Nurr1 receptor modulators

Abstract

Described herein, inter alia, are modulators of the Nurr1 receptor and uses thereof. In one aspect, provided is a method for treating a disease associated with dysregulation and / or degeneration of dopaminergic neurons of the central nervous system in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 807,642, filed February 19, 2019, which is incorporated by reference herein in its entirety for all purposes.

[0003] Reference to "Sequence Listing," Table, or Computer Program Appendix Submitted on Compact Disc, ASCII File, or Computer Program Listing Appendix

[0004] The sequence listing in file 048536-637001WO_Sequence_Listing_ST25.txt created on January 14, 2020, 19,310 bytes, machine format IBM-PC, MS Windows operating system, is incorporated by reference herein.

[0005] Statement as to Federally Sponsored Research and Development

[0006] This application was made with government support under contract no. R01 NS108404 awarded by the National Institutes of Health. The government has certain rights in the application. BACKGROUND

[0007] More than one million Americans currently have Parkinson’s disease (PD), and approximately 60,000 new cases are diagnosed each year. In an estimated 90% of PD patients, the cause of the disease is unknown, with no clear genetic or environmental origin. The most prominent neuropathological feature of PD is the progressive degeneration of dopaminergic neurons in the substantia nigra compacta and the consequent reduction of dopamine levels in the striatum, which manifests as impaired motor function (e.g., rigidity, tremor, bradykinesia). Although the molecular basis of idiopathic PD is not fully understood, it has been proposed to involve oxidative stress, mitochondrial dysfunction, and dysregulation of dopamine homeostasis. Currently, there are no available treatments that arrest or even slow the progression of PD. Existing therapies alleviate PD symptoms by increasing dopaminergic signaling through one of three mechanisms: (1) increasing dopamine levels by increasing the amount of its biosynthetic precursor, L-DOPA; (2) blocking the breakdown of dopamine by inhibiting its metabolic enzymes (monoamine oxidases (MAOs), COMT); (3) mimicking dopamine’s activity by directly agonizing dopamine receptors. However, these drugs only partially alleviate symptoms and can produce significant side effects, especially as the disease progresses. There is an urgent need for new therapies to combat the symptoms and progression of PD. Solutions to these and other problems in the art are particularly disclosed herein. SUMMARY

[0008] In one aspect, a compound having the following formula is provided:

[0009]

[0010] Ring A is aryl or heteroaryl.

[0011] L 1 For L 101 -L 102 -L 103 .

[0012] L 101 For bond, -S(O)2-, -N(R) 101 )-, -O-, -S-, -C(O)-, -C(O)N(R 101 )-、-N(R 101 )C(O)-、-N(R 101 )C(O)NH-、-NHC(O)N(R 101 -, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, L 104 -L 105 L 104 -NH-L 105 or L 104 -CH2-L 105 .

[0013] L 102 For bond, -S(O)2-, -N(R) 102 )-, -O-, -S-, -C(O)-, -C(O)N(R 102 )-、-N(R 102 )C(O)-、-N(R 102 )C(O)NH-、-NHC(O)N(R 102 -, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0014] L 103 For bond, -S(O)2-, -N(R) 103 )-, -O-, -S-, -C(O)-, -C(O)N(R 103 )-、-N(R 103 )C(O)-、-N(R 103 )C(O)NH-、-NHC(O)N(R 103)-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0015] L 104 is a bond, -O-, -NH-, -S-, -S(O)2-, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0016] L 105 is a bond, -O-, -NH-, -S-, -S(O)2-, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene.

[0017] R 101 , R 102 , and R 103 are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, 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.

[0018] R 1 is hydrogen, halogen, -CX 1 3, -CHX 1 2, -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 12, -CN, -N(O) m1 , -N3, -SP(O)(OH)2, E, 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.

[0019] E is an electrophilic moiety.

[0020] R 2 independently halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 , -OCHX 2 2, -CN, -N(O) m2 , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R 2 substituents can be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0021] and independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and and substituents can join to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and and substituents can join to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0022] n1and n2are independently an integer from 0 to 4.

[0023] m1, m2, v1, and v2are independently 1 or 2.

[0024] X 1 and X 2 independently -F, -Cl, -Br, or -I.

[0025] z2is an integer from 0 to 5.

[0026] In one aspect, a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable excipient is provided.

[0027] In one aspect, a method for treating a disease associated with dysregulation and / or degeneration of dopaminergic neurons of the central nervous system in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein.

[0028] In one aspect, a method for modulating the level of Nurr1 activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein.

[0029] In one aspect, a method of increasing the level of Nurr1 activity in a cell is provided, the method comprising contacting the cell with a compound described herein.

[0030] In one aspect, a method of increasing the level of dopamine in a cell is provided, the method comprising contacting the cell with a compound described herein. BRIEF DESCRIPTION OF DRAWINGS

[0031] Figures 1A-1C Crystal structures of Nurr1 -screen hit complexes reveal two distinct ligand binding sites and receptor conformations. Figure 1A Structure of screen hits 19.49 and 10.25. Figure 1B Structure of 19.49 screen hit covalently bound to Cys566. Figure 1C Structure of 10.25 screen hit covalently bound to Cys566.

[0032] Figures 2A-2B Compounds 85 ( Figure 2A ) and 87 ( Figure 2B ) both bind to the Nurr1 ligand binding domain with high nanomolar affinity. Binding was measured by microscale thermophoresis.

[0033] Figures 3A-3B Compounds 85 ( Figure 3A ) and 87 ( Figure 3B ) stimulate transcription of Nurr1 target genes in MN9D cells. Gene expression was normalized to Hprt.

[0034] Figures 4A-4D Reaction scheme for selection of compounds. DETAILED DESCRIPTION

[0035] I. DEFINITIONS

[0036] Abbreviations used herein have their conventional meanings within the chemical and biological arts. The chemical structures and formulas described herein are constructed according to standard rules of chemical valence known in the chemical arts.

[0037] When a substituent is indicated as being "optionally substituted" it can be either unsubstituted or substituted. When a substituent is designated as "substituted" a specified substituent or group of substituents is intended. As used herein, the term "substituted" is intended to describe

[0038] Unless otherwise indicated, the term "alkyl," by itself or as part of another substituent, means a straight-chain (i.e., unbranched) or branched-chain carbon chain (or carbons) that can be fully saturated, monounsaturated, or polyunsaturated and can contain single, double, and multiple bonds and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple bonds, and can contain single, double, and triple10 Alkyl means a straight chain or branched hydrocarbon group having from one to ten carbon atoms (i.e., one carbon to ten carbons). Alkyl is an un-cyclized chain. Examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, methyl, e.g., n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like homologs and isomers. Unsaturated alkyl is an alkyl group having one or more double or triple bonds. Examples of unsaturated alkyl include, but are not limited to, ethenyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3- propynyl, 3-butynyl, and higher homologs and isomers. Alkoxy is an alkyl group attached to the rest of the molecule by an oxygen linker (-O-). The alkyl moiety can be an alkenyl moiety. The alkyl moiety can be an alkynyl moiety. The alkyl moiety can be fully saturated. The alkenyl can include more than one double bond and / or one or more triple bonds in addition to the one or more double bonds. The alkynyl can include more than one triple bond and / or one or more double bonds in addition to the one or more triple bonds.

[0039] The term "alkylene," by itself or as part of another substituent means, unless otherwise stated, a divalent group derived from an alkyl, as (but not limited to) exemplified by -CH2CH2CH2CH2-. Typically, the alkyl (or alkylene) will have from 1 to 24 carbon atoms, with those having 10 or fewer carbon atoms being preferred herein. "Lower alkyl" or "lower alkylene" is a short chain alkyl or alkylene group, typically having eight or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent means, unless otherwise stated, a divalent group derived from an alkene.

[0040] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight-chain or branched-chain or combinations thereof, comprising at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen, sulfur, and heteroatoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. One or more heteroatoms (e.g., N, S, Si, or P) can be placed at any interior position of the heteroalkyl group or located between the alkyl portion and the rest of the molecule. Heteroalkyl is an acyclic group. 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 can be consecutive, such as, for example, -CH2-NH-OCH3and -CH2-O-Si(CH3)3. A heteroalkyl moiety can contain one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain up to eight 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 group containing at least one double bond. A heteroalkenyl group can optionally contain more than one double bond, and / or in addition to the double bond(s) one or more triple bonds. The term "heteroalkynyl," by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl group containing at least one triple bond. A heteroalkynyl group can optionally contain more than one triple bond, and / or in addition to the triple bond(s) one or more double bonds.

[0041] Similarly, the term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a divalent radical derived from a heteroalkyl group, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkyl groups, heteroatoms can also occupy either or both of the chain termini (e.g., oxy, aminido, imino, amido, etc.). Still further, for alkylene and heteroalkylene linking groups, the direction of writing the formula is not intended to imply orientation of the group in the context of complete molecules, For example, -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 via a heteroatom to the rest of the molecule, such as -C(O)R', -C(O)NR', -NR'R", -OR', -SR', and / or -SO2R'. It will be understood that where an otherwise complete heteroalkyl group is named, such as -NR'R", the term heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is recited to increase clarity. Thus, the term "heteroalkyl" should not be interpreted to exclude specific heteroalkyl groups such as -NR'R".

[0042] Unless otherwise stated, the terms "cycloalkyl" and "heterocycloalkyl" by themselves or in combination with other terms, mean the cyclic versions of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, the heteroatoms can occupy any position of the heterocycle, including chain termini. 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-tetrahydropyridinyl), 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. "Cycloalkylene" and "heterocycloalkylene" mean, by themselves or as part of another substituent, divalent radicals derived from cycloalkyl and heterocycloalkyl, respectively.

[0043] Unless otherwise indicated, 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 both mono and polyhaloalkyl groups. 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.

[0044] Unless otherwise indicated, the term "acyl" means -C(O)R, wherein R is 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.

[0045] The term "aryl" means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (preferably 1 to 3 rings) that are fused together (i.e., fused rings) or linked covalently (preferably 1 to 3 rings). A fused ring aryl refers to rings that are fused together wherein at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to aryl groups (or rings) that contain at least one heteroatom (such as N, O, or S), wherein the nitrogen and sulfur atoms are optionally oxidized and one or more nitrogen atoms are optionally quaternized. The term "heteroaryl" therefore includes fused ring heteroaryls (i.e., multiple rings that are fused together wherein at least one of the fused rings is a heteroaryl ring). A 5,6-fused ring heteroarylene refers to two rings that are fused together wherein one ring has 5 members and the other ring has 6 members, and wherein at least one of the rings is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings that are fused together wherein one ring has 6 members and the other ring has 6 members, and wherein at least one of the rings is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings that are fused together wherein one ring has 6 members and the other ring has 5 members, and wherein at least one of the rings is a heteroaryl ring. The heteroaryl group can be attached to the rest of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thiophenyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalyl, quinolinyl, 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-furanyl, 3-furanyl, 2-thiophenyl, 3-thiophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalyl, 5-quinoxalyl, 3-quinolinyl, and 6-quinolinyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. "Arylene" and "heteroarylene" mean, alone or as part of another substituent, divalent groups derived from an aryl and heteroaryl group, respectively. A heteroaryl substituent can be -O- attached to a ring heteroatom nitrogen.

[0046] A spirocycle is two or more rings in which adjacent rings are connected by a single atom. The single rings within a spirocycle can be the same or different. The single rings in a spirocycle can be substituted or unsubstituted, and can have different substituents from the other single rings in the spirocycle collection. Possible substituents for each ring within a spirocycle are the possible substituents for the same ring when not part of a spirocycle (e.g., substituents for a cycloalkyl ring or a heterocycloalkyl ring). A spirocycle can be a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylidene, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkylidene, and each ring within the spirocycle group can be any of the rings of the preceding list, including having all rings of one type (e.g., all rings are substituted heterocycloalkylidene, where each ring can be the same or different substituted heterocycloalkylidene). When referring to a spirocycle system, heterocyclospiro refers to a spirocycle in which at least one ring is a heterocycle and in which each ring can be different. When referring to a spirocycle system, substituted spiro refers to at least one ring being substituted and each substituent can optionally be different.

[0047] Symbol denotes the point of attachment of a chemical moiety to the rest of the molecule or chemical formula.

[0048] As used herein, the term“oxo” means an oxygen doubly bonded to a carbon atom.

[0049] The term“alkylarylene” is an arylene moiety covalently linked to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the following formula:

[0050]

[0051] The alkylarylene moiety can be substituted (e.g., with a substituent) on the alkylene moiety or the arylene linker (e.g., at carbon 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.

[0052] Each of the above terms (e.g.,“alkyl,”“heteroalkyl,”“cycloalkyl,”“heterocycloalkyl,”“aryl,” and“heteroaryl”) includes substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0053] Substituents of alkyl and heteroalkyl groups (including those commonly referred to as alkylene, alkenylene, heteroalkylene, heteroalkenylene, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, without limitation: -OR', =0, =NR', =N-OR', -NR'R", -SR', halogen, - SiR'R"R'", -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", - NR"C(O)R', -NR'-C(O)NR"R'", -NR"C(O)2R', -NR-C(NR'R"R'")=NR"", - NR-C(NR'R")=NR', -S(O)R', -S(O)2R', -S(O)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", a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such a group. R, R', R", R' ", and R"" each preferably independently designate 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, or aralkyl. When compounds described herein contain more than one R group, such as, for example, when there are multiple R' groups, R" groups, R'" groups, and R"" groups, each of the R groups is independently selected, as are each of the R' groups, R" groups, R'" groups, and R"" groups, when there is more than one of these groups present. When R' and R" are attached to the same nitrogen atom, they can combine 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. In accordance with the foregoing discussion of substituents, it will be understood by those skilled in the art that the term "alkyl" means a group including a carbon atom that is bonded to a group other than a hydrogen group, such as haloalkyl (e.g., -CF3and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0054] Similar to the substituents described for alkyl groups, substituents of aryl and heteroaryl groups are varied and selected from, for example: -OR', -NR'R", -SR', halo, - SiR'R"R'", -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", - NR"C(O)R', -NR'-C(O)NR"R'", -NR"C(O)2R', -NR-C(NR'R"R'")=NR"", - NR-C(NR'R")=NR'", -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -NR'NR"R'", - ONR'R", -NR'C(O)NR"NR'"R"", -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(Ci-C4)alkoxy, and fluoro(Ci-C4)alkyl, -NR'SO2R", -NR'C(O)R", -NR'C(O)-OR", - NR'OR", the number of each ranging from zero up to the total number of open valences of aromatic systems; 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 comprises more than one R group, each of the R groups is independently selected, e.g., each R' group, R" group, R'" group, and R"" group, is independently selected when more than one of these groups is present.

[0055] Substituents of a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) can be depicted as substituents on the ring and not on a particular atom of the ring (often referred to as a floating substituent). In this case, the substituent can be attached to any of the ring atoms (following the rules of chemical valency) and, in the case of fused or spiro rings, a substituent depicted as being associated with one member of a fused or spiro ring (a floating substituent on a single ring) can be a substituent on any of the members of the fused or spiro ring (a floating substituent on multiple rings). When a substituent is attached to a ring and not a particular atom (a floating substituent) and the subscript for the substituent is an integer greater than one, multiple substituents can be on the same atom, the same ring, different atoms, different fused rings, different spiro rings, and each substituent can optionally be different. In cases where the point of attachment of a ring to the rest of the molecule is not limited to a single atom (a floating substituent), the point of attachment can be any atom of the ring and, in the case of fused or spiro rings, can be any atom of any of the members of the fused or spiro ring (following the rules of chemical valency). In cases where a ring, fused ring, or spiro ring contains one or more ring heteroatoms and the ring, fused ring, or spiro ring is shown with yet another floating substituent (including but not limited to the point of attachment to the rest of the molecule), the floating substituent can be attached to a heteroatom. When a ring heteroatom is shown bonded to one or more hydrogens in a structure or formula with a floating substituent (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen), the substituent will be understood to replace the hydrogen when the heteroatom is attached to the floating substituent, while following the rules of chemical valency.

[0056] Two or more substituents can be optionally joined into a ring aryl, heteroaryl, cycloalkyl, or heterocycloalkyl. Such so-called ring-forming substituents are typically (although not necessarily) 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 result in 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 result in a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0057] Two substituents on adjacent atoms of an aryl or heteroaryl ring can optionally form a ring of the general formula -T-C(O)-(CRR')q-C(O)-U-, where T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of an aryl or heteroaryl ring can optionally be replaced with a fused ring or spirocyclic ring of the general formula -A-(CH2) q where T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of an aryl or heteroaryl ring can optionally be replaced with a fused ring or spirocyclic ring of the general formula -A-(CH2) rsubstituted with substituents of -B-, wherein A and B are independently -CRR'-, -0-, -NR-, -S-, -S(O)-, -S(0)2-, -S(0)2NR'- or a single bond, and r is an integer from 1 to 4. One of the single bonds of the newly formed ring can optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring can optionally be replaced with a substituted or unsubstituted -0-0-, -0-C(O)-, -0-C(O)O-, -O-C(O)-NR'-, -NR'-C(O)O-, -O-CNR'-, -NR'-C(O)NR'-, -NR'-NR'-, -S-C(O)-, -S-C(O)O-, -SH-, -S-S-, -S-0-, -0-S-C(O)-, or -0-S(O)2-. s - X'-(C"R"R"') where s and d are independently integers from 0 to 3, and X' is -0-, -NR'-, -S-, -S(O)-, -S(0)2-, or -S(0)2NR'-. d - X'-(C"R"R"') where s and d are independently integers from 0 to 3, and X' is -0-, -NR'-, -S-, -S(O)-, -S(0)2-, or -S(0)2NR'-.

[0058] As used herein, the term "heteroatom" or "ring heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si). In embodiments, the term "heteroatom" or "ring heteroatom" means including oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0059] As used herein, "substituents" means groups selected from:

[0060] (A) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, unsubstituted alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and

[0061] (B) alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6-C 10 aryl, C 10 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:

[0062] (i) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, unsubstituted alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and

[0063] (ii) alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6-C 10 aryl, C 10 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 chosen from:

[0064] (a) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, unsubstituted alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and

[0065] (b) alkyl (e.g., C1-C8alkyl, C1-C6alkyl, or C1-C4alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6-C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and 10The group is substituted with at least one substituent selected from the following: oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHO H, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl groups (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl groups (e.g., C6-C... 10 Aryl, C 10 Aryl or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl or 5- to 6-membered heteroaryl).

[0066] As used herein, “size-limited substituent (size-limited substituent group)” means a group selected from all the substituents described above for “substituent”, wherein each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C2 group. 20 Alkyl groups, each substituted or unsubstituted heteroalkyl group being a substituted or unsubstituted 2- to 20-membered heteroalkyl group; each substituted or unsubstituted cycloalkyl group being a substituted or unsubstituted C3-C8 cycloalkyl group; each substituted or unsubstituted heterocycloalkyl group being a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group; each substituted or unsubstituted aryl group being a substituted or unsubstituted C6-C8 cycloalkyl group. 10 Aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0067] As used herein, "lower substituent" or "lower substituent group" means a group selected from all of the substituents described above for "substituent," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C8alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-Ci2aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. 10 As used herein, "lower substituent" or "lower substituent group" means a group selected from all of the substituents described above for "substituent," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C8alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-Ci2aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.

[0068] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent. 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 is substituted with at least one substituent. In other embodiments, at least one or all of these groups is substituted with at least one size-limited substituent. In other embodiments, at least one or all of these groups is substituted with at least one lower substituent.

[0069] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C 20 In other embodiments of the compounds herein, each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C 10 In other embodiments of the compounds herein, each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C 20alkyl is substituted or unsubstituted C1-C8alkyl, each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C3-C7cycloalkyl, each substituted or unsubstituted heterocycloalkyl is substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is substituted or unsubstituted C6-C 10 substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, each substituted or unsubstituted alkyl is substituted or unsubstituted C1-C8alkyl, each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C3-C7cycloalkyl, each substituted or unsubstituted heterocycloalkyl is substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is substituted or unsubstituted C6-C

[0070] substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, each substituted or unsubstituted alkyl is substituted or unsubstituted C1-C8alkyl, each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C3-C7cycloalkyl, each substituted or unsubstituted heterocycloalkyl is substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is substituted or unsubstituted C6-C 10 substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, each substituted or unsubstituted alkyl is substituted or unsubstituted C1-C8alkyl, each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C3-C7cycloalkyl, each substituted or unsubstituted heterocycloalkyl is substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is substituted or unsubstituted C6-C 10 substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, each substituted or unsubstituted alkyl is substituted or unsubstituted C1-C8alkyl, each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C3-C7cycloalkyl, each substituted or unsubstituted heterocycloalkyl is substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is substituted or unsubstituted C6-C

[0071] In embodiments, a substituted or unsubstituted moiety (e.g., a 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., 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., a 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., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene, respectively).

[0072] 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, wherein each substituent can optionally be different if the substituted moiety is substituted with multiple substituents. In embodiments, each substituent is different if the substituted moiety is substituted with multiple substituents.

[0073] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one size-limited substituent, wherein each size-limited substituent can optionally be different if the substituted moiety is substituted with multiple size-limited substituents. In embodiments, each size-limited substituent is different if the substituted moiety is substituted with multiple size-limited substituents.

[0074] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one lower substituent, wherein each lower substituent can optionally be different if the substituted moiety is substituted with multiple lower substituents. In embodiments, each lower substituent is different if the substituted moiety is substituted with multiple lower substituents.

[0075] 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, size-limited substituent, or lower substituent; wherein each substituent, size-limited substituent, and / or lower substituent can optionally be different if the substituted moiety is substituted with multiple groups selected from substituents, size-limited substituents, and lower substituents. In embodiments, each substituent, size-limited substituent, and / or lower substituent is different if the substituted moiety is substituted with multiple groups selected from substituents, size-limited substituents, and lower substituents.

[0076] Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds; the (R)- or (S)- or (D)- or (L)-enantiomers, racemates, diastereomeric mixtures, tautomers, geometric isomers, stereoisomeric forms, and individual isomers are embraced within the scope of the present disclosure, according to the absolute stereochemistry described. The present disclosure is meant to include compounds known in the art to be too unstable to be synthesized and / or isolated. The present disclosure is meant to include compounds in racemic and optically pure forms. Optical active (R)- and (S)- or (D)- and (L)- isomers can 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 indicated otherwise, it is intended that: the compounds include both E and Z geometric isomers.

[0077] As used herein, the term "isomer" refers to a compound having the same number and kind of atoms, and thus the same molecular weight, but differing in the structural arrangement or configuration of the atoms.

[0078] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted into each other.

[0079] It will be apparent to those skilled in the art that certain compounds of the present disclosure can exist in tautomeric forms, and all such tautomers are within the scope of the present disclosure.

[0080] 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. Thus, single stereochemical isomers, as well as enantiomeric and diastereomeric mixtures, of the present compounds are within the scope of the disclosure.

[0081] Unless otherwise stated, structures depicted herein are also meant to include all isotope forms of the structure, in which at least one of the atoms is replaced by an isotope of that atom. For example, compounds having a hydrogen atom replaced by a deuterium or tritium atom or a carbon atom replaced by a13C or14C atom are within the scope of this disclosure. 13 C- or 14 C-enriched carbon in place of the carbon of the present structures are within the scope of the present disclosure.

[0082] The compounds of the present disclosure can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14C) isotopes, both radioactive and non-radioactive. All isotopic variations of compounds of the present disclosure, whether radioactive or non-radioactive, are encompassed within the scope of the present disclosure.

[0083] It should be noted that throughout the application, alternatives are written in Markush groups, for example in each amino acid position containing more than one possible amino acid. It is specifically envisaged that each member of the Markush group should be considered individually, thus including another embodiment, and that the Markush group should not be understood as a single unit.

[0084] As used herein, the terms “bioconjugate” and “bioconjugate linker” refer to an association between atoms or molecules of a bioconjugate reactive group or a bioconjugate reactive moiety. The association can be direct or indirect. For example, conjugation between a first bioconjugate reactive group (e.g., -NH2, -COOH, -N-hydroxysuccinimidyl, or -maleimide) and a second bioconjugate reactive group (e.g., a thiol, a sulfur-containing amino acid, an amine, an amine side chain containing an amino acid, or a carboxylate salt) provided herein can occur, for example, directly through a covalent bond or linker (e.g., a first linker of a second linker), or indirectly, for example, through a non-covalent bond (e.g., an electrostatic interaction (e.g., ionic bond, hydrogen bond, halogen bond), a van der Waals interaction (e.g., dipole-dipole, dipole-induced dipole, London dispersion), a ring stacking (pi effect), a hydrophobic interaction, etc.). In embodiments, a bioconjugate or bioconjugate linker is formed using bioconjugate chemistry (i.e., association of two bioconjugate reactive groups), including but not limited to nucleophilic substitution (e.g., reaction of amines and alcohols with acyl halides, active esters), electrophilic substitution (e.g., enamine reactions), and addition 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; Chemical Progress Series, Vol. 1, 198, American Chemical Society, Washington, D.C., 1982. In embodiments, a first bioconjugate reactive group (e.g., a maleimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., a thiol). In embodiments, a first bioconjugate reactive group (e.g., a haloacetyl moiety) is covalently linked to a second bioconjugate reactive group (e.g., a thiol). In embodiments, a first bioconjugate reactive group (e.g., a pyridyl moiety) is covalently linked to a second bioconjugate reactive group (e.g., a thiol). In embodiments, a first bioconjugate reactive group (e.g., a N-hydroxysuccinimidyl moiety) is covalently linked to a second bioconjugate reactive group (e.g., a thiol).In embodiments, the first bioconjugate reactive group (e.g., a maleimide moiety) is covalently linked to the second bioconjugate reactive group (e.g., a thiol). In embodiments, the first bioconjugate reactive group (e.g., a -sulfo N-hydroxysuccinimide moiety) is covalently linked to the second bioconjugate reactive group (e.g., an amino group).

[0085] Useful bioconjugate reactive moieties for bioconjugate chemistry include, for example:

[0086] (a) carboxyl groups and various derivatives thereof, including but not limited to N- hydroxysuccinimide esters, N-hydroxysbenzotriazole esters, acid halides, acylimidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl, and aromatic esters;

[0087] (b) hydroxyl groups, which can be converted to esters, ethers, aldehydes, and the like;

[0088] (c) haloalkyl groups, where the halide can be subsequently displaced with a nucleophilic group such as an amine, carboxylate anion, thiol anion, carbanion, or alkoxide anion, thereby resulting in a new group covalently attached at the site of the halogen atom;

[0089] (d) dienophiles, which are capable of participating in a Diels-Alder reaction, such as, for example, a maleimide group;

[0090] (e) aldehyde or ketone groups, which allow for subsequent derivatization by formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones, or oximes, or by mechanisms such as Grignard addition or alkyl lithium addition;

[0091] (f) sulfonyl halide groups, which are used for subsequent reaction with amines, for example, to form sulfonamides;

[0092] (g) thiol groups, which can be converted to disulfides, reacted with acyl halides, or attached to metals such as gold, or reacted with maleimides;

[0093] (h) amine or thiol groups (e.g., present in cysteine), which can be acylated, alkylated, or oxidized, for example;

[0094] (i) alkenes, which can undergo cycloaddition, acylation, Michael addition, and the like, for example;

[0095] (j) epoxides, which can react with amines and hydroxyl compounds, for example;

[0096] (k) phosphoramidites and other standard functionalities useful for nucleic acid synthesis;

[0097] (l) metal oxide silica linkages;

[0098] (m) metal linkage to a reactive phosphorus group (e.g., phosphine) to form, for example, a phosphodiester linkage;

[0099] (n) azide linkage to alkyne using copper catalyzed cycloaddition click chemistry; and

[0100] (o) biotin conjugates can react with avidin or strepavidin to form an avidin-biotin complex or a strepavidin-biotin complex.

[0101] The bioconjugate reactive groups can be selected such that they do not participate in or interfere with the chemical stability of the conjugates described herein. Alternatively, the reactive functional groups can be protected from participating in cross-linking reactions by the presence of protecting groups. In embodiments, the bioconjugate includes a molecular entity derived from the reaction of an unsaturated bond such as a maleimide with a thiol.

[0102] “Analog” or “analogue” or “derivative” is used according to its plain ordinary meaning within chemistry and biology and refers to a compound that is structurally similar but compositionally different from another compound (i.e., the so-called “reference” compound), for example, in one atom being replaced by an atom of a different element, or in the presence of a particular functional group, or one functional group being replaced by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Thus, an analog is a compound that is similar or comparable in function and appearance to the reference compound, but not similar or comparable in structure or origin.

[0103] As used herein, the term “a” or “an” means one or more. Additionally, as used herein, the phrase “substituted with” means that the specified group can be substituted with one or more of any or all of the recited substituents. For example, when a group such as alkyl or heteroaryl is “substituted with unsubstituted C1-C 20 alkyl, and / or one or more unsubstituted 2- to 20-membered heteroalkyl groups. 20

[0104] ​Further, where a moiety is substituted with an R substituent, the group can be referred to as "R-substituted." Where a moiety is substituted with R, the moiety is substituted with at least one R substituent, and each R substituent is optionally different. Where there are specific R groups in the description of a chemical genus (such as Formula (I)), the Roman letter symbol can be used to distinguish each occurrence of the specific R group. For example, where there are multiple R 13 substituents, each R 13 substituent can be distinguished as R1, R2, R3, etc., each of which is defined within the scope of the definition of R and optionally different. 13

[0105] The description of the compounds of the present disclosure is limited by the principles of chemical linkage known to one of skill in the art. Thus, where a group can be substituted with one or more of multiple substituents, such substitutions are chosen so as to comply with the principles of chemical linkage and to result in compounds that 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 group is attached to the remainder of the molecule via a ring heteroatom in accordance with the principles of chemical linkage known to one of skill in the art, thereby avoiding inherently unstable compounds.

[0106] ​The term "pharmaceutically acceptable salt" is intended to encompass salts of active compounds which are relatively non-toxic, according to the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts or like- salts. 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 salts of

[0107] Accordingly, the compounds of the present disclosure can exist in the form of, for example, salts with pharmaceutically acceptable acids. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, propionate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or a mixture thereof including racemic mixtures), succinate, benzoate, and salts with amino acids such as glutamic acid and quaternary ammonium salts (e.g., iodomethane, iodoethane, and the like). These salts can be prepared by methods known to those skilled in the art.

[0108] The neutral form of the compounds is preferably regenerated by contacting the salt with base or acid and isolating the parent compound in the conventional manner. The parent form of the compound can differ from the various salt forms in certain physical properties such as solubility in polar solvents.

[0109] In addition to salt forms, the present disclosure provides compounds in 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 can be converted by in vivo chemical or biochemical processes into the compounds of the present disclosure. Additionally, prodrugs can be converted by chemical or biochemical processes in an ex vivo environment, such as, for example, when in contact with appropriate enzymes or chemical reagents.

[0110] Certain compounds of the present disclosure can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms, and are intended to be encompassed within the scope of the present disclosure. Certain compounds of the present disclosure can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent and intended to be within the scope of the present disclosure.

[0111] A polypeptide or cell is "recombinant" when it is man-made or engineered or derived from a man-made or engineered protein or nucleic acid or contains a man-made or engineered protein or nucleic acid (e.g., non-native or non-wild type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, such as the genome of a recombinant organism, such that it is not associated with the 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 occur in nature (e.g., a variant of a naturally occurring gene) is recombinant.

[0112] "Co-administration" means administration of a composition described herein at the same time, immediately before or immediately after administration of one or more additional therapies. The compounds of the present invention can be administered alone or can be co-administered to a patient. Co-administration means administration of the compounds (more than one compound) either simultaneously or sequentially, either separately or in a single composition. Thus, the formulations can also be combined with other active substances (for example to reduce metabolic degradation) if desired.

[0113] "Cell" as used herein refers to a cell that performs metabolic functions or other functions sufficient to maintain or replicate its genomic DNA. Cells can be identified by methods well known in the art, including, for example, the presence of an intact membrane, staining with particular dyes, the ability to reproduce offspring, or, if gametes, the ability to combine with a second gamete to produce a viable offspring. Cells can include prokaryotic cells and eukaryotic 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, such as mammalian cells, insect (e.g., Spodoptera) cells, and human cells. Cells can be useful when they are naturally non-adherent or treated to be non-adherent to surfaces, for example, by trypsinization.

[0114] The terms“treating” or“treatment” refer 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 elimination; reduction in severity; reduction in recurrence; reduction in symptoms; or the like. Treatment or amelioration can be based on objective or subjective parameters including physical parameters, mental parameters, and / or the like. For example, certain methods presented herein successfully treat cancer by reducing the incidence and / or causing regression of cancer. In some embodiments of the compositions or methods described herein, treating cancer includes slowing the rate of growth or spread of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors. The term“treatment” and conjugations thereof includes preventing harm, pathology, condition, or disease. In embodiments, treatment is prophylactic. In embodiments, treatment does not include prophylactic. In embodiments, treating or treatment is not prophylactic treatment.

[0115] An“effective amount” is an amount sufficient to effect at least partial treatment for a condition (e.g., to achieve an effect for which the compound was administered, to treat a disease, to reduce enzyme activity, to increase enzyme activity, to reduce a signaling pathway, to reduce one or more symptoms of a disease or condition) in comparison to the absence of the compound. An example of an“effective amount” when referred to in this context is an amount sufficient to contribute to treatment, prevention, or reduction of one or more symptoms of a disease, which can also be referred to as a“therapeutically effective amount.” A“reduction” of one or more symptoms (and grammatical equivalents of this phrase) means decreasing the severity or frequency of the one or more symptoms, or eliminating the one or more symptoms. A“prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have a prophylactic effect on the condition, e.g., preventing or delaying the onset of a disease, pathology, or condition (or recurrence thereof), or reducing the likelihood of the onset of a disease, pathology, or condition, or symptoms thereof. A full prophylactic effect need not occur in order for the drug to be considered a prophylactic effective amount, and may, for example, only occur in a subset of subjects to whom the drug is administered. Thus, a prophylactically effective amount can be administered in one or more administrations. As used herein, an“activity reducing amount” refers to the amount of antagonist required to reduce the activity of an enzyme relative to the absence of the antagonist. As used herein, a“function disrupting amount” refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. As used herein, an“activity increasing amount” refers to the amount of agonist required to increase the activity of an enzyme relative to the absence of the agonist. As used herein, a“function increasing amount” refers to the amount of agonist required to increase the function of an enzyme or protein relative to the absence of the agonist. The precise amount 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, Gennaro, Ed., Lippincott, Williams & Wilkins, 2003).

[0116] “Control” or “control experiment” is used according to its general and ordinary meaning and refers to an experiment in which the subject or reagent of the experiment is treated as in a parallel experiment, except that a procedure, reagent, or variable of the experiment is omitted. In some cases, a control is used as a standard for comparison in assessing the effect of an experiment. In some embodiments, a control is a measure of the activity of a protein (e.g., a signaling pathway) in the absence of a compound as described herein (including embodiments, examples, figures, or tables).

[0117] “Contacting” is used according to its ordinary general meaning and refers to the process of bringing at least two different species (e.g., chemical compounds including biomolecules or cells) in close enough proximity to react, interact, or physically touch. However, it will be appreciated that the resulting reaction product can be produced directly from a reaction between the added reagents, or from an intermediate of one or more of the added reagents that can be produced in the reaction mixture.

[0118] The term “contacting” can include allowing two species to react, interact, or physically touch, where the two species can be a compound as described herein and a cellular component (e.g., a 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., a 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) involved in a signaling pathway.

[0119] The term “activation / activate / activating” and the like with respect to a protein, as defined herein, means the conversion of a protein from an initial unactivated or deactivated state to a biologically activated derivative. The term refers to the activation or activating, sensitizing, or upregulating of a signal transduction or enzymatic activity or amount of a protein that is decreased in disease.

[0120] The terms “agonist,” “activator,” “upregulator,” and the like refer to a substance that is capable of detectably increasing the expression or activity of a given gene or protein. An agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% compared to a control in the absence of the agonist. In certain cases, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more higher compared to expression or activity in the absence of the agonist.

[0121] As defined herein, the term "inhibition," "inhibit," "inhibiting," and the like in reference to a cellular component-inhibitor interaction means negatively affecting (e.g., reducing) the activity or function of the cellular component relative to the activity or function of the cellular component in the absence of the inhibitor (e.g., reducing the cellular component stimulated signaling pathway (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microbe, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)). In embodiments, inhibition means negatively affecting (e.g., reducing) the concentration or level 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 a reduction in a disease or a symptom of a disease. In some embodiments, inhibition refers to a reduction in a signaling pathway or signaling pathway activity (e.g., a reduction in a pathway involving the cellular component). Thus, inhibition at least partially comprises partially or completely blocking stimulation, reducing, preventing, or delaying activation, desensitization, or downregulation of a signaling pathway or enzymatic activity or the amount of a cellular component.

[0122] Alternatively, the term "inhibitor," "repressor," "antagonist," or "downregulator" refers to an agent capable of detectably reducing the expression or activity of a given gene or protein. The antagonist can reduce the expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% compared to a control in the absence of the antagonist. In certain instances, the expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more lower compared to the expression or activity in the absence of the antagonist.

[0123] The term "modulator" refers to increasing or decreasing the level of a target molecule or the function of a target molecule or the physical state of a target of a molecule relative to the absence of the composition (e.g., the target can be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microbe, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)).

[0124] The term "expression" encompasses any step involved in the production of a polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using routine techniques for detecting proteins (e.g., ELISA, Western blot, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0125] The term "modulate" is used according to its ordinary and customary meaning and refers to the act of changing or altering one or more properties. "Modulation" refers to the process of changing or varying one or more properties. For example, when applied to the effect of a modulator on a target protein, modulation means making a change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.

[0126] A "patient" or "subject in need thereof refers to a living organism that is suffering from or susceptible 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, goats, sheep, cattle, deer, and other non-mammalian animals. In some embodiments, the patient is a human.

[0127] A "disease" or "condition" refers to a state or health status of a patient or subject that can be treated with a compound or method provided herein. In some embodiments, the disease is a disease associated with (caused by) a cellular component (e.g., a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microbe, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In embodiments, the disease is a neurodegenerative disease. In embodiments, the disease is cancer.

[0128] As used herein, the term "neurodegenerative disease" refers to a disease or condition in which a subject's nervous system function is impaired. Examples of neurodegenerative diseases that can be treated with a compound, pharmaceutical composition, or method described herein include Alexander's disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Guillain-Barre syndrome, Hallervorden-Spatz syndrome, Huntington's disease, inclusion body myositis, Kennedy's disease, Lewy body dementia, multiple sclerosis, multiple system atrophy, myoclonus epilepsy ragged red fibers syndrome, Niemann-Pick disease, Parkinson's disease, Pelizaeus-Merzbacher disease, progressive supranuclear palsy, Sandhoff disease, Schilder's disease, spinal muscular atrophy, Steele-Richardson-Olzewski disease, and Tay-Sachs disease. Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewy body dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher Disease, Pick's disease, primary lateral sclerosis, prion diseases, Refsum's disease, Sandhoff's disease, Schilder's disease, subacute combined degeneration of spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (in multiple types with distinct features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, or tabes dorsalis.

[0129] The term "inflammatory disease" as used herein refers to a disease or condition characterized by abnormal inflammation (e.g., increased levels of inflammation compared to a control, such as a healthy person not suffering from the 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, type 1 diabetes, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune 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, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis.

[0130] As used herein, the term "cancer" refers to all types of cancer, tumors, or malignant tumors found in mammals (e.g., humans), including leukemias, lymphomas, carcinomas, and sarcomas. Exemplary cancers that can be treated with the compounds or methods provided herein include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterine cancer, 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, carcinoma, malignant pancreatic intraepithelial neoplasia, malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortex cancer, endocrine or exocrine pancreatic neoplasms, medullary thyroid carcinoma, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular cancer, or prostate cancer.

[0131] The term "leukemia" refers to a progressive, malignant disease of the blood-forming organs, and is generally characterized by the unregulated growth and development of leukocytes and their precursors in the blood and bone marrow. Leukemias are generally classified clinically on the basis of: (1) the duration and characteristics of the disease - acute or chronic; (2) the type of cells involved - myeloid, lymphoid, or monocytic; and (3) the increase or non-increase in the number of abnormal cells in the blood - leukemic or aleukemic (subleukemic). Exemplary leukemias that can be treated with the compounds or methods 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, agranulocytic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, cutaneous leukemia, 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, lymphoid leukemia, lymphoid leukemia, lymphosarcellar cell leukemia, mast cell leukemia, megakaryocyte leukemia, micromyeloblast leukemia, monocyte leukemia, myeloblastocytic leukemia, myelocytic leukemia, myelogenous leukemia, myelomonocytic leukemia, Naegeli's 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.

[0132] As used herein, the term "lymphoma" refers to a group of cancers that affect the hematopoietic and lymphoid tissues. It begins in lymphocytes, which are blood cells primarily found in lymph nodes, the spleen, the thymus, and the bone marrow. The two main types of lymphoma are non-Hodgkin's lymphoma and Hodgkin's disease. Hodgkin's disease accounts for about 15% of all diagnosed lymphomas. It is a cancer associated with Reed-Sternberg malignant B lymphocytes. Non-Hodgkin's lymphoma (NHL) can be classified based on the rate of growth of the cancer and the type of cell involved. There are aggressive (high-grade) and indolent (low-grade) types of NHL. Based on the type of cell involved, there are B-cell and T-cell NHLs. Exemplary B-cell lymphomas that can be treated with the compounds or methods provided herein include, but are not limited to, small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, lymphoma extranodal (MALT), nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T-cell lymphomas that can be treated with the compounds or methods provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, pleomorphic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.

[0133] The term "sarcoma" generally refers to a tumor composed of substance similar to embryonic connective tissue and is usually composed of closely packed cells embedded in a fibrous or homogeneous substance. Sarcomas that can be treated with the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanotic sarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, interstitial 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.

[0134] The term "melanoma" is understood to mean a tumor derived from the melanocyte system of the skin and other organs. Melanomas that can be treated with the compounds or methods provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0135] The term "cancer" refers to a malignant new growth composed of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary cancers that can be treated with the compounds or methods provided herein include, for example, medullary carcinoma of the thyroid, familial medullary carcinoma of the thyroid, acinar carcinoma, alveolar carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenocarcinoma, carcinoma of the adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basaloid cell tumor, basal cell-like carcinoma, basal squamous cell carcinoma, bronchiolar alveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirscroti), signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, potato carcinoma, globular 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 villoglandular carcinoma.

[0136] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that aids in the administration of an active agent to a subject and facilitates absorption by the subject and can be included in the compositions of the present application without posing a significant toxicological risk to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorants, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates (such as lactose, amylose or starch), fatty acid esters, carboxymethylcellulose, polyvinylpyrrolidone, and pigments, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents not detrimental to the compounds of the present application, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents and / or aromatic substances and the like. Those of skill in the art will recognize additional pharmaceutical excipients useful in the present application.

[0137] The term "formulation" is intended to encompass preparations made by the mixing, dissolving, or agitating of active compounds and the carrier, in solid, liquid, or other form, into which the active compound is incorporated to provide a delivery system for the active compound. Similarly, included are sachets and tablets. Tablets, powders, capsules, pills, sachets, and tablets can be used as solid dosage forms suitable for oral administration.

[0138] As used herein, the term "about" means a range of values that a person of ordinary skill in the art would consider to reasonably resemble a specified value. In embodiments, about means within the standard deviation of a measurement that is generally acceptable in the art. In embodiments, about means a range extending + / - 10% of a specified value. In embodiments, about includes a specified value.

[0139] As used herein, the term "administering" means orally administering, administering in suppository form, contacting topically, intravenously, intraperitoneally, intramuscularly, intralesionally, intrathecally, intranasally, or subcutaneously, or implanting slow-release devices (e.g., microosmotic pumps). Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatine, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, use of liposome formulations, intravenous infusion, transdermal patches, and the like. "Co-administration" means that the compositions described herein are administered at the same time as, just prior to, or just after one or more additional therapies (e.g., cancer therapies such as chemotherapy, hormonal therapy, radiation therapy, or immunotherapy). The compounds of the present invention can be administered to a patient alone or can be co-administered. Co-administration means administration of the compounds (more than one compound) either simultaneously or sequentially, either separately or in a combination. Thus, the formulations can also be combined with other active substances (e.g., to reduce metabolic degradation) if desired. The compositions of the present invention can be delivered transdermally, formulated as an applicator stick, solution, suspension, emulsion, gel, cream, ointment, paste, jelly, paint, powder, and aerosol.

[0140] The compounds described herein can be used in combination with other active agents known to be useful in treating diseases associated with cells expressing the cellular component associated with the disease or with adjunct agents that can not themselves prevent, treat, or diagnose the disease or condition, but which can enhance the effectiveness of the active agent(s).

[0141] In some embodiments, co-administration includes administration of one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the second active agent. Co-administration includes administration of both active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in either order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparation of a single pharmaceutical composition containing both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active agents and / or adjunct agents can be linked or conjugated to each other.

[0142] The compounds described herein can be co-administered with conventional neurodegenerative disease treatments including, but not limited to, Parkinson's disease treatments such as levodopa, carbidopa, selegiline, amantadine, donepezil, galanthamine, rivastigmine, tacrine, dopamine agonists (e.g., bromocriptine, pergolide, pramipexole, ropinirole), anticholinergics (e.g., trihexyphenidyl, benztropine, biperiden, procyclidine), and catechol-O-methyl-transferase inhibitors (e.g., tolcapone, entacapone).

[0143] The compounds described herein can also be co-administered with conventional anti-inflammatory disease treatments including, but not limited to, analgesics (e.g., acetaminophen, duloxetine), non-steroidal anti-inflammatory drugs (e.g., aspirin, ibuprofen, naproxen, diclofenac), corticosteroids (e.g., prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone), and opioids (e.g., codeine, fentanyl, hydrocodone, hydromorphone, morphine, meperidine, oxycodone).

[0144] 111 In、 90 Y or 131 I conjugated anti-CD20 monoclonal antibodies, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, an EGFR inhibitor, an epidermal growth factor receptor (EGFR)-targeting therapy or therapeutic agent (e.g., gefitinib (Iressa TM ), erlotinib (Tarceva TM ), cetuximab (Erbitux TM ), lapatinib (Tykerb TM ), panitumumab (Vectibix TM ), vandetanib (Caprelsa TM ), afatinib (BIBW2992), CI-1033 / canertinib, neratinib (HKI-272), CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib (PF299804), OSI-420 / desmethyl erlotinib, AZD8931, AEE788, pelitinib (EKB-569), CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, etc. A portion of the anti-cancer agents are monovalent anti-cancer agents (e.g., monovalent forms of the agents listed above).

[0145] In therapeutic uses for treating diseases, the compounds used in the pharmaceutical compositions of the application can be administered at an initial dose of about 0.001 mg / kg to about 1000 mg / kg per day. The daily dose can range from about 0.01 mg / kg to about 500 mg / kg, or from about 0.1 mg / kg to about 200 mg / kg, or from about 1 mg / kg to about 100 mg / kg, or from about 10 mg / kg to about 50 mg / kg. However, the dose can vary according to the needs of the patient, the severity of the condition being treated, and the compound or drug employed. For example, the dose can be empirically determined based on the type and stage of cancer diagnosed in a particular patient. In the context of the present application, the dose administered to the patient should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose will also depend on the existence, nature, and extent of any adverse side effects that accompany the administration of the compound in a particular patient. Determining the appropriate dose for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages that 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 can be divided and administered in portions during the day as required. The compounds described herein can be used in combination with other active agents known to be useful in the treatment of cancer, or with adjuncts that can not be effective by themselves but can serve to enhance the effectiveness of the active agent.

[0146] The compounds described herein can be used in combination with other active agents known to be useful in the treatment of cancer, or with adjuncts that can not be effective by themselves but can serve to enhance the effectiveness of the active agent.

[0147] In the context of a substance or substance activity or function associated with a disease (e.g., a protein-related disease, a disease associated with a cellular component), the term “associated” or “associated with” means that the disease (e.g., a neurodegenerative disease, a cancer) is caused (in whole or in part) by the substance or substance activity or function, or that a symptom of the disease is caused (in whole or in part) by the substance or substance activity or function, or that the disease or the symptom of the disease can be treated by modulating (e.g., inhibiting or activating) the substance (e.g., cellular component). For example, a neurodegenerative disease associated with abnormal protein aggregation can be a neurodegenerative disease caused (in whole or in part) by abnormal protein aggregation or a neurodegenerative disease in which a particular symptom of the disease is caused (in whole or in part) by abnormal protein aggregation. As used herein, a pathogen is described as being associated with a disease if it can be a target for treating the disease. For example, a neurodegenerative disease associated with abnormal protein aggregation or a neurodegenerative disease associated with protein aggregation can be treated with a protein aggregation modulator.

[0148] As used herein, the term "abnormal" means different from normal. When used to describe enzymatic activity, abnormal refers to an activity that is greater or less than the average of normal controls or normal, non-diseased control samples. An abnormal activity can refer to an amount of activity that causes a disease, wherein returning the abnormal activity to a normal or non-disease associated amount (e.g., by administering a compound or using a method as described herein) results in a reduction of the disease or one or more symptoms of the disease.

[0149] As used herein, the term "electrophilic" 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-deficient chemical group, substituent, or moiety (monovalent chemical group) that can react with an electron-donating group, such as a nucleophile, to form a bond by accepting an electron pair or electron density. In some embodiments, an electrophilic substituent of a compound is capable of reacting with a cysteine residue. In some embodiments, an electrophilic substituent is capable of forming a covalent bond with a cysteine residue and can be referred to as a "covalent cysteine modification moiety" or "covalent cysteine modification substituent." The covalent bond formed between an electrophilic substituent and the thiol group of a cysteine can be a reversible or irreversible bond. In some embodiments, an electrophilic substituent of a compound is capable of reacting with a lysine residue. In some embodiments, an electrophilic substituent of a compound is capable of reacting with a serine residue. In some embodiments, an electrophilic substituent of a compound is capable of reacting with a methionine residue.

[0150] As used herein, "nucleophilic" refers to a chemical group that is capable of providing electron density.

[0151] The term "isolated" when applied to a nucleic acid or protein means that the nucleic acid or protein is substantially free of other cellular components with which it is associated in nature. It can, for example, be in a homogeneous state and can be in a dry state or in aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques, such as polyacrylamide gel electrophoresis or high performance liquid chromatography. The predominant protein present in the preparation is substantially purified.

[0152] The term "amino acid" refers to naturally occurring amino acids 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, such as those amino acids later modified, for example, hydroxyproline, gamma-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure (i.e., an alpha carbon bonded to a hydrogen, a carboxyl, an amino, and an R group) as a naturally occurring amino acid, such as homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium. The analogs have modified R groups (e.g., norleucine) or modified peptide backbone, but otherwise function in a manner similar to the naturally occurring amino acids. 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 that are not found in nature.

[0153] Amino acids are represented herein by their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, can be referred to by their commonly accepted single-letter codes.

[0154] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acid residues, in which the polymers can be conjugated in the embodiments to moieties that do not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residues are synthetic chemical mimetics of a corresponding naturally occurring amino acid, as well as to naturally occurring and non-naturally occurring amino acid polymers.

[0155] The "position" of an amino acid or nucleotide base is indicated by a number that identifies each amino acid (or nucleotide base) in a reference sequence in order based on its position relative to the N-terminal (or 5' end). Because deletions, insertions, truncations, fusions, and the like must be taken into account when determining the best alignment, the number of an amino acid residue in a test sequence determined by counting only from the N-terminal will not necessarily be the same as the number of its corresponding position in the reference sequence. For example, in the case of a deletion in a variant relative to the aligned reference sequence, there will be no amino acid in the variant corresponding to the position at the site of the deletion in the reference sequence. In the case of an insertion in the aligned reference sequence, the insertion will not correspond to the numbered amino acid position in the reference sequence. In the case of a truncation or fusion, there can be stretches of amino acids in the reference sequence or aligned sequence that do not correspond to any amino acid in the respective sequence.

[0156] The term "numbered with respect to" or "numbered corresponding to" when used in the context of numbering a given amino acid or polynucleotide sequence refers to the numbering of the residues of a specified reference sequence when comparing the given amino acid or polynucleotide sequence to the reference sequence.

[0157] The term "protein complex" is used according to its plain ordinary meaning and refers to a protein associated with another substance (e.g., another protein, protein subunit, or compound). Protein complexes typically have a well-defined quaternary structure. The association between the protein and the additional substance can be a covalent bond. In embodiments, the association between the protein and the additional substance (e.g., a compound) is by a non-covalent interaction. In embodiments, a protein complex refers to a set of two or more polypeptide chains. The proteins in a protein complex are connected by non-covalent protein-protein interactions. A non-limiting example of a protein complex is a proteasome.

[0158] The term "protein aggregate" is used according to its plain ordinary meaning and refers to an abnormal collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are often associated with diseases (e.g., amyloidosis). Generally, unfolded / misfolded proteins can aggregate when the proteins misfold due to changes in the amino acid sequence or changes in the native environment that disrupt normal non-covalent interactions, and the misfolded proteins are not corrected or degraded. There are three main types of protein aggregates that can form: amorphous aggregates, oligomers, and amyloid fibrils. In embodiments, protein aggregates are referred to as aggresomes.

[0159] The term "Nurr1" or "NR4A2" refers to a protein encoded by the NR4A2 gene in humans. Nurr1 is a nuclear receptor and plays a key role in maintaining the brain dopaminergic system. The term "Nurr1" can refer to the nucleotide sequence or protein sequence of human NR4A2 (e.g., Entrez 4929, Uniprot P43354, RefSeq NM_006186.3, or RefSeq NP_006177.1). In embodiments, Nurr1 has the following amino acid sequence:

[0160]

[0161] The term “Pituitary Homeobox 3” or “Pitx3” refers to a gene that encodes a RIEG / PITX homeobox family member, which belongs to the bipartite class of homeodomain proteins and acts as a transcription factor. Pitx3 is involved in the maintenance of dopaminergic neurons. The term “Pitx3” can refer to the nucleotide sequence or protein sequence of human Pitx3 (e.g., Entrez 5309, Uniprot O75364, RefSeq NM_005029.3, or RefSeq NP_005020.1). In embodiments, Pitx3 has the following amino acid sequence:

[0162]

[0163] The term “Tyrosine Hydroxylase” or “Tyrosine 3-monooxygenase” refers to an enzyme that catalyzes the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). In humans, Tyrosine Hydroxylase is encoded by the TH gene. The term “TH” can refer to the nucleotide sequence or protein sequence of human TH (e.g., Entrez 7054, Uniprot P07101, RefSeq NM_199292.2, or RefSeq NP_954986.2). In embodiments, TH has the following amino acid sequence:

[0164]

[0165] The term “Vesicular Monoamine Transporter 2” or “VMAT2” refers to an integral membrane protein that transports neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine from the cytosol to synaptic vesicles. The term “VMAT2” can refer to the nucleotide sequence or protein sequence of human VMAT2 (e.g., Entrez 6571, Uniprot Q05940, RefSeq NM_003054.4, or RefSeq NP_003045.2). In embodiments, VMAT2 has the following amino acid sequence:

[0166]

[0167] II. COMPOUNDS

[0168] In one aspect, a compound having the following formula is provided:

[0169]

[0170] Ring A is aryl or heteroaryl.

[0171] L 1 is L 101 -L 102 -L 103 .

[0172] L 101 is a bond, -S(O)2-, -N(R 101 )-, -O-, -S-, -C(O)-, -C(O)N(R 101 )-, -N(R 101 )C(O)-, -N(R 101 )C(O)NH-, -NHC(O)N(R 101 )-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, L 104 -L 105 , L 104 -NH-L 105 , or L 104 -CH2-L 105 .

[0173] L 102 is a bond, -S(O)2-, -N(R 102 )-, -O-, -S-, -C(O)-, -C(O)N(R 102 )-, -N(R 102 )C(O)-, -N(R 102 )C(O)NH-, -NHC(O)N(R 102 )-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0174] L 103 is a bond, -S(O)2-, -N(R 103 )-, -O-, -S-, -C(O)-, -C(O)N(R 103 )-, -N(R 103 )C(O)-, -N(R 103 )C(O)NH-, -NHC(O)N(R 103 )-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0175] L 104is a bond, -O-, -NH-, -S-, -S(O)2-, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0176] L 105 is a bond, -O-, -NH-, -S-, -S(O)2-, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene.

[0177] R 101 , R 102 , and R 103 are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0178] R 1 is hydrogen, halogen, -CX 1 3, -CHX 1 2, -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 1 2, -CN, -N(O) m1 , -N3, -SP(O)(OH)2, E, 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.

[0179] E is an electrophilic moiety.

[0180] R 2 independently halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 , -OCHX 2 2, -CN, -N(O) m2 , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R 2 substituents can be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0181] and independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, 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 and The substituents can be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; and and The substituents can be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0182] n1and n2are independently an integer from 0 to 4.

[0183] m1, m2, v1, and v2are independently 1 or 2.

[0184] X 1 and X 2 are independently -F, -CI, -Br, or -I.

[0185] z2is an integer from 0 to 5.

[0186] In embodiments, L 101 is a bond, -S(O)2-, -N(R 101 )-, -O-, -S-, -C(O)-, -C(O)N(R 101 )-, -N(R 101 )C(O)-, -N(R 101 )C(O)NH-, -NHC(O)N(R 101 )-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0187] In embodiments, L 101 is a bond, -S(O)2-, -N(R 101 )-, -O-, -S-, -C(O)-, -C(O)N(R 101 )-, -N(R 101 )C(O)-, -N(R 101 )C(O)NH-, -NHC(O)N(R 101 )-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., Ci-C8, Ci-C6, or Ci-C4), substituted or unsubstituted heteroalkylene (e.g., 2 to 10 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C 10or substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered), L 104 -L 105 , L 104 -NH-L 105 or L 104 -CH2-L 105 .

[0188] In embodiments, L 101 is a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHC(O)NH-, -C(O)O-, -OC(O)-, R 101 substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), R 101 substituted or unsubstituted heteroalkylene (e.g., 2 to 10 membered, 2 to 6 membered, or 2 to 4 membered), R 101 substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), R 101 substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), R 101 substituted or unsubstituted arylene (e.g., C6-C 10 or phenylene), R 101 substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered), L 104 -L 105 , L 104 -NH-L 105 or L 104 -CH2-L 105 .

[0189] In embodiments, L 102 is a bond, -S(O)2-, -N(R 102 )-, -O-, -S-, -C(O)-, -C(O)N(R 102 )-, -N(R 102 )C(O)-, -N(R 102 )C(O)NH-, -NHC(O)N(R 102)-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., Ci-C8, Ci-C6, or Ci-C4), substituted or unsubstituted heteroalkylene (e.g., 2 to 10 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C 10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0190] In embodiments, L 102 is a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHC(O)NH-, -C(O)O-, -OC(O)-, R 102 substituted or unsubstituted alkylene (e.g., Ci-C8, Ci-C6, or Ci-C4), R 102 substituted or unsubstituted heteroalkylene (e.g., 2 to 10 membered, 2 to 6 membered, or 2 to 4 membered), R 102 substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), R 102 substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), R 102 substituted or unsubstituted arylene (e.g., C6-C 10 or phenylene), or R 102 substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0191] In embodiments, L 103 is a bond, -S(O)2-, -N(R 103 )-, -O-, -S-, -C(O)-, -C(O)N(R 103 )-, -N(R 103 )C(O)-, -N(R 103 )C(O)NH-, -NHC(O)N(R 103)-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., Ci-C8, Ci-C6, or Ci-C4), substituted or unsubstituted heteroalkylene (e.g., 2 to 10 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C 10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5- to 10- membered, 5- to 9-membered, or 5- to 6-membered).

[0192] In embodiments, L 103 is a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHC(O)NH-, -C(O)O-, -OC(O)-, R 103 substituted or unsubstituted alkylene (e.g., Ci-C8, Ci-C6, or Ci-C4), R 103 substituted or unsubstituted heteroalkylene (e.g., 2 to 10 membered, 2 to 6 membered, or 2 to 4 membered), R 103 substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), R 103 substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), R 103 substituted or unsubstituted arylene (e.g., C6-C 10 or phenylene), or R 103 substituted or unsubstituted heteroarylene (e.g., 5- to 10- membered, 5- to 9-membered, or 5- to 6-membered).

[0193] In embodiments, L and independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 10 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); and and substituents can be connected to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 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).

[0194] In embodiments, and independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, R 10substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, or Ci-C4), R 10 substituted or unsubstituted heteroalkyl (e.g., 2 to 10 membered, 2 to 6 membered, or 2 to 4 membered), R 10 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 10 substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), R 10 substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 10 substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); both occurrences of R and substituents can be joined to form a substituted or unsubstituted R 10 substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), or R 10 substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0195] In embodiments, and are independently hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, or Ci-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 10 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); both occurrences of R and Substituents can join to form a substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0196] In embodiments, and independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, R 20 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), R 20 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered, 2- to 6-membered, or 2- to 4-membered), R 20 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 20 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 20 substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 20 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); and and substituents can join to form R 20 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered) or R 20 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0197] In embodiments, -L 1 -R 1 is and R 1As described herein, including in embodiments.

[0198] In embodiments, the compound is of Formula

[0199] Ring A, R 1 , R 2 , L 103 , L 104 , L 105 and z2are as described herein.

[0200] W is N or CH.

[0201] In embodiments, L 103 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0202] In embodiments, L 104 is a bond, -S(O)2-, -C(O)-, -NHC(O)-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0203] In embodiments, L 105 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene.

[0204] In embodiments, ring A is aryl (e.g., C6-C 10 or phenyl) or heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In embodiments, ring A is C6-C 10 aryl. In embodiments, ring A is phenyl. In embodiments, ring A is 5- to 10-membered heteroaryl. In embodiments, ring A is 5- to 9-membered heteroaryl. In embodiments, ring A is 5- to 6-membered heteroaryl.

[0205] In embodiments, ring A is phenyl or 5- to 10-membered heteroaryl. In embodiments, ring A is phenyl. In embodiments, ring A is naphthyl. In embodiments, ring A is quinolinyl. In embodiments, ring A is isoquinolinyl. In embodiments, ring A is benzoxazolyl. In embodiments, ring A is

[0206] In embodiments, ring A is phenyl or 5- to 10-membered heteroaryl. In embodiments, ring A is phenyl. In embodiments, ring A is naphthyl. In embodiments, ring A is quinolinyl. In embodiments, ring A is isoquinolinyl. In embodiments, ring A is benzoxazolyl. In embodiments, ring A is wherein represents -L 1 -R 1a point of attachment to -L wherein represents a point of attachment to -L 1 -R 1 a point of attachment to -L

[0207] In embodiments, ring A is phenyl or 5- to 10-membered heteroaryl. In embodiments, ring A is phenyl. In embodiments, ring A is naphthyl. In embodiments, ring A is quinolinyl. In embodiments, ring A is 3-quinolinyl. In embodiments, ring A is isoquinolinyl. In embodiments, ring A is benzoxazolyl. In embodiments, ring A is 6-benzoxazolyl.

[0208] In embodiments, the compound is of Formula

[0209] R 1 , L 103 , L 104 , L 105 and W are as described herein.

[0210] and are independently hydrogen or can independently take on any of the values of R 2 , including in embodiments.

[0211] In embodiments, and are independently hydrogen, halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 , -OCHX 2 2, -CN, -N(O) m2 , -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); and Substituents can be linked to form substituted or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl groups (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), or substituted or unsubstituted aryl groups (e.g., C6-C). 10 (or phenyl), or substituted or unsubstituted heteroaryl groups (e.g., 5 to 10 yuan, 5 to 9 yuan or 5 to 6 yuan); and Substituents can be linked to form substituted or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl groups (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), or substituted or unsubstituted aryl groups (e.g., C6-C). 10 (or phenyl), or substituted or unsubstituted heteroaryl groups (e.g., 5 to 10 yuan, 5 to 9 yuan, or 5 to 6 yuan).

[0212] In an embodiment, and Independently hydrogen, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 -OCX 2 3. -OCH2X 2 -OCHX 2 2. -CN -N(O) m2 , -N3、R 20 -substituted or unsubstituted alkyl groups (e.g., C1-C8, C1-C6, or C1-C4), R 20 -substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), R 20 -substituted or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, or C5-C6), R 20 -substituted or unsubstituted heterocyclic alkyl groups (e.g., ternary to octyl, ternary to septary, or 5 to 6 ternary), R 20 -Substituted or unsubstituted aryl groups (e.g., C6-C) 10 (or phenyl) or R 20 - Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10 yuan, 5 to 9 yuan, or 5 to 6 yuan); and Substituents can be linked to form R 20 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, or C5-C6), R 20Substituted or unsubstituted heterocyclic alkyl groups (e.g., ternary to octyl, ternary to septyl, or quinary to septyl), R 20 -Substituted or unsubstituted aryl groups (e.g., C6-C) 10 (or phenyl), or R 20 Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10 yuan, 5 to 9 yuan, or 5 to 6 yuan); and Substituents can be linked to form R 20 -substituted or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, or C5-C6), R 20 Substituted or unsubstituted heterocyclic alkyl groups (e.g., ternary to octyl, ternary to septary, or quinary to septary), R 20 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 (or phenyl), or R 20 Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10 yuan, 5 to 9 yuan, or 5 to 6 yuan).

[0213] In an embodiment, It is independently a halogen or an unsubstituted heteroalkyl group; Independently hydrogen or halogen; and Independently hydrogen, halogen, -CN, Unsubstituted heteroalkyl or substituted or unsubstituted heterocyclic alkyl.

[0214] In an embodiment, Independently, it is a halogen or an unsubstituted heteroalkyl group. In the examples, It can be hydrogen or halogen independently. In the examples, Independently hydrogen, halogen, -CN, Unsubstituted heteroalkyl or substituted or unsubstituted heterocyclic alkyl. In the examples, It is a halogen independently. In the embodiments, Independently, it is an unsubstituted heteroalkyl group. In the examples, Independently hydrogen. In the examples, It is a halogen independently. In the embodiments, Independently hydrogen. In the examples, It is a halogen independently. In the embodiments, Independently designated as -CN. In the embodiment, Independently In an embodiment, R2Z is ​​independently an unsubstituted heteroalkyl group. In the examples, R2Z is ​​independently a substituted or unsubstituted heterocyclic alkyl group.

[0215] In an embodiment, Halogens are independent of each other; Independently halogenated; and It is hydrogen independently.

[0216] In an embodiment, It is a halogen independently. In the embodiments, It is a halogen independently. In the embodiments, It is hydrogen independently.

[0217] In an embodiment, Independently halogenated or unsubstituted 2- to 4-membered heteroalkyl groups; Independently hydrogen; Independent of halogen, -CN, Unsubstituted 2- to 4-membered heteroalkyl groups or substituted or unsubstituted 5- to 6-membered heterocyclic alkyl groups; Independently hydrogen; and It is independently an unsubstituted C1-C2 alkyl group.

[0218] In an embodiment, Independently, it is a halogen or an unsubstituted 2- to 4-membered heteroalkyl group. In the examples, Independently hydrogen. In the examples, Independent of halogen, -CN, Unsubstituted 2- to 4-membered heteroalkyl groups or substituted or unsubstituted 5- to 6-membered heterocyclic alkyl groups. In the examples, Independently hydrogen. In the examples, Independently, it is an unsubstituted C1-C2 alkyl group. In the examples, It is a halogen independently. In the embodiments, Independently, it is an unsubstituted 2- to 4-membered heteroalkyl group. In the examples, It is a halogen independently. In the embodiments, Independently designated as -CN. In the embodiment, Independently In an embodiment, Independently, it is an unsubstituted 2- to 4-membered heteroalkyl group. In the examples, It is independently a substituted or unsubstituted 5- to 6-membered heterocyclic alkyl group.

[0219] In an embodiment, It can be halogenated or -OCH3 independently; Independently hydrogen; It is independently a halogen, -CN, -NHC(O)CH3, -OCH3 or a substituted or unsubstituted 5- to 6-membered heterocyclic alkyl group; Independently hydrogen; and independently hydrogen or -OCH3. In embodiments,

[0220] In embodiments, independently hydrogen or -OCH3. In embodiments, independently hydrogen. In embodiments, independently halogen, -CN, -NHC(O)CH3, -OCH3, or substituted or unsubstituted 5- to 6- membered heterocycloalkyl. In embodiments, independently hydrogen. In embodiments, independently unsubstituted C1-C2 alkyl. In embodiments, independently halogen. In embodiments, independently -OCH3. In embodiments, independently halogen. In embodiments, independently -CN. In embodiments, independently -NHC(O)CH3. In embodiments, independently -OCH3. In embodiments, independently substituted or unsubstituted 5- to 6- membered heterocycloalkyl.

[0221] In embodiments, independently hydrogen or -OCH3. In embodiments, independently hydrogen. In embodiments, independently halogen, -CN, -NHC(O)CH3, -OCH3, or substituted or unsubstituted 5- to 6- membered heterocycloalkyl. In embodiments, independently substituted or unsubstituted 5- to 6- membered heterocycloalkyl. In embodiments, independently substituted 5- to 6- membered heterocycloalkyl. In embodiments, independently hydrogen or -OCH3. In embodiments,

[0222] In embodiments, L 103 is a bond, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4) or substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L 103 is a bond. In embodiments, L 103 is substituted or unsubstituted C1-C8 alkylene. In embodiments, L 103 is substituted or unsubstituted C1-C6 alkylene. In embodiments, L 103 is substituted or unsubstituted C1-C4 alkylene. In embodiments, L 103 is substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L103 substituted or unsubstituted 2- to 6-membered heteroalkylene. In embodiments, L 103 substituted or unsubstituted 2- to 4-membered heteroalkylene.

[0223] In embodiments, L 103 unsubstituted alkylene. In embodiments, L 103 unsubstituted C1-C4 alkylene. In embodiments, L 103 unsubstituted ethylene.

[0224] In embodiments, L 103 a bond, R 103 substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4) or R 103 substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).

[0225] In embodiments, R 101 , R 102 , and R 103 independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 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-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0226] In embodiments, R101 R 102 and R 103 independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 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-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0227] In embodiments, R 101 independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, R 111 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R 111substituted 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 111 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R 111 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 111 substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 111 substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0228] R 101 independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, R 111 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R 111 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 111 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R 111 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 111 substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 111 substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0229] R 111independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, or Ci-C4), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0230] In embodiments, R 101 independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, or Ci-C4), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C 10or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0231] In embodiments, R 102 independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, R 112 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R 112 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 112 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R 112 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 112 substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl) or R 112 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0232] In embodiments, R 102independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, R 112 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R 112 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 112 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R 112 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 112 substituted or unsubstituted aryl (e.g., C6-C 16 or phenyl), or R 112 substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0233] R 112independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, or Ci-C4), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0234] In embodiments, R 102 independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, or Ci-C4), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C 10substituted or unsubstituted aryl (e.g., C6-C10, C6-C9, or C6-C8) or R

[0235] In embodiments, R 103 independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH2, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, R 113 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), R 113 substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), R 113 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 113 substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), R 113 substituted or unsubstituted aryl (e.g., C6-C 10 or R 113 substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0236] In embodiments, R 103independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH2, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, R 113 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), R 113 substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), R 113 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 113 substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), R 113 substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 113 substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0237] R 113independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, or Ci-C4), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0238] In embodiments, R 103 independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, or Ci-C4), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C 10or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0239] In embodiments, L 104 is a bond, -S(O)2-, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0240] In embodiments, L 104 is a bond, -O-, -NH-, -S-, -S(O)2-, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), or substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered). In embodiments, L 104 is a bond. In embodiments, L 104 is -O-. In embodiments, L 104 is -NH-. In embodiments, L 104 is -S-. In embodiments, L 104 is -S(O)2-. In embodiments, L 104 is -C(O)-. In embodiments, L 104 is -NHC(O)-. In embodiments, L 104 is -C(O)NH-. In embodiments, L 104 is -OC(O)-. In embodiments, L 104 is -C(O)O-. In embodiments, L 104 is substituted or unsubstituted C1-C8 alkylene. In embodiments, L 104 is substituted or unsubstituted C1-C6 alkylene. In embodiments, L 104 is substituted or unsubstituted C1-C4 alkylene. In embodiments, L 104 is substituted or unsubstituted 2- to 8-membered heteroalkylene. In embodiments, L 104 is substituted or unsubstituted 2- to 6-membered heteroalkylene. In embodiments, L 104 is substituted or unsubstituted 2- to 4-membered heteroalkylene. In embodiments, L 104 is unsubstituted C1-C8 alkylene. In embodiments, L 104 is unsubstituted 2- to 8-membered heteroalkylene.

[0241] In embodiments, L 104is a bond, -S(O)2-, -C(O)-, -NHC(O)-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), or substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L 104 is a bond. In embodiments, L 104 is -S(O)2-. In embodiments, L 104 is -C(O)-. In embodiments, L 104 is -NHC(O)-. In embodiments, L 104 is -OC(O)-. In embodiments, L 104 is substituted or unsubstituted C1-C8 alkylene. In embodiments, L 104 is substituted or unsubstituted C1-C6 alkylene. In embodiments, L 104 is substituted or unsubstituted C1-C4 alkylene. In embodiments, L 104 is substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L 104 is substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 104 is substituted or unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L 104 is unsubstituted C1-C8 alkylene. In embodiments, L 104 is unsubstituted 2 to 8 membered heteroalkylene.

[0242] In embodiments, L 104 is a bond, -O-, -NH-, -S-, -S(O)2-, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, R 104 substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), or R 104 substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).

[0243] In embodiments, L 104 is a bond, -S(O)2-, -C(O)-, -NHC(O)-, -OC(O)-, R 104 substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), or R 104 substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).

[0244] R 104independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH2, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, or Ci-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0245] In embodiments, R 104 independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH2, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, R 114 substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, or Ci-C4), R 114 substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), R114 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 114 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 114 substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 114 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0246] R 114 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH2, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0247] In embodiments, L 105 is a bond, -O-, -NH-, -S-, -S(O)2-, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), or substituted or unsubstituted heterocycloalkylene (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered).

[0248] In embodiments, L 105 is a bond, -O-, -NH-, -S-, -S(O)2-, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, substituted or unsubstituted alkylene (e.g., Ci-C8, Ci-C6, or Ci-C4), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), or substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, L 105 is a bond. In embodiments, L 105 is -O-. In embodiments, L 105 is -NH-. In embodiments, L 105 is -S-. In embodiments, L 105 is -S(O)2-. In embodiments, L 105 is -C(O)-. In embodiments, L 105 is -NHC(O)-. In embodiments, L 105 is -C(O)NH-. In embodiments, L 105 is -OC(O)-. In embodiments, L 105 is -C(O)O-. In embodiments, L 105 is substituted or unsubstituted Ci-C8alkylene. In embodiments, L 105 is substituted or unsubstituted Ci-C6alkylene. In embodiments, L 105 is substituted or unsubstituted Ci-C4alkylene. In embodiments, L 105 is substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L 105 is substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 105 is substituted or unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L 105 is substituted or unsubstituted C3-C8 cycloalkylene. In embodiments, L 105 is substituted or unsubstituted C3-C6 cycloalkylene. In embodiments, L 105 is substituted or unsubstituted C5-C6 cycloalkylene. In embodiments, L 105 is substituted or unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L 105 is substituted or unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, L 105It is a substituted or unsubstituted 5- to 6-membered heterocyclic alkyl group. In the examples, L 105 It is an unsubstituted C1-C8 alkylene group. In the examples, L 105 It is an unsubstituted 2- to 8-membered heteroalkylene group. In the examples, L 105 It is an unsubstituted C3-C8 cycloalkylene group. In the examples, L 105 It is an unsubstituted 3- to 8-membered heterocyclic alkyl group.

[0249] In the embodiment, L 105 The alkylene group is a bond, substituted or unsubstituted alkylene group (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene group (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), substituted or unsubstituted cycloalkylene group (e.g., C3-C8, C3-C6, or C5-C6), or substituted or unsubstituted heteroalkylene group (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered). In the examples, L 105 As a key. In the embodiment, L 105 It is a substituted or unsubstituted C1-C8 alkylene group. In the examples, L 105 It is a substituted or unsubstituted C1-C6 alkylene group. In the examples, L 105 It is a substituted or unsubstituted C1-C4 alkylene group. In the examples, L 105 It is a substituted or unsubstituted 2- to 8-membered heteroalkylene group. In the examples, L 105 It is a substituted or unsubstituted 2- to 6-membered heteroalkylene group. In the examples, L 105 It is a substituted or unsubstituted 2- to 4-membered heteroalkylene group. In the examples, L 105 It is a substituted or unsubstituted C3-C8 cycloalkylene group. In the examples, L 105 It is a substituted or unsubstituted C3-C6 cycloalkylene group. In the examples, L 105 It is a substituted or unsubstituted C5-C6 cycloalkylene group. In the examples, L 105 It is a substituted or unsubstituted 3- to 8-membered heterocyclic alkyl group. In the examples, L 105 It is a substituted or unsubstituted 3- to 6-membered heterocyclic alkyl group. In the examples, L 105 It is a substituted or unsubstituted 5- to 6-membered heterocyclic alkyl group. In the examples, L 105 It is an unsubstituted C1-C8 alkylene group. In the examples, L 105 It is an unsubstituted 2- to 8-membered heteroalkylene group. In the examples, L 105 It is an unsubstituted C3-C8 cycloalkylene group. In the examples, L 105substituted 3- to 8-membered heterocycloalkylene.

[0250] In embodiments, L 105 substituted C1-C4 alkylene. In embodiments, L 105 substituted C1-C4 alkylene. In embodiments, L 105 In embodiments, L 105

[0251] In embodiments, L 105 a bond, -O-, -NH-, -S-, -S(O)2-, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, R 105 substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), R 105 substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), R 105 substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), or R 105 substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered).

[0252] In embodiments, L 105 a bond, R 105 substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), R 105 substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), R 105 substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), or R 105 substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered).

[0253] R 105 ​​independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH2, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, or Ci-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0254] In embodiments, R 105 independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH2, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, R 115 substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, or Ci-C4), R 115 substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), R115 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 115 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 115 substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 115 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0255] R 115 independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH2, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0256] In embodiments, W is N. In embodiments, W is CH.

[0257] In embodiments, is

[0258] In embodiments, is In embodiments, is In embodiments, is In embodiments, is

[0259] In embodiments, is

[0260] In embodiments, is In embodiments, is In embodiments, is In embodiments, is In embodiments, is In embodiments, is In embodiments, is In embodiments, is

[0261] In embodiments, R 1 is hydrogen, halogen, -CX 1 3, -CHX 1 2, -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 1 2, -CN, -N(O) m1 , -N3, E, 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.

[0262] In embodiments, R 1 is hydrogen, halogen, -CX 1 3, -CHX 1 2, -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 1 2, -CN, -N(O) m1 , -N3, E, 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.

[0263] In embodiments, R 1 is hydrogen, halogen, -CX 1 3, -CHX 1 2, -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 1 2, -CN, -N(O) m1 , -N3, -SP(O)(OH)2, E, substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, or Ci-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 10 members, 2 to 6 members, or 2 to 4 members), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members).

[0264] In embodiments, R 1 is hydrogen, halogen, -CX 1 3, -CHX 1 2, -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 1 2, -CN, -N(O) m1 , -N3, -SP(O)(OH)2, E, R 10 substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, or Ci-C4), R 10 substituted or unsubstituted heteroalkyl (e.g., 2 to 10 members, 2 to 6 members, or 2 to 4 members), R 10 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 10Substituted or unsubstituted heterocyclic alkyl groups (e.g., ternary to octyl, ternary to septary, or quinary to septary), R 10 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 (or phenyl) or R 10 Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10 yuan, 5 to 9 yuan, or 5 to 6 yuan).

[0265] In the embodiment, R 1 Independently

[0266] In the embodiment, R 1 Independently

[0267] In an embodiment, Independently, it can be hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC( O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -N3, -PO3H2, substituted or unsubstituted alkyl groups (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl groups (e.g., 2- to 10-membered, 2- to 6-membered, or 2- to 4-membered), substituted or unsubstituted aryl groups (e.g., C6-C... 10 (or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9 or 5 to 6).

[0268] In an embodiment, independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -N3, -PO3H2, R 10 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), R 10 substituted or unsubstituted heteroalkyl (e.g., 2 to 10 membered, 2 to 6 membered, or 2 to 4 membered), R 10 substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 10 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0269] In embodiments, independently substituted or unsubstituted C1-C4 alkyl. In embodiments, independently unsubstituted C1-C4 alkyl. In embodiments, independently unsubstituted methyl. In embodiments, independently unsubstituted ethyl. In embodiments, independently unsubstituted propyl. In embodiments, independently unsubstituted n-propyl. In embodiments, independently unsubstituted isopropyl. In embodiments, independently unsubstituted butyl. In embodiments, independently unsubstituted n-butyl. In embodiments, independently unsubstituted t-butyl.

[0270] In embodiments, independently substituted or unsubstituted aryl. In embodiments, independently R 10 substituted or unsubstituted aryl. In embodiments, independently R 10substituted or unsubstituted phenyl. In embodiments, independently unsubstituted phenyl.

[0271] In embodiments, R 1 independently and As described herein, included in embodiments. In embodiments, R 1 independently -C(O)OH. In embodiments, R 1 independently -C(O)NH2.

[0272] In embodiments, R 1 is

[0273] In embodiments, independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -N3, -PO3H2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), or substituted or unsubstituted heteroalkyl (e.g., 2 to 10 membered, 2 to 6 membered, or 2 to 4 membered).

[0274] In embodiments, independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -N3, -PO3H2, R 10 substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, or Ci-C4) or R 10 substituted or unsubstituted heteroalkyl (e.g., 2 to 10 membered, 2 to 6 membered, or 2 to 4 membered).

[0275] In embodiments, independently substituted or unsubstituted alkyl. In embodiments, independently R 10 substituted or unsubstituted alkyl. In embodiments, independently R 10 substituted or unsubstituted Ci-C 16 alkyl. In embodiments, independently unsubstituted Ci-C 16 alkyl.

[0276] In embodiments, R 1 is E, unsubstituted alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl; independently hydrogen or unsubstituted Ci-C4alkyl; independently hydrogen or unsubstituted Ci-C4alkyl; and Independently, it can be hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC( -NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -N3, -PO3H2 or substituted or unsubstituted alkyl groups (e.g., C1-C8, C1-C6 or C1-C4).

[0277] In the embodiment, R 1 for E. Unsubstituted alkyl groups, substituted or unsubstituted phenyl groups, or substituted or unsubstituted 5- to 6-membered heteroaryl groups. In the examples, Independently hydrogen or unsubstituted C1-C4 alkyl. In the examples, Independently hydrogen or unsubstituted C1-C4 alkyl. In the examples, Independently, it can be hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC( -NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -N3, -PO3H2 or substituted or unsubstituted alkyl groups (e.g., C1-C8, C1-C6 or C1-C4).

[0278] In the embodiment, R 1 for E, unsubstituted C1-C4 alkyl, R 10 Substituted or unsubstituted phenyl or R 10substituted or unsubstituted 5- to 6-membered heteroaryl; independently hydrogen or unsubstituted C1-C4alkyl; independently hydrogen or unsubstituted C1-C4alkyl; and independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -N3, -PO3H2, R 10 substituted or unsubstituted C1-C4alkyl.

[0279] In embodiments, R 1 is E, unsubstituted C1-C4alkyl, R 10 substituted or unsubstituted phenyl or R 10 substituted or unsubstituted 5- to 6-membered heteroaryl. In embodiments, independently hydrogen or unsubstituted C1-C4alkyl. In embodiments, independently hydrogen or unsubstituted C1-C4alkyl. In embodiments, independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -N3, -PO3H2, R 10 substituted or unsubstituted C1-C4alkyl.

[0280] R 10 independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5- to 6- membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). 10 or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0281] In embodiments, R 1 is or R 10 substituted phenyl; independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -N3, -PO3H2, R 10 substituted or unsubstituted C1-C4 alkyl; and R 10independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted C1-C4alkyl, unsubstituted 2- to 4-membered heteroalkyl, unsubstituted C5-C6cycloalkyl, unsubstituted 5- to 6-membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5- to 6-membered heteroaryl.

[0282] In embodiments, R 1 is or R 10 substituted phenyl. In embodiments, independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -N3, -PO3H2, R 10 substituted or unsubstituted C1-C4alkyl. In embodiments, R 10independently -F. In embodiments, R is independently -Cl. In embodiments, R is independently -Br. In embodiments, R is independently -I. In embodiments, R is independently -NO2. In embodiments, R is independently -SH. In embodiments, R is independently -SeH. In embodiments, R is independently -SO3H. In embodiments, R is independently -SC(O)CH3. In embodiments, R is independently -SSCH3.

[0283] In embodiments, R 1 is -SH, -SC(O)CH3, or -SSCH3. In embodiments, R 1 is -SH. In embodiments, R 1 is -SC(O)CH3. In embodiments, R 1 is -SSCH3.

[0284] In embodiments, R 1 is independently halogen, -NO2, -SH, -SeH, -SO3H, -SC(O)CH3, -SSCH3, -SP(O)(OH)2, R 10 substituted or unsubstituted heteroalkyl, or R 10 substituted or unsubstituted heteroaryl; and R 10 As described herein, including in embodiments. In embodiments, R 1 is independently -F. In embodiments, R 1 is independently -Cl. In embodiments, R 1 is independently -Br. In embodiments, R 1 is independently -I. In embodiments, R 1 is independently -NO2. In embodiments, R 1 is independently -SH. In embodiments, R 1 is independently -SeH. In embodiments, R 1 is independently -SO3H. In embodiments, R 1 is independently -SC(O)CH3. In embodiments, R 1independently -SCH3. In embodiments, R 1 independently -SP(O)(OH)2. In embodiments, R 1 independently -SCH3. In embodiments, R 10 substituted or unsubstituted heteroalkyl. In embodiments, R 1 independently -SCH3. In embodiments, R 10 substituted or unsubstituted 2 to 20 membered heteroalkyl. In embodiments, R 1 independently -SCH3. In embodiments, R 10 substituted 2 to 20 membered heteroalkyl. In embodiments, R 1 independently unsubstituted 2 to 20 membered heteroalkyl. In embodiments, R 1 independently -S-(C1-C 20 alkyl). In embodiments, R 1 independently -SCH3. In embodiments, R 1 independently -S(O)2CH3. In embodiments, R 1 independently -Si(CH3)3. In embodiments, R wherein m is independently an integer from 0 to 4. In embodiments, R 1 independently -Si(CH3)3. In embodiments, R independently -Si(CH3)3. In embodiments, R 1 independently -Si(CH3)3. In embodiments, R 1 independently -Si(CH3)3. In embodiments, R 1 independently -Si(CH3)3. In embodiments, R 1 independently -Si(CH3)3. In embodiments, R 1 independently -Si(CH3)3. In embodiments, R 1 independently -Si(CH3)3. In embodiments, R 1 independently -Si(CH3)3. In embodiments, R 10 substituted or unsubstituted heteroaryl. In embodiments, R 1 independently -Si(CH3)3. In embodiments, R 10 substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 1 independently unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 1 independently unsubstituted phenylthio. In embodiments, R 1 independently unsubstituted furanyl. In embodiments, R 1 independently unsubstituted pyrrolyl. In embodiments, R 1 independently unsubstituted imidazolyl. In embodiments, R 1 independently unsubstituted tetrazolyl. In embodiments, R1 Independently In the embodiment, R 1 Independently In the embodiment, R 1 Independently

[0285] In the embodiment, R 1 For R 10 Substituted phenyl groups, and R 10 Independently, it is a halogen. In the embodiments, R 1 for Where R 10.1 and R 10.2 They can each be hydrogen or R as described in this article, independently. 10 Any value of R is included in the embodiments. In the embodiments, R 10.1 and R 10.2 Each is an independent halogen. In the embodiments, R 1 for

[0286] In the embodiment, R 1 Independently for R 10 Substituted or unsubstituted 2- to 8-membered heteroalkyl groups, and R 10 As described herein, it is included in the embodiments. In the embodiments, R 1 Independently for R 10 Substituted 2- to 8-membered heteroalkyl groups, and R 10 Independently an oxo group. In the examples, R 1 Independently -NHC(O)-(R 10 (substituted or unsubstituted C1-C4 alkyl groups). In the examples, R 1 Independently -NHC(O)-(R 10 Substituted C1-C4 alkyl groups). In the examples, R 1 Independently -NHC(O)- (unsubstituted C1-C4 alkyl). In the examples, R 1 Independently In the embodiment, R 1 Independently In the embodiment, R 1 Independently In the embodiment, R 1 Independently In the embodiment, R 1 Independently -NHS(O)2- (unsubstituted C1-C4 alkyl). In the examples, R 1 Independently

[0287] In the embodiment, R1 E is F.

[0288] In embodiments, E is

[0289] R 16 independently hydrogen, halogen, -CX 16 3, -CHX 16 2, -CH2X 16 , -CN, -N(O) m16 , -OCX 16 3, -OCHX 16 2, -OCH2X 16 , substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, Ci-C4, or Ci-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-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-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10- membered, 5- to 9- membered, or 5- to 6- membered).

[0290] R 17 independently hydrogen, halogen, -CX 17 3, -CHX 17 2, -CH2X 17 , -CN, -N(O) m17 , -OCX 17 3, -OCHX 17 2, -OCH2X 17 , substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, Ci-C4, or Ci-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-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 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0291] R 18 independently hydrogen, halogen, -CX 18 3, -CHX 18 2, -CH2X 18 , -CN, -N(O) m18 , -OCHX 18 2, -OCH2X 18 , 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-C 10 or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0292] R 19 independently hydrogen, halogen, -CX 19 3, -CHX 19 2, -CH2X 19 , -CN, -N(O) m19 , -OCX 19 3, -OCHX 19 2, -OCH2X 19 , 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-C 10(or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9 or 5 to 6).

[0293] and Independently, it is hydrogen, -CX3, -CHX2, -CH2X, -CN, -OH, -COOH, -CONH2, 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-C... 10 (or phenyl) or substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-, 5- to 9-, or 5- to 6-membered); bonded to the same nitrogen atom and Substituents may optionally be linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; those linked to the same nitrogen atom and Substituents may optionally be linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; those linked to the same nitrogen atom and Substituents may optionally be linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; those linked to the same nitrogen atom and Substituents may optionally be linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups.

[0294] X, X 16 X 17 X 18 and X 19 It can be -F, -Cl, -Br, or -I independently.

[0295] n16, n17, n18, and n19 are independent integers from 0 to 4.

[0296] m16, m17, m18, m19, v16, v17, v18, and v19 are independently 1 or 2.

[0297] In the embodiment, R 16 Independently hydrogen, halogen, -CX 16 3. -CHX 162, -CH2X 16 , -CN, -N(O) m16 , -OCX 16 3, -OCHX 16 2, -OCH2X 16 , substituted (e.g., with at least one substitutent, size-limited substitutent, or lower substitutent) or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, Ci-C4, or Ci-C2), substituted (e.g., with at least one substitutent, size-limited substitutent, or lower substitutent) 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 (e.g., with at least one substitutent, size-limited substitutent, or lower substitutent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., with at least one substitutent, size-limited substitutent, or lower substitutent) 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 (e.g., with at least one substitutent, size-limited substitutent, or lower substitutent) or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted (e.g., with at least one substitutent, size-limited substitutent, or lower substitutent) or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0298] In embodiments, substituted R 16 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substitutent, size-limited substitutent, or lower substitutent; wherein each substitutent, size-limited substitutent, and / or lower substitutent can optionally be different if substituted R 16 is substituted with multiple groups selected from substitutents, size-limited substitutents, and lower substitutents. In embodiments, when R 16 is substituted, it is substituted with at least one substitutent. In embodiments, when R 16 is substituted, it is substituted with at least one size-limited substitutent. In embodiments, when R 16 is substituted, it is substituted with at least one lower substitutent.

[0299] In embodiments, R 16independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, 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-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0300] In embodiments, R 17 is independently hydrogen, halogen, -CX 17 3, -CHX 17 2, -CH2X 17 , -CN, -N(O) m17 , -OCX 17 3, -OCHX 17 2, -OCH2X 17, substituted (e.g., with at least one substitutent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, Ci-C4, or Ci-C2), substituted (e.g., with at least one substitutent, size-limited substituent, or lower substituent) 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 (e.g., with at least one substitutent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., with at least one substitutent, size-limited substituent, or lower substituent) 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 (e.g., with at least one substitutent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 or phenyl) or substituted (e.g., with at least one substitutent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0301] In embodiments, substituted R 17 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substitutent, size-limited substituent, or lower substituent; wherein each substitutent, size-limited substituent, and / or lower substituent can optionally be different if substituted R 17 is substituted with multiple groups selected from substitutents, size-limited substitutents, and lower substitutents. In embodiments, when R 17 is substituted, it is substituted with at least one substitutent. In embodiments, when R 17 is substituted, it is substituted with at least one size-limited substitutent. In embodiments, when R 17 is substituted, it is substituted with at least one lower substitutent.

[0302] In embodiments, R 17independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, 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-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0303] In embodiments, R 18 independently hydrogen, halogen, -CX 18 3, -CHX 18 2, -CH2X 18 , -CN, -N(O) m18 , -OCX 18 9, -OCHX 18 2, -OCH2X 18, substituted (e.g., with at least one substitutent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, Ci-C4, or Ci-C2), substituted (e.g., with at least one substitutent, size-limited substituent, or lower substituent) 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 (e.g., with at least one substitutent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., with at least one substitutent, size-limited substituent, or lower substituent) 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 (e.g., with at least one substitutent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 or phenyl) or substituted (e.g., with at least one substitutent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0304] In embodiments, substituted R 18 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substitutent, size-limited substituent, or lower substituent; wherein each substitutent, size-limited substituent, and / or lower substituent can optionally be different if substituted R 18 is substituted with multiple groups selected from substitutents, size-limited substitutents, and lower substitutents. In embodiments, when R 18 is substituted, it is substituted with at least one substitutent. In embodiments, when R 18 is substituted, it is substituted with at least one size-limited substitutent. In embodiments, when R 18 is substituted, it is substituted with at least one lower substitutent.

[0305] In embodiments, R 18independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, 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-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0306] In embodiments, R 19 independently hydrogen, halogen, -CX 19 3, -CHX 19 2, -CH2X 19 , -CN, -N(O) m19 , -OCX 19 3, -OCHX 19 2, -OCH2X 19, substituted (e.g., with at least one substitutent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, Ci-C4, or Ci-C2), substituted (e.g., with at least one substitutent, size-limited substituent, or lower substituent) 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 (e.g., with at least one substitutent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., with at least one substitutent, size-limited substituent, or lower substituent) 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 (e.g., with at least one substitutent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 or phenyl) or substituted (e.g., with at least one substitutent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0307] In embodiments, substituted R 19 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substitutent, size-limited substituent, or lower substituent; wherein each substitutent, size-limited substituent, and / or lower substituent can optionally be different if substituted R 19 is substituted with multiple groups selected from substitutents, size-limited substitutents, and lower substitutents. In embodiments, when R 19 is substituted, it is substituted with at least one substitutent. In embodiments, when R 19 is substituted, it is substituted with at least one size-limited substitutent. In embodiments, when R 19 is substituted, it is substituted with at least one lower substitutent.

[0308] In embodiments, R 19independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, 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-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0309] In embodiments, 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-C 10or substituted (e.g., with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0310] In embodiments, substituted (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 each substituent group, size-limited substituent group, and / or lower substituent group can optionally be different. In embodiments, when 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 can optionally be different. In embodiments, when substituted, it is substituted with at least one substituent group. In embodiments, when substituted, it is substituted with at least one size-limited substituent group. In embodiments, when substituted, it is substituted with at least one lower substituent group.

[0311] In embodiments, is independently hydrogen, -CX3, -CHX2, -CH2X, -CN, -OH, -COOH, -CONH2, substituted (e.g., with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., with at least one substituent group, size-limited substituent group, or lower substituent group) 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 (e.g., with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., with at least one substituent group, size-limited substituent group, or lower substituent group) 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 (e.g., with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., C6-C 10 or substituted (e.g., with at least one substituent group, size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0312] In embodiments, substituted (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent; wherein if the substituted substituted with multiple groups selected from substituent, size-limited substituent, and lower substituent; then each substituent, size-limited substituent, and / or lower substituent can optionally be different. In embodiments, when the substituted substituted, it is substituted with at least one substituent. In embodiments, when the substituted substituted, it is substituted with at least one size-limited substituent. In embodiments, when the substituted substituted, it is substituted with at least one lower substituent.

[0313] In embodiments, the and substituents can optionally be joined to form a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl or a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl.

[0314] In embodiments, the and substituents are joined to form a substituted moiety (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) that is substituted with at least one substituent, size-limited substituent, or lower substituent; wherein if the substituted moiety formed by joining the and substituents is substituted with multiple groups selected from substituent, size-limited substituent, and lower substituent; then each substituent, size-limited substituent, and / or lower substituent can optionally be different. In embodiments, when the moiety formed by joining the and substituents is substituted, the moiety is substituted with at least one substituent. In embodiments, when the moiety formed by joining the and substituents is substituted, the moiety is substituted with at least one size-limited substituent. In embodiments, when the moiety formed by joining the and substituents is substituted, the moiety is substituted with at least one lower substituent.

[0315] In embodiments, the independently hydrogen, -CX3, -CHX2, -CH2X, -CN, -OH, -COOH, -CONH2, substituted (e.g., with at least one substitutent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., with at least one substitutent, size-limited substituent, or lower substituent) 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 (e.g., with at least one substitutent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., with at least one substitutent, size-limited substituent, or lower substituent) 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 (e.g., with at least one substitutent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 or phenyl) or substituted (e.g., with at least one substitutent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0316] In embodiments, substituted (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substitutent, size-limited substituent, or lower substituent; wherein each substitutent, size-limited substituent, and / or lower substituent can optionally be different. In embodiments, when substituted with a plurality of groups selected from substitutents, size-limited substitutents, and lower substitutents; each substitutent, size-limited substitutent, and / or lower substitutent can optionally be different. In embodiments, when substituted, it is substituted with at least one substitutent. In embodiments, when substituted, it is substituted with at least one size-limited substitutent. In embodiments, when substituted, it is substituted with at least one lower substitutent.

[0317] In embodiments, independently hydrogen, -CX3, -CHX2, -CH2X, -CN, -OH, -COOH, -CONH2, substituted (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) 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 (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) 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 (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0318] In embodiments, substituted (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group; wherein each substituent group, size-limited substituent group, and / or lower substituent group can optionally be different. In embodiments, when 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 can optionally be different. In embodiments, when substituted, it is substituted with at least one substituent group. In embodiments, when substituted, it is substituted with at least one size-limited substituent group. In embodiments, when substituted, it is substituted with at least one lower substituent group.

[0319] In embodiments, R1and R2, R2and R3, R3and R4, R4and R5, R5and R6, R6and R7, R7and R8, R8and R9, R9and R10, R10and R11, R11and R12, R12and R13, R13and R14, R14and R15, R15and R16, R16and R17, R17and R18, R18and R19, R19and R20, R20and R21, R21and R22, R22and R23, R23and R24, R24and R25, R25and R26, R26and R27, R27and R28, R28and R29, R29and R30, R30and R31, R31and R32, R32and R33, R33and R34, R34and R35, R35and R36, R36and R37, R37and R38, R38and R39, R39and R40, R40and R41, R41and R42, R42and R43, R43and R44, R44and R45, R45and R46, R46and R47, R47and R48, R48and R49, R49and R50, R50and R51, R51and R52, R52and R53, R53and R54, R54and R55, R55and R56, R56and R57, R57and R58, R58and R59, R59and R60, R60and R61, R61and R62, R62and R63, R63and R64, R64and R65, R65and R66, R66and R67, R67and R68, R68and R69, R69and R70, R70and R71, R71and R72, R72and R73, R73and R74, R74and R75, R75and R76, R76and R77, R77and R78, R78and R79, R79and R80, R80and R81, R81and R82, R82and R83, R83and R84, R84and R85, R85and R86, R86and R87, R87and R88, R88and R89, R89and R90, R90and R91, R91and R92, R92and R93, R93and R94, R94and R95, R95and R96, R96and R97, R97and R98, R98and R99, and / or R99and R100are optionally connected to form a substituted (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) or unsubstituted heterocycloalkyl or a substituted (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) or unsubstituted heteroaryl. and substituent groups can optionally be connected to form a substituted (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) or unsubstituted heterocycloalkyl or a substituted (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) or unsubstituted heteroaryl.

[0320] In an embodiment, by connecting with the same nitrogen atom and The substituted portion formed by the linkage of substituents (e.g., a substituted heterocyclic alkyl and / or a substituted heteroaryl) is substituted by at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituent is linked to the same nitrogen atom... and The substituted portion formed by the linkage of substituents is replaced by a plurality of groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In an embodiment, when the substituents are linked to the same nitrogen atom... and When a portion formed by the connection of substituents is substituted, the portion is substituted by at least one substituent. In an embodiment, when the substituent is connected to the same nitrogen atom... and When a portion formed by substituent linkage is substituted, the portion is substituted by at least one size-restricted substituent. In an embodiment, when the substituent is linked to the same nitrogen atom... and When a portion formed by substituent linkage is substituted, the portion is substituted by at least one lower substituent.

[0321] In an embodiment, Independently hydrogen, -CX3, -CHX2, -CH2X, -CN, -OH, -COOH, -CONH2, substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) 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 (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) 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 (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C8, C3-C6, C4-C6, or C5-C6 ...). 10 (or phenyl) or substituted (e.g., substituted by at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9, or 5 to 6).

[0322] In embodiments, substituted (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substitutent, size-limited substituent, or lower substituent; wherein if substituted with multiple groups selected from substitutent, size-limited substituent, and lower substituent; then each substitutent, size-limited substituent, and / or lower substituent can optionally be different. In embodiments, when is substituted, it is substituted with at least one substitutent. In embodiments, when is substituted, it is substituted with at least one size-limited substitutent. In embodiments, when is substituted, it is substituted with at least one lower substitutent.

[0323] In embodiments, is independently hydrogen, -CX3, -CHX2, -CH2X, -CN, -OH, -COOH, -CONH2, substituted (e.g., substituted with at least one substitutent, size-limited substitutent, or lower substitutent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with at least one substitutent, size-limited substitutent, or lower substitutent) 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 (e.g., substituted with at least one substitutent, size-limited substitutent, or lower substitutent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with at least one substitutent, size-limited substitutent, or lower substitutent) 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 (e.g., substituted with at least one substitutent, size-limited substitutent, or lower substitutent) or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted (e.g., substituted with at least one substitutent, size-limited substitutent, or lower substitutent) or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0324] In embodiments, substituted (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substitutent, size-limited substituent, or lower substituent; wherein if substituted substituents, size-limited substituents, and lower substituents; then each substituent, size-limited substituent, and / or lower substituent can optionally be different. In embodiments, when a moiety formed by linking substituents attached to the same nitrogen atom is substituted, the moiety is substituted with at least one substituent. In embodiments, when a moiety formed by linking substituents attached to the same nitrogen atom is substituted, the moiety is substituted with at least one size-limited substituent. In embodiments, when a moiety formed by linking substituents attached to the same nitrogen atom is substituted, the moiety is substituted with at least one lower substituent. substituted, it is substituted with at least one substituent. In embodiments, when substituted, it is substituted with at least one size-limited substituent. In embodiments, when substituted, it is substituted with at least one lower substituent.

[0325] In embodiments, substituents attached to the same nitrogen atom are linked to form a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl or a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl. and substituents can optionally be linked to form a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl or a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl.

[0326] In embodiments, a moiety formed by linking substituents attached to the same nitrogen atom is substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent). In embodiments, when a moiety formed by linking substituents attached to the same nitrogen atom is substituted, the moiety is substituted with at least one substituent. In embodiments, when a moiety formed by linking substituents attached to the same nitrogen atom is substituted, the moiety is substituted with at least one size-limited substituent. In embodiments, when a moiety formed by linking substituents attached to the same nitrogen atom is substituted, the moiety is substituted with at least one lower substituent. and substituents can optionally be linked to form a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl or a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl. and substituents can optionally be linked to form a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl or a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl. and substituents can optionally be linked to form a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl or a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl. and substituents can optionally be linked to form a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl or a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl. and substituents can optionally be linked to form a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl or a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl.

[0327] In embodiments, a moiety formed by linking substituents attached to the same nitrogen atom is substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent). In embodiments, when a moiety formed by linking substituents attached to the same nitrogen atom is substituted, the moiety is substituted with at least one substituent. In embodiments, when a moiety formed by linking substituents attached to the same nitrogen atom is substituted, the moiety is substituted with at least one size-limited substituent. In embodiments, when a moiety formed by linking substituents attached to the same nitrogen atom is substituted, the moiety is substituted with at least one lower substituent. independently hydrogen, -CX3, -CHX2, -CH2X, -CN, -OH, -COOH, -CONH2, substituted (e.g., substituted with at least one substitutent, size-limited substitutent, or lower substitutent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with at least one substitutent, size-limited substitutent, or lower substitutent) 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 (e.g., substituted with at least one substitutent, size-limited substitutent, or lower substitutent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with at least one substitutent, size-limited substitutent, or lower substitutent) 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 (e.g., substituted with at least one substitutent, size-limited substitutent, or lower substitutent) or unsubstituted aryl (e.g., C6-C 10 or phenyl) or substituted (e.g., substituted with at least one substitutent, size-limited substitutent, or lower substitutent) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0328] In embodiments, substituted (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substitutent, size-limited substitutent, or lower substitutent; wherein each substitutent, size-limited substitutent, and / or lower substitutent can optionally be different. In embodiments, when substituted with a plurality of groups selected from substitutents, size-limited substitutents, and lower substitutents; each substitutent, size-limited substitutent, and / or lower substitutent can optionally be different. In embodiments, when substituted, it is substituted with at least one substitutent. In embodiments, when substituted, it is substituted with at least one size-limited substitutent. In embodiments, when substituted, it is substituted with at least one lower substitutent.

[0329] In embodiments, independently hydrogen, -CX3, -CHX2, -CH2X, -CN, -OH, -COOH, -CONH2, substituted (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) 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 (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) 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 (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0330] In embodiments, substituted (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group; wherein each substituent group, size-limited substituent group, and / or lower substituent group can optionally be different. In embodiments, when 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 can optionally be different. In embodiments, when substituted, it is substituted with at least one substituent group. In embodiments, when substituted, it is substituted with at least one size-limited substituent group. In embodiments, when substituted, it is substituted with at least one lower substituent group.

[0331] In embodiments, R1and R2, R2and R3, R3and R4, R4and R5, R5and R6, R6and R7, R7and R8, R8and R9, R9and R10, R10and R11, R11and R12, R12and R13, R13and R14, R14and R15, R15and R16, R16and R17, R17and R18, R18and R19, R19and R20, R20and R21, R21and R22, R22and R23, R23and R24, R24and R25, R25and R26, R26and R27, R27and R28, R28and R29, R29and R30, R30and R31, R31and R32, R32and R33, R33and R34, R34and R35, R35and R36, R36and R37, R37and R38, R38and R39, R39and R40, R40and R41, R41and R42, R42and R43, R43and R44, R44and R45, R45and R46, R46and R47, R47and R48, R48and R49, R49and R50, R50and R51, R51and R52, R52and R53, R53and R54, R54and R55, R55and R56, R56and R57, R57and R58, R58and R59, R59and R60, R60and R61, R61and R62, R62and R63, R63and R64, R64and R65, R65and R66, R66and R67, R67and R68, R68and R69, R69and R70, R70and R71, R71and R72, R72and R73, R73and R74, R74and R75, R75and R76, R76and R77, R77and R78, R78and R79, R79and R80, R80and R81, R81and R82, R82and R83, R83and R84, R84and R85, R85and R86, R86and R87, R87and R88, R88and R89, R89and R90, R90and R91, R91and R92, R92and R93, R93and R94, R94and R95, R95and R96, R96and R97, R97and R98, R98and R99, and / or R99and R100are optionally connected to form a substituted (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) or unsubstituted heterocycloalkyl or a substituted (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) or unsubstituted heteroaryl. and substituent groups can optionally be connected to form a substituted (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) or unsubstituted heterocycloalkyl or a substituted (e.g., substituted with at least one substituent group, a size-limited substituent group, or a lower substituent group) or unsubstituted heteroaryl.

[0332] In embodiments, a substituted moiety formed by linking substituents attached to the same nitrogen atom is substituted with at least one substituent, a size-limited substituent, or a lower substituent; wherein if the substituted moiety formed by linking substituents attached to the same nitrogen atom is substituted with multiple groups selected from substituents, size-limited substituents, and lower substituents; then each substituent, size-limited substituent, and / or lower substituent can optionally be different. and In embodiments, a substituted moiety formed by linking substituents attached to the same nitrogen atom is substituted with at least one substituent, a size-limited substituent, or a lower substituent; wherein if the substituted moiety formed by linking substituents attached to the same nitrogen atom is substituted with multiple groups selected from substituents, size-limited substituents, and lower substituents; then each substituent, size-limited substituent, and / or lower substituent can optionally be different. and In embodiments, a substituted moiety formed by linking substituents attached to the same nitrogen atom is substituted with at least one substituent, a size-limited substituent, or a lower substituent; wherein if the substituted moiety formed by linking substituents attached to the same nitrogen atom is substituted with multiple groups selected from substituents, size-limited substituents, and lower substituents; then each substituent, size-limited substituent, and / or lower substituent can optionally be different. and In embodiments, a substituted moiety formed by linking substituents attached to the same nitrogen atom is substituted with at least one substituent, a size-limited substituent, or a lower substituent; wherein if the substituted moiety formed by linking substituents attached to the same nitrogen atom is substituted with multiple groups selected from substituents, size-limited substituents, and lower substituents; then each substituent, size-limited substituent, and / or lower substituent can optionally be different. and In embodiments, a substituted moiety formed by linking substituents attached to the same nitrogen atom is substituted with at least one substituent, a size-limited substituent, or a lower substituent; wherein if the substituted moiety formed by linking substituents attached to the same nitrogen atom is substituted with multiple groups selected from substituents, size-limited substituents, and lower substituents; then each substituent, size-limited substituent, and / or lower substituent can optionally be different. and In embodiments, a substituted moiety formed by linking substituents attached to the same nitrogen atom is substituted with at least one substituent, a size-limited substituent, or a lower substituent; wherein if the substituted moiety formed by linking substituents attached to the same nitrogen atom is substituted with multiple groups selected from substituents, size-limited substituents, and lower substituents; then each substituent, size-limited substituent, and / or lower substituent can optionally be different.

[0333] In embodiments, and are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -COOH, 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-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); substituents attached to the same nitrogen atom can optionally be linked to form unsubstituted heterocycloalkyl or unsubstituted heteroaryl. and In embodiments, a substituted moiety formed by linking substituents attached to the same nitrogen atom is substituted with at least one substituent, a size-limited substituent, or a lower substituent; wherein if the substituted moiety formed by linking substituents attached to the same nitrogen atom is substituted with multiple groups selected from substituents, size-limited substituents, and lower substituents; then each substituent, size-limited substituent, and / or lower substituent can optionally be different. and In embodiments, a substituted moiety formed by linking substituents attached to the same nitrogen atom is substituted with at least one substituent, a size-limited substituent, or a lower substituent; wherein if the substituted moiety formed by linking substituents attached to the same nitrogen atom is substituted with multiple groups selected from substituents, size-limited substituents, and lower substituents; then each substituent, size-limited substituent, and / or lower substituent can optionally be different. and The substituents can optionally be linked to form an unsubstituted heterocycloalkyl or an unsubstituted heteroaryl; and and The substituents can optionally be linked to form an unsubstituted heterocycloalkyl or an unsubstituted heteroaryl.

[0334] In embodiments, E is

[0335] In embodiments, E is In embodiments, E is In embodiments, E is In embodiments, E is In embodiments, E is In embodiments, E is In embodiments, E is

[0336] In embodiments, the compound is of Formula Ring A, R 1 , R 2 , L 103 , L 104 , L 105 , and z2 are as described herein.

[0337] In embodiments, L 103 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0338] In embodiments, L 104 is a bond, -O-, -NH-, -S-, or substituted or unsubstituted alkylene.

[0339] In embodiments, L 105 is -S(O)2-, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, or -C(O)O-.

[0340] In embodiments, L 105 is -S(O)2-, -C(O)-, -NHC(O)-, or -OC(O)-.

[0341] n is an integer from 0 to 4.

[0342] In embodiments, the compound is of Formula R 1 , L 103 , L 104 , L 105, n and z2 are as described herein. In embodiments, L 103 is a bond, substituted or unsubstituted C1-C6alkylene, or substituted or unsubstituted 2 to 6 membered heteroalkylene; L 104 is a bond, -O-, -NH-, -S-, or substituted or unsubstituted C1-C4alkylene; L 105 is -S(O)2-, -C(O)-, -NHC(O)-, or -OC(O)-; n is an integer from 0 to 4; and and are independently hydrogen, halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 , -OCHX 2 2, -CN, -N(O) m2 , -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); and substituents can be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0343] In embodiments, L 103 is a bond, substituted or unsubstituted C1-C6alkylene, or substituted or unsubstituted 2 to 6 membered heteroalkylene; L 104 is a bond, -O-, -NH-, -S-, or substituted or unsubstituted C1-C4alkylene; L 105 is -S(O)2-, -C(O)-, -NHC(O)-, or -OC(O)-; n is an integer from 0 to 4; and and independently hydrogen, halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 , -OCHX 2 2, -CN, -N(O) m2 , -N3, R 20 substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, or Ci-C4), R 20 substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), R 20 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 20 substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), R 20 substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 20 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); and substituents can be joined to form a R 20 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 20 substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), R 20 substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 20 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0344] In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, when n is 0, L 104 and L 105 is not a bond.

[0345] In embodiments, and are independently halogen. In embodiments, and are independently -Cl.

[0346] In embodiments, L 103is unsubstituted alkylene. In embodiments, L 103 is unsubstituted C1-C6 alkylene. In embodiments, L 103 is unsubstituted C1-C4 alkylene. In embodiments, L 103 is a bond.

[0347] In embodiments, L 104 is a bond, -O-, -NH-, -S-, or substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4). In embodiments, L 104 is a bond. In embodiments, L 104 is -O-. In embodiments, L 104 is -NH-. In embodiments, L 104 is -S-. In embodiments, L 104 is substituted or unsubstituted C1-C8 alkylene. In embodiments, L 104 is substituted or unsubstituted C1-C6 alkylene. In embodiments, L 104 is substituted or unsubstituted C1-C4 alkylene. In embodiments, L 104 is unsubstituted C1-C8 alkylene.

[0348] In embodiments, L 104 is a bond, -O-, -NH-, -S-, or R 104 substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4). R 104 As described herein, including in embodiments.

[0349] In embodiments, L 105 is -S(O)2-, -C(O)-, -NHC(O)-, or -OC(O)-. In embodiments, L 105 is -S(O)2-. In embodiments, L 105 is -C(O)-. In embodiments, L 105 is -NHC(O)-. In embodiments, L 105 is -OC(O)-.

[0350] In embodiments, -L 104 -CH2-L 105 NH-L 103 - is

[0351] In embodiments, -L 104 -CH2-L 105 NH-L 103 - is In embodiments, -L 104 -CH2-L 105 NH-L 103 - is In embodiments, -L 104 -CH2-L 105 NH-L 103 - is In embodiments, -L 104 -CH2-L 105 -NH-L 103 - is In embodiments, -L 104 -CH2-L 105 NH-L 103 - is

[0352] In embodiments, -L 104 -CH2-L 105 -NH-L 103 - is In embodiments, -L 104 -CH2-L 105 -NH-L 103 - is

[0353] In embodiments, R 1 is hydrogen, E, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstituted C5-C6 cycloalkyl, substituted or unsubstituted 5 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; E is an electrophilic moiety; and independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C5-C6 cycloalkyl, substituted or unsubstituted 5 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0354] In embodiments, R 1 is hydrogen, E, R 10 substituted or unsubstituted C1-C6alkyl, R 10 substituted or unsubstituted 2 to 10 membered heteroalkyl, R 10 substituted or unsubstituted C5-C6 cycloalkyl, R 10 substituted or unsubstituted 5 to 6 membered heterocycloalkyl, R 10 substituted or unsubstituted phenyl, or R 10 substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, and independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, R 10 substituted or unsubstituted C1-C6alkyl, R10 substituted or unsubstituted 2- to 10-membered heteroalkyl, R 10 substituted or unsubstituted C5-C6 cycloalkyl, R 10 substituted or unsubstituted 5- to 6-membered heterocycloalkyl, R 10 substituted or unsubstituted phenyl or R 10 substituted or unsubstituted 5- to 6-membered heteroaryl.

[0355] R 10 independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R 11 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), R 11 substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), R 11 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 11 substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), R 11 substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl) or R 11 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0356] R 11independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R 12 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), R 12 substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), R 12 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 12 substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), R 12 substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 12 substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0357] R 12 independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R 13 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), R 13substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), R 13 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 13 substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), R 13 substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 13 substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0358] R 13 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0359] In embodiments, R 2 is independently halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 , -OCHX 2 2, -CN, -N(O) m2 , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R 2 Substituents can join to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0360] In embodiments, R 2 independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two R 2 Substituents can join to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0361] In embodiments, R 2independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, R 20 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), R 20 substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), R 20 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 20 substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), R 20 substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 20 substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two R 2 substituents can be joined to form a substituted or unsubstituted R 20 substituted or unsubstituted cycloalkyl, R 20 substituted or unsubstituted heterocycloalkyl, R 20 substituted or unsubstituted aryl, or R 20 substituted or unsubstituted heteroaryl.

[0362] R 20independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, R 21 substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, or Ci-C4), R 21 substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), R 21 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 21 substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), R 21 substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 21 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0363] R 21 independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, R 22 substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, or Ci-C4), R 22Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), R 22 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, or C5-C6), R 22 Substituted or unsubstituted heterocyclic alkyl groups (e.g., ternary to octyl, ternary to septary, or quinary to septary), R 22 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 (or phenyl) or R 22 Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10 yuan, 5 to 9 yuan, or 5 to 6 yuan).

[0364] R 22 Independently, it can be an oxo group, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3. -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, unsubstituted aryl groups (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl groups (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl groups (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), unsubstituted aryl groups (e.g., C6-C... 10 (or phenyl) or unsubstituted heteroaryl) (e.g., 5 to 10 yuan, 5 to 9 yuan or 5 to 6 yuan).

[0365] In the embodiments, the compound is

[0366] In the embodiments, the compound is

[0367] In the embodiments, the compound is

[0368] In the embodiments, the compound is

[0369] In the embodiments, the compound is

[0370] In embodiments, the compound is

[0371] In embodiments, the compound is

[0372] In embodiments, the compound is

[0373] In embodiments, the compound is

[0374] In embodiments, the compound is

[0375] In embodiments, the compound is

[0376] In embodiments, the compound is

[0377] In embodiments, the compound is

[0378] In embodiments, the compound is

[0379] In embodiments, the compound is

[0380] In embodiments, the compound is

[0381] In embodiments, the compound is

[0382] In embodiments, the compound is

[0383] In embodiments, the compound is

[0384] In embodiments, the compound is

[0385] In embodiments, the compound is

[0386] In embodiments, the compound is

[0387] In embodiments, the compound is

[0388] In embodiments, the compound is

[0389] In embodiments, the compound is

[0390] In embodiments, the compound is

[0391] In embodiments, the compound is

[0392] In embodiments, the compound is

[0393] In embodiments, the compound is

[0394] In embodiments, the compound is

[0395] In embodiments, the compound is

[0396] In embodiments, the compound is

[0397] In embodiments, the compound is

[0398] In embodiments, the compound is

[0399] In embodiments, the compound is

[0400] In embodiments, the compound is

[0401] In embodiments, the compound is

[0402] In embodiments, the compound is

[0403] In embodiments, the compound is

[0404] In embodiments, the compound is

[0405] In embodiments, the compound is

[0406] In embodiments, the compound is

[0407] In embodiments, the compound is

[0408] In embodiments, the compound is

[0409] In embodiments, the compound is

[0410] In embodiments, the compound is

[0411] In embodiments, the compound is

[0412] In embodiments, the compound is

[0413] In embodiments, the compound is

[0414] In embodiments, the compound is

[0415] In embodiments, the compound is

[0416] In embodiments, the compound is

[0417] In embodiments, the compound is

[0418] In embodiments, the compound is

[0419] In embodiments, the compound is

[0420] In embodiments, the compound is

[0421] In embodiments, the compound is

[0422] In embodiments, the compound is

[0423] In embodiments, the compound is

[0424] In embodiments, the compound is

[0425] In embodiments, the compound is

[0426] In embodiments, the compound is

[0427] In embodiments, the compound is

[0428] In embodiments, the compound is

[0429] In embodiments, the compound is

[0430] In embodiments, the compound is

[0431] In embodiments, the compound is

[0432] In embodiments, the compound is

[0433] In embodiments, the compound is

[0434] In embodiments, the compound is

[0435] In embodiments, the compound is

[0436] In embodiments, the compound is

[0437] In embodiments, the compound is

[0438] In embodiments, the compound is

[0439] In embodiments, the compound is

[0440] In embodiments, the compound is

[0441] In embodiments, the compound is

[0442] In embodiments, the compound is

[0443] In embodiments, the compound is

[0444] In embodiments, the compound is

[0445] In embodiments, the compound is

[0446] In embodiments, the compound is

[0447] In embodiments, the compound is

[0448] In embodiments, the compound is

[0449] In embodiments, the compound is

[0450] In embodiments, the compound is

[0451] In embodiments, the compound is

[0452] In embodiments, the compound is

[0453] In embodiments, the compound is

[0454] In embodiments, the compound is

[0455] In embodiments, the compound is

[0456] In embodiments, the compound is

[0457] In embodiments, the compound is

[0458] In embodiments, the compound is

[0459] In embodiments, the compound is

[0460] In embodiments, the compound is

[0461] In embodiments, the compound is

[0462] In embodiments, the compound is

[0463] In embodiments, the compound is

[0464] In embodiments, the compound is

[0465] In embodiments, the compound is

[0466] In embodiments, the compound is

[0467] In embodiments, the compound is

[0468] In embodiments, the compound is

[0469] In embodiments, the compound is

[0470] In embodiments, the compound is

[0471] In embodiments, the compound is

[0472] In embodiments, the compound is

[0473] In embodiments, ring A is not In embodiments, ring A is not In embodiments, ring A is not X 2 is independently -F, -Cl, -Br, or -I. In embodiments, X 2 is independently -Cl.

[0474] In embodiments, R 1 is not as described herein.

[0475] In embodiments, E is not -SS-(unsubstituted C1-C7 alkyl). In embodiments, E is not -SS-(3- to 7-membered unsubstituted heteroalkyl). In embodiments, E is not -SSCH2CH2N(CH3)2.

[0476] In embodiments, the compound is not In embodiments, the compound is not In embodiments, the compound is not

[0477] In embodiments, the compound is covalently attached to Nurr1 (e.g., human Nurr1). In embodiments, the compound is irreversibly covalently bound to Nurr1 (e.g., human Nurr1). In embodiments, the compound is reversibly covalently bound to Nurr1 (e.g., human Nurr1).

[0478] In embodiments, the compound contacts an amino acid corresponding to Cys566 of human Nurr1. In embodiments, the compound contacts an amino acid corresponding to Cys475 of human Nurr1. In embodiments, the compound contacts an amino acid corresponding to Cys534 of human Nurr1.

[0479] In embodiments, the compound contacts an amino acid corresponding to Arg515 of human Nurr1. In embodiments, the compound contacts an amino acid corresponding to Arg563 of human Nurr1. In embodiments, the compound contacts an amino acid corresponding to Glu445 of human Nurr1.

[0480] In embodiments, the compound covalently links to an amino acid corresponding to Cys566 of human Nurr1. In embodiments, the compound irreversibly covalently binds to an amino acid corresponding to Cys566 of human Nurr1. In embodiments, the compound reversibly covalently binds to an amino acid corresponding to Cys566 of human Nurr1.

[0481] In embodiments, the compound stabilizes Nurr1 homomonomer. In embodiments, the compound stabilizes Nurr1 homodimer. In embodiments, the compound stabilizes head-to-tail Nurr1 homodimer. In embodiments, the compound stabilizes Nurr1 heterodimer. In embodiments, the Nurr1 heterodimer is a heterodimer with RXRa.

[0482] In embodiments, the compound stabilizes Nurr1 monomer relative to a control (e.g., in the absence of the compound). In embodiments, the compound stabilizes Nurr1 homodimer relative to a control (e.g., in the absence of the compound). In embodiments, the compound stabilizes head-to-tail Nurr1 homodimer relative to a control (e.g., in the absence of the compound). In embodiments, the compound stabilizes Nurr1 heterodimer relative to a control (e.g., in the absence of the compound). In embodiments, the Nurr1 heterodimer is a heterodimer with RXRa.

[0483] In embodiments, the compound contacts Nurr1 homomonomer. In embodiments, the compound contacts Nurr1 homodimer. In embodiments, the compound contacts head-to-tail Nurr1 homodimer. In embodiments, the compound contacts Nurr1 heterodimer. In embodiments, the Nurr1 heterodimer is a heterodimer with RXRa.

[0484] In embodiments, the compound links Nurr1 homomonomer. In embodiments, the compound links Nurr1 homodimer. In embodiments, the compound links head-to-tail Nurr1 homodimer. In embodiments, the compound links Nurr1 heterodimer. In embodiments, the Nurr1 heterodimer is a heterodimer with RXRa.

[0485] In embodiments, the compound excludes formation of Nurr1:RXR heterodimer. In embodiments, the compound inhibits formation of Nurr1:RXR heterodimer. In embodiments, the compound linked to Nurr1 inhibits linking of the resulting compound:Nurr1 complex to RXR.

[0486] In embodiments, the compound stabilizes a Nurr1 dimer conformation in which the distance between the N-termini is about (e.g., about 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or ) In embodiments, the compound stabilizes a Nurr1 dimer conformation in which the distance between the N-termini is at least (e.g., at least 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or ) In embodiments, the compound stabilizes a Nurr1 dimer conformation in which the distance between the N-termini is less than (e.g., less than 73, 72, 71, 70, 69, 68, 67, 66, 65, 65, 64, 63, 62, 61, or ).

[0487] In embodiments, the compound contacts a Nurr1 dimer conformation in which the distance between the N-termini is about (e.g., about 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or ) In embodiments, the compound contacts a Nurr1 dimer conformation in which the distance between the N-termini is at least (e.g., at least 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or ) In embodiments, the compound contacts a Nurr1 dimer conformation in which the distance between the N-termini is less than (e.g., less than 73, 72, 71, 70, 69, 68, 67, 66, 65, 65, 64, 63, 62, 61, or ).

[0488] In embodiments, the compound binds a Nurr1 dimer conformation in which the distance between the N-termini is about (e.g., about 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or ). In embodiments, the compound binds to a Nurr1 dimer conformation in which the distance between the N-termini is less than (e.g., less than 73, 72, 71, 70, 69, 68, 67, 66, 65, 65, 64, 63, 62, 61, or ) In embodiments, the compound binds to a Nurr1 dimer conformation in which the distance between the N-termini is less than (e.g., less than 73, 72, 71, 70, 69, 68, 67, 66, 65, 65, 64, 63, 62, 61, or ) In embodiments, the compound binds to a Nurr1 dimer conformation in which the distance between the N-termini is less than

[0489] In embodiments, the compound stabilizes a Nurr1 dimer conformation in which the distance between the N-termini is about (e.g., about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or ) In embodiments, the compound stabilizes a Nurr1 dimer conformation in which the distance between the N-termini is less than (e.g., at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or ) In embodiments, the compound stabilizes a Nurr1 dimer conformation in which the distance between the N-termini is less than (e.g., less than 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, or ) In embodiments, the compound stabilizes a Nurr1 dimer conformation in which the distance between the N-termini is less than

[0490] In embodiments, the compound contacts a Nurr1 dimer conformation in which the distance between the N-termini is about (e.g., about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or ) In embodiments, the compound contacts a Nurr1 dimer conformation in which the distance between the N-termini is less than (e.g., at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or ). In embodiments, the compound contacts the Nurr1 dimer conformation in which the distance between the N-termini is less than (e.g., less than 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, or ).

[0491] In embodiments, the compound contacts the Nurr1 dimer conformation in which the distance between the N-termini is about (e.g., about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or ). In embodiments, the compound contacts the Nurr1 dimer conformation in which the distance between the N-termini is at least (e.g., at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or ). In embodiments, the compound contacts the Nurr1 dimer conformation in which the distance between the N-termini is less than (e.g., less than 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, or ).

[0492] In embodiments, the compound contacts Nurr1 and induces Nurr1 binding to NBRE, NuRE, or DR-5 response element. In embodiments, the compound contacts Nurr1 and induces Nurr1 binding to NBRE. In embodiments, the compound contacts Nurr1 and induces Nurr1 binding to NuRE. In embodiments, the compound contacts Nurr1 and induces Nurr1 binding to DR-5 response element.

[0493] 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 example section, figures, tables, claims, or appendices).

[0494] III. Pharmaceutical Compositions

[0495] In one aspect, there is provided a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable excipient.

[0496] In embodiments, the pharmaceutical composition comprises an effective amount of the compound. In embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound.

[0497] In embodiments, the pharmaceutical composition comprises an effective amount of a second agent, wherein the second agent is an agent for treating a neurodegenerative disease. In embodiments, the neurodegenerative disease is Parkinson’s disease. In embodiments, the second agent is a Parkinson’s disease drug, e.g., levodopa, carbidopa, selegiline, amantadine, donepezil, galantamine, rivastigmine, tacrine, bromocriptine, pergolide, pramipexole, ropinirole, trihexphenidyl, benztropine, biperiden, procyclidine, tolcapone, or entacapone. In embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the second agent.

[0498] In embodiments, the pharmaceutical composition comprises an effective amount of a second agent, wherein the second agent is an agent for treating an inflammatory disease, e.g., acetaminophen, duloxetine, aspirin, ibuprofen, naproxen, diclofenac sodium, prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, codeine, fentanyl, hydrocodone, hydromorphone, morphine, meperidine, or oxycodone. In embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the second agent.

[0499] In embodiments, the pharmaceutical composition comprises an effective amount of a second agent, wherein the second agent is an anticancer agent.

[0500] In embodiments, the pharmaceutical composition comprises an effective amount of a second agent, wherein the second agent is an anticancer agent.

[0501] IV. Methods of use

[0502] In an aspect, a method for treating a disease of the central nervous system associated with dysregulation and / or degeneration of dopaminergic neurons in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein.

[0503] In an aspect, a method for treating a disease of the central nervous system associated with dysregulation and / or degeneration of dopaminergic neurons in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of 5,6-dihydroxyindole (DHI).

[0504] In embodiments, the disease associated with dysregulation and / or degeneration of dopaminergic neurons is Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, or drug addiction. In embodiments, the disease is Parkinson’s disease. In embodiments, the disease is Alzheimer’s disease. In embodiments, the disease is multiple sclerosis. In embodiments, the disease is amyotrophic lateral sclerosis. In embodiments, the disease is schizophrenia. In embodiments, the disease is drug addiction.

[0505] In embodiments, the disease associated with dysregulation and / or degeneration of dopaminergic neurons is cancer.

[0506] In one aspect, a method for treating a disease in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein.

[0507] In one aspect, a method for treating a disease in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of 5,6-dihydroxyindole (DHI).

[0508] In embodiments, the disease is Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, or drug addiction. In embodiments, the disease is Parkinson’s disease. In embodiments, the disease is Alzheimer’s disease. In embodiments, the disease is multiple sclerosis. In embodiments, the disease is amyotrophic lateral sclerosis. In embodiments, the disease is schizophrenia. In embodiments, the disease is drug addiction.

[0509] In embodiments, the disease is cancer.

[0510] In embodiments, the cancer is breast cancer, pancreatic cancer, bladder cancer, mucoepidermoid carcinoma, gastric cancer, prostate cancer, colorectal cancer, lung cancer, adrenocortical cancer, or cervical cancer.

[0511] In one aspect, a method for reducing inflammation in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein.

[0512] In embodiments, the method is for reducing inflammation of the central nervous system in a subject in need thereof.

[0513] In one aspect, a method for reducing oxidative stress in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein.

[0514] In embodiments, the method is for reducing oxidative stress in the central nervous system of a subject in need thereof.

[0515] In an aspect, a method of modulating a level of Nurr1 activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of Nurr1 activity in the subject is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of Nurr1 activity in the subject is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0516] In an aspect, a method of increasing a level of Nurr1 activity in a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of Nurr1 activity in the cell is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of Nurr1 activity in the cell is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0517] In an aspect, a method of increasing a level of Pitx3 activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of Pitx3 activity in the subject is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of Pitx3 activity in the subject is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0518] In an aspect, a method of increasing a level of Pitx3 activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of Pitx3 activity in the subject is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of Pitx3 activity in the subject is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0519] In an aspect, a method of increasing a level of TH activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of TH activity in the subject is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of TH activity in the subject is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0520] In an aspect, a method of increasing a level of TH activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of TH activity in the subject is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of TH activity in the subject is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0521] In an aspect, a method of increasing a level of VMAT2 activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of VMAT2 activity in the subject is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of VMAT2 activity in the subject is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0522] In an aspect, a method of increasing a level of VMAT2 activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of VMAT2 activity in the subject is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of VMAT2 activity in the subject is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0523] On one hand, a method is provided for increasing the dopa decarboxylase (DDC) activity level in a subject in need, the method comprising administering to the subject in need a therapeutically effective amount of the compound described herein. In embodiments, the DDC activity level of the subject is increased by approximately 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 150 times, 200 times, 250 times, 300 times, 350 times, 400 times, 450 times, 500 times, 600 times, 700 times, 800 times, 900 times, or 1000 times. In the examples, the subjects' DDC activity levels increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times.

[0524] On one hand, a method for increasing the activity level of dopa decarboxylase (DDC) in cells is provided, the method comprising contacting the cells with a compound described herein. In embodiments, the DDC activity level of cells is increased by approximately 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 times. In the examples, the DDC activity level of the cells was increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times.

[0525] In an aspect, a method of increasing a level of dopamine transporter (DAT) activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of DAT activity in the subject is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of DAT activity in the subject is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0526] In an aspect, a method of increasing a level of dopamine transporter (DAT) activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of DAT activity in the subject is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of DAT activity in the subject is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0527] In an aspect, a method of increasing the level of BDNF activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of BDNF activity in the subject is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of BDNF activity in the subject is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0528] In an aspect, a method of increasing the level of BDNF activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of BDNF activity in the subject is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of BDNF activity in the subject is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0529] In an aspect, a method of increasing the level of NGF activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of NGF activity in the subject is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of NGF activity in the subject is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0530] In an aspect, a method of increasing the level of NGF activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of NGF activity in the subject is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of NGF activity in the subject is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0531] In an aspect, a method of increasing the level of GDNF receptor c-Ret activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of GDNF receptor c-Ret activity in the subject is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of GDNF receptor c-Ret activity in the subject is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0532] In an aspect, a method of increasing the level of GDNF receptor c-Ret activity in a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of GDNF receptor c-Ret activity in the cell is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of GDNF receptor c-Ret activity in the cell is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0533] In an aspect, a method of increasing the level of SOD1 activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of SOD1 activity in the subject is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of SOD1 activity in the subject is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0534] In an aspect, a method of increasing the level of SOD1 activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of SOD1 activity in the subject is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of SOD1 activity in the subject is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0535] In an aspect, a method of reducing the level of TNFa activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of TNFa activity in the subject is reduced by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of TNFa activity in the subject is reduced by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0536] In an aspect, a method of reducing the level of TNFa activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of TNFa activity in the subject is reduced by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of TNFa activity in the subject is reduced by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0537] In an aspect, a method of reducing the level of iNOS activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of iNOS activity in the subject is reduced by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of iNOS activity in the subject is reduced by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0538] In an aspect, a method of reducing the level of iNOS activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of iNOS activity in the subject is reduced by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of iNOS activity in the subject is reduced by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0539] In an aspect, a method of reducing IL-1β activity level in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the IL-1β activity level in the subject is reduced by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the IL-1β activity level in the subject is reduced by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0540] In an aspect, a method of reducing IL-1β activity level in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the IL-1β activity level in the subject is reduced by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the IL-1β activity level in the subject is reduced by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0541] In embodiments, the methods comprise a method of increasing dopamine levels in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the dopamine levels of the subject are increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the dopamine levels of the subject are increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0542] In embodiments, the methods comprise a method of increasing dopamine levels in a cell, the method comprising contacting the cell with a compound described herein. In embodiments, the dopamine levels of the cell are increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the dopamine levels of the cell are increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0543] In embodiments, the methods comprise increasing the synthesis of dopamine by a cell using a compound described herein compared to a control (e.g., in the absence of the compound). In embodiments, the level of dopamine synthesis is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of dopamine synthesis is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0544] In embodiments, the methods comprise increasing the packaging of dopamine by a cell using a compound described herein compared to a control (e.g., in the absence of the compound). In embodiments, the level of dopamine packaging is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of dopamine packaging is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0545] In embodiments, the methods comprise increasing reuptake of dopamine by a cell using a compound described herein compared to a control (e.g., in the absence of the compound). In embodiments, the level of reuptake of dopamine is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of reuptake of dopamine is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0546] In embodiments, the methods comprise increasing development of a dopaminergic neuron using a compound described herein compared to a control (e.g., in the absence of the compound). In embodiments, the level of development of a dopaminergic neuron is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of development of a dopaminergic neuron is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0547] In embodiments, the methods comprise increasing maintenance of dopaminergic neurons using the compounds described herein compared to a control (e.g., in the absence of the compound). In embodiments, the level of maintenance of dopaminergic neurons is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of maintenance of dopaminergic neurons is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0548] In embodiments, the methods comprise increasing survival of dopaminergic neurons using the compounds described herein compared to a control (e.g., in the absence of the compound). In embodiments, the level of survival of dopaminergic neurons is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of survival of dopaminergic neurons is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0549] In embodiments, the method comprises covalently linking Nurr1 (e.g., human Nurr1) to a compound de...

Claims

1. A compound having the formula (It); in Ring A is phenyl; W is either N or CH; L 103 It is an unsubstituted C1-C8 alkylene group; L 104 It is -C(O)-; L 105 It is an unsubstituted C1-C8 alkylene group; R 1 -SC(O)R 1C Or -SH; R 2 Independent of halogen, -CN, -OR 2D -NR 2A C(O)R 2C ,or ; R 1C It is an unsubstituted C1-C4 alkyl or an unsubstituted phenyl; R 2A It is hydrogen; R 2C and R 2D Independently, it is an unsubstituted C1-C2 alkyl group; and z2 is an integer from 0 to 2.

2. The compound according to claim 1, wherein the compound has the formula... (Iaa); and R 2X R 2Y and R 2Z Independently hydrogen, halogen, -CN, -OR 2D -NR 2A C(O)R 2C ,or .

3. The compound according to claim 2, wherein... R 2X It is a halogen; R 2Y It is hydrogen or halogen; and R 2Z Hydrogen, halogen, -CN, -NR 2A C(O)R 2C ,or .

4. The compound according to claim 2, wherein... R 2X It is a halogen; R 2Y It is a halogen; and R 2Z It is hydrogen.

5. The compound according to claim 2, wherein... R 2X It is -OCH3; R 2Y It is hydrogen; and R 2Z It is -OCH3.

6. The compound according to claim 2, wherein... R 2X It is a halogen; R 2Y It is hydrogen; and R 2Z Halogen, -CN, -NR 2A C(O)R 2C ,or .

7. The compound according to claim 1, wherein L 105 It is an unsubstituted C1-C8 alkylene group.

8. The compound according to claim 1, wherein L 105 It is an unsubstituted C1-C4 alkylene group.

9. The compound according to claim 1, wherein L 105 for .

10. The compound according to claim 1, wherein W is N.

11. The compound according to claim 1, wherein L 103 It is an unsubstituted C1-C8 alkylene group.

12. The compound according to claim 1, wherein L 103 It is an unsubstituted C1-C4 alkylene group.

13. The compound according to claim 1, wherein L 103 It is an unsubstituted ethylene.

14. The compound according to claim 1, wherein... for or .

15. The compound according to claim 1, wherein R 1 It is either -SH or -SC(O)CH3.

16. The compound according to claim 1, having the following formula: , , , , , , , , , , , , ,or .

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and a pharmaceutically acceptable excipient.

18. Use of the compound of any one of claims 1 to 16 in the preparation of a medicament for treating a disease of the central nervous system associated with dopaminergic neuronal dysfunction and / or degeneration in a subject of need, wherein said disease associated with dopaminergic neuronal dysfunction and / or degeneration is Parkinson's disease, Alzheimer's disease, or multiple sclerosis.

19. The use according to claim 18, wherein the disease associated with dopaminergic neuronal dysfunction and / or degeneration is Parkinson's disease.

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