In embodiments, the compound is a compound of formula (I). (II), (III), (IV). (V), or (VI), including all embodiments thereof.

IV. Methods of use

[0247] In an aspect is provided a method of treating a cancer, neurodegenerative disorder, inflammatory disease, fibrosing disorder, demyelinating disorder, dermatologic disorder. rheumatic disease, autoimmune disease, metabolic disorder, or eye disease in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0248] In embodiments, the cancer is breast cancer, ovarian cancer, colon adenocarcinoma, lung adenocarcinoma, lung small cell carcinoma, pancreatic adenocarcinoma, pancreatic neuroendocrine tumors, glioblastoma, prostate cancer, hepatocellular carcinoma, myeloma, leukemia, or lymphoma. In embodiments, the cancer is a solid cancer or a hematologic cancer. In embodiments, the cancer is an ovarian cancer, a colon carcinoma, a bladder cancer, hepatocellular carcinoma, a breast cancer, a pancreatic adenocarcinoma, a prostate cancer, a gliobastoma, or a lung cancer. In embodiments, the cancer is a leukemia, lymphoma, or multiple myeloma. In embodiments, the cancer is multiple myeloma. In embodiments, the cancer is a cancer of the breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, lary nx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and bi 1 i ary passages, kidney carcinoma, pancreatic, myeloid disorders, lymphoma, hairy cells, buccal cavity, naso- pharyngeal, pharynx, lip, tongue, mouth, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin’s, leukemia, bronchus, thyroid, liver and intrahepatic bile duct, hepatocellular, gastric, glioma/glioblastoma, endometrial, melanoma, kidney and renal pelvis, urinary⁷ bladder, uterine corpus, uterine cervix, multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, chronic lymphoid leukemia (CLL), myeloid leukemia, oral cavity and pharynx. non-Hodgkin lymphoma, melanoma, and villous colon adenoma. In embodiments, the cancer is squamous cell cancer, small-cell lung cancer, non-small cell lung cancer (NSCLC), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, stomach cancer, gastrointestinal cancer, esophageal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary⁷ gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, or head and neck cancer. In embodiments, the cancer is a hematological malignancy selected from the group consisting of lymphomas, lymphocytic leukemia, myeloma, acute and chronic myelogenous leukemia, myelodysplastic syndrome and myeloproliferative disease.

[0249] In embodiments, the compound is administered to the subject intravenously. In embodiments, the compound is administered to the subject orally.

[0250] In embodiments, the inflammatory' disease is a gastrointestinal disease or chronic inflammatory' lung disease. In embodiments, the gastrointestinal disease is an inflammatory bowel disease, Crohn’s disease, or colitis. In embodiments, the chronic inflammatory lung disease is bronchial asthma, chronic obstructive pulmonary disease, bronchiectasis, or cystic fibrosis. In embodiments, the fibrosing disorder is pulmonary' fibrosis. In embodiments, the autoimmune disease is a peripheral neuropathy. In embodiments, the metabolic disorder is a diabetes mellitus.

[0251] In an aspect is provided a method of treating a disease associated with IRE1 a activity in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0252] In embodiments, the disease is a neurodegenerative disease (ND) (e.g., amyotrophic lateral sclerosrs (ALS), Parkinson’s disease. Alzhermer’s disease, prion disorders (e.g.. BSE), frontotemporal dementia), posterior eye indication (e.g., retinal degeneration (e.g., a subset of ND), retinitis pigmentosa (ADRP), Stargardt’s disease, wet AMD (choroidal neovascularization-CNV), dry AMD), Anterior eye indication (e.g., glaucoma, Fuch's dystrophy), Diabetes mellitus (e.g., type 1 (autoimmune), type 2 (e.g., obesity- induced/insulin-resistant), monogenic (e.g., MODY syndromes, for example pro-insulin mutations), recessive genetic disorders in which diabetes mellitus is a prominent component (e.g., Wolcott Rallisson syndrome (e.g., associated with Perk genetic deficiency), Wolfram syndrome (WFS 1 or WFS2 deficiency)), fibrosing disorder or fibrosis (e.g., idiopathic pulmonary fibrosis (IPF), familial pulmonary fibrosis (FPF), scleroderma (systemic sclerosis), renal fibrosis, hepatic fibrosis), demyelinating disorder (e.g., multiple sclerosis (MS), Guillan-Barre, adrenoleukodystrophy, adrenomyeloneuropathy, optic neuritis, transverse myelitis), peripheral neuropathy (e.g., primary such as Charcot-Marie Tooth (CMT) or secondary from diabetes mellitus), dermatologic disease (e.g., psoriasis), rheumatologic disease, or autoimmune disease (e.g., rheumatoid arthritis, Grave’s disease, Hashimoto’s Disease, Addison’s disease, Lupus, ankylosing spondylitis, sarcoidosis). In embodiments, the disease is Type 1 Diabetes Melllitus, Type 2 Diabetes Mellitus, Mature Onset diabetes of the Young (MODY), Mutant INS -gene-induced Diabetes of the young (MIDY), Immune Checkpoint-induced Diabetes Mellitus, Wolfram’s Syndrome, Wolcott- Rallison Syndrome, Idiopathic Pulmonary fibrosis (IPF), Familial Pulmonary Fibrosis (FPF), Asthma, Alzheimer’s disease, Amyotrophic lateral sclerosis, Charcot-Mari e-Tooth disease, Chronic traumatic encephalopathy, Cystic fibrosis, cytochrome c oxidase deficiency, degenerative Leigh syndrome, Ehlers-Danlos syndrome, Fibrodysplasia ossificans progressiva, Friedreich's ataxia, Frontotemporal dementia, cardiovascular diseases, coronary' artery disease, aortic stenosis, Huntington's disease, Infantile neuroaxonal dystrophy, Keratoconus. Keratoglobus, Leukodystrophies, Wet Macular degeneration. Dry Macular degeneration, Marfan’s syndrome, Some mitochondrial myopathies. Mitochondrial DNA depletion syndrome, Multiple sclerosis, Multiple system atrophy, Muscular dystrophies, Neuronal ceroid lipofuscinosis, Niemann-Pick diseases, Osteoarthritis, Osteoporosis, Parkinson's disease, Pulmonary arterial hypertension, prion disease, Creutzfeldt-Jakob disease, fatal familial insomnia, Progressive supranuclear palsy, Retinitis pigmentosa, Rheumatoid arthritis, Sandhoff Disease, Scleroderma, Spinal muscular atrophy, Subacute sclerosing panencephalitis, Tay-Sachs disease, Vascular dementia. In embodiments, the disease is a neurodegenerative disease (ND) (e.g., amyotrophic lateral sclerosis (ALS). Parkinson’s disease, Alzheimer’s disease, prion disorders (e.g.. BSE), frontotemporal dementia). In embodiments, the disease is a posterior eye indication (e.g., retinal degeneration (e.g., a subset of ND), retinitis pigmentosa (ADRP), Stargardt’s disease, wet AMD (choroidal neovascularization-CNV), dry AMD). In embodiments, the disease is an anterior eye indication (e.g., glaucoma, Fuch’s dystrophy). In embodiments, the disease is diabetes mellitus (e.g., ty pe 1 (autoimmune), type 2 (e.g., obesity-induced/insulin-resistant), monogenic (e.g. MODY syndromes, for example pro-insulin mutations), recessive genetic disorders in which diabetes mellitus is a prominent component (e.g., Wolcott Rallisson syndrome (e.g., associated with Perk genetic deficiency), Wolfram syndrome (WFS1 or WFS2 deficiency)). In embodiments, the disease is a fibrosing disorder or fibrosis (e.g., idiopathic pulmonary' fibrosis (IPF), familial pulmonary' fibrosis (FPF), scleroderma (systemic sclerosis), renal fibrosis, hepatic fibrosis). In embodiments, the disease is a demyelinating disorder (e.g.. multiple sclerosis (MS), Guillan-Barre, adrenoleukodystrophy, adrenomyeloneuropathy. optic neuritis, transverse myelitis). In embodiments, the disease is a peripheral neuropathy (e.g., primary such as Charcot-Marie Tooth (CMT) or secondary from diabetes mellitus). In embodiments, the disease is a dermatologic disease (e.g., psoriasis). In embodiments, the disease is a rheumatologic disease. In embodiments, the disease is an autoimmune disease (e.g., rheumatoid arthritis, Grave’s disease, Hashimoto’s Disease, Addison’s disease, Lupus, ankylosing spondylitis, sarcoidosis). In embodiments, the compound treats an autoimmune disease associated with checkpoint inhibitor treatment (e.g., cancer treatment). In embodiments, the compound treats a disease (e.g., diabetes mellitus) associated with checkpoint inhibitor treatment (e.g., cancer treatment).

[0253] In embodiments, the compound is a compound of formula (I), (II), (III), (IV), (V), or (VI), including all embodiments thereof.

[0254] In an aspect is provided a method of decreasing the level of IRE la protein activity in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the activity is kinase activity. In embodiments, the activity is RNase activity.

[0255] In embodiments, the level of IREla protein activity 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 level of IREla protein activity is decreased by about 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IREla protein activity is decreased by about 2-fold relative to a control (e.g.. absence of the compound). In embodiments, the level of IREla protein activity is decreased by about 5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IREla protein activity⁷ is decreased by about 10-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IREla protein activity is decreased by about 25-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IREla protein activity is decreased by about 50-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IREla protein activity⁷ is decreased by about 100-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IREla protein activity is decreased by about 250-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IREla protein activity is decreased by about 500-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IREla protein activity is decreased by about 1000-fold relative to a control (e.g., absence of the compound).

[0256] In embodiments, the level of IREla protein activity 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 level of IREla protein activity is decreased by at least 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IREla protein activity is decreased by at least 2-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IREla protein activity is decreased by at least 5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IREla protein activity is decreased by at least 10-fold relative to a control (e.g.. absence of the compound). In embodiments, the level of IREla protein activity is decreased by at least 25-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IREla protein activity is decreased by at least 50-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IREla protein activity is decreased by at least 100-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IREla protein activity is decreased by at least 250-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IREla protein activity is decreased by at least 500-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IREla protein activity is decreased by at least 1000-fold relative to a control (e.g., absence of the compound).

V. Embodiments

[0257] Embodiment Pl. A compound, or a pharmaceutically acceptable salt thereof, having the formula:

(I) or (II); wherein Ring A is substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene;

L¹ is a bend, -O-, -S-, -S(O)-, -S(O)₂-, -NR¹⁰-. -C(O)-, -C(O)NR¹⁰-. -NR¹⁰C(O)-, -C(O)O-. -OC(O)-. -NR¹⁰S(O)-, -S(O)NR¹⁰-, -NR¹⁰S(O)₂-, -S(O)₂NR¹⁰-, -NR¹⁰C(O)O-, -OC(O)NR¹⁰-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

L² is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R¹ is hydrogen, 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, -OCH₂C1, -OCH₂Br, -OCH₂F, -OCH₂I, -OCHCb, -OCHBr₂, -OCHF₂, -OCHI₂, -SF5, -N₃, unsubstituted alky 1, or unsubstituted heteroalkyl;

R² is -N(R^2A)(R^2B) or a substituted or unsubstituted nitrogen-containing heterocycloalkyl;

R^2A and R^2B are 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 heterocycloalkyd, substituted or unsubstituted ary 1. or substituted or unsubstituted heteroaryl;

R³, R^3A, and R^3B are independently hydrogen, halogen, -CC1₃, -CBr₃, -CF₃, -CI₃, -CH₂C1, -CH₂Br. -CH₂F. -CH₂I, -CHC1₂, -CHBr₂. -CHF₂. -CH1₂, -CN, -OH, -NH₂. -COOH, -CONH₂, -NO2, -SH, -SOsH, -OSOsH, -SO2NH2, -NHNH₂, -ONH₂, -NHC(O)NH₂, -NHSO₂H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCC1₃, -OCBr₃, -OCF₃, -OCI3, -OCH₂C1, -OCH₂Br, -OCH₂F, -OCH₂I. -OCHCh, -OCHBr₂. -OCHF₂. -OCHI₂, -SF₅, -N₃. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalky 1, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary 1, or substituted or unsubstituted heteroaryl; R⁴ is independently halogen, -CCh, -CBn. -CF3, -CI3, -CH2CI, -ClrbBr, -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, -OCCk, -OCBr₃, -OCF3, -OCI3, -OCH2CI, -OCH₂Br, -OCH₂F, -OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, -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 2; and

R¹⁰ is hydrogen, -CCI3, -CBr₃, -CF3, -Ch, -CHCI2, -CHBr₂, -CHF₂, -CHI₂, -CH2CI, -CH₂Br, -CH2F, -CH2I, -CN. -OH. -NH₂, -COOH. -CONH2, -OCCI3, -OCF3, -OCBr₃, -OCI3, -OCHCI2. -OCHBr₂, -OCHI2, -OCHF2, -OCH2CI, -OCH₂Br, -OCH₂L -OCH₂F. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyd, substituted or unsubstituted heterocycloalky l, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0258] Embodiment P2. The compound of embodiment Pl, having the formula:

R³ is independently halogen, -CX⁵3, -CHX²^, -CH2X⁵, -OCX⁵3, -OCH2X⁵, -OCHX⁵2, -CN, -SO_n5R^5D, -SO_v5NR^5AR^5B, NR^5CNR^5AR^5B, ONR^5AR^5B, -NR^5CC(O)NR^5AR^5B, -N(0)m5, -NR^3AR^3B, -C(O)R^5C, -C(O)OR^5C, -OC(O)R^5C, -OC(O)OR^5C, -C(O)NR^5AR^5B, -OC(O)NR^5AR^5B, -OR^3D, -SR^5D. -NR^3ASO₂R^3D. -NR^5AC(O)R^5C, -NR^3AC(O)OR^5C, -NR^5AOR^5C, -SFs, -N₃, substituted or unsubstituted alky 1, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

RSA RSB R5C _ANC| RSD _are i_nd_ep_en(j_entiy hydrogen. -CCI3, -CBr?, -CF3, -CI3. -CHCI2, -CHBr₂, -CHF2, -CHh, -CH2CI, -CH₂Br, -CH₂F, -CH₂I, -CN, -OH, -NH₂, -COOH, -CONH2, -OCCI3, -OCF3, -OCBr₃, -OCI3, -OCHCI2, -OCHBr₂, -OCHI₂, -OCHF₂, -OCH₂C1, -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; R^3A and R^5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X⁵ is independently -F. -Cl, -Br, or -I; n5 is an integer from 0 to 4; m5 and v5 are independently 1 or 2; and z5 is an integer from 0 to 6. [0259] Embodiment P3. The compound of embodiment P2, having the formula:

HN_{X L}2

R² (V).

[0260] Embodiment P4. The compound of embodiment P2, having the formula:

R² (VI).

[0261] Embodiment P5. The compound of one of embodiments Pl to P4. wherein when L¹ is a substituted alkylene or substituted heteroalkylene, then the substituted alkylene or substituted heteroalkylene is substituted with a substituent group; wherein the substituent group is selected from the following moi eties:

(A) oxo, halogen, -CCh, -CBr?, -CF3, -CI3, -CHCI2, -CHBr₂, -CHF₂, -CHI₂, -CH₂C1, -CH₂Br, -CH₂F, -CH₂I. -OCCh, -OCF3, -OCBr₃, -OCI3. -OCHCh, -OCHBr₂. -OCHI₂, -OCHF₂, -OCH₂C1, -OCH₂Br, -OCH₂I, -OCH₂F, -CN, -OH, -NH₂, -COOH, -C0NH₂, -N0₂, -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, or unsubstituted heteroalkyl, and

(B) alkyl or heteroalkyl, substituted with at least one substituent selected from:

(1) oxo, halogen, -CCI3, -CBr₃, -CF3, -CI3, -CHC1₂, -CHBr₂, -CHF₂, -CHI₂, -CH₂CL -CH₂Br, -CH₂F, -CH₂I, -OCCh, -OCF3, -OCBr₃, -OCI3, -OCHC1₂, -OCHBr₂, -OCHI₂, -OCHF₂, -OCH₂C1, -OCH₂Br, -OCH₂I, -OCH₂F, -CN, -OH, -NH₂.

-COOH, -CONH₂, -N0₂. -SH, -SO3H. -OSO3H. -SO₂NH₂, -NHNH₂. -0NH₂, -NHC(0)NHNH₂, -NHC(0)NH₂, -NHC(NH)NH₂, -NHSO₂H, -NHC(0)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl, or unsubstituted heteroalkyl, and

(ii) alkyl or heteroalkyl, substituted with at least one substituent selected from:

(a) oxo. halogen. -CCh, -CBr₃. -CF3, -Ch. -CHCh, -CHBr₂. -CHF₂. -CH1₂. -CH₂C1, -CH₂Br, -CH₂F, -CH₂I, -OCCh, -OCF₃, -OCBr,. -OCh, -OCHCh, -OCHBn, -OCHI2, -OCHF2, -OCH2CI, -OCH₂Br, -OCH₂I, -OCH2F, -CN, -OH, -NH₂. -COOH, -CONH2. -NO2, -SH. -SO3H, -OSO3H, -SO2NH2. -NHNH₂, -ONH2, -NHC(O)NHNH₂, -NHC(O)NH₂, -NHC(NH)NH₂, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF₅, unsubstituted alkyl, or unsubstituted heteroalkyl, and

(b) alkyl or heteroalkyl, substituted with at least one substituent selected from: oxo, halogen, -CCI3, -CBr₃, -CFs, -CI₃, -CHCh, -CHBr₂, -CHF₂, -CHI₂, -CH₂C1, -CH₂Br, -CH₂F, -CH2I, -OCCI3, -OCF3, -OCBrs, -OCI3, -OCHCI2, -OCHBr₂, -OCHI2, -OCHF2, -OCH2CI, -OCH₂Br, -OCH2I, -OCH2F, -CN, -OH, -NH₂, -COOH, -CONH2, -NO2. -SH, -SO3H, -OSO3H. -SO2NH2, -NHNH2. -ONH2, -NHC(O)NHNH₂, -NHC(O)NH₂, -NHC(NH)NH₂, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alky l, or unsubstituted heteroalkyl.

[0262] Embodiment P6. The compound of one of embodiments Pl to P5, wherein L¹ is -NR¹⁰S(O)2- or substituted or unsubstituted 2 to 8 membered heteroalkylene.

[0263] Embodiment P7. The compound of one of embodiments Pl to P5, wherein L¹ is -NR¹⁰S(O)2- or -NR¹⁰S(O)2-(unsubstituted Ci-Ce alkylene)-.

[0264] Embodiment P8. The compound of one of embodiments Pl to P7, wherein when R¹⁰ is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl, then the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with a substituent group; wherein the substituent group is selected from the following moieties:

(A) oxo, halogen, -CCI3, -CBr_?, -CF₃, -CI₃, -CHCh, -CHBr₂, -CHF₂, -CHI₂, -CH₂C1, -CH₂Br, -CH₂F, -CH2I, -OCCI3, -OCF3, -OCBr₃, -OCI3, -OCHCh, -OCHBr₂, -OCHI₂, -OCHF2, -OCH2CL -OCH₂Br, -OCH2I, -OCH2F, -CN, -OH, -NH₂, -COOH, -CONH₂, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH₂, -ONH2, -NHC(O)NHNH₂, -NHC(O)NH₂. -NHC(NH)NH₂. -NHSO2H. -NHC(O)H, -NHC(O)OH. -NHOH, -N3, -SF5, unsubstituted alkyl, or unsubstituted heteroalkyl, and

(B) alkyl or heteroalkyl, substituted with at least one substituent selected from: (i) oxo, halogen, -CCh, -CBr₃, -CF₃, -CI₃, -CHCh, -CHBr₂, -CHF₂, -CHI₂, -CH₂C1, -CH₂Br, -CH₂F, -CH₂I. -OCC1₃, -OCF₃, -OCBr₃, -OCI₃. -OCHCh, -OCHBr₂. -OCHI₂, -OCHF₂, -OCH2CI, -OCH₂Br, -OCH₂I, -OCH₂F, -CN, -OH, -NH₂, -COOH, -CONH2, -N0₂, -SH, -SO₃H, -OSO₃H, -SO₂NH₂, -NHNH₂, -ONH₂, -NHC(0)NHNH₂, -NHC(0)NH₂, -NHC(NH)NH₂. -NHSO₂H, -NHC(0)H, -NHC(0)0H, -NHOH, -N₃, -SFs, unsubstituted alkyl, or unsubstituted heteroalkyl, and

(ii) alkyl or heteroalkyl, 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, -OCHCh, -OCHBr₂, -OCHh. -OCHF2. -OCH₂C1, -OCH₂Br. -0CH₂I, -OCH₂F, -CN, -OH, -NH₂, -COOH, -C0NH₂, -N0₂, -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, or unsubstituted heteroalkyl, and

(b) alkyd or heteroalkyl, substituted with at least one substituent selected from: oxo, halogen, -CCh, -CBr₃, -CF₃, -CI₃, -CHCh, -CHBr₂, -CHF₂, -CHI₂, -CH₂C1, -CH₂Br, -CH₂F, -CH2I. -OCCh, -OCF₃, -OCBr₃, -OCI₃, -OCHCh, -OCHBr₂, -OCHh, -OCHF₂, -OCH2CI, -OCH₂Br, -OCH₂I. -OCH₂F. -CN, -OH, -NH₂, -COOH, -CONH2, -NO2, -SH, -SO₃H, -OSO₃H, -SO₂NH₂, -NHNH₂, -0NH₂, -NHC(0)NHNH₂, -NHC(0)NH₂, -NHC(NH)NH₂, -NHS0₂H, -NHC(0)H, -NHC(0)0H, -NHOH. -N₃, -SF5, unsubstituted alkyl, or unsubstituted heteroalkyl.

[0265] Embodiment P9. The compound of one of embodiments Pl to P8, wherein R¹⁰ is hydrogen, -CCh, -CBr₃, -CF₃, -CI₃, -CHCh, -CHBr₂, -CHF₂, -CHI₂, -CH₂C1, -CH₂Br, -CH₂F, -CH₂I, -CN, -OH, -NH₂, -COOH, -CONH₂, -OCCh, -OCF₃, -OCBr₃, -OCI₃, -OCHCh. -OCHBr₂, -OCHh. -OCHF₂. -OCH₂C1, -OCH₂Br. -OCH₂I, -OCH₂F, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0266] Embodiment PIO. The compound of one of embodiments Pl to P8, wherein R¹⁰ is hydrogen or unsubstituted C1-C4 alkyd. [0267] Embodiment P 11. The compound of one of embodiments Pl to P4, wherein L¹

H H N is -NHS(0)₂-, O O O O 0 0 , or 0 0

[0268] Embodiment P12. The compound of one of embodiments Pl to Pl 1, wherein R¹ is -CF? or unsubstituted Ci-Ce alkyl.

[0269] Embodiment Pl 3. The compound of one of embodiments Pl to Pl 1, wherein R¹ is -CFs, unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, or unsubstituted tert-butyl.

[0270] Embodiment P 14. The compound of one of embodiments Pl to P4, wherein -L'-R¹ is

[0271] Embodiment P15. The compound of one of embodiments Pl to P14, wherein L² is a bond.

[0272] Embodiment Pl 6. The compound of one of embodiments Pl to Pl 5, wherein R² is a substituted or unsubstituted nitrogen-containing heterocycloalkyl.

[0273] Embodiment Pl 7. The compound of one of embodiments Pl to Pl 5, wherein R² is a substituted or unsubstituted piperidinyl.

[0274] Embodiment Pl 8. The compound of one of embodiments Pl to Pl 5, wherein R² is an unsubstituted piperidinyl.

[0275] Embodiment Pl 9. The compound of one of embodiments Pl to Pl 5, wherein R² is a piperidinyl substituted with a halogen.

[0276] Embodiment P20. The compound of one of embodiments Pl to Pl 5, wherein R² is a piperidinyl substituted with -F.

[0277] Embodiment P21. The compound of one of embodiments Pl to P15, wherein R² is H or H

[0278] Embodiment P22. The compound of one of embodiments Pl to P21, wherein R³ is hydrogen or unsubstituted C1-C4 alkyl.

[0279] Embodiment P23. The compound of one of embodiments Pl to P21, wherein R³ is hydrogen or unsubstituted methyl.

[0280] Embodiment P24. The compound of one of embodiments Pl to P23, wherein z4 is 0.

[0281] Embodiment P25. The compound of one of embodiments P2 to P24, wherein R⁵ is independently halogen or unsubstituted C1-C4 alkyl.

[0282] Embodiment P26. The compound of one of embodiments P2 to P24, wherein R⁵ is independently -F or unsubstituted methyl.

[0283] Embodiment P27. The compound of one of embodiments P2 to P26, wherein z5 is

1 or 2.

[0284] Embodiment P28. The compound of one of embodiments Pl to P24, wherein

[0285] Embodiment P29. A pharmaceutical composition comprising a compound of one of embodiments Pl to P28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0286] Embodiment P30. A method of treating a cancer, neurodegenerative disorder, inflammatory' disease, fibrosing disorder, demyelinating disorder, dermatologic disorder, rheumatic disease, autoimmune disease, metabolic disorder, or eye disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of embodiments Pl to P28. or a pharmaceutically acceptable salt thereof. [0287] Embodiment P31. The method of embodiment P30, wherein the cancer is breast cancer, ovarian cancer, colon adenocarcinoma, lung adenocarcinoma, lung small cell carcinoma, pancreatic adenocarcinoma, pancreatic neuroendocrine tumors, glioblastoma, prostate cancer, hepatocellular carcinoma, myeloma, leukemia, or lymphoma.

[0288] Embodiment P32. The method of embodiment P30, wherein the inflammatory disease is a gastrointestinal disease or chronic inflammatory lung disease.

[0289] Embodiment P33. The method of embodiment P32, wherein the gastrointestinal disease is an inflammatory bowel disease. Crohn’s disease, or colitis.

[0290] Embodiment P34. The method of embodiment P32, wherein the chronic inflammatory lung disease is bronchial asthma, chronic obstructive pulmonary disease, bronchiectasis, or cystic fibrosis.

[0291] Embodiment P35. The method of embodiment P30, wherein the fibrosing disorder is pulmonary fibrosis.

[0292] Embodiment P36. The method of embodiment P30, wherein the autoimmune disease is a peripheral neuropathy.

[0293] Embodiment P37. The method of embodiment P30, wherein the metabolic disorder is a diabetes mellitus.

[0294] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety⁷ for all purposes.

EXAMPLES

Example 1:

[0295] Described herein are new IRE1 a kinase inhibitors that at full occupancy of the kinase domain cause partial antagonism of the RNase.

[0296] Atomic level resolution co-crystal structures show that these small molecule kinase inhibitors — which we named ‘PAIR’S for (Partial Antagonists of TRElcc PNase) — bind ATP-competi lively in the kinase to partially displace the IREla kinase helix aC, leading to stabilization of dimeric IREla species. In insulin-producing beta cells, PAIRs permit adaptive XBP1 mRNA splicing, while quelling destructive/terminal outputs from extra-XBPl mRNA endonucleolytic decay, thus preventing apoptosis. Preservation of XBP1 splicing by PAIRs permits B-cells to differentiate into immunoglobulin-producing plasma cells.

[0297] In summary, an intermediate RNAse-inhibitory “sweet spof ’, achieved by PAIR- bound IREla, may capture a structural conformation naturally available to IREla that could represent a desirable therapeutic state for drugging this master UPR sensor/effector.

[0298] We have show n that it is possible to design ATP-competitive inhibitors, which we call Partial Antagonists of ZREla PNase (PAIRs). that /i/Py engage IREla s kinase domain but only partially inhibit its RNase activity. By systematically defining the structural features of PAIRs that lead to stabilization of the kinase domain of IREla in this “intermediate” activation mode, we highlight new understanding of both the structure-activity relationships of PAIRs while comparing these to previous activators and full inhibitors of IREla.

Example 2: Experimental procedures

[0299] General synthetic scheme for compounds 13 or 14 o<?

R₁''^S'CI Pyridine, 25 °C, 18h

1

PCC, DCM DMF, DMA

CH₃Mgl, THF 25 ° 80 °C, 8h -40 °C, 30 min C, 6h

4 5

K₂CO₃, EtOH 80 °C, 18h

10

DCM, TFA 25 °C, 2h

[0300] Compound 2: To a solution of compound 1 (0.78 mmol, 1.0 eq) in py ridine (2 mL) at 25 °C is added Vitamin K5 (0.78 mmol, 1.0 eq). The reaction mixture is stirred for 18 h and then concentrated to provide crude material. The crude material is treated with water (10 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers are washed with brine solution (2 x 20 mL), dried over anhydrous Na2SC>4, filtered and the solvent is removed in vacuo. The residue is purified by silica gel column chromatography to give compound 2. [0301] Compound 4: To a solution of compound 3 (1 g. 6.76mmol, l.Oeq.) in THF (30 mL) at -40 °C was added methyl magnesium iodide (3.0 M in THF, 3.4 mL. 10.14 mmol, 1.5 eq.). After stirring for 30 min, a saturated NH4CI solution (2 mL) was added and the reaction mixture was extracted with EtOAc (3x20 ml). The combined organic layers were dried over sodium sulfate, concentrated and purified by column chromatography (60-120 silica gel; gradient elution with 10% EtOAC in Hexane) to afford 4 (970 mg, 98%) as a pale yellow solid. MS (ESI pos. ion) m/z: 164.2; 'H-NMR (300MHz, CDCh): 5 8.64 (s, 1H). 5.32-5.24 (m, 1H), 1.57 (d, J=2.7Hz, 3H).

[0302] Compound 5: To a solution of compound 4 (970 mg, 5.95 mmol, 1.0 eq.) in DCM (30 mL) at 25 °C was added pyridinium chlorochromate (3.85 g, 17.85 mmol, 3.0 eq.) portion-wise over a period of 5 min. The reaction mixture was stirred for 6h at same temperature, filtered through a celite pad and washed with DCM (15 mL). The filtrate was concentrated and the residue was purified by column chromatography (60-120 silica gel; gradient elution with 20% EtOAC in Hexane) to afford 5 (800 mg, 83%) as a white solid. MS (ESI pos. ion) m/z\ 162.1; 'H-NMR (300MHZ, CDCh): 5 8.84 (s, 1H), 2.72 (s, 3H).

[0303] Compound 6: A solution of compound 5 (800 mg. 4.90 mmol, 1.0 eq.) in DMF:DMA (8 mL, 95%) was stirred at 80 °C for 8 h. After reaction completion, the mixture was poured into ice water and extracted with EtOAc (3x20 mL). The combined organic layers were dried and concentrated to obtain 6 (880 mg, 82%) as a brown solid. MS (ESI pos. ion) m/z\ 217.2; ’H-NMR (300MHz. CDCh): 5 8.71 (s, 1H), 7.85 (d, J-7.2Hz. 1H), 6.03 (d, J=7.2Hz. 1H), 3.20 (s, 3H), 2.97 (s, 3H).

[0304] Compounds 9 or 10: To a solution of compound 6 (4.62 mmol, 2.0 eq.) in EtOH (10 mL) at 25 °C is added K2CO3 (1.91 g, 13.9 mmol, 6.0 eq.) followed by compound 8 or 9 (2.31 mmol, 1.0 eq ). The mixture is stirred at 80 °C for 18 h, filtered, concentrated and purified by column chromatography (60-120 silica gel, gradient elution with 20% EtOAc in Hexane) to afford compounds 9 or 10.

[0305] Compounds 11 or 12: To the solution of 2 (0.18 mmol, 1.0 eq.) in DMF (2 mL) is added CS2CO3 (124 mg, 0.37 mmol, 2.0 eq.) followed by 8 or 9 (0.18 mmol, 1.0 eq.). The reaction mixture is microwaved at 130 °C for 4 h, poured into ice w ater (10 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers are washed with brine solution (2 x 20 mL), dried over anhydrous Na2SO4, filtered and the solvent is removed in vacuo. The residue is purified by silica gel column chromatography to give compounds 11 or 12. [0306] Compounds 13 or 14: To a solution of compounds 11 or 12 (0.04 mmol) in DCM (5 mL) is added TFA (0.1 mL). The reaction mixture is stirred for 2 h, concentrated and the residue is purified by prep-HPLC to afford compounds 13 or 14 (10 mg, 40%) as a TFA salt. [0307] General synthetic scheme for compounds 21 or 22 [0308] Compounds 15 or 16: To the solution of compound 2 (0.18 mmol, 1.0 eq.) in DMF (2 mL) is added Cs2CO3 (124 mg, 0.37 mmol, 2.0 eq.) followed by 9 or 10 (0.18 mmol, 1.0 eq.). The reaction mixture is microwaved at 130°C for 4 h, poured into ice water (10 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers are washed with brine solution (2 x 20 mL), dried over anhydrous Na₂SO₄, filtered and the solvent is removed in vacuo. The residue is purified by silica gel column chromatography to give compounds 15 or 16. [0309] Compounds 17 or 18: A stirred solution of compounds 15 or 16 (0.0019 mol) and triethylamine (0.70 mL, 0.0049 mol) in ethanol (20 mL) is cooled to 15 ^oC and Selectfluor (1.7 g, 0.0049 mol) is added portion-wise for a period of 15 min and stirred at the same temperature for 24 h. After completion of the reaction by TLC, the reaction mixture is poured into ice water and the solids are filtered and dried. The crude residue is purified by Combi- flash purifier (reverse phase) using 0.1% HCOOH in water/CH₃CN (40:60) as an eluent to give compounds 17 or 18. [0310] Compounds 19 or 20: To a solution of compounds 17 or 18 (0.78 mmol, 1.0 eq) in pyridine (2 mL) at 25 °C is added compound 1 (0.78 mmol, 1.0 eq). The reaction mixture is stirred for 18 h and then concentrated to provide crude material. The crude material is treated with water (10 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers are washed with brine solution (2 x 20 mL), dried over anhydrous Na2SO4, filtered and the solvent is removed in vacuo. The residue is purified by silica gel column chromatography to give compounds 19 or 20. [0311] Compounds 21 or 22: To a solution of compounds 19 or 20 (0.04 mmol) in DCM (5 mL) is added TFA (0.1 mL). The reaction mixture is stirred for 2 h, concentrated and the residue is purified by prep-HPLC to afford compounds 21 or 22 (10 mg, 40%) as a TFA salt.

[0312] General synthetic scheme for compounds 35 or 36

[0313] General synthetic scheme for compounds 39 or 40

DCM, TFA, 25 °C, 2 h

[0314] Compound 25: To a solution of compound 23 (1.02 g, 5.34 mmol, 1.0 eq.) in DMF (17 mL) was added DBU (0.8 mL. 5.34 mmol, 1.0 eq.) and 24 (1 g. 5.34 mmol, 1.0 eq.). The reaction mixture was heated at 70 °C for 20 h. then cooled to room temperature and quenched and with ice water. The aqueous layer was extracted with ethyl acetate (3 x 30 mL) and the combined organic layers were washed with a brine solution (2 x 30 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to give a residue that was purified by silica gel column chromatography (60-120 basic silica gel) using hexane/ethyl acetate as eluent (93:7) to afford compound 25 (1 ,27g, 33%) as a white solid. MS (ESI pos. ion) m/z: 359.2.

[0315] Compound 26: To the solution of compound 25 (1.25 g, 3.49 mmol, 1.0 eq.) in 1,4- dioxane (12 mL) was added sodium hydroxide (349 mg, 8.72 mmol, 2.5 eq.) and water (3.12 mL). The reaction mixture was stirred for 6 h. concentrated, dissolved in water (50 mL) and acidified with 2N HC1 (10 mL). The mixture was extracted with ethyl acetate (3 x 150 mL) and the combined organic layers were washed with a brine solution (2 x 50 mL), dried over anhydrous Na2S€>4 and filtered. The solvent was removed in vacuo to afford compound 26 (750 mg, 65%) as a yellow solid. MS (ESI pos. ion) m/z: 331.2.

[0316] Compound 27: To the solution of compound 26 (650 mg, 1.96 mmol. 1.0 eq.) in DCM (5 mL) was added A'-methyl morpholine (0.65 mL, IV), V,(?-dimethyl hydroxyl amine hydrochloride (192 mg, 1.96 mmol, 1.0 eq.) and HOBt (266 mg, 1.96 mmol, 1.0 eq.). The reaction mixture was cooled to 0 °C and EDC:HC1 (453 mg, 2.36 mmol, 1.2 eq.) was added. The reaction mixture was then stirred for 18 h, quenched and with IN 14C1 (30 mL) and neutralized with a sat. NaHCCh solution (30 mL). The mixture was extracted with EtOAc (3 x 30 mL) and the combined organic layers were washed with a brine solution (2 x 30 mL), dried over anhydrous Na2SO4, filtered and the solvent was removed in vacuo to afford compound 27 (644 mg, 47%) as a yellow oil.

[0317] Compound 28: To the solution of compound 27 (640 mg, 1.71 mmol. 1.0 eq) in AcOH (6.4 mL) was added Fe powder (325 mg, 5.83 mmol, 3.4 eq.). The reaction mixture was stirred for 18 h, then quenched with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with a brine solution (2 x 20 mL), dried over anhydrous Na2SO4, filtered and the solvent was removed in vacuo to afford compound 28 (550 mg, 93%) as a brown solid. MS (ESI pos. ion) m/z: 344.2.

[0318] Compound 29: To a solution of compound 28 (1.60 mmol, 1.0 eq) in pyridine (5 mL) is added compounds 1 (1.60 mmol, 1.0 eq). The reaction mixture is stirred for 4 h, concentrated and dissolved in water (20 mL). The mixture is extracted with ethyl acetate (3 x 30 mL) and the combined organic layers are washed with a brine solution (2 x 30 mL). dried over anhydrous Na2SO4. filtered and the solvent was removed in vacuo. The residue is purified by silica gel column chromatography (60-120 silica gel) using hexane/ethyl acetate as eluent to afford compound 29.

[0319] Compound 30: To a solution of compound 29 (1.25 mmol, l.Oeq.) in THF (10 mL) at 0 °C is added methyl magnesium iodide (3.0 M in ether, 0.83 mL, 2.50 mmol, 2.0 eq.) dropwise. The reaction mixture is stirred at 25 °C for 30 min and then quenched with a sat. NH4CI solution (15 mL). The organic layer is separated, and the aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers are then washed with a brine solution (2 x 20 mL), dried over anhydrous Na2SO4, filtered and the solvent is removed in vacuo. The residue is purified by silica gel column chromatography (60-120 silica gel) using hexane/ethyl acetate as eluent to afford compound 30. [0320] Compound 31 : To a solution of compound 30 (0.31 mmol, 1.0 eq) in THF (10 mL) is added EtsN (0.05 mL, 0.38 mmol. 1.2 eq.), (Boc)2O (0.07 mL, 0.31 mmol, 1.0 eq.) and DMAP (8 mg, 0.06 mmol, 0.2 eq.). The reaction mixture is stirred for 4 h and concentrated to a residue. The residue is purified by silica gel column chromatography (60-120 silica gel) using hexane/ ethyl acetate as eluent to afford compound 31.

[0321] Compound 32: Compound 31 (0.27 mmol. 1.0 eq) is dissolved in DMF-DMA (1 mL). The reaction mixture is stirred at 60 °C for 8 h, then poured into ice water to give a solid. The solid is filtered, washed with water (10 mL) and dried to give compound 32.

[0322] Compounds 33 or 34: To a solution of compound 32 (0.38 mmol, 2.0 eq.) in EtOH (10 mL) is added K2CO3 (158 mg, 1.14 mmol, 6.0 eq.) and 7 or 8 (0.19 mmol, 1.0 eq.). The reaction mixture is stirred at 80 °C for 48 h, then cooled to room temperature and filtered. The solvent is concentrated, and the residue is purified by silica gel column chromatography (60-120 silica gel) using hexane/acetone as eluent to afford compounds 33 or 34.

[0323] Compounds 35 or 36: To a solution of compounds 33 or 34 (0.09 mmol) in DCM (5 mL) was added TFA (0.3 mL). The reaction mixture is stirred for 2 h, concentrated and then purified by prep-HPLC to afford compounds 35 or 36.

[0324] Compounds 37 or 38: A stirred solution of compounds 33 or 34 (0.0019 mol) and tri ethylamine (0.70 mL, 0.0049 mol) in ethanol (20 mL) is cooled to 15 °C and Selectfluor (1.7 g, 0.0049 mol) is added portion-wise for a period of 15 mins and stirred at the same temperature for 24 h. After completion of the reaction by TLC, the reaction mixture is poured into ice water and the solids are filtered and dried. The crude residue is purified by Combi- flash purifier (reverse phase) using 0. 1% HCOOH in water/CHsCN (40:60) as an eluent to give compounds 37 or 38.

[0325] Compounds 39 or 40: To a solution of compounds 37 or 38 (0.09 mmol) in DCM (5 mL) is added TFA (0.3 mL). The reaction mixture is stirred for 2 h, concentrated and then purified by prep-HPLC to afford compounds 39 or 40. [0326] General synthetic scheme for compounds 47 or 48

[0327] General synthetic scheme for compounds 51 or 52 [0328] Compound 42: To a solution of compound 2 (0.57 mmol, 1.0 eq.) in DMF (3 mL) is added Cs2CO3 (372 mg, 01.14 mmol, 2.0 eq.) and 39 (0.57 mmol, 1.0 eq.). The reaction mixture is heated at 80 °C for 8 h, then cooled and quenched and with ice water (15 mL). The mixture is extracted with EtOAc (3 x 15 mL), and the combined organic layers are washed with a brine solution (2 x 20 mL), dried over anhydrous Na₂SO₄, filtered and the solvent is removed in vacuo. The residue was purified by silica gel column chromatography (60-120 silica gel) using hexane/ethyl acetate as eluent to give compound 42. [0329] Compound 43: To the solution of compound 42 (0.39 mmol, 1.0 eq) in THF (15 mL) is added Et3N (0.06 mL, 0.46 mmol, 1.2 eq.), (Boc)2O (0.09 mL, 0.39 mmol, 1.0 eq.) and DMAP (2.4 mg, 0.019 mmol, 0.2 eq.). The reaction mixture is stirred for 4 h and concentrated to residue. The residue is purified by silica gel column chromatography (60-120 silica gel) using hexane/ethyl acetate as eluent to give compound 43. [0330] Compound 44: Compound 43 (0.29 mmol, 1.0 eq) are dissolved in DMF-DMA (3 mL). The reaction mixture is stirred at 80 °C for 8 h, quenched with ice water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers are washed with a brine solution (2 x 10 mL), dried over anhydrous Na₂SO₄, filtered and the solvent is removed in vacuo to give compound 44. [0331] Compounds 45 or 46: To a solution of compound 44 (0.25 mmol, 2.0 eq.) in EtOH (5 mL) is added K₂CO₃ (104 mg, 0.75 mmol, 6.0 eq.) and compounds 7 or 8 (0.12 mmol, 1.0 eq.). The reaction mixture is stirred at 80 °C for 8 h, cooled to room temperature and filtered. The solvent is concentrated to residue and purified by silica gel column chromatography (60- 120 silica gel) using DCM/MeOH as eluent to afford compounds 45 or 46. [0332] Compounds 47 or 48: To a solution of compounds 45 and 46 (0.05 mmol) in DCM (5 mL) is added TFA (0.2 mL). The reaction mixture was stirred for 2 h, concentrated and purified by prep-HPLC to afford compounds 47 or 48. [0333] Compounds 49 or 50: A stirred solution of compounds 45 or 46 (0.0019 mol) and triethylamine (0.70 mL, 0.0049 mol) in ethanol (20 mL) is cooled to 15 ^oC and Selectfluor (1.7 g, 0.0049 mol) is added portion-wise for a period of 15 min and stirred at the same temperature for 24 h. After completion of the reaction by TLC, the reaction mixture is poured into ice water and the solids are filtered and dried. The crude residue is purified by Combi- flash purifier (reverse phase) using 0.1% HCOOH in water/CH₃CN (40:60) as an eluent to give compounds 49 or 50. [0334] Compounds 51 or 52: To a solution of compounds 49 or 50 (0.09 mmol) in DCM (5 mL) is added TFA (0.3 mL). The reaction mixture is stirred for 2 h, concentrated and then purified by prep-HPLC to afford compounds 51 or 52.

Claims

WHAT IS CLAIMED IS: 1 1. A compound, or a pharmaceutically acceptable salt thereof, having the 2 formula: 3 (I) or (II); 4 wherein 5 Ring A is substituted or unsubstituted arylene or substituted or unsubstituted 6 heteroarylene; 7 L¹ is a bond, -O-, -S-, -S(O)-, -S(O)2-, -NR¹⁰-, -C(O)-, -C(O)NR¹⁰-, 8 -NR¹⁰C(O)-, -C(O)O-, -OC(O)-, -NR¹⁰S(O)-, -S(O)NR¹⁰-, -NR¹⁰S(O)₂-, -S(O)₂NR¹⁰-, 9 -NR¹⁰C(O)O-, -OC(O)NR¹⁰-, substituted or unsubstituted alkylene, or substituted or 10 unsubstituted heteroalkylene; 11 L² is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted 12 heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted 13 heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted 14 heteroarylene; 15 R¹ is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, 16 -CH₂I, -CHCl₂, -CHBr₂, -CHF₂, -CHI₂, -CN, -OH, -NH₂, -COOH, -CONH₂, -NO₂, -SH, 17 -SO₃H, -OSO₃H, -SO₂NH₂, ^NHNH₂, ^ONH₂, ^NHC(O)NH₂, -NHSO₂H, -NHC(O)H, 18 -NHC(O)OH, -NHOH, -OCCl₃, -OCBr₃, -OCF₃, -OCI₃, -OCH₂Cl, -OCH₂Br, -OCH₂F, 19 -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, unsubstituted alkyl, or 20 unsubstituted heteroalkyl; 21 R² is –N(R^2A)(R^2B) or a substituted or unsubstituted nitrogen-containing 22 heterocycloalkyl; 23 R^2A and R^2B are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, 24 -CHBr₂, -CHF₂, -CHI₂, -CH₂Cl, -CH₂Br, -CH₂F, -CH₂I, -CN, -OH, -NH₂, -COOH, -CONH₂, 25 -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, 26 -OCH₂I, -OCH₂F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, 27 substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, 28 substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 29 R³, R^3A, and R^3B are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, 30 -CI₃, -CH₂Cl, -CH₂Br, -CH₂F, -CH₂I, -CHCl₂, -CHBr₂, -CHF₂, -CHI₂, -CN, -OH, -NH₂, 31 -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, 32 ^NHC(O)NH₂, -NHSO₂H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl₃, -OCBr₃, -OCF₃, 33 -OCI₃, -OCH₂Cl, -OCH₂Br, -OCH₂F, -OCH₂I, -OCHCl₂, -OCHBr₂, -OCHF₂, -OCHI₂, -SF₅, 34 -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or 35 unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or 36 unsubstituted aryl, or substituted or unsubstituted heteroaryl; 37 R⁴ is independently halogen, -CCl₃, -CBr₃, -CF₃, -CI₃, -CH₂Cl, -CH₂Br, 38 -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, 39 -SH, -SO₃H, -OSO₃H, -SO₂NH₂, ^NHNH₂, ^ONH₂, ^NHC(O)NH₂, -NHSO₂H, -NHC(O)H, 40 -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, 41 -OCH₂I, -OCHCl₂, -OCHBr₂, -OCHF₂, -OCHI₂, -SF₅, -N₃, substituted or unsubstituted alkyl, 42 substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or 43 unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or 44 unsubstituted heteroaryl; 45 z4 is an integer from 0 to 2; and 46 R¹⁰ is hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, 47 -CH₂Cl, -CH₂Br, -CH₂F, -CH₂I, -CN, -OH, -NH₂, -COOH, -CONH₂, -OCCl₃, -OCF₃, 48 -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, 49 -OCH₂F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, 50 substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, 51 substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 1 2. The compound of claim 1, having the formula:

2 (III) or (IV); 3 wherein 4 R⁵ is independently halogen, -CX⁵3, -CHX⁵2, -CH2X⁵, -OCX⁵3, -OCH2X⁵, 5 -OCHX⁵ ₂, -CN, -SO_n5R^5D, -SO_v5NR^5AR^5B, ^NR^5CNR^5AR^5B, ^ONR^5AR^5B, 6 -NR^5CC(O)NR^5AR^5B, -N(O)m5, -NR^5AR^5B, -C(O)R^5C, -C(O)OR^5C, -OC(O)R^5C, -OC(O)OR^5C, 7 -C(O)NR^5AR^5B, -OC(O)NR^5AR^5B, -OR^5D, -SR^5D, -NR^5ASO₂R^5D, -NR^5AC(O)R^5C, 8 -NR^5AC(O)OR^5C, -NR^5AOR^5C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or 9 unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted 10 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 11 R^5A, R^5B, R^5C, and R^5D are independently hydrogen, -CCl₃, -CBr₃, -CF₃, -CI₃, 12 -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, 13 -CONH₂, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃, -OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, -OCH₂Cl, 14 -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted 15 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted 16 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 17 R^5A and R^5B substituents bonded to the same nitrogen atom may optionally be joined to form 18 a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; 19 each X⁵ is independently –F, -Cl, -Br, or –I; 20 n5 is an integer from 0 to 4; 21 m5 and v5 are independently 1 or 2; and 22 z5 is an integer from 0 to 6. 1 3. The compound of claim 2, having the formula:

2 (V). 1 4. The compound of claim 2, having the formula: 2 (VI). 1 5. The compound of claim 1, wherein when L¹ is a substituted alkylene or 2 substituted heteroalkylene, then the substituted alkylene or substituted heteroalkylene is 3 substituted with a substituent group; wherein the substituent group is selected from the 4 following moieties: 5 (A) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, 6 -CH₂Br, -CH₂F, -CH₂I, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃, -OCHCl₂, -OCHBr₂, -OCHI₂, 7 -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, 8 -NO₂, -SH, -SO₃H, –OSO₃H, -SO₂NH₂, ^NHNH₂, ^ONH₂, ^NHC(O)NHNH₂, 9 ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, 10 -SF5, unsubstituted alkyl, or unsubstituted heteroalkyl, and 11 (B) alkyl or heteroalkyl, substituted with at least one substituent selected from: 12 (i) oxo, halogen, -CCl₃, -CBr₃, -CF₃, -CI₃, -CHCl₂, -CHBr₂, -CHF₂, -CHI₂, -CH₂Cl, 13 -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, 14 -OCHI₂, -OCHF₂, -OCH₂Cl, -OCH₂Br, -OCH₂I, -OCH₂F, -CN, -OH, -NH₂, 15 -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, 16 ^NHC(O)NHNH₂, ^NHC(O)NH₂, –NHC(NH)NH₂, -NHSO₂H, -NHC(O)H, 17 -NHC(O)OH, -NHOH, -N₃, -SF₅, unsubstituted alkyl, or unsubstituted heteroalkyl, 18 and 19 (ii) alkyl or heteroalkyl, substituted with at least one substituent selected from: 20 (a) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, 21 -CH₂Cl, -CH₂Br, -CH₂F, -CH₂I, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃, -OCHCl₂, 22 -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, 23 -NH₂, -COOH, -CONH₂, -NO₂, -SH, -SO₃H, –OSO₃H, -SO₂NH₂, ^NHNH₂, 24 ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, 25 -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl, or 26 unsubstituted heteroalkyl, and 27 (b) alkyl or heteroalkyl, substituted with at least one substituent selected from: 28 oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, 29 -CH₂Br, -CH₂F, -CH₂I, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃, -OCHCl₂, -OCHBr₂, 30 -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, 31 -COOH, -CONH₂, -NO₂, -SH, -SO₃H, –OSO₃H, -SO₂NH₂, ^NHNH₂, ^ONH₂, 32 ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, 33 -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl, or unsubstituted 34 heteroalkyl. 1 6. The compound of claim 1, wherein L¹ is -NR¹⁰S(O)2- or substituted or 2 unsubstituted 2 to 8 membered heteroalkylene. 1 7. The compound of claim 1, wherein L¹ is -NR¹⁰S(O)₂- or 2 -NR¹⁰S(O)2-(unsubstituted C1-C6 alkylene)-. 1 8. The compound of claim 1, wherein when R¹⁰ is a substituted alkyl, 2 substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, 3 or substituted heteroaryl, then the substituted alkyl, substituted heteroalkyl, substituted 4 cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is 5 substituted with a substituent group; wherein the substituent group is selected from the 6 following moieties: 7 (A) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, 8 -CH₂Br, -CH₂F, -CH₂I, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃, -OCHCl₂, -OCHBr₂, -OCHI₂, 9 -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, 10 -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, 11 ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, 12 -SF5, unsubstituted alkyl, or unsubstituted heteroalkyl, and 13 (B) alkyl or heteroalkyl, substituted with at least one substituent selected from: 14 (i) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, 15 -CH₂Br, -CH₂F, -CH₂I, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃, -OCHCl₂, -OCHBr₂, 16 -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, 17 -COOH, -CONH₂, -NO₂, -SH, -SO₃H, –OSO₃H, -SO₂NH₂, ^NHNH₂, ^ONH₂, 18 ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, 19 -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl, or unsubstituted heteroalkyl, 20 and 21 (ii) alkyl or heteroalkyl, substituted with at least one substituent selected from: 22 (a) oxo, halogen, -CCl₃, -CBr₃, -CF₃, -CI₃, -CHCl₂, -CHBr₂, -CHF₂, -CHI₂, 23 -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, 24 -OCHBr₂, -OCHI₂, -OCHF₂, -OCH₂Cl, -OCH₂Br, -OCH₂I, -OCH₂F, -CN, -OH, 25 -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, 26 ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, 27 -NHC(O)H, -NHC(O)OH, -NHOH, -N₃, -SF₅, unsubstituted alkyl, or 28 unsubstituted heteroalkyl, and 29 (b) alkyl or heteroalkyl, substituted with at least one substituent selected from: 30 oxo, halogen, -CCl₃, -CBr₃, -CF₃, -CI₃, -CHCl₂, -CHBr₂, -CHF₂, -CHI₂, -CH₂Cl, 31 -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, 32 -OCHI₂, -OCHF₂, -OCH₂Cl, -OCH₂Br, -OCH₂I, -OCH₂F, -CN, -OH, -NH₂, 33 -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, ^NHNH2, ^ONH2, 34 ^NHC(O)NHNH2, ^NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, 35 -NHC(O)OH, -NHOH, -N₃, -SF₅, unsubstituted alkyl, or unsubstituted36 heteroalkyl. 1 9. The compound of claim 1, wherein R¹⁰ is hydrogen, -CCl3, 2 -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, 3 -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, 4 -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, or 5 substituted or unsubstituted heteroalkyl. 1 10. The compound of claim 1, wherein R¹⁰ is hydrogen or unsubstituted 2 C1-C4 alkyl. 1 11. The compound of claim 1, wherein L¹ is -NHS(O)₂-, , 2 , , or . 1 12. The compound of claim 1, wherein R¹ is –CF3 or unsubstituted C1-C6 2 alkyl. 1 13. The compound of claim 1, wherein R¹ is –CF3, unsubstituted methyl, 2 unsubstituted ethyl, unsubstituted isopropyl, or unsubstituted tert-butyl. 1 14. The compound of claim 1, wherein -L¹-R¹ is 2 , , , , , 3 , , or . 1 15. The compound of claim 1, wherein L² is a bond. 1 16. The compound of claim 1, wherein R² is a substituted or unsubstituted 2 nitrogen-containing heterocycloalkyl.

1 17. The compound of claim 1, wherein R² is a substituted or unsubstituted 2 piperidinyl. 1 18. The compound of claim 1, wherein R² is an unsubstituted piperidinyl. 1 19. The compound of claim 1, wherein R² is a piperidinyl substituted with 2 a halogen. 1 20. The compound of claim 1, wherein R² is a piperidinyl substituted 2 with -F. 1 21. The compound of claim 1, wherein R² is 2 or . 1 22. The compound of claim 1, wherein R³ is hydrogen or unsubstituted C₁- 2 C₄ alkyl. 1 23. The compound of claim 1, wherein R³ is hydrogen or unsubstituted 2 methyl. 1 24. The compound of claim 1, wherein z4 is 0. 1 25. The compound of claim 2, wherein R⁵ is independently halogen or 2 unsubstituted C1-C4 alkyl. 1 26. The compound of claim 2, wherein R⁵ is independently –F or 2 unsubstituted methyl. 1 27. The compound of claim 2, wherein z5 is 1 or 2. 1 28. The compound of claim 1, wherein is 2 or . 1 29. A pharmaceutical composition comprising a compound of one of 2 claims 1 to 28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically 3 acceptable excipient. 1 30. A method of treating a cancer, neurodegenerative disorder, 2 inflammatory disease, fibrosing disorder, demyelinating disorder, dermatologic disorder, 3 rheumatic disease, autoimmune disease, metabolic disorder, or eye disease in a subject in 4 need thereof, said method comprising administering to the subject in need thereof a 5 therapeutically effective amount of a compound of one of claims 1 to 28, or a 6 pharmaceutically acceptable salt thereof. 1 31. The method of claim 30, wherein the cancer is breast cancer, ovarian 2 cancer, colon adenocarcinoma, lung adenocarcinoma, lung small cell carcinoma, pancreatic 3 adenocarcinoma, pancreatic neuroendocrine tumors, glioblastoma, prostate cancer, 4 hepatocellular carcinoma, myeloma, leukemia, or lymphoma. 1 32. The method of claim 30, wherein the inflammatory disease is a 2 gastrointestinal disease or chronic inflammatory lung disease. 1 33. The method of claim 32, wherein the gastrointestinal disease is an 2 inflammatory bowel disease, Crohn’s disease, or colitis. 1 34. The method of claim 32, wherein the chronic inflammatory lung 2 disease is bronchial asthma, chronic obstructive pulmonary disease, bronchiectasis, or cystic 3 fibrosis. 1 35. The method of claim 30, wherein the fibrosing disorder is pulmonary 2 fibrosis. 1 36. The method of claim 30, wherein the autoimmune disease is a 2 peripheral neuropathy.

1 37. The method of claim 30, wherein the metabolic disorder is a diabetes

2 mellitus.