NURR1 receptor modulator

Abstract

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

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 807,642, filed February 19, 2019, which is incorporated herein by reference in its entirety for all purposes.

[0002] Reference to a "Sequence Listing," table, or computer program listing appendix submitted as an ASCII file The sequence listing set forth in file 048536-637001WO_Sequence_Listing_ST25.txt, 19,310 bytes, machine format IBM-PC, MS Windows operating system, created on January 14, 2020, is incorporated herein by reference.

[0003] STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant No. R01 NS108404 awarded by the National Institutes of Health. The government has certain rights in this invention. [Background technology]

[0004] Currently, over one million Americans suffer from Parkinson's disease (PD), with approximately 60,000 new cases 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 pars compacta and the resulting decreased dopamine levels in the striatum, manifested as impaired motor function (e.g., rigidity, tremor, bradykinesia). The molecular basis of idiopathic PD remains incompletely understood but has been proposed to involve oxidative stress, mitochondrial dysfunction, and dysregulation of dopamine homeostasis. Currently, there are no available treatments that can halt or slow the progression of PD. Existing therapies alleviate PD symptoms by increasing dopaminergic signaling through one of three mechanisms: (1) increasing dopamine levels by supplementing the amount of its biosynthetic precursor, L-DOPA; (2) preventing the breakdown of dopamine by inhibiting its metabolic enzyme (monoamine oxidase (MAO), COMT); or (3) mimicking the activity of dopamine by directly stimulating dopamine receptors. However, these drugs only partially alleviate symptoms and can have significant side effects, especially as the disease progresses. New types of therapies are desperately needed to combat both the symptoms and progression of PD. Solutions to these and other problems in the art, among others, are disclosed herein. Summary of the Invention

[0005] In one aspect, a compound is provided having the formula: [ka]

[0006] Ring A is aryl or heteroaryl.

[0007] L 1 L 101 -L 102 -L 103 is.

[0008] 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 is.

[0009] 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.

[0010] 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.

[0011] 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.

[0012] 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.

[0013] 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, -N HC(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.

[0014] R 1 is hydrogen, halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)OR 1C , -SC(O)R 1C , -C(O)NR 1A R 1B , -OR 1D , -SR 1D , -SeR 1D , -NR 1A SO2R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -N3, -SSR 1D , -SiR 1A R 1B R 1C , —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.

[0015] E is an electrophilic moiety.

[0016] R 2 are independently halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -OCX 23. -OCH2X 2 , -OCHX 2 2, -CN, -SO n2 R 2D , -SO v2 NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -SC(O)R 2C , -C(O)OR 2C , -C(O)NR 2A R 2B , -OR 2D , -SR 2D , -SeR 2D , -NR 2A SO2R 2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and two R bonded to adjacent atoms are 2 The substituents may be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0017] R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2Dare 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 R bonded to the same nitrogen atom 1A and R 1B The substituents may join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R 2A and R 2B The substituents may be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0018] n1 and n2 are independently an integer of 0 to 4.

[0019] m1, m2, v1, and v2 are independently 1 or 2.

[0020] X 1 and X 2 are independently -F, -Cl, -Br, or -I.

[0021] z2 is an integer of 0 to 5.

[0022] In one aspect, a pharmaceutical composition is provided comprising a compound described herein and a pharmaceutically acceptable excipient.

[0023] In one aspect, there is provided a method for treating a disease associated with dysregulation and / or degeneration of dopaminergic neurons in the central nervous system of a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0024] In one aspect, a method is provided for modulating the level of activity of Nurr1 in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0025] In one aspect, a method of increasing the level of activity of Nurr1 in a cell is provided, the method comprising contacting the cell with a compound described herein.

[0026] 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 explanation of the drawings]

[0027] [Figure 1A] Crystal structures of Nurr1 screening hit complexes reveal two distinct ligand-binding sites and receptor conformations. Figure 1A: Structures of screening hits 19.49 and 10.25. Figure 1B: Structure of the 19.49 screening hit covalently bound to Cys566. Figure 1C: Structure of the 10.25 screening hit covalently bound to Cys566. [Figure 1B] Crystal structures of Nurr1 screening hit complexes reveal two distinct ligand-binding sites and receptor conformations. Figure 1A: Structures of screening hits 19.49 and 10.25. Figure 1B: Structure of the 19.49 screening hit covalently bound to Cys566. Figure 1C: Structure of the 10.25 screening hit covalently bound to Cys566. [Figure 1C]Crystal structures of Nurr1 screening hit complexes reveal two distinct ligand-binding sites and receptor conformations. Figure 1A: Structures of screening hits 19.49 and 10.25. Figure 1B: Structure of the 19.49 screening hit covalently bound to Cys566. Figure 1C: Structure of the 10.25 screening hit covalently bound to Cys566. [Figure 2A] Both compounds 85 (Figure 2A) and 87 (Figure 2B) bind to the Nurr1 ligand-binding domain with high nanomolar affinity, as measured by microscale thermophoresis. [Figure 2B] Both compounds 85 (Figure 2A) and 87 (Figure 2B) bind to the Nurr1 ligand-binding domain with high nanomolar affinity, as measured by microscale thermophoresis. [Figure 3A] Compounds 85 (Figure 3A) and 87 (Figure 3B) stimulate the transcription of Nurr1 target genes in MN9D cells. Gene expression was normalized to Hprt. [Figure 3B] Compounds 85 (Figure 3A) and 87 (Figure 3B) stimulate the transcription of Nurr1 target genes in MN9D cells. Gene expression was normalized to Hprt. [Figure 4A] Reaction schemes for selected compounds. [Figure 4B] Reaction schemes for selected compounds. [Figure 4C] Reaction schemes for selected compounds. [Figure 4D] Reaction schemes for selected compounds. DETAILED DESCRIPTION OF THE INVENTION

[0028] I. Definition The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0029] Substituents, when specified by their conventional chemical formula written from left to right, equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0030] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a linear (i.e., unbranched) or branched carbon chain (or carbons), or combinations thereof, which may be fully saturated, monounsaturated, or polyunsaturated, and which may include monovalent, divalent, and polyvalent radicals. An alkyl may contain the specified number of carbons (e.g., C-C 10 (meaning 1 to 10 carbons). An alkyl is a non-cyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, and methyl, as well as homologs and isomers of groups such as n-pentyl, n-hexyl, n-heptyl, and n-octyl. Unsaturated alkyl groups are those containing one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). The alkyl moiety may be an alkenyl moiety. The alkyl moiety may be an alkynyl moiety. The alkyl moiety may be fully saturated. In addition to one or more double bonds, alkenyl may contain more than one double bond and / or one or more triple bonds. In addition to one or more triple bonds, alkynyl may contain more than one triple bond and / or one or more double bonds.

[0031] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from alkyl, exemplified by, but not limited to, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 8 or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0032] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise specified, a stable linear or branched chain, or combination thereof, containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is a non-cyclizing chain. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S-CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain up to eight optionally different heteroatoms (e.g., O, N, S, Si, or P). The term "heteroalkenyl," alone or in combination with another term, means, unless otherwise stated, a heteroalkyl containing at least one double bond.Heteroalkenyl may optionally contain, in addition to one or more double bonds, more than one double bond and / or one or more triple bonds. The term "heteroalkynyl", alone or in combination with another term, means, unless otherwise stated, a heteroalkyl containing at least one triple bond. Heteroalkynyl may optionally contain, in addition to one or more triple bonds, more than one triple bond and / or one or more double bonds.

[0033] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, exemplified by, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- represents both -C(O)R'- and -R'C(O)-. As noted above, heteroalkyl groups as used herein include groups attached to the remainder of the molecule via a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -SOR'. When "heteroalkyl" is recited followed by a specific heteroalkyl group, e.g., -NR'R'', it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is recited for clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyl groups, e.g., -NR'R'', etc.

[0034] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A "cycloalkylene" and a "heterocycloalkylene," alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0035] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl.

[0036] The term "acyl," unless otherwise stated, means -C(O)R, where 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.

[0037] The term "aryl," unless otherwise specified, refers to a polyunsaturated, aromatic, hydrocarbon substituent, which may be a single ring or multiple rings (preferably 1 to 3 rings) fused together (i.e., fused-ring aryl) or covalently linked together. Fused-ring aryl refers to multiple rings fused together, at least one of which is an aryl ring. The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom, such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together, at least one of which is an aromatic heterocycle). 5,6-fused-ring heteroarylene refers to two rings fused together, one ring having five members and the other having six members, and at least one ring being a heteroaryl ring. Similarly, a 6,6-fused ring heteroarylene refers to two rings fused together, one having 6 members and the other having 6 members, and at least one ring is a heteroaryl ring. A 6,5-fused ring heteroarylene refers to two rings fused together, one having 6 members and the other having 5 members, and at least one ring is a heteroaryl ring. The heteroaryl group can be attached to the remainder of the molecule through a carbon atom or a heteroatom.Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, and the like. aryl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An "arylene" and a "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. The heteroaryl group substituent may be -O-bonded to a ring heteroatom nitrogen.

[0038] Spirocyclic rings are two or more rings in which adjacent rings are connected via a single atom. The individual rings within a spirocyclic ring may be the same or different. The individual rings within a spirocyclic ring may be substituted or unsubstituted and may have different substituents from the other individual rings within a set of spirocyclic rings. The possible substituents of the individual rings within a spirocyclic ring are the possible substituents of the same ring (e.g., the substituents of a cycloalkyl ring or heterocycloalkyl ring) when they are not part of a spirocyclic ring. The spirocyclic ring may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkylene, and the individual rings within a spirocyclic ring group may be any of the rings in the previous list, including all rings of one type (e.g., all rings may be substituted heterocycloalkylene, and each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, a heterocyclic spirocyclic ring means a spirocyclic ring in which at least one ring is heterocyclic, and each ring may be a different ring. When referring to a spirocyclic ring system, a substituted spirocyclic ring means that at least one ring is substituted, and each substituent may optionally be different.

[0039] symbol [ka] indicates the point of attachment of the chemical moiety to the rest of the molecule or chemical formula.

[0040] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom.

[0041] The term "alkylarylene" as an arylene moiety covalently linked to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula: [ka]

[0042] The alkylarylene moiety may be substituted (e.g., by a substituent) at the alkylene portion or in the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, -N, -CF, -CCl, -CBr, -CI, -CN, -CHO, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOCH, -SOH, -OSOH, -SONH, -NH, -ONH, -NHC(O)NHNH, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2-5 membered heteroalkyl. In embodiments, the alkylarylene is unsubstituted.

[0043] Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl") includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0044] Substituents for alkyl and heteroalkyl radicals (including groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) range in number from zero to (2m'+1), where m' is the total number of carbon atoms in such radical, and include -OR', ═O, ═NR', ═N-OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -CONR'R'', -OC(O)NR'R' may be one or more of a variety of groups selected from, but not limited to, —NR″C(O)R′, —NR′—C(O)NR″R′′, —NR″C(O)R′, —NR—C(NR′R″R′′)═NR′′, —NR—C(NR′R″)═NR′′, —S(O)R′, —S(O)R′, —S(O)NR′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″. R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 to 3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy group, or arylalkyl group. When the compounds described herein include more than one R group, for example, each of the R groups is independently selected as each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they may 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.From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is intended to include groups that contain carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF and -CHCF) and acyl (e.g., -C(O)CH, -C(O)CF, -C(O)CHOCH, etc.).

[0045] Similar to the substituents described for the alkyl radical, the substituents on the aryl and heteroaryl groups vary and include, for example, —OR′, —NR′R″, —SR′, halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —COR′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′-C(O)NR″R′″, —NR″C(O)R′, —NR-C(NR′R″R′″)═NR′″, —NR-C(NR′R″)═NR′″, —S(O)R′, —S(O)R′, —S(O)NR′R″, —NRSOR′, —NR′NR 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 the compounds described herein include more than one R group, for example, each of the R groups is independently selected for each R', R", R'", and R"" group when more than one of these groups is present.

[0046] Substituents for a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be shown as substituents on the ring (commonly referred to as floating substituents) rather than on a specific atom of the ring. In such cases, the substituent may be attached to any of the ring atoms (according to the rules of chemical valence), and in the case of a fused or spirocyclic ring, a substituent shown as attached to one member of the fused or spirocyclic ring (a floating substituent on a single ring) may also be a substituent on either the fused or spirocyclic ring (a floating substituent on a polycyclic ring). When a substituent is attached to a ring rather than to a specific atom (a floating substituent), and the substituent subscript is an integer greater than 1, multiple substituents may be on the same atom, the same ring, different atoms, different fused rings, or different spirocyclic rings, and each substituent may optionally be different. When 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 may be any atom of the ring, or, in the case of a fused or spirocyclic ring, any atom of the fused or spirocyclic ring, according to the rules of chemical valence. When a ring, fused ring, or spirocyclic ring contains one or more ring heteroatoms and the ring, fused ring, or spirocyclic ring is shown with another floating substituent (including, but not limited to, the point of attachment to the rest of the molecule), the floating substituent may be attached to the heteroatom. When a ring heteroatom is shown to be attached to one hydrogen 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), it will be understood that when the heteroatom is attached to the floating substituent, the substituent replaces the hydrogen, according to the rules of chemical valence.

[0047] Two or more substituents may optionally join to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. These so-called ring-forming substituents are typically, but not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure form a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0048] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -TC(O)-(CRR') q -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 the aryl or heteroaryl ring may optionally form a ring of the formula -A-(CH2) r A and B may be optionally replaced with a substituent of the formula -B-, where A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer from 1 to 4. One of the single bonds in the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') s -X'-(C''R''R'') dwhere s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0049] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si). In embodiments, "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0050] As used herein, a "substituent" means a group selected from the following moieties: (A) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO 2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2 Cl, -OCH2Br, -OCHI, -OCH2F, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-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 (B) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C6-C 10 Aryl, C 10aryl, or phenyl), heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), each of which is substituted with at least one substituent selected from the following: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl: (i) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO 2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2 Cl, -OCH2Br, -OCHI, -OCH2F, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-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 (ii) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C6-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), each of which is substituted with at least one substituent selected from the following: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl: (a) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO 2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2 Cl, -OCH2Br, -OCHI, -OCH2F, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (b) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C6-C 10 Aryl, C 10aryl, or phenyl), heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), each of which is substituted with at least one substituent selected from the following: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, oxo, halogen, —CCl3, —CBr3, —CF3, —CI3, —CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SON2NH2, —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-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0051] As used herein, "size-limited substituent" or "size-limited substituent" means a group selected from all of the substituents described above for "substituent," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C-C 20each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl; each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl; each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0052] As used herein, a "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 C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 9-membered heteroaryl.

[0053] In some embodiments, each substituent 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 are substituted with at least one size-limited substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower-rank substituent.

[0054] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl is a substituted or unsubstituted C-C 20 each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl; each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl; each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C-C 20 each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 20-membered heteroalkylene; each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene; each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene; and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C8 10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 10-membered heteroarylene.

[0055] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-7 membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C7 10 In some embodiments, each substituted or unsubstituted alkylene is substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is substituted or unsubstituted 2-8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is substituted or unsubstituted 3-7 membered heterocycloalkylene, and each substituted or unsubstituted arylene is substituted or unsubstituted C6-C8 10 and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 9-membered heteroarylene. In some embodiments, the compound is a species described in the Examples section, Figures, or Tables below.

[0056] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and / or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is substituted (e.g., 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).

[0057] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, and when a substituted moiety is substituted with multiple substituents, each substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple substituents, each substituent is different.

[0058] 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-limiting substituent, and when a substituted moiety is substituted with multiple size-limiting substituents, each size-limiting substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple size-limiting substituents, each size-limiting substituent is different.

[0059] 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, and when a substituted moiety is substituted with multiple lower substituents, each lower substituent may optionally be different. In embodiments, when a substituted moiety is substituted with multiple lower substituents, each lower substituent is different.

[0060] In embodiments, a substituted moiety (e.g., a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when a substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent is different.

[0061] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds and can be defined in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids, as (D)- or (L). Enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include compounds known in the art to be too unstable to synthesize and / or isolate. The present disclosure is intended to include compounds in racemic and optically pure form. Optically active (R)- and (S)- or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other geometric centers, it is intended that the compounds include both E and Z geometric isomers, unless otherwise specified.

[0062] As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ with regard to the structural arrangement or configuration of the atoms.

[0063] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0064] It will be apparent to one of ordinary skill in the art that certain compounds of the present disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.

[0065] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure, i.e., R and S configurations for each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0066] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-enriched carbon, are within the scope of this disclosure.

[0067] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain unnatural proportions of atomic isotopes, such as tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0068] It should be noted that throughout this application, alternatives, e.g., each amino acid position containing more than one possible amino acid, are described in terms of a Markush group. It is specifically contemplated that each member of a Markush group should be considered separately, thereby including alternative embodiments, and that a Markush group should not be read as a single unit.

[0069] As used herein, the terms "bioconjugate" and "bioconjugate linker" refer to the resulting association between atoms or molecules of a bioconjugate reactive group or bioconjugate reactive moiety. The association can be direct or indirect. For example, provided herein, a conjugate between a first bioconjugate reactive group (e.g., -NH, -COOH, -N-hydroxysuccinimide, or -maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine side chain-containing amino acid, or carboxylate) can be direct, e.g., via a covalent bond or linker (e.g., a first linker of a second linker), or indirect, e.g., via a non-covalent bond (e.g., electrostatic interactions (e.g., ionic bonds, hydrogen bonds, halogen bonds), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effect), hydrophobic interactions), etc. In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the 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 reaction), and addition across carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are described, for example, in March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, Inc. & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198, American Chemical Society, Washington, DC, 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 sulfhydryl). In embodiments, a first bioconjugate reactive group (e.g., a haloacetyl moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, a first bioconjugate reactive group (e.g., a pyridyl moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, a first bioconjugate reactive group (e.g., an -N-hydroxysuccinimide moiety) is covalently attached to a second bioconjugate reactive group (e.g., an amine). In embodiments, a first bioconjugate reactive group (e.g., a maleimide moiety) is covalently attached to a second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, a first bioconjugate reactive group (e.g., a -sulfo-N-hydroxysuccinimide moiety) is covalently attached to a second bioconjugate reactive group (e.g., an amine).

[0070] Useful bioconjugate reactive moieties for use in the bioconjugate chemistry herein include, for example: (a) Carboxyl groups and their various derivatives, including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acylimidazoles, thioesters, p-nitrophenyl esters, alkyls, alkenyls, alkynyls, and esters (b) Hydroxyl groups that can be converted into esters, ethers, aldehydes, etc. (c) haloalkyl groups, in which the halide is subsequently replaced with a nucleophilic group, such as an amine, a carboxylate anion, a thiol anion, a carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom. (d) Dienophile groups capable of participating in Diels-Alder reactions, such as maleimide or maleimido groups (e) an aldehyde or ketone group that is capable of subsequent derivatization, for example, via formation of a carbonyl derivative such as an imine, hydrazone, semicarbazone, or oxime, or via mechanisms such as Grignard addition or alkyllithium addition; (f) sulfonyl halide groups for subsequent reaction with amines to form, for example, sulfonamides (g) Thiol groups that can be converted to disulfides, react with acyl halides, conjugated to metals such as gold, or reacted with maleimides. (h) amine or sulfhydryl groups (e.g., those present in cysteine), which may be, for example, acylated, alkylated, or oxidized. (i) Alkenes that can undergo, for example, cycloaddition, acylation, Michael addition, etc. (j) epoxides, which can react with, for example, amines and hydroxyl compounds. (k) Phosphoramidites and other standard functional groups useful in nucleic acid synthesis (l) Metal-silicon oxide bond (m) metal binding to a reactive phosphorus group (e.g., phosphine) to form, for example, a phosphodiester bond (n) Azides coupled to alkynes using copper-catalyzed cycloaddition click chemistry (o) The biotin conjugate can react with avidin or streptavidin to form an avidin-biotin complex or a streptavidin-biotin complex.

[0071] Bioconjugate reactive groups can be selected so that they do not contribute to or interfere with the chemical stability of the conjugates described herein. Alternatively, reactive functional groups can be protected from participating in crosslinking reactions by the presence of protecting groups. In embodiments, bioconjugates include molecular entities resulting from the reaction of an unsaturated bond, such as a maleimide, with a sulfhydryl group.

[0072] "Analog," "analogue," or "derivative" is used according to its plain and ordinary meaning within chemistry and biology to refer to a compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, e.g., the substitution of one atom with an atom of a different element, or the presence of a particular functional group, or the substitution of one functional group with 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 equivalent in function and appearance to the reference compound, but differs in structure or origin.

[0073] As used herein, the terms "a" or "an" mean one or more. Additionally, the phrase "substituted with a[n]" as used herein means that the specified group may be substituted with one or more of any or all of the specified substituents. For example, when a group such as an alkyl group or heteroaryl group is "unsubstituted C-C 20 When "substituted with alkyl or unsubstituted 2-20 membered heteroalkyl," the group is also substituted with one or more unsubstituted C-C 20 It may contain alkyl and / or one or more unsubstituted 2-20 membered heteroalkyl groups.

[0074] Furthermore, when a moiety is substituted with an R substituent, the group may be referred to as "R-substituted." When a moiety is R-substituted, the moiety is substituted with at least one R substituent, and each R substituent is optionally different. When a particular R group occurs in a description of a chemical species (such as formula (I)), Roman alphabet symbols may be used to distinguish between each occurrence of that particular R group. For example, multiple R 13 When substituents are present, each R 13 The substituents are R 13A , R 13B , R 13C , R 13D It may be distinguished from R 13A , R 13B , R 13C , R 13D etc. are R 13 are defined within the definition of and optionally differ from.

[0075] The description of the compound of the present disclosure is limited by the principles of chemical bonding known to those skilled in the art.Therefore, when group can be substituted with one or more of several substituents, such substitution is selected to comply with the principles of chemical bonding and to bring about a compound that is not inherently unstable and / or is known to those skilled in the art to be likely to be unstable under ambient conditions, such as aqueous, neutral and some known physiological conditions.For example, heterocycloalkyl or heteroaryl is bonded to the rest of the molecule through ring heteroatom according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0076] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein.When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either directly or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts.When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either directly or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are amino acid salts such as arginate salts, and organic acid salts such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0077] Therefore, the compounds of the present disclosure may exist as salts with pharmaceutically acceptable acids, etc. 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 a racemic mixture), succinate, benzoate, and salts with amino acids, such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, etc.). These salts may be prepared by methods known to those skilled in the art.

[0078] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0079] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that easily undergo chemical changes under physiological conditions to produce the compounds of the present disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration. In addition, prodrugs may be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, for example, when contacted with a suitable enzyme or chemical reagent.

[0080] Certain compounds of the present disclosure can exist in unsolvated form and solvated form, including hydrated form.In general, solvated form is equivalent to unsolvated form and is included within the scope of the present disclosure.Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the use contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0081] A polypeptide or cell is "recombinant" if it is artificially or engineered, or if it is derived from or contains an artificially or engineered protein or nucleic acid (e.g., non-naturally occurring or non-wild-type). For example, a polynucleotide inserted into a vector or any other heterologous location, e.g., in the genome of a recombinant organism, so that it is not associated with nucleotide sequences that normally flank the polynucleotide as 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. Similarly, a polynucleotide sequence not found in nature, e.g., a variant of a naturally occurring gene, is recombinant.

[0082] "Co-administered" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapeutic agents. The compounds of the present invention can be administered to a patient alone or simultaneously. Co-administration is intended to include simultaneous or sequential administration of compounds (more than one compound) individually or in combination. Thus, the preparations can also be combined with other active agents, if desired (e.g., to reduce metabolic degradation).

[0083] As used herein, "cell" refers to a cell that performs metabolic or other functions sufficient to preserve 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 a particular dye, the ability to produce progeny, or, in the case of gametes, the ability to combine with a second gamete to produce viable progeny. Cells may include prokaryotic 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 cells (e.g., Spodoptera), and human cells. Cells may be naturally non-adherent or may be useful if they have been treated to prevent them from adhering to a surface, for example, by trypsinization.

[0084] The term "treating" or "treatment" refers to any indication of success in treating or ameliorating an injury, disease, pathology, or condition, including any objective or subjective parameter, such as remission, remission; reducing symptoms or making the injury, pathology, or condition more tolerable to the patient; slowing the rate of degeneration or decline; making the end point of degeneration less debilitating; or improving the patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric testing, and / or psychiatric evaluation. For example, certain methods provided herein successfully treat cancer by reducing the incidence of cancer and / or by causing remission 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 "treating" and its conjugations include preventing an injury, lesion, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. In an embodiment, the treating or treatment is not a prophylactic treatment.

[0085] An "effective amount" is an amount sufficient for a compound to achieve a predetermined purpose (e.g., achieve the effect of being administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signal transduction pathway, or reduce one or more symptoms of a disease or condition) compared to the absence of the compound. An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or alleviation of a symptom or symptoms of a disease, which may also be referred to in this context as a "therapeutically effective amount." "Alleviation" of a symptom(s) (and grammatical equivalents of this phrase) means a reduction in the severity or frequency of the symptom, or the elimination of the symptom. A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have an intended preventative effect, for example, an amount of a drug that prevents or delays the onset (or recurrence) of an injury, disease, pathology, or condition, or reduces the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition, or a symptom thereof. A complete preventative effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a prophylactically effective amount may 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 compared to the absence of the antagonist. As used herein, a "function-interfering amount" refers to the amount of antagonist required to interfere with the function of an enzyme or protein compared 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 compared 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 compared to the absence of the agonist.The exact 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, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0086] "Control" or "control experiment" is used according to its plain and ordinary meaning to refer to an experiment in which the experimental subject or reagent is treated the same as in a parallel experiment except for the omission of an experimental procedure, reagent, or variable. In some cases, a control is used as a standard of comparison in evaluating experimental efficacy. In some embodiments, a control is a measurement of a protein activity (e.g., a signaling pathway) in the absence of a compound described herein (including in any embodiment, example, figure, or table).

[0087] "Contacting" is used according to its plain and ordinary meaning to refer to a process that allows at least two distinct species (e.g., chemical compounds, including biological molecules or cells) to come into sufficient proximity to react, interact, or physically contact each other. However, it should be understood that the resulting reaction product may be produced directly from the reaction between the added reagents, or may be produced from an intermediate that may be produced in the reaction mixture from one or more of the added reagents.

[0088] The term "contacting" can include allowing two species to react, interact, or come into physical contact, where the two species can be a compound described herein and a cellular component (e.g., a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, subcellular 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, subcellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) involved in a signaling pathway.

[0089] As defined herein, the terms "activation," "activate," "activating," and the like, with respect to proteins, refer to the conversion of a protein from an initial, inactive, or inactivated state to a biologically active derivative. These terms refer to activating, or activating, sensitizing, or upregulating signal transduction or enzymatic activity or the amount of a protein that is decreased in a disease.

[0090] Terms such as "agonist," "activator," "up-regulator," and the like refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. An agonist can increase expression or activity by 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 instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more, higher than expression or activity in the absence of the agonist.

[0091] As defined herein, the terms "inhibition," "inhibit," "inhibiting," and the like, with respect to cellular component-inhibitor interactions, mean to adversely affect (e.g., reduce) the activity or function of the cellular component (e.g., reduce a signal transduction pathway stimulated by the cellular component (e.g., a protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, subcellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) compared to the activity or function of the cellular component in the absence of the inhibitor. In embodiments, inhibition means adversely affecting (e.g., reducing) the concentration or level of the cellular component compared to the concentration or level of the cellular component in the absence of the inhibitor. In embodiments, inhibition refers to the alleviation of a disease or disease symptom. In some embodiments, inhibition refers to a decrease in the activity of a signal transduction or signaling pathway (e.g., a decrease in a pathway involving the cellular component). Thus, inhibiting includes at least partially, partially or completely blocking a stimulus, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating a signaling pathway or enzymatic activity or amount of a protein.

[0092] The terms "inhibitor," "suppressor," "antagonist," or "down-regulator" refer interchangeably to a substance capable of detectably reducing the expression or activity of a given gene or protein. Antagonists can reduce expression or activity by 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, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more lower than expression or activity in the absence of the antagonist.

[0093] The term "modulator" refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of a target of the molecule compared to the absence of the composition (e.g., the target may be a cellular component (e.g., a protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)).

[0094] The term "expression" includes 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 conventional techniques for detecting proteins (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0095] The term "modulate" is used according to its plain and ordinary meaning to refer to the act of changing or varying one or more properties. "Modulation" refers to the process of changing or varying one or more properties. For example, as applied to the effect of a modulator on a target protein, modulating means changing the property or function of the target molecule or the amount of the target molecule by increasing or decreasing it.

[0096] A "patient" or "subject in need thereof" refers to an organism 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, cows, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammals. In some embodiments, the patient is a human.

[0097] "Disease" or "condition" refers to an existing state or state of health of a patient or subject that can be treated with the compounds or methods provided herein. In some embodiments, the disease is a disease associated with (e.g., caused by) a cellular component (e.g., a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, subcellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In embodiments, the disease is a neurodegenerative disease. In embodiments, the disease is cancer.

[0098] As used herein, the term "neurodegenerative disease" refers to the disease or condition that the function of the nervous system of a subject is impaired.Examples of neurodegenerative diseases that can be treated by the compounds, pharmaceutical compositions or methods described herein include Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia-telangiectasia, Batten disease (also known as Spillmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne's syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-related disease, These include Kennedy disease, Krabe disease, Kuhl disease, dementia with Lewy bodies, Macado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pellizers-Merzbach disease, Pick's disease, primary lateral sclerosis, prion diseases, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (various types with varying features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, or tabes dorsalis.

[0099] As used herein, the term "inflammatory disease" refers to a disease or condition characterized by abnormal inflammation (e.g., increased levels of inflammation compared to a control, such as a healthy individual without 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 mellitus, Guillain-Barré syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, and others. Diseases that may be affected include 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.

[0100] As used herein, the term "cancer" refers to all types of cancers, neoplasms, or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers that may 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, gastric cancer, uterine cancer, medulloblastoma, colorectal cancer, or pancreatic cancer. Further examples include Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulanoma, malignant carcinoid, bladder cancer, premalignant skin lesion, testicular cancer, lymphoma, thyroid cancer, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic neoplasm, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, or prostate cancer.

[0101] The term "leukemia" broadly refers to progressive, malignant diseases of the hematopoietic organs and is generally characterized by distorted proliferation and development of white blood cells and their precursor cells in the blood and bone marrow. Leukemias are generally classified clinically based on (1) the duration and character of the disease—acute or chronic, (2) the type of cells involved, i.e., bone marrow (myeloid), lymphatic (lymphoid), or monocytic, and (3) the increased or non-increased number of abnormal cells in the blood—leukemic or non-leukemic (subleukemic). Exemplary leukemias that may 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, and non-leukemic leukemia. leukemia), leukemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, fetal leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoblastic leukemia, These include lymphocytic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, and anaplastic cell leukemia.

[0102] As used herein, the term "lymphoma" refers to a group of cancers that affect hematopoietic and lymphatic tissues. It develops primarily in lymphocytes, which are blood cells found in lymph nodes, spleen, thymus, and bone marrow. The two main types of lymphoma are non-Hodgkin's lymphoma and Hodgkin's disease. Hodgkin's disease accounts for approximately 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 at which the cancer grows and the type of cell involved. NHL includes aggressive (high-grade) and indolent (low-grade) types. Based on the type of cell involved, there are B-cell and T-cell NHL. 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, extranodal (MALT) lymphoma, nodal (monocytic B-cell) lymphoma, splenic lymphoma, diffuse large B-cell 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, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.

[0103] The term "sarcoma" generally refers to tumors composed of a substance like embryonic connective tissue and generally made up of tightly packed cells embedded in a fibrous or homogeneous substance. Sarcomas that may be treated with the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, green sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, and fibroblastic sarcoma. These include sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal osteosarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0104] The term "melanoma" is intended to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with the compounds or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0105] The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.Exemplary carcinomas that may be treated with the compounds or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, lobular cell carcinoma, acinic cell carcinoma, adenocell carcinoma, adenoid cystic carcinoma, carcinoma adenomatous carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, armor carcinoma, skin carcinoma, cylindrical carcinoma, cylindrical cell carcinoma, ductal carcinoma, and compact carcinoma. durum, embryonal carcinoma, encephalomyocellular carcinoma, epidermoid carcinoma, epidermoid carcinoma, tonsillar carcinoma, exophytic carcinoma, ulcer carcinoma, fibrous carcinoma, gelatinous carcinoma, colloid adenocarcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, glassy carcinoma, adrenal carcinoma, infantile embryonal carcinoma, carcinoma in situ, epidermal carcinoma, carcinoma in situ, Krompecher's carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucus-secreting carcinoma muciparum, mucocytic carcinoma, mucoepidermoid carcinoma, carcinoma mucosum, mucosal carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, bony carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, pasty carcinoma, renal cell carcinoma of the kidney, storage cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, porotic carcinoma, squamous cell carcinoma, squamous cell carcinoma, string carcinoma, telangiectatic carcinoma, telangiectatic-like carcinoma, transitional cell carcinoma, nodular carcinoma, carcinoma tuberosum, nodular carcinoma, verrucous carcinoma, and choriocarcinoma.

[0106] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that aid in the administration and absorption of active agents to and by a subject and can be included in the compositions of the present invention without causing significant adverse toxic effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, saline (such as Ringer's solution), alcohol, oil, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations can be sterilized and, if desired, can be mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for affecting osmotic pressure, buffers, coloring agents, and / or aromatic substances that do not adversely react with the compounds of the present invention. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0107] The term "preparation" is intended to include a formulation of an active compound with an encapsulating material as a carrier to provide a capsule in which the active ingredient, with or without other carriers, is surrounded by the carrier and is therefore associated with the carrier. Also included are cachets and lozenges. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0108] As used herein, the term "about" refers to a range of values ​​that includes the particular value and that one of ordinary skill in the art would consider reasonably similar to the particular value. In embodiments, about refers to within a standard deviation using measurements generally accepted in the art. In embodiments, about refers to a range that covers + / - 10% of the particular value. In embodiments, about includes the particular value.

[0109] As used herein, the term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration, or implantation of a sustained-release device, such as a mini-osmotic pump, to a subject. Administration can be by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other delivery modes include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. "Coadministration" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of 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 alone or simultaneously to a patient. Co-administration is intended to include simultaneous or sequential administration of compounds (more than one compound) individually or in combination. Thus, the preparation can be combined with other active substances, if desired (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered transdermally or topically, and can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, nanoparticles, pastes, jellies, paints, powders, and aerosols.

[0110] The compounds described herein can be used in combination with each other, in combination with other active agents known to be useful in treating diseases associated with cells expressing disease-associated cellular components, or in combination with adjunct agents that may not be effective alone but may contribute to the effectiveness of the active agents.

[0111] In some embodiments, simultaneous administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Simultaneous administration includes administering two active agents simultaneously, nearly simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, simultaneous administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition containing both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active agent and / or adjunct may be linked or conjugated to each other.

[0112] 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, galantamine, 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).

[0113] 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), nonsteroidal anti-inflammatory drugs (e.g., aspirin, ibuprofen, naproxen, diclofenac), corticosteroids (e.g., prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone), and opoids (e.g., codeine, fentanyl, hydrocodone, hydromorphone, morphine, meperidine, oxycodone).

[0114] "Anticancer agent" is used according to its plain and ordinary meaning to refer to a composition (e.g., a compound, drug, antagonist, inhibitor, modulator) that has anti-neoplastic properties or the ability to inhibit cell growth or proliferation. In some embodiments, the anti-cancer agent is a chemotherapeutic agent. In some embodiments, the anti-cancer agent is an agent identified herein that is useful in methods of treating cancer. In some embodiments, the anti-cancer agent is an agent approved by the FDA or a similar regulatory body in a country other than the United States to treat cancer. In embodiments, the anti-cancer agent is an agent with anti-tumor properties that has not (e.g., not yet) been approved by the FDA or a similar regulatory body in a country other than the United States for the treatment of cancer. Examples of anticancer drugs include MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g., XL518, CI-1040, PD035901, selumetinib / AZD6244, GSK1120212 / trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD 318088, AS703026, BAY869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meifalan), ethyleneimines and methylmelamines (e.g., For example, hexamethylmelamine, thiotepa), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin), triazenes (decarbazine)), antimetabolites (e.g., 5-azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxolidine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan,topotecan, amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g., cisplatin, oxaloplatin, carboplatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical suppressants (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors of mitogen-activated protein kinase signaling (e.g., For example, U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY43-9006, wortmannin, or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., Rituxan), gossyfol, genasense, polyphenol E, chlorofusin, all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor Retinoic acid-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352, 20-epi-1,25-dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubicin, acylfulvene, adecipenol, adzelesin, aldesleukin, ALL-TK antagonist, altretamine, ambamustine, amidox, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, andrographolide, angiogenesis inhibitor, antagonist D, antagonist G, antarelix, dorsal dorsal morphogenetic protein-1, antiandrogen,prostate cancer, antiestrogens, antineoplastic agents, antisense oligonucleotides, aphidicolin glycinate, apoptotic gene regulators, apoptosis modulators, apurinic acid, ara-CDP-DL-PTBA, arginine deaminase, asulaculin, atamestane, atrimustine, axinastatin 1, axinastatin 2, axinastatin 3, azasetron, azatoxin, azatyrosine, baccatin III derivatives, balanol, batimastat, BCR / ABL antagonists, benzochlorins , benzoylstaurosporine, beta-lactam derivatives, beta-arretin, betaclamycin B, betulinic acid, bFGF inhibitors, bicalutamide, bisantrene, bisaziridinylspermine, bisnafide, bistrene A, bizeresin, brefulate, bropirimine, budotitanium, buthionine sulfoximine, calcipotriol, calphostin C, camptothecin derivatives, canarypox IL-2, capecitabine, carboxamido-amino-triazole, carboxyamidotriazole, CaRest M3, CARN 700, cartilage-derived inhibitors, carzelesin, casein kinase inhibitor (ICOS), castanospermine, cecropin B, cetrorelix, clorins, chloroquinoxaline sulfonamides, cicaprost, cis-porphyrin, cladribine, clomiphene analogs, clotrimazole, colismycin A, colismycin B, combretastatin A4, combretastatin analogs, conagenin, clambecidin 816, crisnatol, cryptophycin 8, cryptophycin A derivatives, curacin A, cyclopentaquinone, cycloplatam, sipemycin, cytarabine ocfosf Art, cytolytic factors, cytostatin, dacliximab, decitabine, dehydrodydemnin B, deslorelin, dexamethasone, dexphosphamide, dexrazoxane, dexverapamil, diaziquone, didemnin B, didox, diethylnorspermine, dihydro-5-azacytidine, 9-dioxamycin, diphenylspiromustine, docosanol, dolasetron, doxifluridine, droloxifene, dronabinol, duocarmycin SA, ebselen, ecomustine, edelfosine, edrecolomab, eflornithine, elemene, emitefur, epirubicin,Epristeride, estramustine analogs, estrogen agonists, estrogen antagonists, etanidazole, etoposide phosphate, exemestane, fadrozole, fazarabine, fenretinide, filgrastim, finasteride, flavopiridol, flezelastine, fluasterone, fludarabine, fluorodaunorubicin hydrochloride, forfenimex, formestane, fostriecin, fotemustine, gadolinium texaphyrin, gallium nitrate, gallocitabine, ganirelix, gelatinase inhibitors, gemcitabine, glutathione inhibitors, hepsulfam, heregulin, hexamethylenebisacetamide bisacetamide), hypericin, ibandronic acid, idarubicin, idoxifene, idramantone, ilmofosine, ilomastat, imidazoacridone, imiquimod, immunostimulatory peptides, insulin-like growth factor-1 receptor inhibitors, interferon agonists, interferons, interleukins, iobenguane, iododoxorubicin, ipomeanol, 4-, irinotecan, ilopract, irsogladine, isobengazole, isohomohalichondrin B, itasetron, jasplakinolide, kahalalide F, lamellarin-N triacetate, lanreotide, leinamycin, lenograstim, lentinan sulfate, leptolstatin, letrozole, leukemia inhibitory factor, leukocyte alpha interferon, leuprolide + estrogen + protease Gesterone, leuprorelin, levamisole, liarozole, linear polyamine analogues, lipophilic disaccharide peptides, lipophilic platinum compounds, lysocrine amide 7, lobaplatin, lombricin, lometrexol, lonidamine, losoxantrone, lovastatin, loxoribine, lurtotecan, lutetium texaphyrin, lysofylline, lytic peptides, maytansine, mannostatin A, marimastat, massoprocol, maspin, matrilysin inhibitors, matrix metalloproteinase inhibitors, menogaril, mervalone, meterelin, methioninase, metoclopramide, MIF inhibitors, mifepristone, miltefosine, mirimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitomycin analogues, mitonafide,Mitoxin fibroblast growth factor-saporin, mitoxantrone, mofalotene, molgramostim, monoclonal antibodies, human chorionic gonadotropin, monophosphoryl lipid A + myobacterium cell wall sk, mopidamol, multidrug resistance gene inhibitors, multiple tumor suppressor 1-based therapeutics, mustard anticancer drugs, mycaperoxide B, mycobacterium cell wall extract, myriaporone, N-acetyldinaline, N-substituted benzamides, nafarelin, nagressip, naloxone + pentazocine, napavine, naphterpine, nartograstim, nedaplatin, nemorubicin, neridronic acid, neutral endopeptidase, nilutamide, nisamycin, nitric oxide regulators, nitroxide antioxidants, nitrulline, O6-benzylguanine, octo Reotide, oxenon, oligonucleotides, onapristone, ondansetron, ondansetron, oracin, oral cytokine inducers, ormaplatin, osateron, oxaliplatin, oxaunomycin, palauamine, palmitoylrhizoxin, pamidronate, panaxytriol, panomifen, parabactin, pazelliptin, pegaspargase, perdecin, pentosan polysulfate sodium, pentostatin, pentrolozole, perflubron, perfosfamide, perillyl alcohol, phenazinomycin, phenylacetate, phosphatase inhibitors, picibanil, pilocarpine hydrochloride, pirarubicin, piritrexim, prasetin A, prasetin B, plasminogen activator inhibitors, platinum complexes, Platinum compounds, platinum-triamine complexes, porfimer sodium, porfiromycin, prednisone, propyl bis-acridone, prostaglandin J2, proteasome inhibitors, protein A-based immunomodulators, protein kinase C inhibitors, protein kinase C inhibitors, microalgae, protein tyrosine phosphatase inhibitors, purine nucleoside phosphorylase inhibitors, purpurins, pyrazoloacridines, pyridoxylated hemoglobin polyoxyethylene conjugates, raf antagonists, raltitrexed, ramosetron, ras farnesyl protein transferase inhibitors, ras inhibitors, ras-GAP inhibitors, demethylated reterliptin, rhenium etidronate 186, rhizoxin, ribozyme, RII retinamide, rogletimide, rohitukin, romurtide, roquinimex, rubiginone B1, ruboxil, safingol, saintpine, SarCNU, sarcophytol A, sargramostim, Sdi 1 mimetic, semustine, senescence-derived inhibitor 1, sense oligonucleotide, signal transduction inhibitor, signal transduction modulator, single-stranded antigen binding protein, schizofuran, sobuzoxane, borocaptate sodium, sodium phenylacetate, sorberol, somatomedin binding protein, sonermin, sparfosic acid, spicamycin D, spiromustine, splenopentin, spongistatin 1, squalamine, stem cell inhibitor, stem cell division inhibitor, stipiramide, stromelysin inhibitor, sulfinosine, superactive vasoactive intestinal peptide antagonist, suradista, suramin, swainsonine, synthetic glycosaminoglycans minoglycan, tallimustine, tamoxifen methiodide, tauromustine, tazarotene, tecogalan sodium, tegafur, terlapyrylium, telomerase inhibitors, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, tetrazomine, saliblastine, thiocoraline, thrombopoietin, thrombopoietin mimetics, thymalfasin, thymopoietin receptor agonists, thymotrin, thyroid-stimulating hormone, tin ethyl etiopurpurin, tirapazamine, titanocene dichloride, topsentin, toremifene, totipotent stem cell factor, translation inhibitors, tretinoin, triacetyluridine, triciribine,Trimetrexate, triptorelin, tropisetron, turosteride, tyrosine kinase inhibitors, tyrphostin, UBC inhibitors, ubenimex, urogenital sinus-derived growth inhibitory factor, urokinase receptor antagonists, vapreotide, variolin B, vector-based, erythrocyte gene therapy drugs, veraresol, veramine, verdins, verteporfin, vinorelbine, vinxartin, vitaxin, vorozole, zanoteron, zeniplatin, zilascorb, zinostatin stimalamer, adriamycin riamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin, aclarubicin, acodazole hydrochloride, acronine, adzelesin, aldesleukin, altretamine, ambomycin, amethantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacytidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizeresin, bleomycin sulfate, brequinar Sodium, bropirimine, busulfan, cactinomycin, calsterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil, ciloremycin, cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, daunorubicin hydrochloride, decitabine, dexorumaplatin, dezaguanine, dezaguanine mesylate, diaziconazole, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, propionate Drostanolone acid, duazomycin, edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin hydrochloride, elbrozole, esorubicin hydrochloride, estramustine, estramustine sodium phosphate, etanidazole, etoposide, etoposide phosphate, etopurine, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, fluorocitabine, foskidone, phosphotriestrin sodium, gemcitabine, gemcitabine hydrochloride,Hydroxyurea, idarubicin hydrochloride, ifosfamide, iimofosine, interleukin I1 (including recombinant interleukin II or rlL.sub.2), interferon alpha-2a, interferon alpha-2b, interferon alpha-nl, interferon alpha-n3, interferon beta-Ia, interferon gamma-Ib, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, lometrexol sodium, lomustine, losoxantrone hydrochloride, Masoprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide, mitocalcin, mitochromin, mitodilline, mitomarcine, mitomycin, mitospar, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazoie, nogalamycin, ormaplatin, oxisuran, pegaspargase, periomycin, pentamstine, peploycin sulfate sulfate), perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, promestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, rhizoxin, rogletimide, safingol, safingol hydrochloride, semustine, simtrazene, sparfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptomycin Putozocin, sulofenur, tallysomycin, tecogalan sodium, tegafur, teroxantrone hydrochloride, temoporfin, teniposide, teroxilon, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, toremifene citrate, trestrone acetate, triciribine phosphate, trimetrexate, trimetrexate glucuronate, triptorelin, tuburosol hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate,Vindesine, vindesine sulfate, vinedipine sulfate, vinglisinate sulfate, vinleurosine sulfate, vinorelbine tartrate, vinrocidine sulfate, vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicin hydrochloride, agents that arrest cells in the G2-M phase and / or modulate microtubule formation or stability (e.g., Taxol™ (i.e., paclitaxel), Taxotere™, compounds containing a taxane skeleton, elbrozole (i.e., R-55104), dolastatin 10 (i.e., DLS-10 and NSC-376128), mibobrin isethionate (i.e., as CI-980), vincristine, NSC-639829, discodermolide (i.e., as NVP-XX-A-296) , ABT-751 (Abbott, i.e., E-7010), altoruchitin (e.g., altoruchitin A and altoruchitin C), spongistatins (e.g., spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, and spongistatin 9), cemadotin hydrochloride (i.e., LU-103793 and NSC-D-669356), epothilones (e.g., epothilone A, epothilone B, epothilone C (i.e., deoxyepothilone A or dEpoA), epothilone D (i.e., KOS-862, dEpoB, and deoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (i.e., BMS-310705), 21-hydroxyepothilone D (i.e., deoxyepothilone F and dEpoF), 26-fluoroepothilone, auristatin PE (i.e., NSC-654663), soblidotin (i.e., TZT-1027), LS-4559-P (Pharmacia, i.e., LS-4577), LS-4578 (Pharmacia, i.e., LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, i.e., WS-9885B),GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, i.e. ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa) Hakko), IDN-5005 (Indena), cryptophycin 52 (i.e., LY-355703), AC-7739 (Ajinomoto, i.e., AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, i.e., AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), vitilevuamide, tubulysin A, canadensol, centaureidin (i.e., NSC-106969), T-138067 (Tularik, i.e., T-67, TL-138067, and TI-138067), COBRA-1 (Parker Hughes Institute, i.e., DDE-261 and WHI-261), H10 (Kansas State University), University), H16 (Kansas State University), oncocidin A1 (i.e., BTO-956 and DIME), DDE-313 (Parker Hughes Institute), physianolide B, laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, i.e., SPIKET-P), 3-IAABU (cytoskeleton / Mt. Sinai School of Medicine, i.e., MF-569), narcosine (also known as NSC-5366), nascapine, D-24851 (Asta Medica), A-105972 (Abbott), hemiasterlin, 3-BAABU (cytoskeleton / Mt. Sinai School of Medicine, i.e., MF-191), TMPN (Arizona State University),vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, inanosin (i.e., NSC-698666), 3-IAABE (cytoskeleton / Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, i.e., T-900607), RPR-115781 (Aventis), eleutherobin (such as desmethyleleutherobin, desaetyleleutherobin, isoeutherobin A, and Z-eleutherobin), carybeoside, carybeolin, halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), diozostatin, (-)-phenylahistine (i.e., NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), myoseverin B, D-43411 (Zentaris, i.e., D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e., SPA-110, trifluoroacetate) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), resverastatin sodium phosphate, BPR-OY-007 (National Health Research Institute) Institutes), and SSR-250411 (Sanofi)), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH), such as goserelin or leuprolide, corticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., BacillusCalmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., 111 In, 90 Y, or 131 anti-CD20 monoclonal antibodies conjugated to IFN-γ or the like), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR) targeted therapies or therapeutic agents (e.g., gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OS Anticancer drug moieties include, but are not limited to, I-420 / desmethylerlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, etc. The anticancer drug moiety is a monovalent anticancer drug (e.g., a monovalent form of the drugs listed above).

[0115] In therapeutic use for the treatment of disease, the compounds utilized in the pharmaceutical compositions of the present invention may be administered at an initial dosage of about 0.001 mg / kg to about 1000 mg / kg daily. Daily dosage ranges of about 0.01 mg / kg to about 500 mg / kg, or about 0.1 mg / kg to about 200 mg / kg, or about 1 mg / kg to about 100 mg / kg, or about 10 mg / kg to about 50 mg / kg can be used. However, dosages may vary depending on the requirements of the patient, the severity of the condition being treated, and the compound or drug being used. For example, dosages can be empirically determined taking into account the type and stage of cancer diagnosed in a particular patient. In accordance with the present invention, the dose administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects associated with the administration of the compound in a particular patient. Determining the appropriate dosage for a particular situation is within the capabilities of one of ordinary skill in the art. Generally, treatment is initiated with a smaller dosage that is less than the optimal dose of the compound.Then, the dosage is gradually increased until the optimal effect under the circumstances is reached.For convenience, if desired, the total daily dose can be divided and administered in portions throughout the day.

[0116] The compounds described herein can be used in combination with each other, in combination with other active agents known to be useful in the treatment of cancer, or in combination with adjuvants that may not be effective alone but may contribute to the effectiveness of the active agent.

[0117] In the context of a substance or the activity or function of a substance related to a disease (e.g., a protein-related disease, a disease associated with a cellular component), the term "related to" or "associated with" means that the substance or the activity or function of the substance causes (in whole or in part) the disease (e.g., a neurodegenerative disease, cancer) or causes (in whole or in part) the symptoms of the disease, or that the symptoms of the disease can be treated by modulating (e.g., inhibiting or activating) the substance (e.g., a cellular component). For example, a neurodegenerative disease associated with protein aggregates can be a neurodegenerative disease caused (in whole or in part) by abnormal protein aggregation, or a neurodegenerative disease in which certain symptoms of the disease are caused (in whole or in part) by abnormal protein aggregation. As used herein, something that is described as associated with a disease can be a target for treating the disease if it is a causative agent. For example, a neurodegenerative disease associated with abnormal protein aggregation or a protein aggregate-associated neurodegenerative disease can be treated with a protein aggregation modulator.

[0118] The term "abnormal" as used herein refers to something that is different from normal. When used to describe enzyme activity, abnormal refers to activity that is greater or less than the average of normal control or normal non-disease control samples. Abnormal activity can refer to the amount of activity that causes disease, and restoring the abnormal activity to a normal or non-disease-related amount (e.g., by administering a compound or using the methods described herein) results in a reduction of the disease or one or more symptoms.

[0119] As used herein, the term "electrophilic" refers to a chemical group that can accept electron density. "Electrophilic substituent," "electrophilic chemical moiety," or "electrophilic moiety" refers to an electron-deficient chemical group, substituent, or moiety (a monovalent chemical group) that can react with an electron-donating group, such as a nucleophile, by accepting an electron pair or electron density to form a bond. In some embodiments, the electrophilic substituent of a compound can react with a cysteine ​​residue. In some embodiments, the electrophilic substituent can form a covalent bond with a cysteine ​​residue and may be referred to as a "covalent cysteine ​​modifying moiety" or "covalent cysteine ​​modifying substituent." The covalent bond formed between the electrophilic substituent and the sulfhydryl group of a cysteine ​​can be a reversible or irreversible bond. In some embodiments, the electrophilic substituent of a compound can react with a lysine residue. In some embodiments, the electrophilic substituent of a compound can react with a serine residue. In some embodiments, the electrophilic substituent of a compound can react with a methionine residue.

[0120] As used herein, "nucleophile" refers to a chemical group that can donate electron density.

[0121] The term "isolated," when applied to a nucleic acid or protein, means that the nucleic acid or protein is essentially free from other cellular components with which it is naturally associated. It can be, for example, in a homogeneous state, either dry or in an aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.

[0122] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function similarly to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those that are later modified, such as hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an α-carbon bonded to a hydrogen, a carboxyl group, an amino group, and an R group, such as homoserine, norleucine, methionine sulfoxide, and methionine methylsulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refer to compounds that have a structure different from the general chemical structure of an amino acid but function similarly 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.

[0123] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Similarly, nucleotides may be referred to by their commonly accepted single-letter codes.

[0124] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, which may, in embodiments, be conjugated to moieties not composed of amino acids. The term applies to amino acid polymers in which one or more amino acid residues are artificial chemical mimetics of corresponding naturally occurring amino acids, as well as to naturally occurring and non-naturally occurring amino acid polymers.

[0125] The "position" of an amino acid or nucleotide base is indicated by a number sequentially identifying each amino acid (or nucleotide base) in a reference sequence based on its position relative to the N-terminus (or 5'-terminus). Because of deletions, insertions, truncations, fusions, etc., which must be considered when determining optimal alignment, the number of amino acid residues in a test sequence, determined simply by counting from the N-terminus, is generally not necessarily the same as the number of corresponding positions in the reference sequence. For example, if a variant has a deletion compared to the aligned reference sequence, no amino acid in the variant will correspond to the position in the reference sequence at the deletion site. If the aligned reference sequence has an insertion, the insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of a truncation or fusion, there may be a stretch of amino acids in either the reference sequence or the aligned sequence that does not correspond to any amino acid in the corresponding sequence.

[0126] When used in the context of the numbering of a given amino acid or polynucleotide sequence, the term "numbered with reference to" or "corresponding to" refers to the numbering of residues in a particular reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence.

[0127] The term "protein complex" is used according to its plain and ordinary meaning and refers to a protein associated with an additional substance (e.g., another protein, a protein subunit, or a compound). A protein complex typically has a defined quaternary structure. The association between the protein and the additional substance may be a covalent bond. In embodiments, the association between the protein and the additional substance (e.g., a compound) is via a non-covalent interaction. In embodiments, a protein complex refers to a group of two or more polypeptide chains. The proteins in a protein complex are linked by non-covalent protein-protein interactions. A non-limiting example of a protein complex is the proteasome.

[0128] The term "protein aggregate" is used according to its plain and ordinary meaning to refer to an abnormal collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are often associated with disease (e.g., amyloidosis). Typically, proteins misfold as a result of changes in amino acid sequence or changes in the native environment that disrupt normal non-covalent interactions, and if this misfolded protein is not corrected or degraded, the unfolded / misfolded protein may aggregate. There are three main types of protein aggregates that can form: amorphous aggregates, oligomers, and amyloid fibrils. In embodiments, the protein aggregates are referred to as aggresomes.

[0129] The term "Nurr1" or "NR4A2" refers to the protein encoded by the NR4A2 gene in humans. Nurr1 is a nuclear receptor and plays an important role in maintaining the brain's dopaminergic system. The term "Nurr1" may 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 an embodiment, Nurr1 has the following amino acid sequence: MPCVQAQYGSSPQGASPASQSYSYHSSGEYSSDFLTPEFVKFSMDLTNTEITATTSLPSF STFMDNYSTGYDVKPPCLYQMPLSGQQSSIKVEDIQMHNYQQHSHLPPQSEEMMPHSGSV YYKPSSPPTPTTPGFQVQHSPMWDDPGSLHNFHQNYVATTHMIEQRKTPVSRLLSLFSFKQ SPPGTPVSSCQMRFDGPLHVPMNPEPAGSHHVVDGQTFAVPNPIRKPASMGFPGLQIGHA SQLLDTQVPSPPSRGSPSNEGLCAVCGDNAACQHYGVRTCEGCKGFFKRTVQKNAKYVCL ANKNCPVDKRRRNRCQYCRFQKCLAVGMVKEVVRTDSLKGRRGRLPSKPKSPQEPSPPSP PVSLISALVRAHVDSNPAMTSLDYSRFQANPDYQMSGDDTQHIQQFYDLLTGSMEIIRGW AEKIPGFADLPKADQDLLFESAFLELFVLRLAYRSNPVEGKLIFCNGVVLHRLQCVRGFG EWIDSIVEFSSNLQNMNIDISAFSCIAALAMVTERHGLKEPKRVEELQNKIVNCLKDHVT FNNGGLNRPNYLSKLLGKLPELRTLCTQGLQRIFYLKLEDLVPPPAIIDKLFLDTLPF (SEQ ID NO: 1)

[0130] The term "pituitary homeobox 3" or "Pitx3" refers to a gene encoding a member of the RIEG / PITX homeobox family, which is in the bicoid class of homeodomain proteins and functions as a transcription factor. Pitx3 is involved in the maintenance of dopaminergic neurons. The term "Pitx3" may 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: MEFGLLSEAEARSPALSLSDAGTPHPQLPEHGCKGQEHSDSEKASASLPGGSPEDGSLKK KQRRQRTHFTSQQLQELEATFQRNRYPDMSTREEIAVWTNLTEARVRVWFKNRRAKWRKR ERSQQAELCKGSFAAPLGGLVPPYEEVYPGYSYGNWPPKALAPPLAAKTFPFAFNSVNVG PLASQPVFSPPSSIAASMVPSAAAAPGTVPGPGALQGLGGGPPGLAPAAVSSGAVSCPYA SAAAAAAAAASSPYVYRDPCNSSLASLRLKAKQHASFSYPAVHGPPPAANLSPCQYAVER PV (SEQ ID NO: 2)

[0131] The term "tyrosine hydroxylase" or "tyrosine 3-monooxygenase" refers to an enzyme responsible for catalyzing 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" may 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 an embodiment, TH has the following amino acid sequence: MPTPDATTPQAKGFRRAVSELDAKQAEAIMVRGQGAPGPSLTGSPWPGTAAPAASYTPTP RSPRFIGRRQSLIEDARKEREAAVAAAAAAVPSEPGDPLEAVAFEEKEGKAVLNLLFSPR ATKPSALSRAVKVFETFEAKIHHLETRPAQRPRAGGPHLEYFVRLEVRRGDLAALLSGVR QVSEDVRSPAGPKVPWFPRKVSELDKCHHLVTKFDPDLDLDHPGFSDQVYRQRRKLIAEI AFQYRHGDPIPRVEYTAEEIATWKEVYTTLKGLYATHACGEHLEAFALLERFSGYREDNI PQLEDVSRFLKERTGFQLRPVAGLLSARDFLASLAFRVFQCTQYIRHASSPMHSPEPDCC HELLGHVPMLADRTFAQFSQDIGLASLGASDEEIEKLSTLYWFTVEFGLCKQNGEVKAYG AGLLSSYGELLHCLSEEPEIRAFDPEAAAVQPYQDQTYQSVYFVSESFSDAKDKLRSYAS RIQRPFSVKFDPYTLAIDVLDSPQAVRRSLEGVQDELDTLAHALSAIG (SEQ ID NO: 3)

[0132] 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 cell cytosol to synaptic vesicles. The term "VMAT2" may 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 sequence: MALSELALVRWLQESRRSRKLILFIVFLALLLDNMLLTVVVPIIPSYLYSIKHEKNATEI QTARPVHTASISDSFQSIFSYYDNSTMVTGNATRDLTLHQTATQHMVTNASAVPSDCPSE DKDLLNENVQVGLLFASKATVQLITNPFIGLLTNRIGYPIPIFAGFCIMFVSTIMFAFSS SYAFLLIARSLQGIGSSCSSVAGMGMLASVYTDDEERGNVMGIALGGLAMGVLVGPPFGS VLYEFVGKTAPFLVLAALVLLDGAIQLFVLQPSRVQPESQKGTPLTTLLKDPYILIAAGS ICFANMGIAMLEPALPIWMMETMCSRKWQLGVAFLPASISYLIGTNIFGILAHKMGRWLC ALLGMIIVGVSILCIPFAKNIYGLIAPNFGVGFAIGMVDSSMMPIMGYLVDLRHVSVYGS VYAIADVAFCMGYAIGPSAGGAIAKAIGFPWLMTIIGIDILFAPLCFFLRSPPAKEEKM AILMDHNCPIKTKMYTQNNIQSYPIGEDEESESD (SEQ ID NO: 4)

[0133] II. Compounds In one aspect, a compound is provided having the formula: [ka]

[0134] Ring A is aryl or heteroaryl.

[0135] L 1 is L 101 -L 102 -L 103 is.

[0136] 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 is.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] R 101 , R 102 , and R 103are 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, -N HC(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.

[0142] R 1 is hydrogen, halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -SC(O)R 1C , -C(O)OR 1C , -C(O)NR 1A R 1B , -OR 1D , -SR 1D , -SeR 1D , -NR 1A SO2R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR1C , -NR 1A OR 1C , -N3, -SSR 1D , -SiR 1A R 1B R 1C , —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.

[0143] E is an electrophilic moiety.

[0144] R 2 are independently halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -OCX 2 3. -OCH2X 2 , -OCHX 2 2, -CN, -SO n2 R 2D , -SO v2 NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -SC(O)R 1C , -C(O)OR 2C , -C(O)NR 2A R 2B , -OR 2D , -SR 2D , -SeR 2D , -NR 2A SO2R 2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and two R bonded to adjacent atoms are 2 The substituents may be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0145] R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are 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 R bonded to the same nitrogen atom 1A and R 1B The substituents may join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R 2A and R 2B The substituents may be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0146] n1 and n2 are independently an integer of 0 to 4.

[0147] m1, m2, v1, and v2 are independently 1 or 2.

[0148] X 1 and X 2 are independently -F, -Cl, -Br, or -I.

[0149] z2 is an integer of 0 to 5.

[0150] In an embodiment, 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.

[0151] In an embodiment, 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., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene (e.g., 2-10 membered, 2-6 membered, or 2-4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted or unsubstituted arylene (e.g., C6-C 10 or phenylene), 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 is.

[0152] In an embodiment, 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., 2-10 membered, 2-6 membered, or 2-4 membered), R 101 substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), R 101 substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 101 Substituted or unsubstituted arylene (e.g., C6-C 10 or phenylene), R 101 substituted or unsubstituted heteroarylene (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), L 104 -L 105 , L 104 -NH-L 105 , or L 104 -CH2-L 105 is.

[0153] In an embodiment, 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., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene (e.g., 2-10 membered, 2-6 membered, or 2-4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted or unsubstituted arylene (e.g., C6-C 10 or phenylene), or substituted or unsubstituted heteroarylene (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0154] In an embodiment, 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., C1-C8, C1-C6, or C1-C4), R 102 substituted or unsubstituted heteroalkylene (e.g., 2-10 membered, 2-6 membered, or 2-4 membered), R 102 substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), R 102 substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 102 Substituted or unsubstituted arylene (e.g., C6-C 10 or phenylene), or R 102 It is a substituted or unsubstituted heteroarylene (eg, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).

[0155] In an embodiment, 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., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene (e.g., 2-10 membered, 2-6 membered, or 2-4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted or unsubstituted arylene (e.g., C6-C 10 or phenylene), or substituted or unsubstituted heteroarylene (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0156] In an embodiment, 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., C1-C8, C1-C6, or C1-C4), R 103 substituted or unsubstituted heteroalkylene (e.g., 2-10 membered, 2-6 membered, or 2-4 membered), R 103 substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), R 103 substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 103 Substituted or unsubstituted arylene (e.g., C6-C 10 or phenylene), or R 103 It is a substituted or unsubstituted heteroarylene (eg, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).

[0157] In embodiments, R1A , R 1B , R 1C , and R 1D are 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, -OCH 2Cl, -OCH2Br, -OCH2F, -OCHI, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2-10 membered, 2-6 membered, or 2-4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 1A and R 1B The substituents may be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered) or a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0158] In embodiments, R 1A , R 1B , R 1C , and R 1Dare 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 alkyl (e.g., C1-C8, C1-C6, or C1-C4), R 10 substituted or unsubstituted heteroalkyl (e.g., 2-10 membered, 2-6 membered, or 2-4 membered), R 10 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 10 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 10 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 10 Substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered) and R 1A and R 1B The substituents are joined to form R 10 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered) or R 10 It may form a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0159] In embodiments, R 2A , R 2B , R 2C , and R 2Dare 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, -OCH 2Cl, -OCH2Br, -OCH2F, -OCHI, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2-10 membered, 2-6 membered, or 2-4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 2A and R 2B The substituents may be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered) or a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0160] In embodiments, R 2A , R 2B , R 2C , and R 2Dare 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., 2-10 membered, 2-6 membered, or 2-4 membered), R 20 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 20 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 20 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 20 Substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered) and R 2A and R 2B The substituents are joined to form R 20 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered) or R 20 It may form a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0161] In an embodiment, -L 1 -R 1 teeth [ka] and R 1is as described herein, including embodiments.

[0162] In embodiments, the compound has the formula [ka] Ring A, R 1 , R 2 , L 103 , L 104 , L 105 , and z2 are as described herein.

[0163] W is N or CH.

[0164] In an embodiment, L 103 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0165] In an embodiment, L 104 is a bond, —S(O)—, —C(O)—, —NHC(O)—, —OC(O)—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0166] In an embodiment, L 105 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene.

[0167] In embodiments, ring A is aryl (e.g., C-C 10 or phenyl) or heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). In embodiments, Ring A is C6-C 10 In embodiments, Ring A is aryl. In embodiments, Ring A is phenyl. In embodiments, Ring A is a 5-10 membered heteroaryl. In embodiments, Ring A is a 5-9 membered heteroaryl. In embodiments, Ring A is a 5-6 membered heteroaryl.

[0168] In embodiments, Ring A is phenyl or 5-10 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 [ka] is.

[0169] In embodiments, Ring A is phenyl or 5-10 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 [ka] where: [ka] -L 1 -R 1 In an embodiment, ring A is [ka] where: [ka] -L 1 -R 1 indicates the attachment point to

[0170] In embodiments, Ring A is phenyl or 5-10 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.

[0171] In embodiments, the compound has the formula [ka] R 1 , L 103 , L 104 , L 105 and W is as described herein.

[0172] R 2X , R 2Y , and R 2Z is independently hydrogen or independently, including embodiments, R 2 may take any value of

[0173] In embodiments, R 2X , R 2Y , and R 2Z are independently hydrogen, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -OCX 2 3. -OCH2X 2 , -OCHX 2 2, -CN, -SO n2 R 2D , -SO v2 NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -C(O)OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO2R 2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 2X and R 2Y The substituents may be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), a substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), R 2Y and R 2Z The substituents may be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), a substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0174] In embodiments, R 2X , R 2Y , and R 2Z are independently hydrogen, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -OCX 2 3. -OCH2X 2 , -OCHX 2 2, -CN, -SO n2 R 2D , -SO v2 NR 2A R2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -C(O)OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO2R 2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C , -N3, R 20 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), R 20 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), R 20 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 20 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 20 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 20 substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 2X and R 2Y The substituents are joined to form R 20 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 20 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 20 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 20 may form a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), R 2Y and R 2Z The substituents are joined to form R20 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 20 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 20 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 20 It may form a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0175] In embodiments, R 2X are independently halogen or unsubstituted heteroalkyl, and R 2Y are independently hydrogen or halogen, and R 2Z are independently hydrogen, halogen, -CN, -NR 2A C(O)R 2C , unsubstituted heteroalkyl, or substituted or unsubstituted heterocycloalkyl.

[0176] In embodiments, R 2X is independently halogen or unsubstituted heteroalkyl. In embodiments, R 2Y is independently hydrogen or halogen. 2Z are independently hydrogen, halogen, -CN, -NR 2A C(O)R 2C , unsubstituted heteroalkyl, or substituted or unsubstituted heterocycloalkyl. In embodiments, R 2X is independently halogen. In an embodiment, R 2X is independently unsubstituted heteroalkyl. In embodiments, R 2Y are independently hydrogen. In embodiments, R 2Y is independently halogen. In an embodiment, R 2Z are independently hydrogen. In embodiments, R 2Z is independently halogen. In an embodiment, R 2Z is independently —CN. In an embodiment, R 2Z are independently -NR 2AC(O)R 2C In an embodiment, R 2Z is independently unsubstituted heteroalkyl. In embodiments, R 2Z is independently substituted or unsubstituted heterocycloalkyl.

[0177] In embodiments, R 2X are independently halogen, and R 2Y are independently halogen, and R 2Z are independently hydrogen.

[0178] In embodiments, R 2X is independently halogen. In an embodiment, R 2Y is independently halogen. In an embodiment, R 2Z are independently hydrogen.

[0179] In embodiments, R 2X are independently halogen or unsubstituted 2-4 membered heteroalkyl, and R 2Y are independently hydrogen, and R 2Z are independently halogen, -CN, -NR 2A C(O)R 2C , unsubstituted 2- to 4-membered heteroalkyl, or substituted or unsubstituted 5- to 6-membered heterocycloalkyl; R 2A are independently hydrogen, and R 2C is independently unsubstituted C1-C2 alkyl.

[0180] In embodiments, R 2X is independently halogen or unsubstituted 2-4 membered heteroalkyl. 2Y are independently hydrogen. In embodiments, R 2Z are independently halogen, -CN, -NR 2A C(O)R 2C , unsubstituted 2-4 membered heteroalkyl, or substituted or unsubstituted 5-6 membered heterocycloalkyl. 2A are independently hydrogen. In embodiments, R 2Cis independently an unsubstituted C1-C2 alkyl. In embodiments, R 2X is independently halogen. In an embodiment, R 2X is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 2Z is independently halogen. In an embodiment, R 2Z is independently —CN. In an embodiment, R 2Z are independently -NR 2A C(O)R 2C In an embodiment, R 2Z is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 2Z is independently a substituted or unsubstituted 5- to 6-membered heterocycloalkyl.

[0181] In embodiments, R 2X are independently halogen or -OCH3, and R 2Y are independently hydrogen, and R 2Z are independently halogen, —CN, —NHC(O)CH3, —OCH3, or substituted or unsubstituted 5- to 6-membered heterocycloalkyl; R 2A are independently hydrogen, and R 2C is independently unsubstituted C1-C2 alkyl.

[0182] In embodiments, R 2X is independently halogen or —OCH. In an embodiment, R 2Y are independently hydrogen. In embodiments, R 2Z are independently halogen, —CN, —NHC(O)CH, —OCH, or substituted or unsubstituted 5-6 membered heterocycloalkyl. 2A are independently hydrogen. In embodiments, R 2C is independently an unsubstituted C1-C2 alkyl. In embodiments, R 2X is independently halogen. In an embodiment, R 2X is independently —OCH. In an embodiment, R 2Z is independently halogen. In an embodiment, R 2Zis independently —CN. In an embodiment, R 2Z is independently —NHC(O)CH. In embodiments, R 2Z is independently —OCH. In an embodiment, R 2Z is independently a substituted or unsubstituted 5- to 6-membered heterocycloalkyl.

[0183] In embodiments, R 2X are independently halogen or -OCH3, and R 2Y are independently hydrogen, and R 2Z are independently halogen, —CN, —NHC(O)CH, —OCH, or substituted or unsubstituted 5-6 membered heterocycloalkyl. 2Z is independently a substituted or unsubstituted 5-6 membered heterocycloalkyl. 2Z is independently a substituted 5-6 membered heterocycloalkyl. 2Z is, independently, [ka] is.

[0184] In an embodiment, 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., 2-8 membered, 2-6 membered, or 2-4 membered). 103 is a bond. In embodiments, L 103 is a substituted or unsubstituted C1-C8 alkylene. 103 is a substituted or unsubstituted C1-C6 alkylene. 103 is a substituted or unsubstituted C1-C4 alkylene. 103 is a substituted or unsubstituted 2-8 membered heteroalkylene. 103 is a substituted or unsubstituted 2- to 6-membered heteroalkylene. 103 is a substituted or unsubstituted 2- to 4-membered heteroalkylene.

[0185] In an embodiment, L 103 is unsubstituted alkyl. In embodiments, L 103 is unsubstituted C1-C4 alkyl. In embodiments, L 103 is unsubstituted ethylene.

[0186] In an embodiment, L 103 is a bond, R 103 substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), or R 103 It is a substituted or unsubstituted heteroalkylene (eg, 2 to 8-membered, 2 to 6-membered, or 2 to 4-membered).

[0187] In embodiments, 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, -O CH2F, -OCHI, -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., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0188] In embodiments, R 101 , R 102 , and R 103 are 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, -OC H2F, -OCHI, -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., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0189] In embodiments, R 101are 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, -OCHI 2, 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., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 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., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R 111 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 111 It is a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0190] In embodiments, R 101are 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., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 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., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R 111 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 111 It is a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0191] R 111are 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, -OC Cl3, -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., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0192] In embodiments, R 101are 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., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0193] In embodiments, R 102 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, R 112 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R 112substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 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., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R 112 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 112 It is a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0194] In embodiments, R 102 are 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 112 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R 112 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 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., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R 112 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 112It is a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0195] R 112 are 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, -OC Cl3, -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., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0196] In embodiments, R 102are 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., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0197] In embodiments, 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, -N HC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH2, -NHOH, -OCCl 3, -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 113substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), R 113 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 113 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 113 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 113 It is a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0198] In embodiments, R 103 are 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 113 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), R 113 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), R 113 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 113 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 113 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 113 It is a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0199] R 113 are 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, -OC Cl3, -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., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0200] In embodiments, R 103are 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., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0201] In an embodiment, L 104 is a bond, —S(O)—, —C(O)—, —NHC(O)—, —C(O)NH—, —OC(O)—, —C(O)O—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0202] In an embodiment, 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., 2-8 membered, 2-6 membered, or 2-4 membered). In embodiments, L 104 is a bond. In embodiments, L 104 is —O—. In embodiments, L 104 is —NH—. In embodiments, L 104is -S-. In embodiments, L 104 is -S(O)-. 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 a substituted or unsubstituted C1-C8 alkylene. 104 is a substituted or unsubstituted C1-C6 alkylene. 104 is a substituted or unsubstituted C1-C4 alkylene. 104 is a substituted or unsubstituted 2-8 membered heteroalkylene. 104 is a substituted or unsubstituted 2- to 6-membered heteroalkylene. 104 is a substituted or unsubstituted 2-4 membered heteroalkylene. 104 is unsubstituted C1-C8 alkylene. In embodiments, L 104 is an unsubstituted 2-8 membered heteroalkylene.

[0203] In an embodiment, L 104 is a bond, —S(O)—, —C(O)—, —NHC(O)—, —OC(O)—, substituted or unsubstituted alkylene (e.g., C-C, C-C, or C-C), or substituted or unsubstituted heteroalkylene (e.g., 2-8 membered, 2-6 membered, or 2-4 membered). 104 is a bond. In embodiments, L 104 is -S(O)-. 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 a substituted or unsubstituted C1-C8 alkylene. 104is a substituted or unsubstituted C1-C6 alkylene. 104 is a substituted or unsubstituted C1-C4 alkylene. 104 is a substituted or unsubstituted 2-8 membered heteroalkylene. 104 is a substituted or unsubstituted 2- to 6-membered heteroalkylene. 104 is a substituted or unsubstituted 2-4 membered heteroalkylene. 104 is unsubstituted C1-C8 alkylene. In embodiments, L 104 is an unsubstituted 2-8 membered heteroalkylene.

[0204] In an embodiment, 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 It is a substituted or unsubstituted heteroalkylene (eg, 2 to 8-membered, 2 to 6-membered, or 2 to 4-membered).

[0205] In an embodiment, 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 It is a substituted or unsubstituted heteroalkylene (eg, 2 to 8-membered, 2 to 6-membered, or 2 to 4-membered).

[0206] R 104are 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, -OCF 3, -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., 2-8 membered, 2-6 membered, or 2-4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0207] In embodiments, R 104 are 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 114substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), R 114 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), R 114 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 114 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 114 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 114 It is a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0208] R 114 are 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, -OC Cl3, -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., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0209] In an embodiment, L 105is 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., 2-8 membered, 2-6 membered, or 2-4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), or substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, or 5-6 membered).

[0210] In an embodiment, 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., 2-8 membered, 2-6 membered, or 2-4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), or substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, or 5-6 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)-. 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 a substituted or unsubstituted C1-C8 alkylene. 105 is a substituted or unsubstituted C1-C6 alkylene. 105is a substituted or unsubstituted C1-C4 alkylene. 105 is a substituted or unsubstituted 2-8 membered heteroalkylene. 105 is a substituted or unsubstituted 2- to 6-membered heteroalkylene. 105 is a substituted or unsubstituted 2-4 membered heteroalkylene. 105 is a substituted or unsubstituted C3-C8 cycloalkylene. 105 is a substituted or unsubstituted C-C cycloalkylene. 105 is a substituted or unsubstituted C5-C6 cycloalkylene. 105 is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene. 105 is a substituted or unsubstituted 3- to 6-membered heterocycloalkylene. 105 is a substituted or unsubstituted 5- to 6-membered heterocycloalkylene. 105 is unsubstituted C1-C8 alkylene. In embodiments, L 105 is an unsubstituted 2-8 membered heteroalkylene. 105 is an unsubstituted C3-C8 cycloalkylene. 105 is an unsubstituted 3- to 8-membered heterocycloalkylene.

[0211] In an embodiment, L 105 is a bond, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), or substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, or 5-6 membered). 105 is a bond. In embodiments, L 105 is a substituted or unsubstituted C1-C8 alkylene. 105 is a substituted or unsubstituted C1-C6 alkylene.105 is a substituted or unsubstituted C1-C4 alkylene. 105 is a substituted or unsubstituted 2-8 membered heteroalkylene. 105 is a substituted or unsubstituted 2- to 6-membered heteroalkylene. 105 is a substituted or unsubstituted 2-4 membered heteroalkylene. 105 is a substituted or unsubstituted C3-C8 cycloalkylene. 105 is a substituted or unsubstituted C-C cycloalkylene. 105 is a substituted or unsubstituted C5-C6 cycloalkylene. 105 is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene. 105 is a substituted or unsubstituted 3- to 6-membered heterocycloalkylene. 105 is a substituted or unsubstituted 5- to 6-membered heterocycloalkylene. 105 is unsubstituted C1-C8 alkylene. In embodiments, L 105 is an unsubstituted 2-8 membered heteroalkylene. 105 is an unsubstituted C3-C8 cycloalkylene. 105 is an unsubstituted 3- to 8-membered heterocycloalkylene.

[0212] In an embodiment, L 105 is unsubstituted alkylene. In embodiments, L 105 is unsubstituted C1-C4 alkylene. In embodiments, L 105 teeth, [ka] In an embodiment, L 105 teeth, [ka] is.

[0213] In an embodiment, L105 is 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., 2-8 membered, 2-6 membered, or 2-4 membered), R 105 substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), or R 105 It is a substituted or unsubstituted heterocycloalkylene (eg, 3 to 8-membered, 3 to 6-membered, or 5 to 6-membered).

[0214] In an embodiment, L 105 is 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., 2-8 membered, 2-6 membered, or 2-4 membered), R 105 substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), or R 105 It is a substituted or unsubstituted heterocycloalkylene (eg, 3 to 8-membered, 3 to 6-membered, or 5 to 6-membered).

[0215] R 105are 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, -OCF 3, -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., 2-8 membered, 2-6 membered, or 2-4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0216] In embodiments, R 105 are 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 115substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), R 115 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), R 115 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 115 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 115 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 115 It is a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0217] R 115 are 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, -OC Cl3, -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., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0218] In embodiments, W is N. In embodiments, W is CH.

[0219] In an embodiment, [ka] teeth, [ka] is.

[0220] In an embodiment, [ka] teeth, [ka] In an embodiment, [ka] teeth, [ka] In an embodiment, [ka] teeth, [ka] In an embodiment, [ka] teeth, [ka] is.

[0221] In an embodiment, [ka] teeth, [ka] is.

[0222] In an embodiment, [ka] teeth, [ka] In an embodiment, [ka] teeth, [ka] In an embodiment, [ka] teeth, [ka] In an embodiment, [ka] teeth, [ka] In an embodiment, [ka] teeth, [ka] In an embodiment, [ka] teeth, [ka] In an embodiment, [ka] teeth, [ka] In an embodiment, [ka] teeth, [ka] is.

[0223] In embodiments, R 1 is hydrogen, halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO2R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -N3, -SSR 1D , -SiR 1A R 1B R 1C, 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.

[0224] In embodiments, R 1 is hydrogen, halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO2R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -N3, -SiR 1A R 1B R 1C , 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.

[0225] In embodiments, R 1 is hydrogen, halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X1 , -OCHX 1 2, -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -SC(O)R 1C , -C(O)OR 1C , -C(O)NR 1A R 1B , -OR 1D , -SR 1D , -SeR 1D , -NR 1A SO2R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -N3, -SiR 1A R 1B R 1C , —SP(O)(OH)2, E, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2-10 membered, 2-6 membered, or 2-4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0226] In embodiments, R 1 is hydrogen, halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -SOn1 R 1D , -SO v1 NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -SC(O)R 1C , -C(O)OR 1C , -C(O)NR 1A R 1B , -OR 1D , -SR 1D , -SeR 1D , -NR 1A SO2R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -N3, -SiR 1A R 1B R 1C , -SP(O)(OH)2, E, R 10 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), R 10 substituted or unsubstituted heteroalkyl (e.g., 2-10 membered, 2-6 membered, or 2-4 membered), R 10 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 10 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 10 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 10 It is a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0227] In embodiments, R 1 are independently -C(O)R 1C is.

[0228] In embodiments, R 1are independently -SC(O)R 1C is.

[0229] In embodiments, R 1C are 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), substituted or unsubstituted heteroalkyl (e.g., 2-10 membered, 2-6 membered, or 2-4 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0230] In embodiments, R 1C are 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), R10 substituted or unsubstituted heteroalkyl (e.g., 2-10 membered, 2-6 membered, or 2-4 membered), R 10 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 10 It is a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0231] In embodiments, R 1C is independently substituted or unsubstituted C1-C4 alkyl. In embodiments, R 1C is independently unsubstituted C1-C4 alkyl. In embodiments, R 1C is independently unsubstituted methyl. In embodiments, R 1C is independently unsubstituted ethyl. In embodiments, R 1C is independently unsubstituted propyl. In embodiments, R 1C is independently unsubstituted n-propyl. In embodiments, R 1C is independently unsubstituted isopropyl. In embodiments, R 1C is independently unsubstituted butyl. In embodiments, R 1C is independently unsubstituted n-butyl. In embodiments, R 1C is independently unsubstituted tert-butyl.

[0232] In embodiments, R 1C is independently substituted or unsubstituted aryl. In embodiments, R 1C are independently 10 In embodiments, R is substituted or unsubstituted aryl. 1C are independently 10 In embodiments, R is substituted or unsubstituted phenyl. 1C is independently unsubstituted phenyl.

[0233] In embodiments, R 1 are independently -C(O)R 1C and R 1C is as described herein, including embodiments. In embodiments, R1 is independently —C(O)OH. In embodiments, R 1 are independently —C(O)NH2.

[0234] In embodiments, R 1 -SSR 1D is.

[0235] In embodiments, R 1D are 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., 2-10 membered, 2-6 membered, or 2-4 membered).

[0236] In embodiments, R 1D are 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 10substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), or R 10 It is a substituted or unsubstituted heteroalkyl (eg, 2 to 10 membered, 2 to 6 membered, or 2 to 4 membered).

[0237] In embodiments, R 1D is independently substituted or unsubstituted alkyl. In embodiments, R 1D are independently 10 In embodiments, R is a substituted or unsubstituted alkyl. 1D are independently 10 Substituted or unsubstituted C1-C 16 In embodiments, R 1D are independently unsubstituted C-C 16 It is alkyl.

[0238] In embodiments, R 1 -SR 1D , -NR 1A R 1B , -OR 1D , E, unsubstituted alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl; R 1A are independently hydrogen or unsubstituted C-C alkyl, and R 1B are independently hydrogen or unsubstituted C-C alkyl, and R 1Dare 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)N H2, -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 (e.g., C1-C8, C1-C6, or C1-C4).

[0239] In embodiments, R 1 -SR 1D , -NR 1A R 1B , -OR 1D , E, unsubstituted alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl. 1A is independently hydrogen or unsubstituted C-C alkyl. In an embodiment, R 1B is independently hydrogen or unsubstituted C-C alkyl. In an embodiment, R 1Dare 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)N H2, -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 (e.g., C1-C8, C1-C6, or C1-C4).

[0240] In embodiments, R 1 But, -SR 1D , -NR 1A R 1B , -OR 1D , E, unsubstituted C1-C4 alkyl, R 10 substituted or unsubstituted phenyl, or R 10 substituted or unsubstituted 5- to 6-membered heteroaryl, R 1A are independently hydrogen or unsubstituted C-C alkyl, and R 1B are independently hydrogen or unsubstituted C-C alkyl, and R 1D are 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 10It is a substituted or unsubstituted C1-C4 alkyl.

[0241] In embodiments, R 1 -SR 1D , -NR 1A R 1B , -OR 1D , E, unsubstituted C1-C4 alkyl, R 10 substituted or unsubstituted phenyl, or R 10 In one embodiment, R is a substituted or unsubstituted 5- to 6-membered heteroaryl. 1A is independently hydrogen or unsubstituted C-C alkyl. In an embodiment, R 1B is independently hydrogen or unsubstituted C-C alkyl. In an embodiment, R 1D are 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 It is a substituted or unsubstituted C1-C4 alkyl.

[0242] R 10are 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, -N HC(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., 2-8 membered, 2-6 membered, or 2-4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0243] In embodiments, R 1 -SR 1D or R 10 substituted phenyl, R 1D are 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, R10 substituted or unsubstituted C1-C4 alkyl, R 10 are 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, -CO NH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted C1-C4 alkyl, unsubstituted 2-4 membered heteroalkyl, unsubstituted C5-C6 cycloalkyl, unsubstituted 5-6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5-6 membered heteroaryl.

[0244] In embodiments, R 1 -SR 1D or R 10 In embodiments, R 1D are 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 In an embodiment, R is a substituted or unsubstituted C1-C4 alkyl. 10are 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, -CO NH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted C1-C4 alkyl, unsubstituted 2-4 membered heteroalkyl, unsubstituted C5-C6 cycloalkyl, unsubstituted 5-6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5-6 membered heteroaryl.

[0245] In embodiments, R 1 is -SH, -SC(O)CH, or -SSCH. In embodiments, R 1 is -SH. In embodiments, R 1 is —SC(O)CH. In embodiments, R 1 is -SSCH3.

[0246] In embodiments, R 1 are 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, R 10 is as described herein, including embodiments. In embodiments, R 1 is independently -F. In an embodiment, R 1 is independently -Cl. In an embodiment, R 1 is independently -Br. In an embodiment, R 1 is independently -I. In an embodiment, R 1 is independently —NO. In an embodiment, R1 is independently -SH. In an embodiment, R 1 is independently -SeH. In an embodiment, R 1 is independently —SO3H. In an embodiment, R 1 is independently —SC(O)CH. In embodiments, R 1 is independently -SSCH. In embodiments, R 1 is independently —SP(O)(OH). In embodiments, R 1 are independently 10 In embodiments, R is a substituted or unsubstituted heteroalkyl. 1 are independently 10 In embodiments, R is a substituted or unsubstituted 2- to 20-membered heteroalkyl. 1 are independently 10 In embodiments, R 1 is independently an unsubstituted 2- to 20-membered heteroalkyl. 1 are independently -S-(C1-C 20 In one embodiment, R 1 is independently -SCH3. In an embodiment, R 1 is independently —S(O)2CH3. In an embodiment, R 1 is, independently, [ka] and m is independently an integer from 0 to 4. In an embodiment, R 1 is, independently, [ka] In an embodiment, R 1 is independently —Si(CH). In embodiments, R 1 is independently —Si(CHCH). In embodiments, R 1 is independently —Si(CHCHCH) 1 is independently —Si(CH(CH)). In an embodiment, R1 is independently —Si(CHCHCHCHCH) 1 is independently —Si(C(CH)). In an embodiment, R 1 are independently 10 In embodiments, R is a substituted or unsubstituted heteroaryl. 1 are independently 10 In embodiments, R is a substituted or unsubstituted 5-10 membered heteroaryl. 1 is independently an unsubstituted 5-10 membered heteroaryl. 1 is independently unsubstituted thiophenyl. In embodiments, R 1 is independently unsubstituted furanyl. In embodiments, R 1 is independently unsubstituted pyrrolyl. In embodiments, R 1 is independently unsubstituted imidazolyl. In embodiments, R 1 is independently unsubstituted tetrazolyl. In embodiments, R 1 is, independently, [ka] In an embodiment, R 1 is, independently, [ka] In an embodiment, R 1 is, independently, [ka] is.

[0247] In embodiments, R 1 is R 10 substituted phenyl, R 10 is independently halogen. In an embodiment, R 1 teeth, [ka] where R 10.1 and R10.2 are each independently hydrogen or any of the R 10 In embodiments, R 10.1 and R 10.2 are each independently halogen. In an embodiment, R 1 teeth, [ka] is.

[0248] In embodiments, R 1 are independently 10 substituted or unsubstituted 2- to 8-membered heteroalkyl, R 10 is as described herein, including embodiments. In embodiments, R 1 are independently 10 substituted 2-8 membered heteroalkyl, R 10 is independently oxo. In embodiments, R 1 are independently -NHC(O)-(R 10 In one embodiment, R 1 are independently -NHC(O)-(R 10 In one embodiment, R 1 is independently —NHC(O)—(unsubstituted C-C alkyl). In embodiments, R 1 is, independently, [ka] In an embodiment, R 1 is, independently, [ka] In an embodiment, R 1 is, independently, [ka] In an embodiment, R 1 is, independently, [ka] In an embodiment, R 1 is independently -NHS(O)-(unsubstituted C-C alkyl). In embodiments, R 1 is, independently, [ka] is.

[0249] In embodiments, R 1 is E.

[0250] In an embodiment, E is [ka] is.

[0251] R 16 are independently hydrogen, halogen, -CX 16 3. -CHX 16 2. -CH2X 16 , -CN, -SO n16 R 16A , -SO v16 NR 16A R 16B , -NHNR 16A R 16B , -ONR 16A R 16B , -NHC(O)NHNR 16A R 16B , -NHC(O)NR 16A R 16B , -N(O) m16 , -NR 16A R 16B , -C(O)R 16A , -C(O)-OR 16A , -C(O)NR 16A R 16B , -OR 16A , -NR 16A SO2R 16B , -NR 16A C(O)R 16B , -NR 16A C(O)OR 16B , -NR 16AOR 16B , -OCX 16 3. -OCHX 16 2, -OCH2X 16 , substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0252] R 17 are independently hydrogen, halogen, -CX 17 3. -CHX 17 2. -CH2X 17 , -CN, -SO n17 R 17A , -SO v17 NR 17A R 17B , -NHNR 17A R 17B , -ONR 17A R 17B , -NHC(O)NHNR 17A R 17B , -NHC(O)NR 17A R 17B , -N(O) m17 , -NR 17A R 17B , -C(O)R 17A , -C(O)-OR 17A , -C(O)NR 17A R 17B , -OR 17A , -NR 17A SO2R 17B , -NR 17A C(O)R 17B , -NR 17A C(O)OR 17B , -NR 17A OR 17B , -OCX17 3. -OCHX 17 2, -OCH2X 17 , substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0253] R 18 are independently hydrogen, halogen, -CX 18 3. -CHX 18 2. -CH2X 18 , -CN, -SO n18 R 18A , -SO v18 NR 18A R 18B , -NHNR 18A R 18B , -ONR 18A R 18B , -NHC(O)NHNR 18A R 18B , -NHC(O)NR 18A R 18B , -N(O) m18 , -NR 18A R 18B , -C(O)R 18A , -C(O)-OR 18A , -C(O)NR 18A R 18B , -OR 18A , -NR 18A SO2R 18B , -NR 18A C(O)R 18B , -NR 18A C(O)OR 18B , -NR 18A OR 18B , -OCX 18 3. -OCHX18 2, -OCH2X 18 , substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0254] R 19 are independently hydrogen, halogen, -CX 19 3. -CHX 19 2. -CH2X 19 , -CN, -SO n19 R 19A , -SO v19 NR 19A R 19B , -NHNR 19A R 19B , -ONR 19A R 19B , -NHC(O)NHNR 19A R 19B , -NHC(O)NR 19A R 19B , -N(O) m19 , -NR 19A R 19B , -C(O)R 19A , -C(O)-OR 19A , -C(O)NR 19A R 19B , -OR 19A , -NR 19A SO2R 19B , -NR 19A C(O)R 19B , -NR 19A C(O)OR 19B , -NR 19A OR 19B , -OCX 19 3. -OCHX 19 2, -OCH2X19 , substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0255] R 16A , R 16B , R 17A , R 17B , R 18A , R 18B , R 19A , and R 19B are independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -COOH, -CONH, substituted or unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C-C, C-C, C-C, or C-C), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 16A and R 16B The substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R 17A and R 17BThe substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R 18A and R 18B The substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R 19A and R 19B The substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0256] X, X 16 , X 17 , X 18 , and X 19 are independently -F, -Cl, -Br, or -I.

[0257] n16, n17, n18, and n19 are independently integers of 0 to 4.

[0258] m16, m17, m18, m19, v16, v17, v18, and v19 are independently 1 or 2.

[0259] In embodiments, R 16 are independently hydrogen, halogen, -CX 16 3. -CHX 16 2. -CH2X 16 , -CN, -SO n16 R 16A , -SO v16 NR 16A R 16B , -NHNR 16A R 16B , -ONR 16A R 16B , -NHC(O)NHNR 16A R 16B , -NHC(O)NR 16A R 16B , -N(O) m16 , -NR 16A R 16B , -C(O)R 16A , -C(O)-OR16A , -C(O)NR 16A R 16B , -OR 16A , -NR 16A SO2R 16B , -NR 16A C(O)R 16B , -NR 16A C(O)OR 16B , -NR 16A OR 16B , -OCX 16 3. -OCHX 16 2, -OCH2X 16 , substituted (e.g., substituted with at least one substituent, size-limiting substituent, or 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, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) substituted (e.g., substituted with at least one substituent, size-limited substituent, or 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, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0260] In embodiments, the substitution R 16 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 16When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 16 When substituted, R is substituted with at least one substituent. 16 When substituted, R is substituted with at least one size-limited substituent. 16 When substituted, it is substituted with at least one lower substituent.

[0261] In embodiments, R 16 are 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, -OCH2 Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0262] In embodiments, R 17 are independently hydrogen, halogen, -CX 17 3. -CHX 17 2. -CH2X 17, -CN, -SO n17 R 17A , -SO v17 NR 17A R 17B , -NHNR 17A R 17B , -ONR 17A R 17B , -NHC(O)NHNR 17A R 17B , -NHC(O)NR 17A R 17B , -N(O) m17 , -NR 17A R 17B , -C(O)R 17A , -C(O)-OR 17A , -C(O)NR 17A R 17B , -OR 17A , -NR 17A SO2R 17B , -NR 17A C(O)R 17B , -NR 17A C(O)OR 17B , -NR 17A OR 17B , -OCX 17 3. -OCHX 17 2, -OCH2X 17 , substituted (e.g., substituted with at least one substituent, size-limiting substituent, or 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, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) substituted (e.g., substituted with at least one substituent, size-limited substituent, or 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, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10or phenyl), or substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0263] In embodiments, the substitution R 17 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 17 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 17 When substituted, R is substituted with at least one substituent. 17 When substituted, R is substituted with at least one size-limited substituent. 17 When substituted, it is substituted with at least one lower substituent.

[0264] In embodiments, R 17are 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, -OCH2 Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0265] In embodiments, R 18 are independently hydrogen, halogen, -CX 18 3. -CHX 18 2. -CH2X 18 , -CN, -SO n18 R 18A , -SO v18 NR 18A R 18B , -NHNR 18A R 18B , -ONR 18A R 18B , -NHC(O)NHNR 18A R 18B , -NHC(O)NR 18A R 18B , -N(O) m18 , -NR 18A R 18B , -C(O)R 18A , -C(O)-OR 18A, -C(O)NR 18A R 18B , -OR 18A , -NR 18A SO2R 18B , -NR 18A C(O)R 18B , -NR 18A C(O)OR 18B , -NR 18A OR 18B , -OCX 18 3. -OCHX 18 2, -OCH2X 18 , substituted (e.g., substituted with at least one substituent, size-limiting substituent, or 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, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) substituted (e.g., substituted with at least one substituent, size-limited substituent, or 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, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0266] In embodiments, the substitution R 18 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 18When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 18 When substituted, R is substituted with at least one substituent. 18 When substituted, R is substituted with at least one size-limited substituent. 18 When substituted, it is substituted with at least one lower substituent.

[0267] In embodiments, R 18 are 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, -OCH2 Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0268] In embodiments, R 19 are independently hydrogen, halogen, -CX 19 3. -CHX 19 2. -CH2X 19, -CN, -SO n19 R 19A , -SO v19 NR 19A R 19B , -NHNR 19A R 19B , -ONR 19A R 19B , -NHC(O)NHNR 19A R 19B , -NHC(O)NR 19A R 19B , -N(O) m19 , -NR 19A R 19B , -C(O)R 19A , -C(O)-OR 19A , -C(O)NR 19A R 19B , -OR 19A , -NR 19A SO2R 19B , -NR 19A C(O)R 19B , -NR 19A C(O)OR 19B , -NR 19A OR 19B , -OCX 19 3. -OCHX 19 2, -OCH2X 19 , substituted (e.g., substituted with at least one substituent, size-limiting substituent, or 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, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) substituted (e.g., substituted with at least one substituent, size-limited substituent, or 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, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10or phenyl), or substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0269] In embodiments, the substitution R 19 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 19 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 19 When substituted, R is substituted with at least one substituent. 19 When substituted, R is substituted with at least one size-limited substituent. 19 When substituted, it is substituted with at least one lower substituent.

[0270] In embodiments, R 19are 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, -OCH2 Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0271] In embodiments, R 16Aare independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -COOH, -CONH, substituted (e.g., with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C), substituted (e.g., with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted (e.g., with at least substituted (e.g., substituted with at least one substituent, size-limiting substituent, or 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, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0272] In embodiments, the substitution R 16A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 16A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 16A When substituted, R is substituted with at least one substituent. 16A When substituted, R is substituted with at least one size-limited substituent. 16AWhen substituted, it is substituted with at least one lower substituent.

[0273] In embodiments, R 16B are independently hydrogen, -CX3, -CHX2, -CH2X, -CN, -OH, -COOH, -CONH 2, Substituted (e.g., with at least one substituent, size-limiting 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 substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted (e.g., with at least one substituent, size-limiting substituent, or lower substituent), substituted) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0274] In embodiments, the substitution R 16B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 16B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 16BWhen substituted, R is substituted with at least one substituent. 16B When substituted, R is substituted with at least one size-limited substituent. 16B When substituted, it is substituted with at least one lower substituent.

[0275] In embodiments, R 16A and R 16B Substituents may 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.

[0276] In embodiments, R 16A and R 16B The substituted moiety formed by the joining of substituents (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent and has R 16A and R 16B When the substituted moiety formed by the joining of substituents is substituted with multiple groups selected from a substituent, a size-limited substituent, and a lower substituent, each substituent, size-limited substituent, and / or lower substituent may optionally be different. In embodiments, R 16A and R 16B The moiety formed by the joining of the substituents, if substituted, is substituted with at least one substituent. In embodiments, R 16A and R 16B The moiety formed by the joining of the substituents, if substituted, is substituted with at least one size-limited substituent. In embodiments, R 16A and R 16B The moiety formed by the joining of substituents, when substituted, is substituted with at least one lower substituent.

[0277] In embodiments, R 17A are independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -COOH, -CONH, substituted (e.g., with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C), substituted (e.g., with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted (e.g., with at least substituted (e.g., substituted with at least one substituent, size-limiting substituent, or 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, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0278] In embodiments, the substitution R 17A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 17A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 17A When substituted, R is substituted with at least one substituent. 17AWhen substituted, R is substituted with at least one size-limited substituent. 17A When substituted, it is substituted with at least one lower substituent.

[0279] In embodiments, R 17B are independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -COOH, -CONH, substituted (e.g., with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C), substituted (e.g., with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted (e.g., with at least substituted (e.g., substituted with at least one substituent, size-limiting substituent, or 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, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0280] In embodiments, the substitution R 17B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 17BWhen R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 17B When substituted, R is substituted with at least one substituent. 17B When substituted, R is substituted with at least one size-limited substituent. 17B When substituted, it is substituted with at least one lower substituent.

[0281] In embodiments, R 17A and R 17B Substituents may 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.

[0282] In embodiments, R 17A and R 17B The substituted moiety formed by the joining of substituents (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent and has R 17A and R 17B When the substituted moiety formed by the joining of substituents is substituted with multiple groups selected from a substituent, a size-limited substituent, and a lower substituent, each substituent, size-limited substituent, and / or lower substituent may optionally be different. In embodiments, R 17A and R 17B The moiety formed by the joining of the substituents, if substituted, is substituted with at least one substituent. In embodiments, R 17A and R 17BThe moiety formed by the joining of the substituents, if substituted, is substituted with at least one size-limited substituent. In embodiments, R 17A and R 17B The moiety formed by the joining of substituents, when substituted, is substituted with at least one lower substituent.

[0283] In embodiments, R 18A are independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -COOH, -CONH, substituted (e.g., with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C), substituted (e.g., with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted (e.g., with at least substituted (e.g., substituted with at least one substituent, size-limiting substituent, or 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, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0284] In embodiments, the substitution R 18A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 18AWhen R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 18A When substituted, R is substituted with at least one substituent. 18A When substituted, R is substituted with at least one size-limited substituent. 18A When substituted, it is substituted with at least one lower substituent.

[0285] In embodiments, R 18B are independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -COOH, -CONH, substituted (e.g., with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C), substituted (e.g., with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted (e.g., with at least substituted (e.g., substituted with at least one substituent, size-limiting substituent, or 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, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0286] In embodiments, the substitution R 18B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 18B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 18B When substituted, R is substituted with at least one substituent. 18B When substituted, R is substituted with at least one size-limited substituent. 18B When substituted, it is substituted with at least one lower substituent.

[0287] In embodiments, R 18A and R 18B Substituents may 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.

[0288] In embodiments, R 18A and R 18B The substituted moiety formed by the joining of substituents (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent and has R attached to the same nitrogen atom. 18A and R 18B When the substituted moiety formed by the joining of substituents is substituted with multiple groups selected from substituents, size-limited substituents, and lower substituents, each substituent, size-limited substituent, and / or lower substituent may optionally be different. In embodiments, R 18A and R 18BThe moiety formed by the joining of the substituents, if substituted, is substituted with at least one substituent. In embodiments, R 18A and R 18B The moiety formed by the joining of the substituents, if substituted, is substituted with at least one size-limited substituent. In embodiments, R 18A and R 18B The moiety formed by the joining of substituents, when substituted, is substituted with at least one lower substituent.

[0289] In embodiments, R 19A are independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -COOH, -CONH, substituted (e.g., with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C), substituted (e.g., with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted (e.g., with at least substituted (e.g., substituted with at least one substituent, size-limiting substituent, or 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, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0290] In embodiments, the substitution R 19A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 19A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 19A When substituted, R is substituted with at least one substituent. 19A When substituted, R is substituted with at least one size-limited substituent. 19A When substituted, it is substituted with at least one lower substituent.

[0291] In embodiments, R 19B are independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -COOH, -CONH, substituted (e.g., with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C), substituted (e.g., with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted (e.g., with at least substituted (e.g., substituted with at least one substituent, size-limiting substituent, or 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, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10or phenyl), or substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0292] In embodiments, the substitution R 19B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 19B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 19B When substituted, R is substituted with at least one substituent. 19B When substituted, R is substituted with at least one size-limited substituent. 19B When substituted, it is substituted with at least one lower substituent.

[0293] In embodiments, R 19A and R 19B Substituents may 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.

[0294] In embodiments, R 19A and R 19B The substituted moiety formed by the joining of substituents (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent and has R attached to the same nitrogen atom. 19A and R 19BWhen the substituted moiety formed by the joining of substituents is substituted with multiple groups selected from a substituent, a size-limited substituent, and a lower substituent, each substituent, size-limited substituent, and / or lower substituent may optionally be different. In embodiments, R 19A and R 19B The moiety formed by the joining of the substituents, if substituted, is substituted with at least one substituent. In embodiments, R 19A and R 19B The moiety formed by the joining of the substituents, if substituted, is substituted with at least one size-limited substituent. In embodiments, R 19A and R 19B The moiety formed by the joining of substituents, when substituted, is substituted with at least one lower substituent.

[0295] In embodiments, R 16A , R 16B , R 17A , R 17B , R 18A , R 18B , R 19A , and R 19B are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -COOH, -CONH2, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 16A and R 16BThe substituents may optionally be joined to form an unsubstituted heterocycloalkyl or an unsubstituted heteroaryl, and R 17A and R 17B The substituents may optionally be joined to form an unsubstituted heterocycloalkyl or an unsubstituted heteroaryl, and R 18A and R 18B The substituents may optionally be joined to form an unsubstituted heterocycloalkyl or an unsubstituted heteroaryl, and R 19A and R 19B The substituents may optionally be joined to form an unsubstituted heterocycloalkyl or an unsubstituted heteroaryl.

[0296] In an embodiment, E is [ka] is.

[0297] In an embodiment, E is [ka] In an embodiment, E is [ka] In an embodiment, E is [ka] In an embodiment, E is [ka] In an embodiment, E is [ka] In an embodiment, E is [ka] In an embodiment, E is [ka] is.

[0298] In embodiments, the compound has the formula [ka] Ring A, R 1 , R 2 , L 103 , L 104 , L 105 , and z2 are as described herein.

[0299] In an embodiment, L 103 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0300] In an embodiment, L 104 is a bond, —O—, —NH—, —S—, or substituted or unsubstituted alkylene.

[0301] In an embodiment, L 105 is -S(O)2-, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, or -C(O)O-.

[0302] In an embodiment, L 105 is -S(O)2-, -C(O)-, -NHC(O)-, or -OC(O)-.

[0303] n is an integer of 0 to 4.

[0304] In embodiments, the compound has the formula [ka] and R 1 , R 2X , R 2Y , L 103 , L 104 , L 105, n, and z2 are as described herein. In embodiments, L 103 is a bond, substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted 2- to 6-membered heteroalkylene; L 104 is a bond, -O-, -NH-, -S-, or substituted or unsubstituted C1-C4 alkylene; L 105 is -S(O)2-, -C(O)-, -NHC(O)-, or -OC(O)-, n is an integer of 0 to 4, and R 2X and R 2Y are independently hydrogen, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -OCX 2 3. -OCH2X 2 , -OCHX 2 2, -CN, -SO n2 R 2D , -SO v2 NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -C(O)OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO2R 2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C , -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 2X and R 2Y The substituents may be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), a substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0305] In an embodiment, L 103 is a bond, substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted 2- to 6-membered heteroalkylene; L 104 is a bond, -O-, -NH-, -S-, or substituted or unsubstituted C1-C4 alkylene; L 105 is -S(O)2-, -C(O)-, -NHC(O)-, or -OC(O)-, n is an integer of 0 to 4, and R 2X and R 2Y are independently hydrogen, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -OCX 2 3. -OCH2X 2 , -OCHX 2 2, -CN, -SO n2 R 2D , -SO v2 NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -C(O)OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO2R 2D , -NR 2A C(O)R2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C , -N3, R 20 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), R 20 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), R 20 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 20 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 20 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 20 substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 2X and R 2Y The substituents are joined together to form R 20 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 20 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 20 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 20 It may form a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0306] 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.

[0307] In embodiments, R 2X and R 2Y is independently halogen. In an embodiment, R 2X and R 2Yare independently —Cl.

[0308] In an embodiment, L 103 is 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.

[0309] In an embodiment, L 104 is a bond, —O—, —NH—, —S—, or substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4). 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 a substituted or unsubstituted C1-C8 alkylene. 104 is a substituted or unsubstituted C1-C6 alkylene. 104 is a substituted or unsubstituted C1-C4 alkylene. 104 is an unsubstituted C1-C8 alkylene.

[0310] In an embodiment, L 104 is a bond, -O-, -NH-, -S-, or R 104 R is a substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4). 104 is as described herein, including embodiments.

[0311] In an embodiment, L 105 is —S(O)—, —C(O)—, —NHC(O)—, or —OC(O)—. In embodiments, L 105 is -S(O)-. In embodiments, L 105 is —C(O)—. In embodiments, L 105is —NHC(O)—. In embodiments, L 105 is -OC(O)-.

[0312] In embodiments, -L 104 -CH2-L 105 -NH-L 103 -teeth, [ka] is.

[0313] In embodiments, -L 104 -CH2-L 105 -NH-L 103 -teeth, [ka] In an embodiment, -L 104 -CH2-L 105 -NH-L 103 -teeth, [ka] In an embodiment, -L 104 -CH2-L 105 -NH-L 103 -teeth, [ka] In an embodiment, -L 104 -CH2-L 105 -NH-L 103 -teeth, [ka] In an embodiment, -L 104 -CH2-L 105 -NH-L 103 -teeth, [ka] is.

[0314] In embodiments, -L 104 -CH2-L105 -NH-L 103 -teeth, [ka] In an embodiment, -L 104 -CH2-L 105 -NH-L 103 -teeth, [ka] is.

[0315] In embodiments, R 1 is hydrogen, -SR 1D , -NR 1A R 1B , -OR 1D , -NR 1A SO2R 1D , -NR 1A C(O)R 1C , E, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted C5-C6 cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl, wherein E is an electrophilic moiety; R 1A , R 1B , R 1C , and R 1Dare 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-C6 alkyl, 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.

[0316] In embodiments, R 1 is hydrogen, -SR 1D , -NR 1A R 1B , -OR 1D , -NR 1A SO2R 1D , -NR 1A C(O)R 1C , E, R 10 substituted or unsubstituted C1-C6 alkyl, R 10 substituted or unsubstituted 2-10 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 In one embodiment, R is a substituted or unsubstituted 5- to 6-membered heteroaryl. 1A , R 1B , R 1C , and R 1Dare 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-C6 alkyl, R 10 substituted or unsubstituted 2-10 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 It is a substituted or unsubstituted 5- to 6-membered heteroaryl.

[0317] In embodiments, R 10 are 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., 2-8 membered, 2-6 membered, or 2-4 membered), R 11substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 11 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 11 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 11 It is a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0318] R 11 are 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 12 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), R 12 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), R 12 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 12 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 12 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 12 It is a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0319] R 12are 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 13 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), R 13 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 13 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 13 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 13 It is a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0320] R 13are 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., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0321] In embodiments, R 2 are independently halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -OCX 2 3. -OCH2X 2 , -OCHX 2 2, -CN, -SO n2 R 2D , -SO v2 NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -C(O)OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO2R2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and two R bonded to adjacent atoms are 2 The substituents may be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0322] In embodiments, R 2 are 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, -OCH2 Cl, -OCHBr, -OCHF, -OCHI, -OCHCl, -OCHBr, -OCHF, -OCHI, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and two R 2The substituents may be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), a substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0323] In embodiments, R 2 are 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, R 20 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), R 20 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), R 20 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 20 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 20 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 20 a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered) having two R 2 The substituents are joined together to form R 20 substituted or unsubstituted cycloalkyl, R 20 substituted or unsubstituted heterocycloalkyl, R20 substituted or unsubstituted aryl, or R 20 It may form a substituted or unsubstituted heteroaryl.

[0324] R 20 are 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 21 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), R 21 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), R 21 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 21 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 21 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 21 It is a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0325] R 21are 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., C1-C8, C1-C6, or C1-C4), R 22 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), R 22 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), R 22 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), R 22 Substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or R 22 It is a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0326] R 22are 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, unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0327] In embodiments, the compound is [ka] is.

[0328] In embodiments, the compound is [ka] is.

[0329] In embodiments, the compound is [ka] is.

[0330] In embodiments, the compound is [ka] is.

[0331] In embodiments, the compound is [ka] is.

[0332] In embodiments, the compound is [ka] is.

[0333] In embodiments, the compound is [ka] is.

[0334] In embodiments, the compound is [ka] is.

[0335] In embodiments, the compound is [ka] is.

[0336] In embodiments, the compound is [ka] is.

[0337] In embodiments, the compound is [ka] is.

[0338] In embodiments, the compound is [ka] is.

[0339] In embodiments, the compound is [ka] is.

[0340] In embodiments, the compound is [ka] is.

[0341] In embodiments, the compound is [ka] is.

[0342] In embodiments, the compound is [ka] is.

[0343] In embodiments, the compound is [ka] is.

[0344] In embodiments, the compound is [ka] is.

[0345] In embodiments, the compound is [ka] is.

[0346] In embodiments, the compound is [ka] is.

[0347] In embodiments, the compound is [ka] is.

[0348] In embodiments, the compound is [ka] is.

[0349] In embodiments, the compound is [ka] is.

[0350] In embodiments, the compound is [ka] is.

[0351] In embodiments, the compound is [ka] is.

[0352] In embodiments, the compound is [ka] is.

[0353] In embodiments, the compound is [ka] is.

[0354] In embodiments, the compound is [ka] is.

[0355] In embodiments, the compound is [ka] is.

[0356] In embodiments, the compound is [ka] is.

[0357] In embodiments, the compound is [ka] is.

[0358] In embodiments, the compound is [ka] is.

[0359] In embodiments, the compound is [ka] is.

[0360] In embodiments, the compound is [ka] is.

[0361] In embodiments, the compound is [ka] is.

[0362] In embodiments, the compound is [ka] is.

[0363] In embodiments, the compound is [ka] is.

[0364] In embodiments, the compound is [ka] is.

[0365] In embodiments, the compound is [ka] is.

[0366] In embodiments, the compound is [ka] is.

[0367] In embodiments, the compound is [ka] is.

[0368] In embodiments, the compound is [ka] is.

[0369] In embodiments, the compound is [ka] is.

[0370] In embodiments, the compound is [ka] is.

[0371] In embodiments, the compound is [ka] is.

[0372] In embodiments, the compound is [ka] is.

[0373] In embodiments, the compound is [ka] is.

[0374] In embodiments, the compound is [ka] is.

[0375] In embodiments, the compound is [ka] is.

[0376] In embodiments, the compound is [ka] is.

[0377] In embodiments, the compound is [ka] is.

[0378] In embodiments, the compound is [ka] is.

[0379] In embodiments, the compound is [ka] is.

[0380] In embodiments, the compound is [ka] is.

[0381] In embodiments, the compound is [ka] is.

[0382] In embodiments, the compound is [ka] is.

[0383] In embodiments, the compound is [ka] is.

[0384] In embodiments, the compound is [ka] is.

[0385] In embodiments, the compound is [ka] is.

[0386] In embodiments, the compound is [ka] is.

[0387] In embodiments, the compound is [ka] is.

[0388] In embodiments, the compound is [ka] is.

[0389] In embodiments, the compound is [ka] is.

[0390] In embodiments, the compound is [ka] is.

[0391] In embodiments, the compound is [ka] is.

[0392] In embodiments, the compound is [ka] is.

[0393] In embodiments, the compound is [ka] is.

[0394] In embodiments, the compound is [ka] is.

[0395] In embodiments, the compound is [ka] is.

[0396] In embodiments, the compound is [ka] is.

[0397] In embodiments, the compound is [ka] is.

[0398] In embodiments, the compound is [ka] is.

[0399] In embodiments, the compound is [ka] is.

[0400] In embodiments, the compound is [ka] is.

[0401] In embodiments, the compound is [ka] is.

[0402] In embodiments, the compound is [ka] is.

[0403] In embodiments, the compound is [ka] is.

[0404] In embodiments, the compound is [ka] is.

[0405] In embodiments, the compound is [ka] is.

[0406] In embodiments, the compound is [ka] is.

[0407] In embodiments, the compound is [ka] is.

[0408] In embodiments, the compound is [ka] is.

[0409] In embodiments, the compound is [ka] is.

[0410] In embodiments, the compound is [ka] is.

[0411] In embodiments, the compound is [ka] is.

[0412] In embodiments, the compound is [ka] is.

[0413] In embodiments, the compound is [ka] is.

[0414] In embodiments, the compound is [ka] is.

[0415] In embodiments, the compound is [ka] is.

[0416] In embodiments, the compound is [ka] is.

[0417] In embodiments, the compound is [ka] is.

[0418] In embodiments, the compound is [ka] is.

[0419] In embodiments, the compound is [ka] is.

[0420] In embodiments, the compound is [ka] is.

[0421] In embodiments, the compound is [ka] is.

[0422] In embodiments, the compound is [ka] is.

[0423] In embodiments, the compound is [ka] is.

[0424] In embodiments, the compound is [ka] is.

[0425] In embodiments, the compound is [ka] is.

[0426] In embodiments, the compound is [ka] is.

[0427] In embodiments, the compound is [ka] is.

[0428] In embodiments, the compound is [ka] is.

[0429] In embodiments, the compound is [ka] is.

[0430] In embodiments, the compound is [ka] is.

[0431] In embodiments, the compound is [ka] is.

[0432] In embodiments, the compound is [ka] is.

[0433] In embodiments, the compound is [ka] is.

[0434] In embodiments, the compound is [ka] is.

[0435] In an embodiment, ring A is [ka] but [ka] In an embodiment, ring A is not [ka] In an embodiment, ring A is not [ka] Not. X 2 is independently -F, -Cl, -Br, or -I. 2 are independently —Cl.

[0436] In embodiments, R 1 -SSR 1D Not. R 1D is as described herein.

[0437] 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.

[0438] In embodiments, the compound is [ka] but [ka] In an embodiment, the compound is [ka] In an embodiment, the compound is [ka] isn't it.

[0439] In embodiments, the compound covalently binds to Nurr1 (e.g., human Nurr1). In embodiments, the compound irreversibly covalently binds to Nurr1 (e.g., human Nurr1). In embodiments, the compound reversibly covalently binds to Nurr1 (e.g., human Nurr1).

[0440] 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.

[0441] 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.

[0442] In embodiments, the compound covalently binds 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.

[0443] In embodiments, the compound stabilizes Nurr1 monomers. In embodiments, the compound stabilizes Nurr1 homodimers. In embodiments, the compound stabilizes head-to-tail Nurr1 homodimers. In embodiments, the compound stabilizes Nurr1 heterodimers. In embodiments, the Nurr1 heterodimer is a heterodimer with RXRα.

[0444] In embodiments, the compound stabilizes Nurr1 monomers relative to a control (e.g., the absence of the compound). In embodiments, the compound stabilizes Nurr1 homodimers relative to a control (e.g., the absence of the compound). In embodiments, the compound stabilizes head-to-tail Nurr1 homodimers relative to a control (e.g., the absence of the compound). In embodiments, the compound stabilizes Nurr1 heterodimers relative to a control (e.g., the absence of the compound). In embodiments, the Nurr1 heterodimer is a heterodimer with RXRα.

[0445] In embodiments, the compound contacts a Nurr1 monomer. In embodiments, the compound contacts a Nurr1 homodimer. In embodiments, the compound contacts a head-to-tail Nurr1 homodimer. In embodiments, the compound contacts a Nurr1 heterodimer. In embodiments, the Nurr1 heterodimer is a heterodimer with RXRα.

[0446] In embodiments, the compound binds to a Nurr1 monomer. In embodiments, the compound binds to a Nurr1 homodimer. In embodiments, the compound binds to a head-to-tail Nurr1 homodimer. In embodiments, the compound binds to a Nurr1 heterodimer. In embodiments, the Nurr1 heterodimer is a heterodimer with RXRα.

[0447] In embodiments, the compound prevents the formation of Nurr1:RXR heterodimers. In embodiments, the compound inhibits the formation of Nurr1:RXR heterodimers. In embodiments, a compound that binds to Nurr1 inhibits the binding of the resulting compound:Nurr1 complex to RXR.

[0448] In embodiments, the compounds stabilize a Nurr1 dimeric conformation, wherein the distance between the N-termini is about 74.0 Å (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 90 Å). In embodiments, the compounds stabilize a Nurr1 dimeric conformation, wherein the distance between the N-termini is at least 74.0 Å (e.g., at least 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 Å). In embodiments, the compound stabilizes a Nurr1 dimer conformation, where the distance between the N-termini is less than 74.0 Å (e.g., less than 73, 72, 71, 70, 69, 68, 67, 66, 65, 65, 64, 63, 62, 61, or 60 Å).

[0449] In embodiments, the compound contacts a Nurr1 dimeric conformation, wherein the distance between the N-termini is about 74.0 Å (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 90 Å). In embodiments, the compound contacts a Nurr1 dimeric conformation, wherein the distance between the N-termini is at least 74.0 Å (e.g., at least 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 Å). In embodiments, the compound contacts a Nurr1 dimeric conformation where the distance between the N-termini is less than 74.0 Å (e.g., less than 73, 72, 71, 70, 69, 68, 67, 66, 65, 65, 64, 63, 62, 61, or 60 Å).

[0450] In embodiments, the compound binds to a Nurr1 dimeric conformation, wherein the distance between the N-termini is about 74.0 Å (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 90 Å). In embodiments, the compound binds to a Nurr1 dimeric conformation, wherein the distance between the N-termini is at least 74.0 Å (e.g., at least 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 Å). In embodiments, the compound binds to a Nurr1 dimeric conformation, where the distance between the N-termini is less than 74.0 Å (e.g., less than 73, 72, 71, 70, 69, 68, 67, 66, 65, 65, 64, 63, 62, 61, or 60 Å).

[0451] In embodiments, the compounds stabilize the Nurr1 dimeric conformation, wherein the distance between the N-termini is about 59.3 Å (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 75 Å). In embodiments, the compounds stabilize the Nurr1 dimeric conformation, wherein the distance between the N-termini is at least 59.3 Å (e.g., at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75 Å). In embodiments, the compound stabilizes a Nurr1 dimer conformation, where the distance between the N-termini is less than 59.3 Å (e.g., less than 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, or 40 Å).

[0452] In embodiments, the compound contacts a Nurr1 dimeric conformation, wherein the distance between the N-termini is about 59.3 Å (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 75 Å). In embodiments, the compound contacts a Nurr1 dimeric conformation, wherein the distance between the N-termini is at least 59.3 Å (e.g., at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75 Å). In embodiments, the compound contacts a Nurr1 dimeric conformation where the distance between the N-termini is less than 59.3 Å (e.g., less than 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, or 40 Å).

[0453] In embodiments, the compound binds to a Nurr1 dimeric conformation, wherein the distance between the N-termini is about 59.3 Å (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 75 Å). In embodiments, the compound binds to a Nurr1 dimeric conformation, wherein the distance between the N-termini is at least 59.3 Å (e.g., at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75 Å). In embodiments, the compound binds to a Nurr1 dimeric conformation, where the distance between the N-termini is less than 59.3 Å (e.g., less than 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, or 40 Å).

[0454] In embodiments, the compound binds to Nurr1 and induces binding of Nurr1 to the NBRE, NuRE, or DR-5 response element. In embodiments, the compound binds to Nurr1 and induces binding of Nurr1 to the NBRE. In embodiments, the compound binds to Nurr1 and induces binding of Nurr1 to the NuRE. In embodiments, the compound binds to Nurr1 and induces binding of Nurr1 to the DR-5 response element.

[0455] In embodiments, the compound is a compound described herein, including embodiments thereof. In embodiments, the compound is a compound described herein (e.g., in the Examples section, Figures, Tables, Claims, or Appendix).

[0456] III. Pharmaceutical Compositions In one aspect, a pharmaceutical composition is provided comprising a compound described herein and a pharmaceutically acceptable excipient.

[0457] 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.

[0458] In an embodiment, the pharmaceutical composition comprises an effective amount of a second drug, wherein the second drug is a drug for treating a neurodegenerative disease. In an embodiment, the neurodegenerative disease is Parkinson's disease. In an embodiment, the second drug is a Parkinson's disease drug, such as levodopa, carbidopa, selegiline, amantadine, donepezil, galantamine, rivastigmine, tacrine, bromocriptine, pergolide, pramipexole, ropinirole, trihexyphenidyl, benztropine, biperiden, procyclidine, tolcapone, or entacapone. In an embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the second drug.

[0459] In some embodiments, the pharmaceutical composition comprises an effective amount of a second agent, wherein the second agent is an agent for treating an inflammatory disease, such as acetaminophen, duloxetine, aspirin, ibuprofen, naproxen, diclofenac, prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, codeine, fentanyl, hydrocodone, hydromorphone, morphine, meperidine, or oxycodone. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the second agent.

[0460] In embodiments, the pharmaceutical composition comprises an effective amount of a second agent, wherein the second agent is an anti-cancer agent.

[0461] In one aspect, a pharmaceutical composition is provided comprising 5,6-dihydroxyindole (DHI) and a pharmaceutically acceptable excipient. In an embodiment, the pharmaceutical composition comprises an effective amount of 5,6-dihydroxyindole (DHI). In an embodiment, the pharmaceutical composition comprises a therapeutically effective amount of 5,6-dihydroxyindole (DHI). In an embodiment, the pharmaceutical composition comprises an effective amount of a second agent described herein.

[0462] IV.Usage In one aspect, there is provided a method for treating a disease associated with dysregulation and / or degeneration of dopaminergic neurons in the central nervous system of a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0463] In one aspect, a method is provided for treating a disease associated with dysregulation and / or degeneration of dopaminergic neurons in the central nervous system of a subject in need thereof, the method comprising administering a therapeutically effective amount of 5,6-dihydroxyindole (DHI) to a subject in need thereof.

[0464] 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.

[0465] In an embodiment, the disease associated with dysregulation and / or degeneration of dopaminergic neurons is cancer.

[0466] In one aspect, a method of treating a disease in a subject in need thereof is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0467] In one aspect, a method of treating a disease in a subject in need thereof is provided, the method comprising administering a therapeutically effective amount of 5,6-dihydroxyindole (DHI) to the subject in need thereof.

[0468] 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.

[0469] In embodiments, the disease is cancer.

[0470] In embodiments, the cancer is breast cancer, pancreatic cancer, bladder cancer, mucoepidermoid carcinoma, gastric cancer, prostate cancer, colorectal cancer, lung cancer, adrenocortical carcinoma, or cervical cancer.

[0471] In one aspect, a method of reducing inflammation in a subject in need thereof is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0472] In embodiments, the method is for reducing inflammation in the central nervous system of a subject in need thereof.

[0473] In one aspect, a method of reducing oxidative stress in a subject in need thereof is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0474] In embodiments, the method is for reducing oxidative stress in the central nervous system of a subject in need thereof.

[0475]

[0013] In one aspect, a method of modulating the level of Nurr1 activity in a subject in need thereof is provided, the method comprising administering a therapeutically effective amount of a compound described herein to a subject in need thereof. In embodiments, the level of Nurr1 activity in the subject is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of Nurr1 activity in the subject is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0476]

[0013] In one aspect, a method for increasing the 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, 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 embodiments, the level of Nurr1 activity in the cell is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0477] In one aspect, a method for increasing the activity level of Pitx3 in a subject in need thereof is provided, the method comprising administering a therapeutically effective amount of a compound described herein to the subject in need thereof. In embodiments, the activity level of Pitx3 in the subject is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of Pitx3 activity in the subject is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0478] In one aspect, a method for increasing the activity level of Pitx3 in a cell is provided, the method comprising contacting a cell with a compound described herein. In embodiments, the activity level of Pitx3 in the cell is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of Pitx3 activity in the cell is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0479] In one aspect, a method is provided for increasing the level of TH activity in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound described herein to the subject in need thereof.In embodiments, the level of TH activity in the subject is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of TH activity in the subject is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0480] In one aspect, a method for increasing the activity level of TH in a cell is provided, the method comprising contacting a cell with a compound as described herein.In embodiments, the activity level of TH in a cell is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 times. In embodiments, the level of TH activity in the cell is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0481] In one aspect, a method is provided for increasing the activity level of VMAT2 in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound described herein to the subject in need thereof. In embodiments, the activity level of VMAT2 in the subject is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of VMAT2 activity in the subject is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0482] In one aspect, a method for increasing the activity level of VMAT2 in a cell is provided, the method comprising contacting a cell with a compound as described herein.In embodiments, the activity level of VMAT2 in a cell is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 times. In embodiments, the level of VMAT2 activity in the cell is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0483] In one aspect, a method of increasing the level of dopa decarboxylase (DDC) activity in a subject in need thereof is provided, the method comprising administering a therapeutically effective amount of a compound described herein to a subject in need thereof. In embodiments, the level of DDC activity in the subject is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000-fold. In embodiments, the level of activity of DDC in the subject is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0484]

[0010] In one aspect, a method of increasing the level of dopa decarboxylase (DDC) activity in a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of DDC activity in the cell is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of activity of DDC in the cells is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0485]

[0013] In one aspect, a method of increasing the level of dopamine transporter (DAT) activity in a subject in need thereof is provided, the method comprising administering a therapeutically effective amount of a compound described herein to a subject in need thereof. In embodiments, the level of DAT activity in the subject is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold. In embodiments, the level of activity of the DAT in the subject is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0486]

[0010] In one aspect, a method of increasing the level of dopamine transporter (DAT) activity in a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of DAT activity in the cell is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of activity of the DAT in the cell is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0487] In one aspect, a method is provided for increasing the level of BDNF activity in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound described herein to a subject in need thereof. In embodiments, the level of BDNF activity in the subject is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of BDNF activity in the subject is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0488] In one aspect, a method for increasing the level of BDNF activity in a cell is provided, the method comprising contacting a cell with a compound described herein. In embodiments, the level of BDNF activity in the cell is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of BDNF activity in the cells is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0489] In one aspect, a method is provided for increasing the level of NGF activity in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound described herein to the subject in need thereof.In embodiments, the level of NGF activity in the subject is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of NGF activity in the subject is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0490] In one aspect, a method for increasing the level of NGF activity in a cell is provided, the method comprising contacting a cell with a compound as described herein.In one embodiment, the level of NGF activity in a cell is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of NGF activity in the cells is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0491] In one aspect, there is provided a method for increasing the activity level of the GDNF receptor c-Ret in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound described herein to the subject in need thereof. In embodiments, the activity level of the GDNF receptor c-Ret in the subject is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of activity of the GDNF receptor c-Ret in the subject is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0492] In one aspect, a method for increasing the activity level of GDNF receptor c-Ret in a cell is provided, the method comprising contacting a cell with a compound as described herein.In embodiments, the activity level of GDNF receptor c-Ret in a cell is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 times. In embodiments, the level of activity of the GDNF receptor c-Ret in the cell is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0493] In one aspect, a method of increasing the level of SOD1 activity in a subject in need thereof is provided, the method comprising administering a therapeutically effective amount of a compound described herein to a subject in need thereof. In embodiments, the level of SOD1 activity in the subject is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of SOD1 activity in the subject is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0494] In one aspect, a method for increasing the level of SOD1 activity in a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of SOD1 activity in the cell is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of SOD1 activity in the cell is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0495]

[0013] In one aspect, a method of reducing the level of TNFα activity in a subject in need thereof is provided, the method comprising administering a therapeutically effective amount of a compound described herein to a subject in need thereof. In embodiments, the level of TNFα activity in the subject is reduced by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of TNFα activity in the subject is reduced by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0496] In one aspect, a method for reducing the level of TNFα activity in a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of TNFα activity in the cell is reduced by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of TNFα activity in the cell is reduced by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0497]

[0010] In one aspect, a method of reducing the level of iNOS activity in a subject in need thereof is provided, the method comprising administering a therapeutically effective amount of a compound described herein to a subject in need thereof. In embodiments, the level of iNOS activity in the subject is reduced by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of iNOS activity in the subject is reduced by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0498] In one aspect, a method for reducing the level of iNOS activity in a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of iNOS activity in the cell is reduced by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of iNOS activity in the cells is reduced by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0499]

[0010] In one aspect, a method of reducing the level of IL-1β activity in a subject in need thereof is provided, the method comprising administering a therapeutically effective amount of a compound described herein to a subject in need thereof. In embodiments, the level of IL-1β activity in the subject is reduced by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of IL-1β activity in the subject is reduced by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0500]

[0010] In one aspect, a method of reducing the level of IL-1β activity in a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of IL-1β activity in the cell is reduced by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of IL-1β activity in the cell is reduced by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0501] In embodiments, the method includes increasing dopamine levels in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound described herein to a subject in need thereof, in embodiments, the dopamine levels in the subject are increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of dopamine in the subject is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0502] In embodiments, the method includes increasing the level of dopamine in a cell, the method including contacting the cell with a compound described herein. In embodiments, the level of dopamine in the cell is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 times. In embodiments, the level of dopamine in the cell is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0503] In embodiments, the methods include increasing dopamine synthesis in a cell with a compound described herein compared to a control (e.g., the absence of the compound). In embodiments, the level of dopamine synthesis is increased by about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold. In embodiments, the level of synthesis of dopamine is increased by at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 fold.

[0504] In embodiments, the methods include increasing dopamine packaging in a cell with a compound described herein compared to a control (e.g., the absence of the compound). In emb...

Claims

1. having the formula: 【Chemical 1】 During the ceremony, Ring A is phenyl; W is N or CH; L １０４ is —C(O)—, L １０５ is unsubstituted alkylene or unsubstituted cycloalkylene; L １０３ is a bond or unsubstituted alkylene; R １ is —SC(O)R 1C or —SH, R ２ are independently halogen, -CX ２ ３ , -CHX ２ ２ , -CH ２ X ２ , -OCX ２ ３ , -OCH ２ X ２ , -OCHX ２ ２ , -CN, -OR ２Ｄ , -NR ２Ａ C(O)R ２Ｃ , unsubstituted alkyl, or R 20 -substituted or unsubstituted heterocycloalkyl; R 20 is independently unsubstituted alkyl; R １Ｃ , R ２Ａ , R ２Ｃ , and R ２Ｄ are independently hydrogen, unsubstituted alkyl, or unsubstituted aryl; X ２ is independently —F, —Cl, —Br, or —I; A compound wherein z2 is an integer of 0 to 2.

2. The compound has the formula: 【Chemistry 2】 R ２Ｘ , R ２Ｙ , and R ２Ｚ are independently hydrogen, halogen, -CX ２ ３ , -CHX ２ ２ , -CH ２ X ２ , -OCX ２ ３ , -OCH ２ X ２ , -OCHX ２ ２ , -CN, -OR ２Ｄ , -NR ２Ａ C(O)R ２Ｃ , unsubstituted alkyl, or R 20 -substituted or unsubstituted heterocycloalkyl.

3. R ２Ｘ is a halogen, R ２Ｙ is hydrogen or halogen, R ２Ｚ is hydrogen, halogen, -CN, -NR ２Ａ C(O)R ２Ｃ or R 20 -substituted or unsubstituted heterocycloalkyl.

4. R ２Ｘ is a halogen, R ２Ｙ is hydrogen, R ２Ｚ is halogen, -CN, -NR ２Ａ C(O)R ２Ｃ or R 20 -substituted or unsubstituted 5-6 membered heterocycloalkyl; R ２Ａ is hydrogen, R ２Ｃ is unsubstituted C １ -C ２ The compound of claim 2, wherein the compound is alkyl.

5. R ２Ｘ is a halogen, R ２Ｙ is hydrogen, R ２Ｚ The compound of claim 2, wherein is a halogen.

6. R ２Ｘ is a halogen, R ２Ｙ is a halogen, R ２Ｚ The compound of claim 2, wherein is hydrogen.

7. R ２Ｘ But, -OCH ３ and R ２Ｙ is hydrogen, R ２Ｚ But, -OCH ３ 3. The compound of claim 2, wherein:

8. L １０５ is unsubstituted C １ -C ４ The compound of any one of claims 1 to 7, which is alkylene.

9. L １０５ but 【Chemistry 3】 The compound according to any one of claims 1 to 8, wherein 10. The compound of claim 1, wherein W is N.

11. L １０３ The compound of any one of claims 1 to 10, wherein is unsubstituted ethylene.

12. 【Chemical 4】 but, 【Chemistry 5】 The compound according to any one of claims 1 to 7,

13. R １ The compound of any one of claims 1 to 12, wherein is -SH, or -SC(O)CH3.

14. The compound of claim 1 having the formula: 【Chemistry 6】 【change】

15. A pharmaceutical composition for treating a disease associated with dysregulation and / or degeneration of dopaminergic neurons in the central nervous system in a subject in need thereof, comprising a compound according to any one of claims 1 to 14 and a pharmaceutically acceptable excipient.

16. 16. The pharmaceutical composition of claim 15, wherein 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.

17. 15. A pharmaceutical composition for treating cancer in a subject in need thereof, comprising a compound according to any one of claims 1 to 14 and a pharmaceutically acceptable excipient.

18. 18. The pharmaceutical composition of claim 17, wherein the cancer is breast cancer, pancreatic cancer, bladder cancer, mucoepidermoid carcinoma, gastric cancer, prostate cancer, colorectal cancer, lung cancer, adrenocortical carcinoma, or cervical cancer.

19. A pharmaceutical composition for modulating the level of activity of Nurr1 in a subject in need thereof, comprising a compound according to any one of claims 1 to 14 and a pharmaceutically acceptable excipient.

20. A pharmaceutical composition for increasing the level of Nurr1 activity in a cell, comprising a compound according to any one of claims 1 to 14 and a pharmaceutically acceptable excipient.

21. A pharmaceutical composition for increasing the level of dopamine in a cell, comprising a compound according to any one of claims 1 to 14 and a pharmaceutically acceptable excipient.

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